Erythromycin

Nihon Kokyuki Gakkai Zasshi, 2004 Nov, 42(11), 956 - 60
{A case of Legionella pneumonia complicated with acute respiratory distress syndrome treated with methylprednisolone and sivelestat sodium in combination with intravenous erythromycin and ciprofloxacin}; Oguma A et al.; A 64-year-old man was referred to us because of pneumonia refractory to panipenem/betamipron . His chest radiography showed patchy consolidations in the lower lobe of the right lung and in the middle field of the left lung, and severe hypoxia was present . He was diagnosed as having acute respiratory distress syndrome due to severe pneumonia, and was treated with pulse methylprednisolone and sivelestat sodium in combination with intravenous erythromycin and ciprofloxacin . The patient recovered with this treatment . Serological examination using blood samples collected on the 12th and 28th hospital days revealed elevation of anti-L . pneumophila serogroup I antibody . It is suggested that administration of methylprednisolone and sivelestat sodium in combination with intravenous erythromycin and ciprofloxacin in a case of severe Legionella pneumonia complicated with acute respiratory distress syndrome is effective, and may be of use in similar cases.

Pharmazie, 2004 Dec, 59(12), 957 - 60
Effect of various cytochrome P450 3A and P-glycoprotein modulators on the biliary clearance of bromosulphaphthalein in male wistar rats; Machavaram KK et al.; The main aim of this study was to investigate the effect of various selective cytochrome P4503A (CYP3A) and/or P-glycoprotein (P-gp) modulators on biliary clearance of bromosulphaphthalein (BSP) in male albino wistar rats . Male albino wistar rats were divided into different groups, treated with CYP3A and P-gp modulators and BSP was administered intravenously (bolus or infusion) to each treated group . BSP in serum and bile samples was analyzed using spectrophotometric analysis at 580 nm . There was a statistically significant (p < 0.05) increase in serum BSP levels with CYP3A and P-gp substrates and/or inhibitors, cyclosporine-A, nitrendipine, quinidine, indinavir, daxorubicin, etoposide and erythromycin by 27%, 35%, 32%, 12%, 5%, 22%, and 106%, respectively . There was a slight increase (4%, p > 0.05) observed in serum BSP levels in the presence of ketoconazole, whereas CYP3A and P-gp inducers, rifampicin and sodium butyrate significantly (p < 0,05) decreased the serum BSP levels by 30% and 14% respectively, when compared to control group after 62 min of BSP i.v . bolus administration . In BSP infusion studies, Cyclosporine A, nitrendipine, quinidine, indinavir, ketoconazole, doxorubicin, etoposide, and erythromycin significantly decreased the bile BSP levels by 23%, 22%, 17%, 59%, 3%, 15%, 10%, 29%, respectively . Upon 60 min of BSP infusion, rifampicin and sodium butyrate significantly (p < 0.05) increased bile BSP levels by 33% and 25%, respectively . Finally, we observed that the P-gp and CYP3A inducers significantly decreased the total serum BSP levels and increased the total biliary levels of BSP, this could be by inducing P-gp in biliary canalicular membrane in male wistar rats . P-gp and CYP3A inhibitors and substrates significantly increased the total serum BSP levels and reduced the biliary excretion of BSP by inhibiting P-gp in biliary pathway . There was no significant difference observed between inhibitors and substrates of P-gp on BSP disposition . We suggest that the biliary transport of BSP could be useful as a simple and economical in vivo screening model for identifying P-gp and CYP3A substrates and/or inhibitors and/or inducers in wistar rats.

Biol Pharm Bull, 2005 Jan, 28(1), 130 - 7
Effect of Chronic Administration of Ritonavir on Function of Cytochrome P450 3A and P-Glycoprotein in Rats; Kageyama M et al.; Ritonavir (RTV) is well known as an inhibitor of many drugs that are metabolized by cytochrome P450 (CYP) 3A or fluxed via P-glycoprotein (Pgp), although it is also reported that RTV is a potent inducer for them . In this study, to elucidate these contradictory phenomena, functional changes of CYP3A or Pgp during chronic administration of RTV were examined in rats . After pretreatment with RTV for indicated days (day 3-day 14), rats were used in the experiments . The area under the plasma drug concentration vs . time curve (AUC(0-infinity)) after oral administration of RTV (20 mg/kg) to these rats showed an RTV-treatment period-dependent decrease, and the mean AUC(0-infinity) of RTV in Day 14 rats decreased significantly by 57% as compared to the control . The AUC(0-infinity) after intravenous (i.v.) administration of RTV to Day 3 and Day 5 rats increased significantly by 28% and 22%, respectively, while there were no significant changes in the AUC(0-infinity) in Day 7 and Day 14 rats as compared to the control . As for i.v . administration of erythromycin (EM) or midazolam (MDZ) to RTV-treated rats, the AUC(0-infinity)in Day 3 and Day 5 rats increased significantly as compared to the control, while in Day 7 rats and rifampicin-treated rats, the AUC(0-infinity) of EM decreased significantly by 82% and 42%, respectively, as compared to the control . For MDZ, there were no significant changes in the AUC(0-infinity) in Day 7 or Day 14 rats . After i.v . administration of rhodamine123 (Rho123), the excretion clearances from blood circulation to the intestinal lumen and the biliary excretion clearances in Day 14 rats increased markedly by 2.2-fold and 2.6-fold as compared to the control . It has been confirmed that RTV is not only a potent inhibitor but also a potent inducer of CYP3A, and that RTV is a potent inducer of intestinal Pgp . This property of RTV is responsible for regulating the oral bioavailability of drugs that are mediated by CYP3A and Pgp.

Curr Treat Options Gastroenterol, 2005 Feb, 8(1), 3 - 11
Chronic Intestinal Pseudo-Obstruction; Panganamamula KV et al.; Chronic intestinal pseudo-obstruction (CIP) is a gastrointestinal motility disorder characterized by chronic symptoms and signs of bowel obstruction in the absence of a fixed, lumen-occluding lesion . Radiographic findings consist of dilated bowel with air-fluid levels . Pseudo-obstruction is an uncommon condition and can result from primary or secondary causes . The management is primarily focused on symptom control and nutritional support to prevent weight loss and malnutrition . The principles of management of patients with CIP involve 1) establishing a correct clinical diagnosis and excluding mechanical obstruction; 2) differentiating between idiopathic and secondary forms; 3) performing a symptomatic and physiologic assessment of the parts of the gastrointestinal (GI) tract involved by manometric and whole gut transit scintigraphic studies; 4) careful assessment of nutritional status of the patient; and 5) developing a therapeutic plan addressing the patient's symptoms and nutritional status . Treatment of CIP includes frequent small meals with a low-fat, low-fiber diet, liquid nutritional supplements may be needed; prokinetic agents such as metoclopramide may help to reduce upper GI symptoms . Trials of drugs such as erythromycin, domperidone, cisapride, and tegaserod may be considered if there is no response . Subcutaneous octreotide may be helpful to improve small bowel dysmotility especially in patients with scleroderma . In patients with symptoms suggestive of bacterial overgrowth, courses of antibiotics such as metronidazole, ciprofloxacin, and doxycycline may be needed . Nutritional assessment and support is an important aspect of management . Enteral nutrition is usually preferred . In carefully selected patients, feeding jejunostomy with or without decompression gastrostomy may be tried . Long term parenteral nutrition should be reserved for patients who can not tolerate enteral nutrition . Complications associated with total parenteral nutrition include infections, sepsis, and cholestatic hepatic dysfunction.

Clin Cancer Res, 2004 Dec 15, 10(24), 8341 - 50
Factors affecting cytochrome P-450 3A activity in cancer patients; Baker SD et al.; PURPOSE: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients . EXPERIMENTAL DESIGN: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A . Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6) . RESULTS: CYP3A activity (AUC(0-40 min)) varied up to 14-fold in this population . No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954) . CYP3A activity was reduced by approximately 50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001) . In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, alpha-1 acid glycoprotein, explained approximately 18% of overall variation in CYP3A activity (P < 0.001) . CONCLUSIONS: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer . Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.

J Drug Target, 2004, 12(7), 405 - 13
P-glycoprotein Potentiates CYP3A4-mediated Drug Disappearance during Caco-2 Intestinal Secretory Detoxification; Chan LM et al.; Human intestinal Caco-2 cell monolayers grown in the presence of 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) were used to test the hypothesis that drugs which interact with the apical efflux pump P-glycoprotein (Pgp) may enhance CYP3A4-mediated disappearance of substrates . 6beta-Hydroxytestosterone production, a marker of CYP3A4 activity, was approximately 3- and 7-fold greater in 1,25(OH)(2)D(3)-treated cells compared to untreated cells when incubated with 50 and 500 muM testosterone, respectively, and was unaffected by the addition of digoxin to reduce Pgp activity . In the presence of digoxin, secretory transport of vinblastine and erythromycin, substrates for both Pgp and cytochrome P450 3A4 (CYP3A4), was significantly reduced, whereas absorptive transport was unaffected . In contrast, no directional transport of testosterone, a substrate for CYP3A4 only, was observed, either in the presence or absence of digoxin . Over 2 h, disappearance of erythromycin and vinblastine from the incubation medium was significantly greater from the basolateral than from the apical compartments . In the presence of digoxin, disappearance of both compounds from the basolateral, but not from the apical compartments, was significantly reduced . In contrast, disappearance of testosterone was unaffected by the addition of digoxin, demonstrating that the effect of digoxin on erythromycin and vinblastine disappearance was via inhibition of Pgp function, rather than on CYP3A4 activity . Thus, evidence is provided for Pgp/CYP3A4 co-substrates, Pgp potentiates CYP3A4-mediated drug disappearance during intestinal secretory detoxification.

Drug Metab Pharmacokinet, 2002, 17(5), 437 - 48
Application of Microtiter Plate Assay to Evaluate Inhibitory Effects of Various Compounds on Nine Cytochrome P450 Isoforms and to Estimate their Inhibition Patterns; Yamamoto T et al.; Using a microtiter plate (MTP) assay consists of recombinant cytochromes P450 and fluorescent probes, we evaluated inhibitory effects of commercially available model-compounds, 18 typical substrates and 8 selective inhibitors, on nine cytochromes P450 (CYPs) activities . The IC(50) values obtained from the assay were used to estimate inhibition constant (Ki) values, assuming competitive inhibition . The Ki values calculated from IC(50) (the Ki(-cal)) with the MTP assay using recombinant CYPs were compared with the Ki values (the Ki(-rep)), reported for human liver microsomes (HLM) . Regarding all the inhibitory effects of the 26 test compounds on each CYP activity, a good correlation (r(2)=0.7306) was found between Ki(-cal) and Ki(-rep) . The inhibitory patterns of some compounds on the five major CYP isoforms were estimated, using the MTP assay with the preincubation method . Furafylline and erythromycin, both mechanism based inhibitors, strongly inhibited CYP1A2 and CYP3A4 activity, respectively and their inhibitory effects increased depending on the preincubation time . In contrast, the inhibitory effects of phenacetin, diclofenac, S-mephenytoin, dextromethorphan, bufuralol and terfenadine, typical substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, respectively, on each recombinant CYP activity decreased after preincubation . Therefore, the MTP assay is a useful high throughput screening method to evaluate inhibitory effects of new drug candidates on 9 CYP isoforms in HLM . In addition, the MTP assay with the preincubation method might be beneficial to estimate inhibitory patterns on CYP isoforms of new drug candidates and to estimate main CYP isoforms responsible for metabolism of these compounds.

J Pineal Res, 2005 Jan, 38(1), 27 - 34
Melatonin attenuates lipopolysaccharide-induced down-regulation of pregnane X receptor and its target gene CYP3A in mouse liver; Xu DX et al.; Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates target gene transcription in a ligand-dependent manner . Our earlier study indicated that reactive oxygen species contribute to lipopolysaccharide (LPS)-induced down-regulation of PXR and its target gene CYP3A in mouse liver . Melatonin is a powerful endogenous antioxidants . In this study, we investigated the effects of melatonin on LPS-induced down-regulation of PXR and CYP3A in mouse liver . Mice were intraperitoneally administrated different doses of melatonin before and/or after LPS treatment . PXR and CYP3A11 mRNA levels were measured using RT-PCR . Erythromycin N-demethylase (ERND) was used as an indicator of CYP3A catalytic activity . Results indicated that melatonin significantly attenuated LPS-induced down-regulation of PXR and CYP3A11 mRNA levels in a dose-dependent manner . Repeated doses of melatonin (10 mg/kg) treatments also significantly attenuated LPS-induced down-regulation of dexamethasone-inducible CYP3A11 mRNA level and ERND activity in mouse liver . In addition, the present study also shows that melatonin significantly increased hepatic superoxide dismutase, Se-dependent glutathione peroxidase, glutathione reductase and catalase activities and glutathione levels in LPS-treated mice . These findings suggest that melatonin may exert its protective effects on LPS-induced down-regulation of PXR and CYP3A via counteracting LPS-induced oxidative stress in mouse liver.

Antimicrob Agents Chemother, 2005 Jan, 49(1), 281 - 8
Binding site of the bridged macrolides in the Escherichia coli ribosome; Xiong L et al.; Ketolides represent the latest group of macrolide antibiotics . Tight binding of ketolides to the ribosome appears to correlate with the presence of an extended alkyl-aryl side chain . Recently developed 6,11-bridged bicyclic ketolides extend the spectrum of platforms used to generate new potent macrolides with extended alkyl-aryl side chains . The purpose of the present study was to characterize the site of binding and the action of bridged macrolides in the ribosomes of Escherichia coli . All the bridged macrolides investigated efficiently protected A2058 and A2059 in domain V of 23S rRNA from modification by dimethyl sulfate and U2609 from modification by carbodiimide . In addition, bridged macrolides that carry extended alkyl-aryl side chains protruding from the 6,11 bridge protected A752 in helix 35 of domain II of 23S rRNA from modification by dimethyl sulfate . Bridged macrolides efficiently displaced erythromycin from the ribosome in a competition binding assay . The A2058G mutation in 23S rRNA conferred resistance to the bridged macrolides . The U2609C mutation, which renders E . coli resistant to the previously studied ketolides telithromycin and cethromycin, barely affected cell susceptibility to the bridged macrolides used in this study . The results of the biochemical and genetic studies indicate that in the E . coli ribosome, bridged macrolides bind in the nascent peptide exit tunnel at the site previously described for other macrolide antibiotics . The presence of the side chain promotes the formation of specific interactions with the helix 35 of 23S rRNA.

J Vet Med A Physiol Pathol Clin Med, 2004 Dec, 51(9-10), 456 - 61
Effects of erythromycin on myoelectric activity of the spiral colon of dairy cows; Zanolari P et al.; The effects of erythromycin on myoelectric activity of the spiral colon of dairy cows were investigated in a prospective study . Four Simmental x Red-Holstein crossbred cows of similar body weight and condition with seven pairs of bipolar electrodes implanted in the intestine (one each in the distal ileum, caecum and proximal colon, and four in the spiral colon) were included . Erythromycin lactobionate (1 mg kg(-1)) and 0.9% sodium chloride solution (NaCl) were administered to each cow in a random order . Erythromycin was diluted with NaCl and both treatments were administered slowly intravenously over a period of 5 min 1 h after onset of a phase III of the bovine colonic migrating myoelectric complex (bcMMC) . A 3-6-day washout period was scheduled between trials . Significant differences between the results of the treatments were observed for spike duration in phase I as well as for spike duration and duration of spiking activity during phase II of the second bcMMC, which were significantly higher after erythromycin treatment than after NaCl . These findings suggest an indirect effect of erythromycin on colonic motility in cattle.

Biochemistry, 2004 Dec 28, 43(51), 16301 - 10
Biochemical analysis of the substrate specificity of the beta-ketoacyl-acyl carrier protein synthase domain of module 2 of the erythromycin polyketide synthase; Wu J et al.; The beta-ketoacyl-acyl carrier protein synthase (KS) domain of the modular 6-deoxyerythronolide B synthase (DEBS) catalyzes the fundamental chain building reaction of polyketide biosynthesis . The KS-catalyzed reaction involves two discrete steps consisting of formation of an acyl-enzyme intermediate generated from the incoming acylthioester substrate and an active site cysteine residue, and the conversion of this intermediate to the beta-ketoacyl-acyl carrier protein product by a decarboxylative condensation with a paired methylmalonyl-SACP . We have determined the rate constants for the individual biochemical steps by a combination of protein acylation and transthioesterification experiments . The first-order rate constant (k(2)) for formation of the acyl-enzyme intermediate from {1-(14)C}-(2S,3R)-2-methyl-3-hydroxypentanoyl-SNAC (2) and recombinant DEBS module 2 is 5.8 +/- 2.6 min(-)(1), with a dissociation constant (K(S)) of 3.5 +/- 2.8 mM . The acyl-enzyme adduct was formed at a near-stoichiometric ratio of approximately 0.8:1 . Transthioesterification between unlabeled diketide-SNAC 2 and N-{1-(14)C-acetyl}cysteamine gave a k(exch) of 0.15 +/- 0.06 min(-)(1), with a K(m) for HSNAC of 5.7 +/- 4.9 mM and a K(m) for 2 of 5.3 +/- 0.9 mM . Under the conditions that were used, k(exch) was equal to k(-)(2), the first-order rate constant for reversal of the acyl-enzyme-forming reaction . Since the rate of the decarboxylative condensation is much greater that the rate of reversion to the starting material (k(3) >> k(-)(2)), formation of the acyl-enzyme adduct is effectively irreversible, thereby establishing that the observed value of the specificity constant (k(cat)/K(m)) is solely a reflection of the intrinsic substrate specificity of the KS-catalyzed acyl-enzyme-forming reaction . These findings were also extended to a panel of diketide- and triketide-SNAC analogues, revealing that some substrate analogues that are not converted to product by DEBS module 2 form dead-end acyl-enzyme intermediates.

Prikl Biokhim Mikrobiol, 2004 Nov-Dec, 40(6), 613 - 24
{Biogenesis and regulation of biosynthesis of erythromycins in Saccharopolyspora erythraea: a review}; Comparative study of pharmacokinetic parameters between clarithromycin and erythromycin stearate in relation to their physicochemical properties; Pharmaceutical Research Laboratories, Taisho Pharmaceutical Co., Ltd . Yoshino-cho 1-403, Ohmiya-shi, Saitama, 330, JapanPharmacokinetic parameters for clarithromycin (CAM) and erythromycin stearate (EMS) were obtained from a model including decomposition in the gastrointestinal tract . To confirm the accuracy of the parameters, various physicochemical properties of both drugs were examined . The ratio of the in vivo dissolution rate, the in vivo decomposition rate and the absorption rate between CAM and EMS were well correlated to the ratio of the in vitro intrinsic dissolution rate, the decomposition rate in the acidic solution, and partition coefficient, respectively . One of the reasons for the excellent absorption of CAM compared with that of EMS was the higher stability in the acidic solution and the higher partition coefficient of CAM . These findings indicate that the ratio of the partition coefficient to the decomposition rate constant in acidic solution plays an important role in determining drug bioavailability for macrolide antibiotics.

Eur J Clin Pharmacol . 2004 Dec 14; {Epub ahead of print}
Effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia; Li KY et al.; OBJECTIVE: To study the effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia . METHODS: Nineteen patients received multiple doses of quetiapine (200 mg, twice daily) with or without co-administered erythromycin (500 mg, three times daily) . Blood samples were collected at specified time intervals for determination of plasma concentrations of quetiapine and some of its metabolites . RESULTS: With erythromycin co-administration: for quetiapine, maximal plasma concentration (C (max)), area under concentration-time curve of 0-infinity h (AUC(0-infinity)) and terminal-phase elimination half-life time (t (1/2)) increased 68, 129 and 92%, respectively, and clearance (CL) and terminal elimination rate constant (K (e)) decreased 52% and 55%, respectively; for quetiapine sulfoxide (QTP-SF), C (max), AUC(0-infinity) and AUC ratio decreased 64, 23, and 70%, respectively, and t (1/2) increased 211%; for 7-hydroxy-quetiapine (QTP-H), K (e) and AUC ratio decreased 61% and 45%, respectively, and t (1/2) increased 203%; for 7-hydroxy-N-desalkyl-quetiapine (QTP-ND), C (max), AUC(0-infinity) and AUC ratio decreased 36, 40 and 71%, respectively . CONCLUSION: Erythromycin has a noticeable effect on the metabolism of quetiapine . When quetiapine is co-administered with CYP3A inhibitors such as erythromycin, the dosing regimen should be modified according to quetiapine TDM.

J Chromatogr A, 2004 Nov 12, 1056(1-2), 111 - 20
Identification of impurities in erythromycin by liquid chromatography-mass spectrometric detection; Kumar Chitneni S et al.; A simple, isocratic liquid chromatographic (LC) method using volatile mobile phase constituents for the identification of related substances in erythromycin samples is described . For method development, evaporative light scattering detection (ELSD) was used . An XTerra RP18 column was used at 70 degrees C with a mobile phase consisting of acetonitrile-isopropanol-0.2M ammonium acetate pH 7.0-water (165:105:50:680) . Mass spectral data were acquired on an ion trap mass spectrometer equipped with an electrospray interface operated in the positive ion mode . First, a library was created using MS/MS and MS(n) spectra of reference substances available in the laboratory . Using these reference spectra as interpretative templates, eight novel related substances in erythromycin samples were identified: N-demethylerythromycin E, erythromycin E N-oxide, anhydroerythromycin C, N-demethylerythromycin B, anhydro-N-demethylerythromycin A, pseudoerythromycin E enol ether, EF lacking the neutral sugar and EA lacking the neutral sugar.

AIDS Treat News . 2004 Sep 24;(405):6.
Warning against using erythromycin (even orally) while using protease inhibitors or certain other drugs; Clinical implications of the immunomodulatory effects of macrolides; First Department of Medicine, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shiinjuku, Tokyo, JapanMacrolide antibiotics are known for their efficacy in treating acute airway infections, but just as importantly, they are also effective anti-inflammatory agents . Their anti-inflammatory properties have been studied most thoroughly in chronic inflammatory airway diseases, particularly diffuse panbronchiolitis (DPB) . Erythromycin, azithromycin, clarithromycin, and roxithromycin inhibit chemotaxis and infiltration of neutrophils into the airway and, subsequently, decrease mucus secretion . Mucus formation, a significant cause of morbidity and mortality in patients with chronic airway inflammation, is directly inhibited by macrolides and suppressed by decreased inflammation in the airway . The mechanisms of action for the anti-inflammatory properties of the macrolides are still being investigated, but they are clearly multifactorial . Macrolides inhibit the production of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha, perhaps by suppressing the transcription factor nuclear factor-kappaB or activator protein-1 . Inhibition of cytokine production has been seen in vitro and also in bronchoalveolar lavage fluid, which contains less IL-8 and fewer neutrophils after treatment with macrolides . Macrolides also inhibit formation of leukotriene B4, which attracts neutrophils, and inhibit the release of superoxide anion by neutrophils that may be present in the airway . An important aspect of inflammation is extravasation of neutrophils into the tissues . Macrolides block formation of adhesion molecules necessary for neutrophil migration . Together, these anti-inflammatory effects result in improved pulmonary functions and fewer airway infections . In patients with DPB, the anti-inflammatory effects lead to a significant increase in survival . Further work is needed to characterize the clinical benefits of macrolides in patients with other chronic inflammatory airway diseases.

Kansenshogaku Zasshi, 2004 Oct, 78(10), 898 - 904
{Legionella pneumonia which occurred in a private whirlpool bath user}; Ishikawa A et al.; A 88 year old female with active rheumatoid arthritis treated by low dose of prednisolone and methotrexate was admitted to our hospital because of severe bilateral pulmonary infiltration and acute respiratory distress syndrome . On admission, she had consciousness disturbance and was intubated because of severe respiratory failure . We heard from her family of her habit she had taking a private whirlpool bath 2 or 3 times everyday . So, we suspected a Legionella pneumophila infection . We started intravenous erythromycin (EM) (1,500mg/day) and methylprednisolone pulse therapy (1,000mg x 3days) and full controlled mechanical ventilation supported with PEEP . Her respiratory failure was gradually improved and she was discharged on the 44 the hospital day . Legionella pneumophila (serogroup 6) was isolated in her sputum by B-CYE alpha culture . Legionella pneumophila (serogroup 6) was isolated in her private whirlpool bath too . Both samples revealed the same by genetic analysis with pulse field gel electrophoresis (PFGE) . This is the first adult case of Legionella pneumophila pneumonia infected from a private whirlpool bath confirmed by genetic analysis . We should always suspect Legionella pneumonia as one of the severe community-acquired pneumonia, because Legionella pneumophila were frequently detected among various water sources including the private whirlpool bath.

Curr Pharm Des, 2004, 10(26), 3221 - 8
Effects of macrolides and ketolides on mycobacterial infections; Bermudez LE et al.; New macrolides, such as clarithromycin and azithromycin, are active agents to Mycobacterium avium complex (MAC) . Both clarithromycin and azithromycin are well-known for the ability to improve the prognosis of AIDS patients with disseminated MAC infection . However, the administration of monotherapy with a macrolide is usually associated with the emergence of drug resistance after a few months of use . Therefore, the recommended treatment for MAC infection involved the use of at least two antibiotics, which includes a macrolide in combination with rifabutin, moxifloxacin and/or ethambutol . When used as prophylactic therapy in AIDS patients, azithromycin is more convenient (1200 mg, once a week) than clarithromycin (500 mg, twice a day) . Ketolides are a semi-synthetic derivative of erythromycin A, which differs from erythromycin A by substitution of a 3-keto group for L-cladinose . Telithromycin has a carbamate group linked to an imidazolium and pyridium nucleus at C11-C12 . In mice model, both telithromycin and ABT-733 were active in vivo against MAC.

Curr Drug Metab, 2004 Oct, 5(5), 415 - 42
Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4; Zhou S et al.; Cytochrome P450 (CYP) 3A4 is not only the most abundant isoform in human liver but also metabolizes approximately 60% of the therapeutic drugs . This feature renders CYP3A4 highly susceptible to both reversible and irreversible (mechanism-based) inhibition . The latter is characterized by NADPH-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites . Mechanism-based inactivation of CYP3A4 by drugs can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein . The clinical pharmacokinetic effect of a CYP3A4 inactivator is a function of its KI, kinact and partition ratio and the synthesis rate of new or replacement enzyme . Predicting drug-drug interactions involving CYP3A4 inactivation is possible when proper pharmacokinetic principles are followed . However, the prediction may become difficult, since the clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs and the patients . A number of clinically important drugs have been identified to be mechanism-based CYP3A4 inhibitors . These include antibiotics (e.g . erythromycin and isoniazid), anticancer drugs (e.g . tamoxifen), antidepressants (e.g . fluoxetine and midazolam), anti-HIV agents (e.g . ritonavir and delavirdine), antihypertensives (e.g . dihydralazine and verapamil), steroids and their receptor modulators (e.g . gestodene and raloxifene), and some herbal constituents (e.g . bergamottin and glabridin) . Compared to reversible inhibition, mechanism-based inhibitors of CYP3A4 more frequently cause unfavorable drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesized CYP3A4 protein . Most CYP3A4 inactivators are also PgP substrates/inhibitors, confounding the in vitro-in vivo extrapolation . Clinicians should have good knowledge on these CYP3A4 inactivators and avoid their combination use.

Am J Ther, 2004 Nov-Dec, 11(6), 433 - 42
Cotransport of macrolide and fluoroquinolones, a beneficial interaction reversing P-glycoprotein efflux; Sikri V et al.; The purpose of this study was to determine the interactions of erythromycin and various fluoroquinolones with P-glycoprotein (P-gp) and in turn assess their effects on transport kinetics across a model cell monolayer . MDCKII-MDRI cells were selected as a model monolayer to evaluate the effects of various fluoroquinolones, ie, norfloxacin, lomefloxacin, ofloxacin, enoxacin, grepafloxacin, levofloxacin, and sparfloxacin on the P-gp-mediated efflux of H-cyclosporine (CsA) and C-erythromycin . IC50 values associated with grepafloxacin-, levofloxacin-, and sparfloxacin-mediated inhibition of P-gp were calculated across Caco-2 cells with erythromycin as the model P-gp substrate . Transport of erythromycin was then studied with P-gp saturable concentrations of fluoroquinolones . Western blot analysis was performed on Caco-2 cells to confirm P-gp expression . Only grepafloxacin elevated the uptake of H-CsA across the MDCKII-MDRI cell monolayer, whereas norfloxacin, lomefloxacin, ofloxacin, and enoxacin did not exert any effect on H-CsA uptake . Inhibition studies indicate that grepafloxacin, levofloxacin, and sparfloxacin are potent inhibitors of P-gp-mediated efflux of C-erythromycin in the MDCKII-MDRI cell monolayer . Similar studies were conducted across Caco-2 cells and IC50 values were calculated . Inhibitory potency of sparfloxacin (IC50 = 607.6 microM) exceeded that of levofloxacin (IC50 = 1644 microM) and grepafloxacin (IC50 = 2266 microM) . Permeability ratio (BL-AP/AP-BL) of C-erythromycin was found to be 8.67, which was reduced to 1.18, 1.83, and 1.39 in the presence of grepafloxacin (1 mmol/L), levofloxacin (5 mmol/L), and sparfloxacin (1 mmol/L), respectively . Log partition coefficient of grepafloxacin (1.58), levofloxacin (0.553), and sparfloxacin (0.45) were correlated with the inhibition of P-gp . Western blot analysis indicated the expression of P-gp in Caco-2 cells . Fluoroquinolones like grepafloxacin, levofloxacin, and especially sparfloxacin significantly inhibit the efflux of erythromycin, which can modulate oral absorption and disposition of macrolide drugs when administered concomitantly.

Int J STD AIDS, 2004 Nov, 15(11), 737 - 9
Which treatment for genital tract Chlamydia trachomatis infection?
Tobin JM, Harindra V, Mani R.
A national opportunistic chlamydia screening programme, mainly targeting young sexually active women, is gradually being introduced across the UK and in future will predominantly occur in primary care sites . The relative efficacy of recommended antibiotic treatments for chlamydia has been poorly studied and especially that of single dose azithromycin . In Portsmouth, 1536 patients treated for chlamydia, with four different antibiotic regimens, during the Department of Health pilot study, were asked to return for test of cure . No difference in treatment outcome was found using doxycycline, oxytetracycline, erythromycin or azithromycin . Directly observed therapy with azithromycin may be especially helpful in treating young chlamydia-positive patients.

J Agric Food Chem, 2004 Nov 17, 52(23), 6848 - 56
Development of multiclass methods for drug residues in eggs: silica SPE cleanup and LC-MS/MS analysis of ionophore and macrolide residues; Heller DN et al.; A method was developed that is suitable for screening eggs for a variety of nonpolar residues in a single procedure . Residues are extracted by silica solid-phase extraction (SPE) . Analysis is conducted via reverse-phase gradient liquid chromatography, electrospray ionization, and tandem ion trap mass spectrometry . For screening purposes (based on a single precursor-product ion transition) the method can detect ionophore (lasalocid, monensin, salinomycin, narasin) and macrolide (erythromycin, tylosin) residues in egg at approximately 1 ng/mL (ppb) and above and novobiocin residues at approximately 3 ppb and above . Conditions are described for confirmatory analysis based on multiple ions in the product ion spectrum . The extraction efficiency for ionophores was estimated at 60-85%, depending on drug . Recovery of macrolides and novobiocin was not as good (estimated at 40-55% after a hexane wash of the final extract was included), but the method consistently screened and confirmed these residues at concentrations below the target of 10 ppb . The method was applied to eggs from hens dosed with each drug individually . Lasalocid was found to have the highest probability of detection in eggs based on its high ionization efficiency and higher rate of deposition relative to the other drugs . The method is part of a larger scheme to provide surveillance methods for a wide variety of drug residues in eggs.

Br J Pharmacol . 2004 Nov 8; {Epub ahead of print}
Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression; Sanz MJ et al.; Macrolides have long been used as anti-bacterial agents; however, there is some evidence that may exert anti-inflammatory activity . Therefore, erythromycin was used to characterize the mechanisms involved in their in vivo anti-inflammatory activity . Erythromycin pretreatment (30 mg kg(-1) day(-1) for 1 week) reduced the lipopolysaccharide (LPS; intratracheal, 0.4 mg kg(-1))-induced increase in neutrophil count and elastase activity in the bronchoalveolar lavage fluid (BALF) and lung tissue myeloperoxidase activity, but failed to decrease tumor necrosis factor-alpha and macrophage-inflammatory protein-2 augmented levels in BALF . Erythromycin pretreatment also prevented lung P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mRNA upregulation in response to airway challenge with LPS . Mesentery superfusion with LPS (1 microg ml(-1)) induced a significant increase in leukocyte-endothelial cell interactions at 60 min . Erythromycin pretreatment abolished the increases in these parameters . LPS exposure of the mesentery for 4 h caused a significant increase in leukocyte rolling flux, adhesion and emigration, which were inhibited by erythromycin by 100, 93 and 95%, respectively . Immunohistochemical analysis showed that LPS exposure of the mesentery for 4 h caused a significant enhancement in P-selectin, E-selectin, ICAM-1 and VCAM-1 expression that was downregulated by erythromycin pretreatment . Flow cytometry analysis indicated that erythromycin pretreatment inhibited LPS-induced CD11b augmented expression in rat neutrophils . In conclusion, erythromycin inhibits leukocyte recruitment in the lung and this effect appears mediated through downregulation of CAM expression . Therefore, macrolides may be useful in the control of neutrophilic pulmonary diseases.

Bioorg Chem, 2004 Dec, 32(6), 549 - 59
The role of erythromycin C-12 hydroxylase, EryK, as a substitute for PikC hydroxylase in pikromycin biosynthesis; Lee SK et al.; The substrate flexibility of the erythromycin C-12 hydroxylase from Saccharopolyspora erythraea, EryK, was investigated to test its potential for the generation of novel polyketide structures . We have shown that EryK can accept the substrates of PikC from Streptomyces venezuelae which is responsible for the hydroxylation of YC-17 and narbomycin . In a S . venezuelae pikC deletion mutant, EryK could catalyze the hydroxylation of YC-17 and narbomycin to generate methymycin/neomethymycin and pikromycin, respectively . Molecular modeling of the enzyme-substrate complex suggested the possible interaction of EryK with alternative substrates . The results indicate that EryK is flexible toward some alternative polyketides and can be useful for structural diversification of macrolides by post-polyketide synthase hydroxylation.

World J Gastroenterol, 2004 Dec 1, 10(23), 3470 - 4
Ethanol inhibits the motility of rabbit sphincter of Oddi in vitro; Sari R et al.; AIM: The role of the sphincter of Oddi (SO) in ethanol (ETOH)-induced pancreatitis is controversial . Our aim was to characterise the effect of ETOH on basal and stimulated SO motility . METHODS: SOs removed from white rabbits were placed in an organ bath (Krebs solution, pH7.4, 37 degrees) . The effects of 2 mL/L, 4 mL/L, 6 mL/L and 8 mL/L of ETOH on the contractile responses of the sphincter were determined . SOs were stimulated with either 0.1 mumol/L carbachol, 1 mumol/L erythromycin or 0.1 mumol/L cholecystokinin (CCK) . RESULTS: ETOH at a dose of 4 mL/L significantly decreased the baseline contractile amplitude from 11.98+/-0.05 mN to 11.19+/-0.07 mN . However, no significant changes in the contractile frequency were observed . ETOH (0.6%) significantly decreased both the baseline amplitude and the frequency compared to the control group (10.50+/-0.01 mN, 12.13+/-0.10 mN and 3.53+/-0.13 c/min, 5.5+/-0.13 cycles(c)/min, respectively) . Moreover, 0.8% of ETOH resulted in complete relaxation of the SO . Carbachol (0.1 micromol/L) or erythromycin (1 micromol/L) stimulated the baseline amplitudes (by 82% and 75%, respectively) and the contractile frequencies (by 150% and 106%, respectively) . In the carbachol or erythromycin-stimulated groups 2-6 mL/L of ETOH significantly inhibited both the amplitude and the frequency . Interestingly, a 4-5 min administration of 0.6% ETOH suddenly and completely relaxed the SO . CCK (0.1 micromol/L) stimulated the baseline amplitude from 12.37+/-0.05 mN to 27.40+/-1.82 mN within 1.60+/-0.24 min . After this peak, the amplitude decreased to 17.17+/-0.22 mN and remained constant during the experiment . The frequency peaked at 12.8+/-0.2 c/min, after which the constant frequency was 9.43+/-0.24 c/min throughout the rest of the experiment . ETOH at a dose of 4 mL/L significantly decreased the amplitude from 16.13+/-0.23 mN to 14.93+/-0.19 mN . However, no significant changes in the contractile frequency were observed . ETOH at a dose of 6 mL/L inhibited both the amplitudes and the frequencies in the CCK-stimulated group, while 8 mL/L of ETOH completely relaxed the SO . CONCLUSION: ETOH strongly inhibits the basal, carbachol, erythromycin, and CCK-stimulated rabbit SO motility . Therefore, it is possible that during alcohol-intake the relaxed SO opens the way for pancreatic fluid to flow out into the duodenum in rabbits . This relaxation of the SO may protect the pancreas against alcohol-induced damage.

J Natl Cancer Inst, 2004 Nov 3, 96(21), 1585 - 92
Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes; Mathijssen RH et al.; BACKGROUND: Irinotecan is a topoisomerase I inhibitor that has been approved for use as a first- and second-line treatment for colorectal cancer . The response to irinotecan is variable, possibly because of interindividual variation in the expression of the enzymes that metabolize irinotecan, including cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) . We prospectively explored the relationships between CYP3A phenotype, as assessed by erythromycin metabolism and midazolam clearance, and the metabolism of irinotecan and its active metabolite SN-38 . METHODS: Of the 30 white cancer patients, 27 received at least two treatments with irinotecan administered as one 90-minute infusion (dose, 600 mg) with 3 weeks between treatments, and three received only one treatment . Before the first and second treatments, patients underwent an erythromycin breath test and a midazolam clearance test as phenotyping probes for CYP3A4 . Erythromycin metabolism was assessed as the area under the curve for the flux of radioactivity in exhaled CO2 within 40 minutes after administration of {N-methyl-14C}erythromycin . Midazolam and irinotecan were measured by high-performance liquid chromatography . Genomic DNA was isolated from blood and screened for genetic variants in CYP3A4 and UGT1A1 . All statistical tests were two-sided . RESULTS: CYP3A4 activity varied sevenfold (range = 0.223%-1.53% of dose) among patients, whereas midazolam clearance varied fourfold (range = 262-1012 mL/min), although intraindividual variation was small . Erythromycin metabolism was not statistically significantly associated with irinotecan clearance (P = .090), whereas midazolam clearance was highly correlated with irinotecan clearance (r = .745, P<.001) . In addition, the presence of a UGT1A1 variant with a (TA)7 repeat in the promoter (UGT1A1*28) was associated with increased exposure to SN-38 (435 ng x h/mL, 95% confidence interval {CI} = 339 to 531 ng x h/mL in patients who are homozygous for wild-type UGT1A1; 631 ng x h/mL, 95% CI = 499 to 762 ng . h/mL in heterozygous patients; and 1343 ng x h/mL, 95% CI = 0 to 4181 ng x h/mL in patients who are homozygous for UGT1A1*28) (P = .006) . CONCLUSION: CYP3A4 phenotype, as assessed by midazolam clearance, is statistically significantly associated with irinotecan pharmacokinetics . Evaluation of midazolam clearance combined with UGT1A1*28 genotyping may assist with optimization of irinotecan chemotherapy.

J Obstet Gynaecol, 1999, 19(5), 506 - 8
A prospective study of asymptomatic Chlamydia trachomatis in Barbadian women; A F Attapattu P R Prussia V Boyce P N Levett J; A prospective study to determine the prevalence of asymptomatic female genital tract Chlamydia trachomatis infection was performed on 167 women at the Queen Elizabeth Hospital, Barbados, West Indies and at a private clinic . The ELISA (Microtrak, chlamydia EIA, Syva, CA) method was used to detect Chlamydia trachomatis antigen . Nineteen (11.4% 95% CI 6.5-16.3) women were found positive . The efficacy of a single 1 gram dose of azithromycin given orally to 18 patients was tested after 4 weeks . One patient who was pregnant was given 500 mg erythromycin four times daily orally for 1 week . Only six patients (including the pregnant patient) reported for follow up . All six repeat swabs were negative for C . trachomatis antigen . The prevalence of 11.4% asymptomatic chlamydial infection in endocervical swabs in Barbadian women is in agreement with a previous study which reported a prevalence of 18.4% +/7.8% . Patient compliance was assured, using a single dose of azithromycin . It was found to be as effective as doxycyline and ciprofloxacin as reported by other workers.

Nucleic Acids Res, 2004 Oct 27, 32(19), 5750 - 6 Print 2004.
Multiple defects in translation associated with altered ribosomal protein L4; O'Connor M et al.; The ribosomal proteins L4 and L22 form part of the peptide exit tunnel in the large ribosomal subunit . In Escherichia coli, alterations in either of these proteins can confer resistance to the macrolide antibiotic, erythromycin . The structures of the 30S as well as the 50S subunits from each antibiotic resistant mutant differ from wild type in distinct ways and L4 mutant ribosomes have decreased peptide bond-forming activity . Our analyses of the decoding properties of both mutants show that ribosomes carrying the altered L4 protein support increased levels of frameshifting, missense decoding and readthrough of stop codons during the elongation phase of protein synthesis and stimulate utilization of non-AUG codons and mutant initiator tRNAs at initiation . L4 mutant ribosomes are also altered in their interactions with a range of 30S-targeted antibiotics . In contrast, the L22 mutant is relatively unaffected in both decoding activities and antibiotic interactions . These results suggest that mutations in the large subunit protein L4 not only alter the structure of the 50S subunit, but upon subunit association, also affect the structure and function of the 30S subunit.

Commun Dis Intell, 2003, 27(4), 478 - 87
Laboratory surveillance of invasive pneumococcal disease in Australia in 2001 to 2002--implications for vaccine serotype coverage; Watson M et al.; This paper reports the results of comprehensive laboratory surveillance of invasive pneumococcal disease (IPD) in Australia during 2001 and 2002 . The 7-valent conjugate pneumococcal vaccine was introduced for high risk paediatric groups, including Indigenous children, in late 2001 . Of 1,355 isolates from non-Indigenous children, 86 per cent belonged to serotypes and 93 per cent to serogroups represented in the 7-valent pneumococcal conjugate vaccine . Thirteen per cent and 24 per cent of isolates had reduced susceptibility to penicillin and erythromycin, respectively and of these, more than 99 per cent belonged to serogroups represented in the 7-valent vaccine . Of the 1,504 isolates from non-Indigenous adults, 96 per cent belonged to serotypes included in the 23-valent polysaccharide vaccine; 14 per cent and 15 per cent had reduced susceptibility to penicillin and erythromycin, respectively and more than 95 per cent of these belonged to serotypes included in the 7-valent conjugate vaccine . In Western Australia and the Northern Territory (the only states for which Indigenous status was consistently available), there were 29 cases of IPD in Indigenous children, of which 21 were due to 7-valent vaccine serotypes in 2001, compared with 24 cases, including 10 due to vaccine serotypes, in 2002 . This represents a statistically significant increase in the proportion of total isolates due to non-vaccine serotypes (chi2 = 3.93, p = 0.048) following the introduction of the 7-valent conjugate vaccine, principally due to serotypes 7F and 12F . The number of episodes due to penicillin resistant isolates decreased from nine in 2001 to two in 2002 . Ninety per cent of isolates from Indigenous adults were included in the 23-valent polysaccharide vaccine and six per cent and five per cent had reduced susceptibility to penicillin and erythromycin, respectively . Conjugate pneumococcal vaccines can be expected to reduce the incidence of IPD due to vaccine serotypes in vaccinated children and potentially, their adult contacts . It may also impact favourably on the incidence of IPD due to penicillin and erythromycin resistant strains . Continued surveillance of both serotype distribution and antibiotic susceptibility are required to identify serotype replacement by non-vaccine serotypes and to monitor the overall impact of current and future vaccine programs on invasive pneumococcal disease in Australia.

Expert Opin Pharmacother, 2004 Nov, 5(11), 2251 - 4
Current pharmacological treatment of gastroparesis; Vandenplas Y et al.; The aetiology of gastroparesis differs between children and adults . During childhood, gastroparesis is quite rare, and is mostly seen in preterm infants, with either immaturity of the gastrointestinal tract, or when allergic to cow's milk protein . Acute, delayed gastric emptying may be observed following viral infections . In adults, most patients with gastroparesis are either idiopathic or of diabetic origin . As a consequence, approaches in the treatment of children and adults differ . Metoclopramide, domperidone, cisapride and erythromycin have all been studied . Evidence for benefit is strongest for the latter two drugs, although most studies have methodological shortcomings . From a paediatric perspective, it seems astonishing that more trials with erythromycin analogues have not been performed, as the few data available suggests that these analogues are more powerful, without the side effects of long-term, low-dose administration of antibiotics . Gastric electrical stimulation seems the most promising therapeutic option available at present.

Drug Metab Pharmacokinet, 2004 Apr, 19(2), 96 - 102
Effect of neonatal exposure of 17beta-estradiol and tamoxifen on hepatic CYP3A activity at developmental periods in rats; Murakami T et al.; We evaluated hepatic CYP3A activity during development in male and female rats and the effect of neonatal exposure of 17beta-estradiol and tamoxifen . In untreated and olive oil-treated (control) rats, hepatic CYP3A activities evaluated by erythromycin metabolism in vitro increased several-fold from age 2 to 9 weeks in males . In contrast, activity in females remained at a low and constant level from 2 to 15 weeks . Exposure of 17beta-estradiol to neonates at a dose of 10 micromol/kg daily for 3 days on day 1-3 (approximately) or 4-6 (approximately) after birth significantly increased hepatic CYP3A activity during the developmental period in both males and females, and a greater influence was observed in females exposed during days 4-6 (approximately) . Pubertal exposure of 17beta-estradiol (7-weeks old, 10 micromol/kg daily for 3 days) also increased hepatic CYP3A activity, but only in females . Neonatal exposure to tamoxifen (10 micromol/kg daily for 3 days) showed no appreciable effect in either males or females . In conclusion, a marked sex-difference was observed in hepatic CYP3A activity, and exposure of 17beta-estradiol to neonates increased hepatic CYP3A activity during the developmental period, especially in female rats.

Drug Metab Pharmacokinet, 2004 Feb, 19(1), 55 - 61
Utility of microtiter plate assays for human cytochrome P450 inhibition studies in drug discovery: application of simple method for detecting quasi-irreversible and irreversible inhibitors; Naritomi Y et al.; In this study, a simple in vitro method for detecting human P450 (CYP) quasi-irreversible and irreversible inhibitors was evaluated . For the method, cDNA-expressed CYPs were applied to microtiter plate assays, CYP inhibitors were co-incubated with fluorometric substrates, and IC(50) were continuously measured (without stopping enzyme reactions) . The typical reversible inhibitors (sulfaphenazole, tranylcypromine, quinidine, ketoconazole) showed constant IC(50) throughout the reaction . In contrast, the typical quasi-irrversible inhibitors (isosafrole, erythromycin, troleandomycin, diltiazem) and the typical irreversible inhibitors (furafylline, propranolol, mifepristone) showed time-dependent decreases in IC(50) . For CYP3A4 inhibition studies, two substrates, 7-benzyloxyresorufin (BzRes) and 7-benzyloxy-4-trifluoromethyl-coumarin (BFC), were used . The IC(50) of the CYP3A4 inhibitors were dependent on the substrate . However, the quasi-irreversible and irreversible inhibitors could be detected by examining changes in the IC(50), regardless of the substrate . Further, the detection method was applied to josamycin and bergamottin . Josamycin did not show definite time-dependent decreases in IC(50) for CYP 3A4, suggesting that josamycin is neither a quasi-irrversible nor an irreversible inhibitor of CYP3A4 . On the other hand, bergamottin showed time-dependent decreases in IC(50) for CYP1A2, CYP 2C9, CYP 2C19, CYP 2D6 and CYP 3A4, suggesting that bergamottin is a quasi-irrversible or an irreversible inhibitor of the 5 CYP isoforms . This method provides more rapid and reliable detection of quasi-irreversible and irreversible inhibitors and may be useful in drug discovery.

J Med Microbiol, 2004 Nov, 53(Pt 11), 1101 - 3
Erythromycin resistance in invasive serotype 14 pneumococci is highly related to clonal type; Clarke SC et al.; Sixty-seven serotype 14 pneumococci, isolated from invasive disease in Scotland during the first 6 months of 2003, were characterized . Serotype 14 pneumococci accounted for 18.2 % of the total number of cases . Serotyping, multilocus sequence typing and antibiotic susceptibility testing revealed 10 different sequence types (STs), predominantly ST 9 and ST 124; most ST 9 pneumococci were erythromycin-resistant whilst those of ST 124 were not.

Ann Pharmacother, 2004 Dec, 38(12), 2074 - 7 Epub 2004 Oct 19.
Acute colchicine intoxication during clarithromycin administration; Rollot F et al.; OBJECTIVE: To report a case of colchicine intoxication occurring with institution of clarithromycin . CASE SUMMARY: A 76-year-old man with familial Mediterranean fever (FMF) had received colchicine 1.5 mg daily for 6 years . The patient underwent 7 days of clarithromycin, amoxicillin, and omeprazole treatment for Helicobacter pylori-associated gastritis . Fever, abdominal pain, and diarrhea occurred 3 days after treatment initiation . On day 8, dehydration, pancytopenia, metabolic acidosis, and increased lipase level necessitated hospitalization . Alopecia was observed 2 weeks later . The patient recovered fully after the colchicine dosage was reduced to 0.5 mg/day and rehydration was performed . The previous dosage was then reinstituted without adverse reaction . An objective causality assessment revealed that the adverse event was probable . DISCUSSION: Continuous colchicine administration is used in treatment of microcrystalline arthritis, Behcet's disease, and FMF . Colchicine is primarily eliminated through biliary excretion . Renal elimination and cytochrome P450 metabolism play a less significant role . Colchicine is also a substrate of P-glycoprotein, a transporter involved in cellular efflux and elimination of numerous drugs . Three cases of intoxication have been reported when colchicine was combined with erythromycin, josamycin, or clarithromycin . Macrolides are inhibitors of P-glycoprotein and cytochrome P450-dependent enzymes and may decrease colchicine's biliary excretion through P-glycoprotein inhibition . CONCLUSIONS: Coadministration of colchicine and macrolides may impair colchicine elimination, resulting in excess drug exposure and toxicity . To this end, colchicine should be used with extreme caution in patients receiving P-glycoprotein inhibitors, particularly if they are elderly and/or renally compromised.

J Dermatol, 2004 Aug, 31(8), 610 - 7
Efficiency of benzoyl peroxide-erythromycin gel in comparison with metronidazole gel in the treatment of acne rosacea; Ozturkcan S et al.; Oral wide-spectrum antibiotics are the linchpin of rosacea treatment . Oral and topical metronidazole, topical tretinoin, and topical benzoyl peroxide may also be used in the treatment of rosacea . We aimed to show that benzoyl peroxide-erythromycin gel is efficient in the treatment of acne rosacea . Fifty-six patients with acne rosacea were enrolled in our study . We administered benzoyl peroxide-erythromycin gel to 27 patients and metronidazole gel to 29 patients . In all the patients, the intensities of erythema, telangiectasia, papules/pustules, and nodules were evaluated before, during and after the treatment . The positivity of Demodex folliculorum from skin scratches was compared between the two groups at each visit . At the end of the therapy on the third examination, in the benzoyl peroxide-erythromycin group, 91.7% of the patients showed marked clinical improvement, and 8.3% of them showed complete remission . In the metronidazole group, 73.3% showed marked clinical improvement, and 26.7% of them showed complete remission . Clinical improvement in the papular component was 65.2% for the benzoyl peroxide-erythromycin group, and 81.5% for metronidazole group . In the first examination, the clinical results of the agents were similar . Although both of the drugs were found to be effective in the second and third examinations, metronidazole gel was more effective than benzoyl peroxide-erythromycin . Both of the drugs were found to be significantly effective especially in treating the papular component of rosacea . Demodex folliculorum was found to be positive in 74.1% of the benzoyl peroxide-erythromycin group and in 62.1% of the metronidazole group at the beginning . In the benzoyl peroxide-erythromycin group, 40.7% of Demodex folliculorum positive patients, became negative by the first examination . This was 17.2% for the metronidazole group . In the benzoyl peroxide-erythromycin group, among the patients who were positive for Demodex folliculorum in the first examination, 37.5% of them became negative . This was 36.7% for the metronidazole group . Benzoyl peroxide-erythromycin gel was superior to metronidazole gel in decreasing Demodex folliculorum by the first examination, but the effect of the two drugs on Demodex folliculorum was similar by the second examination . As a result, topically applied combined benzoyl peroxide-erythromycin gel may be an alternative choice of treatment for acne rosacea.

J Ind Microbiol Biotechnol, 2004 Nov, 31(10), 447 - 56 Epub 2004 Nov.
Enhancing of erythromycin production by Saccharopolyspora erythraea with common and uncommon oils; Hamedi J et al.; The enhancing effect of various concentrations of 18 oils and a silicon antifoam agent on erythromycin production by Saccharopolyspora erythraea was evaluated in a complex medium containing soybean flour and dextrin as the main substrates . The oils used consisted of sunflower, pistachio, cottonseed, melon seed, water melon seed, lard, corn, olive, soybean, hazelnut, rapeseed, sesame, shark, safflower, coconut, walnut, black cherry kernel and grape seed oils . The biomass, erythromycin, dextrin and oil concentrations and the pH value were measured . Also, the kinds and frequencies of fatty acids in the oils were determined . The productivity of erythromycin in the oil-containing media was higher than that of the control medium . However, oil was not suitable as a main carbon source for erythromycin production by S . erythraea . The highest titer of erythromycin was produced in medium containing 55 g/l black cherry kernel oil (4.5 g/l) . The titers of erythromycin in the other media were also recorded, with this result: black cherry kernel > water melon seed > melon seed > walnut > rapeseed > soybean > (corn = sesame) > (olive = pistachio = lard = sunflower) > (hazelnut = cotton seed) > grape seed > (shark = safflower = coconut) . In media containing various oils, the hyphae of S . erythraea were longer and remained in a vegetative form after 8 days, while in the control medium, spores were formed and hyphae were lysed.

Zhejiang Da Xue Xue Bao Yi Xue Ban, 2004 Sep, 33(5), 427 - 32, 448
{The expression of transforming growth factor beta-1 in rat model of chronic obstructive pulmonary disease and the effects of early drugs intervention.}; Wu DQ et al.; OBJECTIVE: To evaluate the expression of transforming growth factor beta-1(TGF-beta1) and the effects of early drugs intervention of chronic obstructive pulmonary disease(COPD) in rat model . METHODS: The COPD rat model (group B) was established by intratracheal instillation of lipopolysaccharide twice and daily exposure to cigarette smoking . Drug intervention groups received dongchongxiacao orally daily from the three days before the experiment (group C) and erythromycin by intraperitoneal injection since the third week (group D)and inhalation of budesonide since the forth week (group E) . At the end of 10 weeks, all 40 rats including normal control (group A) were assessed for lung resistance (RL) and dynamic lung compliance (Cdyn) . The expression of TGF-beta1 gene and protein were also observed by immunohistochemistry and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively . RESULTS: The changes of pathology and pathophysiology in rat COPD model were similar to those of human COPD . There was a significant increase in the smooth muscle and collagen thickness in the airway wall of the group B in comparison with that of the group A . RL in group B was significantly higher than that in group A (P<0.01), while it was inhibited by early drugs intervention (P<0.01) . Cdyn was decreased in group B as compared with that in group A, which was limited by erythromycin and budesonide intervention (P<0.01) . The relative content for TGF-beta1 was significantly increased in the epithelial cells of the bronchi, endothelial cells of the pulmonary small vessel and alveolar macrophages of COPD group as compared with those of normal controls (P<0.01).The relative contents for TGF-beta1 in the epithelial of bronchi in group D and group E were significantly lower than that in group B, but not found in group C . There was no difference between group D and group E . There were statistical positive relationships between the RL and the relative content for TGF-beta1 in the bronchial epithelial cells, between the RL and the mRNA level of TGF-beta1 in the lung tissue (P<0.01 approximately 0.05) . CONCLUSION: This rat COPD model could be helpful to obtain more information about airway remodeling . TGF-beta1 may play an important role during the process of airway remodeling, and could be influenced by early drugs intervention such as budesonide and erythromycin, which may imply their potency in the treatment of COPD . But there is not same phenomenon found in dongchongxiacao group.

Clin Pharmacol Ther, 2004 Oct, 76(4), 341 - 9
In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam; Masica AL et al.; BACKGROUND: Previous studies have not demonstrated good correlations between various presumed phenotypic measures of in vivo cytochrome P450 (CYP) 3A activity . However, in reality, few have used appropriate and validated in vivo probes that consider the complexities of CYP3A . Accordingly, the disposition of 3 closely related benzodiazepines with extensive and similar CYP3A-mediated metabolism characteristics but different pharmacokinetics was investigated, and correlations between the drugs were examined . METHODS: The single-dose oral clearances of alprazolam, midazolam, and triazolam and the systemic clearances of the latter 2 drugs were separately determined in 21 healthy subjects (10 men) according to a randomized experimental design with a minimum 1-week period between the individual studies . An erythromycin breath test was also performed . RESULTS: After intravenous administration, systemic clearance varied 3-fold compared with a 6-fold range in clearance after an oral dose for all 3 drugs . However, mean values differed markedly between the drugs, with the systemic clearance of midazolam being almost double that of triazolam (383 +/- 73 mL/min versus 222 +/- 54 mL/min) . Oral clearances were even more dissimilar: alprazolam, 75 +/- 36 mL/min; triazolam, 360 +/- 195 mL/min; and midazolam, 533 +/- 759 mL/min . Estimates of CYP3A-mediated extraction by the intestine and liver indicated approximately equal contributions by both organs but larger values for midazolam than for triazolam, and these differences accounted for the differences in oral bioavailability, 30% +/- 13% versus 55% +/- 20%, respectively . Statistically significant ( P = .001 to .004) correlations between the 3 drugs' oral clearances ranged from 0.60 to 0.68 ( r s value), whereas the correlation for the systemic clearances of midazolam and triazolam was 0.66 ( P = .001) . No statistically significant relationships were observed between any of the clearance parameters and the erythromycin breath test . CONCLUSION: Despite alprazolam, midazolam, and triazolam having markedly different pharmacokinetic characteristics, statistically significant correlations were present between the oral and systemic clearances of the 3 drugs, consistent with a major involvement of CYP3A in their metabolism and elimination . However, the magnitude of the coefficients of determination ( r s ) was such to suggest that an in vivo probe approach, even with the use of valid phenotypic trait values, will be unable to accurately and reliably predict the pharmacokinetic behavior of another CYP3A substrate, as determined by the enzyme's constitutive activity.

Drug Metab Dispos, 2005 Jan, 33(1), 38 - 48 Epub 2004 Oct 01.
High volume bioassays to assess cyp3a4-mediated drug interactions: induction and inhibition in a single cell line; Yueh MF et al.; Exposure to certain xenochemicals can alter the catalytic activity of the major drug-metabolizing enzyme, CYP3A4, either by enhancing expression of this cytochrome P450 or inhibiting its activity . Such alterations can result in adverse consequences stemming from drug-drug interactions . A simplified and reliable tool for detecting the ability of candidate drugs to alter CYP3A4 levels or inhibit catalytic activity was developed by stable integration of human pregnane X receptor and a luciferase vector harboring the CYP3A4 enhancers . Treatment of stable transformants, namely DPX-2, with various concentrations of inducers including rifampicin, mifepristone, troglitazone, methoxychlor, and kava produced dose-dependent increases in luciferase expression (between 2- and 40-fold above dimethyl sulfoxide-treated cells) . Northern blot analyses of CYP3A4 mRNA in DPX-2 cells exhibited a good correlation to results generated with the reporter gene assay (r(2) = 0.5, p < 0.01) . Induction of CYP3A4 protein was examined by measuring catalytic activity with the CYP3A4 substrate, luciferin 6' benzyl ether (luciferin BE) . Metabolism of luciferin BE by DPX-2 cells was enhanced 5.2-fold above dimethyl sulfoxide-treated cells by treatment with rifampicin . Constitutive androstane receptor-mediated regulation of CYP3A4 protein was addressed by measuring catalytic activity in a separate cell line over-expressing this receptor . Phenobarbital and dexamethasone produced 1.5- and 2.0-fold increases, respectively, above control in luciferin BE metabolism . To determine the utility of DPX-2 cells for identifying inhibitors of CYP3A4 catabolism, luciferin BE activity was measured in the presence of various concentrations of ketoconazole, erythromycin, or kava . These agents exhibited dose-dependent decreases in CYP3A4 activity with IC(50) values of 0.3 microM for ketoconazole, 108 microM for erythromycin, and 15.5 microg/ml for kava . Collectively, DPX-2 cells were used to identify xenobiotics that induce or inhibit CYP3A4 in a high throughput manner, demonstrating their applicability to early-stage drug development.

Indian J Exp Biol, 2004 Sep, 42(9), 933 - 6
Isolation of Mycoplasma bovoculi from genitally diseased bovines and its experimental pathogenicity in pregnant guinea pigs; Singh Y et al.; Thirteen strains of M . bovoculi, 6 from frozen bull-semen (3.5% of 168), 3 from neat bull-semen (3.0% of 100), one each from heart blood and stomach contents of aborted foetus of 85 (1.18%) bovine-abortions, one each from stomach contents and pooled internal organs of 9 (11.1%) stillborn calves, were isolated . All the isolates were resistant to ampicillin and sensitive to spiramycin, vibramycin, demeclocyclin, oxytetracycline, lincomycin and tylosin . However, variation in resistance to tetracycline, erythromycin, neomycin, kanamycin and streptomycin was observed . The gross lesions like congestion of lungs, liver, kidney and spleen were noted only in stillborn calf . However, significant microscopic lesions were encountered in internal tissues of both the aborted bovine fetuses and stillborn calf . Thickened alveolar wall, congestion of blood vessels, mesenchymal cell proliferation along with infiltration of lymphocytes and macrophages were observed in lungs . The liver showed mild infiltration of lymphocytes, macrophages in hepatic triad and necrosis of hepatic cells . The kidney tissues had focal lymphocytic infiltration in the interstitium . One strain of M . bovoculi (isolate # SBC-7/84,IO) isolated from a stillborn calf was found abortigenic upon experimental inoculation in pregnant guinea pigs.

Sex Transm Infect, 2004 Oct, 80(5), 395 - 400
Chlamydia and gonorrhoea in pregnancy: effectiveness of diagnosis and treatment in Botswana; Romoren M et al.; BACKGROUND: Millions of patients are prescribed drugs for sexually transmitted infections (STIs) in developing countries each year, yet the treatment effect of these prescriptions is largely unknown . OBJECTIVES: To determine if the prescribing of erythromycin and ceftriaxone to pregnant women with STI symptoms leads to a reduction in the prevalence among these women of chlamydia and gonorrhoea, respectively . METHODS: We compared the prevalence of chlamydia among 116 pregnant women who had been prescribed erythromycin for a history of STI symptoms in their current pregnancy with the prevalence in a control group of 557 pregnant women who had not been prescribed this drug . Similarly we compared the prevalence of gonorrhoea among 110 pregnant women who had and 561 women who had not been prescribed ceftriaxone . RESULTS: There was no significant difference in the prevalence of chlamydia among the women who had and the women who had not been prescribed erythromycin four times daily for 10 days (7% v 8%) . Contrarily, none of the women who had been prescribed a single dose of ceftriaxone had gonorrhoea, whereas 4% of the women who had not had this drug prescribed did have gonorrhoea . CONCLUSIONS: The prescribing of erythromycin seems to have had a limited effect on chlamydia in this population, whereas the prescribing of ceftriaxone led to the curing of gonorrhoea . Ceftriaxone is provided as a single dose injection at the point of care, and the differential effectiveness between the two drugs may reflect low compliance with the complex erythromycin regimen . Interventions to increase compliance could improve cure rates . The use of a simpler drug regimen should be considered when low compliance is likely.

Nihon Kokyuki Gakkai Zasshi, 2004 Aug, 42(8), 767 - 71
{Case of chronic eosinophilic bronchiolitis associated with bronchial asthma}; Nagata N et al.; A 62 year-old woman presented with diffuse, centriacinar nodular densities on chest radiography and CT, and an increase of peripheral blood eosinophils, four years after diagnosis of bronchial asthma . Diffuse panbronchiolitis was diagnosed, and was treated with erythromycin for a long period . One year later, she noticed exertional dyspnea, and her chest radiograph showed increased nodular densities . Lung biopsy under video-assisted thoracoscopy was performed, and revealed chronic bronchiolitis with eosinophilic infiltration, and focal, peribronchiolar eosinophilic infiltration in the alveolar septa and alveoli . She was treated with prednisolone, and her symptoms and nodular densities on chest radiography and CT were improved . We consider that the clinico-pathological findings of this case are consistent with those of chronic eosinophilic bronchiolitis, which has recently been reported in Japan . This case is different from previously reported ones in that eosinophilic bronchiolitis appeared in the course of bronchial asthma, suggesting the possibility that eosinophilic bronchiolitis may be accompanied with bronchial asthma or eosinophilic pneumonia.

Dig Dis Sci, 2004 Aug, 49(7-8), 1335 - 41
Alterations in gallbladder emptying and bile retention in the absence of changes in bile lithogenicity in postmenopausal women on hormone replacement therapy; Dhiman RK et al.; The role of female sex hormones in the pathogenesis of gallstones is well established . Pregnancy, contraceptive use, estrogen replacement therapy in postmenopausal women, and estrogen therapy in men for the treatment of prostatic carcinoma have been found to be associated with increased risk of cholesterol gallstones . Alterations in gallbladder emptying and in bile lithogenicity in postmenopausal women receiving hormone replacement therapy (HRT) have not been studied to date . The present study was undertaken to study the effect of HRT on gallbladder emptying and bile lithogenicity . Sixteen postmenopausal women were included in the study . None of the patients had gallstone disease and none had received prokinetic drugs, such as, erythromycin, metoclopramide, domperidone or cisapride, aspirin, and nonsteroidal antiinflammatory drugs . Gallbladder emptying (n = 16), bile microscopy (n = 7), cholesterol saturation index (CSI) (n = 7), and nucleation time (n = 7) were studied before and 3 months after HRT (conjugated estrogen, 0.625 mg, + medroxyprogesterone acetate, 2.5 mg, everyday) . Fasting and residual volumes increased (fasting volume, 18.2 +/- 2.2 mL pre-HRT vs 27.6 +/- 3.2 mL post-HRT, P = 0.0003; residual volume, 3.9 +/- 0.6 mL pre-HRT vs 10.3 +/- 2.0 mL post-HRT, P = 0.00009) and ejection fraction decreased (78.2 +/- 2.5% pre-HRT vs 62.2 +/- 3.8% post-HRT; P = 0.0017) after 3 months of HRT . There was no change in CSI (2.32 +/- 0.36 pre-HRT vs 2.60 +/- 0.51 post-HRT; P = NS) or in nucleation time (19.0 +/- 1.2 days pre-HRT vs 17.6 +/- 1.3 days post-HRT; P = NS) . None of the bile samples either pre-HRT or post-HRT showed cholesterol monohydrate crystals . Though impairment of gallbladder emptying occurs in the short term with HRT in postmenopausal women, there is no change in CSI and nucleation time.

J Biol Chem, 2004 Dec 17, 279(51), 53506 - 15 Epub 2004 Sep 22.
Kinetics of macrolide action: the josamycin and erythromycin cases; Lovmar M et al.; Members of the macrolide class of antibiotics inhibit peptide elongation on the ribosome by binding close to the peptidyltransferase center and blocking the peptide exit tunnel in the large ribosomal subunit . We have studied the modes of action of the macrolides josamycin, with a 16-membered lactone ring, and erythromycin, with a 14-membered lactone ring, in a cell-free mRNA translation system with pure components from Escherichia coli . We have found that the average lifetime on the ribosome is 3 h for josamycin and less than 2 min for erythromycin and that the dissociation constants for josamycin and erythromycin binding to the ribosome are 5.5 and 11 nM, respectively . Josamycin slows down formation of the first peptide bond of a nascent peptide in an amino acid-dependent way and completely inhibits formation of the second or third peptide bond, depending on peptide sequence . Erythromycin allows formation of longer peptide chains before the onset of inhibition . Both drugs stimulate the rate constants for drop-off of peptidyl-tRNA from the ribosome . In the josamycin case, drop-off is much faster than drug dissociation, whereas these rate constants are comparable in the erythromycin case . Therefore, at a saturating drug concentration, synthesis of full-length proteins is completely shut down by josamycin but not by erythromycin . It is likely that the bacterio-toxic effects of the drugs are caused by a combination of inhibition of protein elongation, on the one hand, and depletion of the intracellular pools of aminoacyl-tRNAs available for protein synthesis by drop-off and incomplete peptidyl-tRNA hydrolase activity, on the other hand.

J Pharmacol Toxicol Methods, 2004 Sep-Oct, 50(2), 93 - 101
Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern; Kirsch GE et al.; INTRODUCTION: In vitro evaluation of drug effects on hERG K(+) channels is a valuable tool for identifying potential proarrhythmic side effects in drug safety testing . Patch-clamp recording of hERG K(+) current in mammalian cells can accurately evaluate drug effects, but the methodology has not been standardized, and results vary widely . Our objective was to evaluate two potential sources of variability: the temperature at which recordings are performed and the voltage pulse protocol used to activate hERG K(+) channels expressed in HEK293 cells . METHODS: A panel of 15 drugs that spanned a broad range of potency for hERG inhibition and pharmacological class was evaluated at both room and near-physiological temperatures using several patch-clamp voltage protocols . Concentration-response analysis was performed with three stimulus protocols: 0.5- and 2-s step pulses, or a step-ramp pattern . RESULTS: Block by 2 of the 15 drugs tested, d,l-sotalol (antiarrhythmic) and erythromycin (antibiotic), was markedly temperature sensitive . hERG inhibition measured using a 2-s step-pulse protocol underestimated erythromycin potency compared with results obtained with a step-ramp protocol . Using conservative acceptance criteria and the step-ramp protocol, the IC(50) values for hERG block differed by less than twofold for 15 drugs . DISCUSSION: Data obtained at near-physiological temperatures using a step-ramp pattern are highly repeatable and provide a conservative safety evaluation of hERG inhibition.

Drug Metab Dispos, 2004 Dec, 32(12), 1434 - 45 Epub 2004 Dec.
Evidence of significant contribution from CYP3A5 to hepatic drug metabolism; Huang W et al.; CYP3A4 and CYP3A5 exhibit significant overlap in substrate specificity but can differ in product regioselectivity and formation activity . To further explore this issue, we compared the kinetics of product formation for eight different substrates, using heterologously expressed CYP3A4 and CYP3A5 and phenotyped human liver microsomes . Both enzymes displayed allosteric behavior toward six of the substrates . When it occurred, the "maximal" intrinsic clearance was used for quantitative comparisons . Based on this parameter, CYP3A5 was more active than CYP3A4 in catalyzing total midazolam hydroxylation (3-fold) and lidocaine demethylation (1.4-fold) . CYP3A5 exhibited comparable metabolic activity as CYP3A4 (90-110%) toward dextromethorphan N-demethylation and carbamazepine epoxidation . CYP3A5-catalyzed erythromycin N-demethylation, total flunitrazepam hydroxylation, testosterone 6beta-hydroxylation, and terfenadine alcohol formation occurred with an intrinsic clearance that was less than 65% that of CYP3A4 . Using two sets of human liver microsomes with equivalent CYP3A4-specific content but markedly different CYP3A5 content (group 1, predominantly CYP3A4; group 2, CYP3A4 + CYP3A5), we assessed the contribution of CYP3A5 to product formation rates determined at low substrate concentrations (< or = Km) . Mean product formation rates for group 2 microsomes were 1.4- to 2.2-fold higher than those of group 1 (p < 0.05 for 5 of 8 substrates) . After adjusting for CYP3A4 activity (itraconazole hydroxylation), mean product formation rates for group 2 microsomes were still significantly higher than those of group 1 (p < 0.05 for 3 substrates) . We suggest that, under conditions when CYP3A5 content represents a significant fraction of the total hepatic CYP3A pool, the contribution of CYP3A5 to the clearance of some drugs may be an important source of interindividual variability.

Zhongguo Yi Xue Ke Xue Yuan Xue Bao, 2004 Aug, 26(4), 467 - 73
{Advance in synthesis of ketolides, a new class of erythromycin derivatives}; Lei PS et al.; Drug-resistance has become a challenging clinical problem . Ketolides, a new class of erythromycin derivatives, have shown promising effectiveness in killing drug-resistant bacteria . This article reviews recent development in synthesis of ketolides, with focus on the modification and synthesis of some important positions on erythromycin A cycles.

Rapid Commun Mass Spectrom, 2004, 18(18), 2041 - 5
On-line laser desorption/ionization mass spectrometry of matrix-coated aerosols; Jackson SN et al.; Matrix-assisted laser desorption/ionization (MALDI) was used for the on-line analysis of single particles . An aerosol was generated at atmospheric pressure and particles were introduced into a time-of-flight (TOF) mass spectrometer through a single-stage differentially pumped capillary inlet . Prior to entering the mass spectrometer, a matrix was added to the particles using a heated saturator and condenser . A liquid matrix, 3-nitrobenzyl alcohol (NBA), and a solid matrix, picolinic acid (PA), were used . Particles were ablated with a 351 nm excimer laser and the resulting ions were mass-separated in a two-stage reflectron TOF mass spectrometer . Aerosol particles containing the biomolecules erythromycin and gramicidin S were analyzed with and without the matrix addition step . The addition of NBA to the particles resulted in mass spectra that contained an intact molecular ion mass peak . In contrast, PA-coated particles did not yield molecular ion peaks from matrix-coated particles .

Drug Metab Dispos, 2004 Oct, 32(10), 1083 - 91
Differences in the inhibition of cytochromes P450 3A4 and 3A5 by metabolite-inhibitor complex-forming drugs; McConn DJ 2nd et al.; The objectives of this study were to characterize and compare the reversible inhibition and time-dependent inactivation of cytochromes P450 3A4 and 3A5 (CYP3A4 and CYP3A5) by erythromycin, diltiazem, and nicardipine . In the following experiments, we used cDNA-expressed CYP3A Supersomes and CYP3A-phenotyped human liver microsomes . We estimated the apparent constants for reversible inhibition (Ki(app) and IC50) and the irreversible kinetic constants (KI and kinact) for time-dependent inhibition . Based on an aggregate of Ki(app) and IC50 measurements, all inhibitors showed a greater inhibitory potency for CYP3A4 compared with CYP3A5 . In addition, for each inhibitor, the kinact for CYP3A4 was approximately 4-fold higher than that for CYP3A5, indicating a greater propensity for time-dependent loss of CYP3A4 activity than of CYP3A5 . Difference spectra experiments revealed an NADPH-dependent peak at approximately 455 nm {metabolite-inhibitor (MI) complex} following incubation of all three drugs with CYP3A4 . There was no discernable MI complex formation following CYP3A5 incubation with any of the inhibitors . However, when CYP3A4 and CYP3A5 were incubated simultaneously with erythromycin, both enzymes appeared to contribute to the formation of a MI complex . Additional experiments revealed that erythromycin caused a comparable type I spectral change when bound to CYP3A5 and CYP3A4 (Ks=48 microM and 52 microM, respectively) . Moreover, CYP3A5 exhibited only a moderately slower rate for the initial N-demethylation than did CYP3A4 (intrinsic clearance=41 versus 99 microl/min/nmol, respectively) . In conclusion, erythromycin, diltiazem, and nicardipine were weaker inhibitors of CYP3A5 and inactivated the enzyme at a slower rate than their respective effects on CYP3A4 . With respect to erythromycin, the failure of CYP3A5 to form a MI complex appears to be the result of slowed or impaired metabolic events downstream from the initial catalytic step, possibly due to a different orientation of the substrate molecule in the active site.

Hautarzt, 2004 Oct, 55(10), 976 - 8
{Confluent and reticulated papillomatosis . Gougerot-Carteaud disease}; Wiesenborn A et al.; Confluent and reticulated papillomatosis is an uncommon dermatosis of unknown etiology which is often difficult to diagnose . Lesions appear on the mid-trunk and affect mostly young females . We report a 15-year-old girl with typical clinical and histologic features of this rare disorder in whom the lesions rapidly improved after minocycline therapy . Topical treatment with isotretinoin and erythromycin was ineffective.

Clin Microbiol Infect, 2004 Oct, 10(10), 911 - 6
Impact of regular attendance by infectious disease specialists on the management of hospitalised adults with community-acquired febrile syndromes; Borer A et al.; The impact of attendance by infectious disease specialists (IDS) on hospitalised adults with community-acquired infection was assessed by studying 402 consecutive febrile adults who were admitted randomly to either of two internal medicine wards over a 4-month period and given intravenous antibiotics . In ward 1, patients were attended by IDS, whereas those in ward 2 were attended by physicians from other specialties . In total, 160 patients were treated in ward 1 and 242 in ward 2 (median age 66 years; 49% male) . The case-mix was comparable . Only 39% of ward 2 patients underwent minimal fever diagnostic tests compared to 82% in ward 1 (p < 0.001) . Ward 1 and 2 patients received 188 and 315 antibiotic courses, respectively, of which 32% and 20% required approval from IDS (p 0.003) . Patients in ward 1 were more likely to receive ceftriaxone (7.5% vs . 2%; p 0.002), erythromycin (7% vs . 1.5%; p 0.002) and cefuroxime (48% vs . 26%; p < 0.0001), but were less likely to receive amoxycillin-clavulanate (8% vs . 28%; p < 0.0001) . The mean durations of therapy were 3.6 and 3.2 days (not significant), and therapy was deemed to be completely appropriate in 55.5% and 43% of cases, respectively (p 0.012) . The crude mortality rates were 6.3% and 7.9%, respectively (not significant), while the medication costs were US dollars 27.4 and US dollars 26.4/patient/antibiotic day, respectively . Regular attendance by IDS resulted in significantly higher rates of accurate diagnosis and appropriate therapy . IDS prescribed more restricted (and expensive) agents, but preferred less expensive agents among unrestricted drugs, thereby offsetting the overall medication costs.

Xenobiotica, 2004 May, 34(5), 403 - 13
Model for the drug-drug interaction responsible for CYP3A enzyme inhibition . II: establishment and evaluation of dexamethasone-pretreated female rats; Kanazu T et al.; 1 . Cytochrome P450 (CYP) 3A catalysis of testosterone 6beta-hydroxylation in female rat liver microsomes was significantly induced, then reached a plateau level after pretreatment with 80 mg kg(-1) day(-1) dexamethasone (DEX) for 3 days . 2 . Midazolam was mainly metabolized by CYP3A in DEX-treated female rat liver microsomes from an immuno-inhibition study, and the apparent K(m) was 1.8 microM, similar to that in human microsomes . 3 . Ketoconazole and erythromycin, typical CYP3A inhibitors, demonstrated extensive inhibition of midazolam metabolism in DEX-treated female rat liver microsomes, and the apparent K(i) values were 0.088 and 91.2 microM, respectively . The values were similar to those in humans, suggesting that DEX-treated female rat liver microsomes have properties similar to those of humans . 4 . After oral administration of midazolam, the plasma midazolam concentration in DEX-treated female rats significantly decreased compared with control female rats . The area under the plasma concentration curve (AUC) and elimination half-life were one-11th and one-20th of those of control female rats, respectively . 5 . Using DEX-treated female rats, the effect of CYP3A inhibitors on midazolam pharmacokinetics was evaluated . The AUC and maximum concentration in plasma (C(max)) increased when ketoconazole was co-administered with midazolam . 6 . It was shown that the drug-drug interaction that occurs in vitro is also observed in vivo after oral administration of midazolam . In conclusion, the DEX-treated female rat could be a useful model for evaluating drug-drug interactions based on CYP3A enzyme inhibition.

Xenobiotica, 2004 May, 34(5), 391 - 402
Model for the drug-drug interaction responsible for CYP3A enzyme inhibition . I: evaluation of cynomolgus monkeys as surrogates for humans; Kanazu T et al.; 1 . Anti-human cytochrome P450 (CYP) 3A4 antiserum completely inhibited midazolam metabolism in monkey liver microsomes, suggesting that midazolam was mainly metabolized by CYP3A enzyme(s) in monkey liver microsomes . 2 . Midazolam metabolism was also inhibited in vitro by typical chemical inhibitors of CYP3A, such as ketoconazole, erythromycin and diltiazem, and the apparent K(i) values for ketoconazole, erythromycin and diltiazem were 0.127, 94.2 and 29.6 microM, respectively . 3 . CYP3A inhibitors increased plasma midazolam concentrations when midazolam and CYP3A inhibitors were co-administered orally . However, the pharmacokinetic parameters of midazolam were not changed by treatment with CYP3A inhibitors when midazolam was given intravenously . This suggests that CYP3A inhibitors modified the first-pass metabolism in the liver and/or intestine, but not systemic metabolism . 4 . The drug-drug interaction responsible for CYP3A enzyme(s) inhibition was observed when midazolam and inhibitors were co-administrated orally . Therefore, it was concluded that monkeys given midazolam orally could be useful models for predicting drug-drug interactions in man based on CYP3A enzyme inhibition.

J Dermatolog Treat, 2004 Sep, 15(5), 295 - 302
A topical azithromycin preparation for the treatment of acne vulgaris and rosacea; McHugh RC et al.; BACKGROUND: Erythromycin is a common therapy for acne and rosacea . A newer macrolide, azithromycin, offers superior tissue distribution and cellular concentration and is an effective oral anti-acne agent . Topical formulations such as erythromycin have been a major clinical therapy for acne . To date, no topical solution of azithromycin is available for the treatment of acne . OBJECTIVE: To prepare a stable topical 2% azithromycin formulation that could be used in an acne clinical trial to determine the efficacy of topical azithromycin in treating subjects with acne vulgaris and acne rosacea . METHODS: The study was divided into two phases . In phase I, azithromycin was prepared over a range of ethanol/water concentrations to determine solubility . The stability of a 2% azithromycin in 60% ethanol/water preparation was assessed by high-pressure liquid chromatography . The temperature, light, and pH dependence of the stability was also assessed . In phase II, a single center, randomized, double-blind, treatment-controlled study compared once-nightly application of topical 2% azithromycin versus 2% erythromycin . A total of 20 subjects with moderate inflammatory acne and 20 with rosacea were examined clinically at 0, 2, 4, 8, and 12 weeks for a 12-week period . Efficacy was evaluated with the Physician's Visual Analog Scale evaluation (PVAS), the papulopustule count, and acne severity rating (in subjects with acne) . RESULTS: In phase I, azithromycin was soluble in 60% ethanol/water . A 2% azithromycin in 60% ethanol/water solution maintained stability at room temperature for up to 26 weeks but at 37 degrees C there was some decay (16%) at 26 weeks . The stability was greatest at pH 6.8 and was unaffected by ambient light exposure . In phase II, the number of inflammatory lesions decreased in both acne and rosacea subjects treated with 2% erythromycin (7.56, p=0.03 and 4.4, p=0.01, respectively) . Azithromycin was not as effective for the treatment of rosacea . Both azithromycin (p=0.01) and erythromycin (p=0.03) treatment significantly reduced the inflammatory lesion count in acne vulgaris . No significant adverse events were identified in the acne group . In patients with rosacea, transient irritation occurred in five patients . CONCLUSIONS: A 2% azithromycin in 60% ethanol/water solution can be prepared and is stable for at least 6 months at room temperature . The methodology and power of the study were adequate to identify improvement in acne vulgaris and rosacea . Though it appears the formulation of topical azithromycin was at least comparable with topical erythromycin, larger studies would be needed to determine whether topical azithromycin has any significant advantage over topical erythromycin.

J Infect Chemother, 2004 Aug, 10(4), 245 - 9
Severe Chlamydophila psittaci pneumonia rapidly diagnosed by detection of antigen in sputum with an immunochromatography assay; Toyokawa M et al.; We report a case of severe Chlamydophila (Chlamydia) psittaci pneumonia rapidly diagnosed by detection of antigen in sputum with an immunochromatography assay . The patient was admitted to our hospital because of shock, disturbance of consciousness, accidental hypothermia, and multiple organ dysfunction syndrome, and he recovered after administration of intravenous erythromycin and high-dose methylpredonisolone therapy . Psittacosis was confirmed by detection of 16S rRNA gene of C . psittasi in sputum with multiplex-polymerase chain reaction analysis . Serological responses to C . psittasi, C . trachomatis, and C . pneumoniae were also evaluated, and serological cross-reactivity was observed between each species . We consider that the commercially available immunochromatography assay for Chlamydia species can be helpful for rapid diagnosis of Chlamydia infection of the respiratory tract . Hereafter, further examination will be necessary regarding pretreatment of specimens or detection sensitivity and specificity.

Toxicol Appl Pharmacol, 2004 Sep 15, 199(3), 295 - 304
Expression and characterization of human cytochrome P450 4F11: Putative role in the metabolism of therapeutic drugs and eicosanoids; Kalsotra A et al.; We previously reported the cDNA cloning of a new CYP4F isoform, CYP4F11 . In the present study, we have expressed CYP4F11 in Saccharomyces cerevisiae and examined its catalytic properties towards endogenous eicosanoids as well as some clinically relevant drugs . CYP4F3A, also known as a leukotriene B4 omega-hydroxylase, was expressed in parallel for comparative purposes . Our results show that CYP4F11 has a very different substrate profile than CYP4F3A . CYP4F3A metabolized leukotriene B4, lipoxins A4 and B4, and hydroxyeicosatetraenoic acids (HETEs) much more efficiently than CYP4F11 . On the other hand, CYP4F11 was a better catalyst than CYP4F3A for many drugs such as erythromycin, benzphetamine, ethylmorphine, chlorpromazine, and imipramine . Erythromycin was the most efficient substrate for CYP4F11, with a Km of 125 microM and Vmax of 830 pmol min(-1) nmol(-1) P450 . Structural homology modeling of the two proteins revealed some interesting differences in the substrate access channel including substrate recognition site 2 (SRS2) . The model of CYP4F11 presents a more open access channel that may explain the ability to metabolize large molecules like erythromycin . Also, some wide variations in residue size, charge, and hydrophobicity in the FG loop region may contribute to differences in substrate specificity and activity between CYP4F3A and CYP4F11.

Vaccine, 2004 Sep 28, 22(29-30), 4014 - 20
Multiplex opsonophagocytosis assay (MOPA): a useful tool for the monitoring of the 7-valent pneumococcal conjugate vaccine; Bogaert D et al.; Pneumococcal conjugate vaccination is highly efficacious against invasive diseases in young children . Since host protection is mainly mediated by opsonin-dependent phagocytosis, the in vitro measurement of opsonophagocytic activity of the anti-capsular antibodies is assumed to be a reliable correlate of protection to monitor vaccine efficacy . Unfortunately, the methods used so far are all tedious to perform and material-consuming . Therefore, we modified the multi-specificity opsonophagocytosis killing assay (MSOPKA) into a high-throughput method, which simultaneously measures the opsonophagocytosis against the seven serotypes covered by the current conjugate vaccine in a single assay . In the so-called multiplex opsonophagocytosis assay (MOPA), a mixture containing equal numbers of colony forming units (CFUs) of chloramphenicol-resistant serotype 4, spectinomycin-resistant serotype 6B, streptomycin-resistant serotype 9V, erythromycin-resistant serotype 14, rifampicin-resistant serotype 18C, tetracycline-resistant serotype 19F, and trimethoprim-resistant serotype 23F pneumococci was used as a target mixture and incubated with serial dilutions of test serum . After opsonophagocytosis by differentiated HL-60 cells in the presence of complement, the samples were spotted onto different blood agar plates containing the seven selective antibiotics, respectively . Opsonophagocytosis was calculated as the highest serum dilution resulting in 90% or more reduction in CFUs . The data obtained by this assay correlated well with the data obtained by the MSOPKA . In conclusion, the MOPA simultaneously measures opsonophagocytosis capacity of serum against the capsular serotypes included in the 7-valent pneumococcal conjugate vaccine in a high-throughput fashion, requiring low volumes of patient sera.

Arch Pharm Res, 2004 Jul, 27(7), 781 - 9
Pretreatment with 1,8-cineole potentiates thioacetamide-induced hepatotoxicity and immunosuppression; Kim NH et al.; The effect of 1,8-cineole on cytochrome P450 (CYP) expression was investigated in male Sprague Dawley rats and female BALB/c mice . When rats were treated orally with 200, 400 and 800 mg/kg of 1,8-cineole for 3 consecutive days, the liver microsomal activities of benzyloxyresorufin- and pentoxyresorufin-omicron-dealkylases and erythromycin N-demethylase were dose-dependently induced . The Western immunoblotting analyses clearly indicated the induction of CYP 2B1/2 and CYP 3A1/2 proteins by 1,8-cineole . At the doses employed, 1,8-cineole did not cause toxicity, including hepatotoxicity . Subsequently, 1,8-cineole was applied to study the role of metabolic activation in thioacetamide-induced hepatotoxicity and/or immunotoxicity in animal models . To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 800 mg/kg of 1 ,8-cineole for 3 days, followed by a single intraperitoneal treatment with 50 and 100 mg/kg of thioacetamide in saline . 24 h later, thioacetamide-induced hepatotoxicity was significantly potentiated by the pretreatment with 1,8-cineole . When female BALB/c mice were pretreated with 800 mg/kg of 1,8-cineole for 3 days, followed by a single intraperitoneal treatment with 100 mg/kg of thioacetamide, the antibody response to sheep red blood cells was significantly potentiated . In addition, the liver microsomal activities of CYP 2B enzymes were significantly induced by 1,8-cineole as in rats . Taken together, our results indicated that 1,8-cineole might be a useful CYP modulator in investigating the possible role of metabolic activation in chemical-induced hepatotoxicity and immunotoxicity.

Arch Oral Biol, 2004 Nov, 49(11), 895 - 901
Evaluation of acetaminophen P-glycoprotein-mediated salivary secretion by rat submandibular glands; Schaiquevich P et al.; The constant ratio between saliva and plasma acetaminophen concentrations (S/P) during the elimination phase is assumed to result from the equilibrium established among the free-drug concentrations in the arterial blood, venous blood and saliva . Salivary secretion of acetaminophen is assumed to result from a passive diffusion of the drug to saliva from the blood that supplies the salivary glands . However, the constant S/P ratio during acetaminophen disposition and the finding that P-glycoprotein (P-gp), a protein recognized to pump substrates out of the cell, is expressed in duct cells of the submandibular glands questions the mechanisms involved in acetaminophen salivary secretion . Thus, we intended to evaluate the existence of a P-glycoprotein-mediated transport of acetaminophen in rat submandibular glands . Acetaminophen (30 mg/kg, i.v.) pharmacokinetics was assessed in controls and in rats pre-treated with erythromycin (100 mg/kg) as a P-glycoprotein inhibitor . Acetaminophen pharmacokinetic parameters were calculated from saliva and plasma levels considering a non-compartmental analysis . Mean plasma and salivary profiles of control and pre-treated animals were almost superimposable . No difference could be found in S/P ratios in control and erythromycin pre-treated animals (P > 0.05) . Moreover, no statistical difference could be found in the kinetic parameters calculated from saliva or plasma drug level (P > 0.05) . These observations indicate that acetaminophen salivary secretion in rat submandibular glands is not related to P-glycoprotein-mediated transport under the experimental conditions of the present work.

J Clin Pharmacol, 2004 Oct, 44(10), 1125 - 31
The effects of modifying in vivo cytochrome P450 3A (CYP3A) activity on etoricoxib pharmacokinetics and of etoricoxib administration on CYP3A activity; Agrawal NG et al.; To investigate the influence of modifying in vivo cytochrome P450 3A (CYP3A) activity on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, and of etoricoxib administration on CYP3A activity, a 3-part, randomized, crossover study was conducted in 3 panels of healthy volunteers . In part I, 8 subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 400 mg ketoconazole, a known strong inhibitor of CYP3A . In part II, 8 different subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 600 mg rifampin, a known strong inducer of CYP3A . In parts I and II, plasma samples were collected following each etoricoxib dose and analyzed for etoricoxib . In part III, 8 different subjects were administered 120 mg etoricoxib or placebo once daily for 11 days, and the erythromycin breath test was administered on day 11 of each period . Coadministration of etoricoxib with daily doses of ketoconazole resulted in an average 43% increase in etoricoxib AUC; based on previous studies, this increase would not be expected to have any clinically meaningful effect . In contrast, coadministration of etoricoxib with daily doses of rifampin had a potentially clinically important effect on etoricoxib pharmacokinetics (average 65% decrease in etoricoxib AUC) . Etoricoxib had no effect on hepatic CYP3A activity, as assessed by the erythromycin breath test .

Drug Metab Dispos, 2004 Dec, 32(12), 1351 - 8 Epub 2004 Dec.
Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract; Iwata H et al.; Schisandra fruit, a Schisandraceae family herb, is used as a component in Kampo medicines (developed from Chinese medicines, but established in Japan) . It can act as a sedative and antitussive, improve hepatic function, and give a general tonic effect . An extract of Schisandra fruit has been shown with a potent inhibitory effect on human liver microsomal erythromycin N-demethylation activity mediated by cytochrome P450 3A4 (CYP3A4) . The present study was conducted to identify Schisandra fruit components having inhibitory effects on CYP3A4 by surveying the effect on human liver microsomal erythromycin N-demethylation activity . Known components of Schisandra fruit, gomisins B, C, G, and N and gamma-shizandrin, showed inhibitory effects on N-demethylation activity . Among these components, gomisin C displayed the most potent and competitive inhibitory effect, with a Ki value of 0.049 microM . Furthermore, the inhibitory effect of gomisin C was stronger than that of ketoconazole (Ki = 0.070 microM), a known potent CYP3A4 inhibitor . Gomisin C, however, inhibited CYP1A2-, CYP2C9-, CYP2C19-, and CYP2D6-dependent activities only to a limited extent (IC50 values >10 microM) . Moreover, gomisin C inactivated human liver microsomal erythromycin N-demethylation activity in a time- and concentration-dependent manner . The inactivation kinetic parameters k(inact) and K(I) were 0.092 min(-1) and 0.399 microM, respectively . The human liver microsomal erythromycin N-demethylation activity inactivated by gomisin C did not recover on dialysis of the microsomes . Spectral scanning of CYP3A4 with gomisin C yielded an absorbance at 455 nm, suggesting that gomisin C inactivated the cytochrome P450 via the formation of a metabolite intermediate complex . This pattern is consistent with the metabolism of the methylenedioxy substituent in gomisin C . These results indicate that gomisin C is a mechanism-based inhibitor that not only competitively inhibits but irreversibly inactivates CYP3A4.

Expert Opin Pharmacother, 2004 Sep, 5(9), 1917 - 28
Recent pharmacological advances in the treatment of preterm membrane rupture, labour and delivery; Doggrell SA; Preterm delivery (before 37 completed weeks of gestation) is the major determinant of infant mortality . In women with a previous preterm birth associated with bacterial vaginosis, prophylactic antibiotics (e.g., metronidazole) reduce the risk of preterm birth and low birth weight . Trichomonas vaginalis increases the risk of preterm delivery, but metronidazole is not beneficial for this and may even be detrimental . Antibiotic use (e.g., erythromycin) prolongs pregnancy in late premature rupture and has health benefits for the neonate . However, antibiotics are probably not useful in preterm labour . Intramuscular 17alpha-progesterone and vaginal progesterone reduce the rate of preterm labour in high-risk pregnancies, including previous spontaneous preterm delivery . Magnesium sulfate, beta2-adrenoceptor agonists and the oxytocin-receptor antagonist, atosiban, are effective in reducing uterine contractions short-term, but there is little evidence that this leads to improved outcomes for the neonate . However, tocolysis with calcium-channel blockers does seem to lead to better outcomes for the neonate . Fetal side effects, such as ductus arteriosus constriction and impaired renal function, are associated with the inhibition of prostaglandin synthesis with indomethacin . New approaches and more effective drugs are required in the treatment of preterm delivery.

Mar Pollut Bull, 2004 Sep, 49(5-6), 436 - 44
The occurrence of selected human pharmaceutical compounds in UK estuaries; Thomas KV et al.; This report describes a scoping study conducted in order to establish whether pharmaceutical compounds may be present in UK estuaries . Surface water samples collected from five UK estuaries were analysed for the presence of 14 pharmaceutical compounds selected from the priority lists of the UK Environment Agency and the Oslo and Paris Commission (OSPAR) . The pharmaceutical compounds/metabolites clofibric acid, clotrimazole, dextropropoxyphene, diclofenac, ibuprofen, mefenamic acid, propranolol, tamoxifen and trimethoprim were detected at measurable concentrations in the samples collected . The concentrations of erythromycin, lofepramine, paracetamol, sulfamethoxazole and acetyl-sulfamethoxazole were all below the limits of detection of the methods used (between 4 and 20 ng l(-1)) . The anti-fungal agent clotrimazole was the most frequently detected at a maximal concentration of 22 ng l(-1) and a median concentration of 7 ng l(-1) . The analgesic compound ibuprofen was detected at a maximal concentration of approximately 930 ng l(-1) and a median concentration of 48 ng l(-1), whilst the other pharmaceutical compounds were detected between the limits of detection of the method used and 570 ng l(-1) .

J Eur Acad Dermatol Venereol, 2004 Sep, 18(5), 622 - 5
Vesicular pityriasis rosea: response to erythromycin treatment; Miranda SB et al.; Pityriasis rosea (PR) is a relatively common disease although its aetiology has not yet been identified . It occurs worldwide and there is no racial susceptibility factor . It usually affects teenagers and young adults between 10 and 35 years of age . Typical PR is much easier to diagnose than the rare atypical forms . We report a rare case of vesicular PR in a black woman who had vesicular lesions limited to her palms and soles in addition to regular typical lesions . We devised an efficient oral erythromycin treatment for this patient .

Chem Pharm Bull (Tokyo), 2004 Aug, 52(8), 943 - 8
Bitterness evaluation of medicines for pediatric use by a taste sensor; Ishizaka T et al.; The purpose of this study was to evaluate the bitterness of 18 different antibiotic and antiviral drug formulations, widely used to treat infectious diseases in children and infants, in human gustatory sensation tests and using an artificial taste sensor . Seven of the formulations were found to have a bitterness intensity exceeding 1.0 in gustatory sensation tests (evaluated against quinine as a standard) and were therefore assumed to have an unpleasant taste to children . The bitterness intensity scores of the medicines were examined using suspensions in water or an acidic sports drink . In the case of three macrolide antibiotic formulations containing erythromycin (ERYTHROCIN dry syrup), clarithromycin (CLARITH dry syrup for pediatric), and azithromycin (ZITHROMAC fine granules for pediatric use), the bitterness intensities of suspensions in acidic sports drinks were dramatically enhanced compared with the corresponding scores of suspensions in water . This enhancement could be predicted using the taste sensor . On the other hand, a reduction of bitterness intensity was observed for an acidic sports drink suspension of an amantadine product (SYMMETREL fine granules) compared with an aqueous suspension . This reduction in bitterness could also be predicted using the taste sensor output value . Thus, the taste sensor could predict whether or not suspension in an acidic sports drink would enhance or reduce the bitterness intensity of pediatric drug formulations, compared with suspensions in water.

Pediatr Infect Dis J, 2004 Aug, 23(8), 726 - 31
Elimination of racial differences in invasive pneumococcal disease in young children after introduction of the conjugate pneumococcal vaccine; Talbot TR et al.; BACKGROUND: Racial differences in the epidemiology of invasive pneumococcal disease (IPD) have been widely recognized, but the impact of conjugate pneumococcal vaccine (PCV) introduction in 2000 on these differences has not been extensively studied . METHODS: IPD episodes in 5 Tennessee counties from January 1995 through December 2002 were collected prospectively using the Centers for Disease Control and Prevention's Active Bacterial Core Surveillance system (ABCs) . Trained nurses collected clinical data, and antibiotic susceptibility testing was performed on available isolates . RESULTS: Before vaccine licensure, IPD rates were highest in children younger than 2 years and in blacks . The disparity in IPD rates between blacks and whites younger than 2 years of age substantially diminished after PCV introduction . In 1999, the IPD rate in black children younger than 2 years was 340.2 per 100,000, representing 176.5 more events per 100,000 than in white children (P < 0.001) . In 2002, this rate had decreased 83% to 57.4 per 100,000, similar to the rate in white children (39.6 per 100,000; P = 0.31) . Before vaccine licensure, a higher percentage of isolates from whites were antibiotic-nonsusceptible . In 2002, the proportion of antibiotic-nonsusceptible pneumococcal isolates was similar in whites and blacks of all ages for the first time during the study period (P > 0.05 for separate comparisons of penicillin, cephalosporin and erythromycin nonsusceptibility) . These changes occurred despite a lower PCV vaccination coverage in Tennessee in blacks than in whites (31.2% versus 47.6%) . CONCLUSIONS: With conjugate pneumococcal vaccine introduction in Tennessee, racial differences in the incidence rates of IPD have largely been eliminated, particularly in young children.

Braz J Infect Dis, 2004 Feb, 8(1), 90 - 100 Epub 2004 Jul 20.
Gatifloxacin in the treatment of community-acquired pneumonias: a comparative trial of ceftriaxone, with or without macrolides, in hospitalized adult patients with mild to moderately severe pneumonia; Mendonca JS et al.; Community-acquired pneumonia is very common, but some of the cases do require hospitalization for treatment, particularly when older patients and/or co-morbidities are involved; both "typical" and "atypical" respiratory pathogens take part etiologically, and there is increasing concern about the emergence of resistance . There is interest in therapeutic options that can: a) comprehend such a spectrum of bacteria and resistance; b) allow parenteral to oral sequential treatment . We made a multicenter, prospective and randomized trial to compare the "standard" treatment of ceftriaxone IV alone or in combination with erythromycin IV, followed by clarithromycin PO (ceftriaxone treatment arm), with gatifloxacin IV, followed by oral administration (gatifloxacin treatment arm) . The need for hospitalization was based on clinical criteria as judged by the investigators . Standardized criteria for diagnosis and follow-up were employed . Fifty-six patients were enrolled, with 48% over 65 years old, and there were frequent co-morbidities . Of these, 51 were clinically evaluable, 26 in the gatifloxacin and 25 in the ceftriaxone arm, with comparable success rates, 92% and 88%, respectively, even when major prognostic factors were considered . There were no serious adverse events or significant laboratory value changes attributable to the study drugs . Gatifloxacin as monotherapy (initially IV then orally until completion of treatment) was shown to be effective and safe, comparable to ceftriaxone IV alone or in combination with a macrolide (initially IV then orally until completion of treatment), in empirical therapy for community-acquired pneumonias, for patients that, at the physician s discretion, require initial treatment as inpatients.

Drug Metab Dispos, 2004 Nov, 32(11), 1239 - 46 Epub 2004 Jul 30.
Effects of uremic toxins on hepatic uptake and metabolism of erythromycin; Sun H et al.; Hepatic clearance of erythromycin (Ery) is significantly reduced in patients with end stage renal disease . Since Ery is primarily eliminated via excretion of unchanged drug in the bile, we suspect that this change could be due to the effect of uremic toxins on hepatic uptake and/or efflux transporters . Using rat hepatocytes and microsomes as model proof of concept systems, we examined six uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), indoxyl sulfate (IS), hippuric acid (HA), indole acetic acid (IA), guanidinosuccinic acid (GSA), and indoxyl-beta-D-glucuronide (IG), for their effects on Ery uptake and metabolism . Ery and the metabolite N-demethyl-Ery were measured by liquid chromatography/tandem mass spectrometry . The uptake of Ery by rat hepatocytes was markedly inhibited by rifampin and digoxin, but not by quinidine, suggesting that Oatp2 plays a major role in the uptake of Ery . At 50 microM, CMPF significantly (p < 0.05) reduced hepatocyte accumulation of Ery and N-demethyl-Ery . At higher concentrations (>200 microM), CMPF appears to also inhibit the enzymatic metabolism of Ery . In contrast, IS did not significantly inhibit the hepatocyte uptake of Ery, even at the highest concentration (800 microM) tested, but reduced metabolite generation (p < 0.001) . The other uremic toxins, HA, IA, IG, and GSA, did not affect either hepatic uptake or microsomal metabolism of Ery . CMPF, IS, and HA were shown not to inhibit differential P-glycoprotein transport of Ery in cellular systems . Our results suggest that CMPF can directly inhibit the uptake of Ery by inhibiting Oatp2, whereas IS is more likely to inhibit the enzymatic metabolism of Ery .

Intern Med, 2004 Jun, 43(6), 503 - 7
Legionella micdadei pneumonia diagnosed by culture isolation and DNA-dNA hybridization from bronchial lavage fluid; Kitahara Y et al.; An 80-year-old man was admitted because of dyspnea on effort . We suspected an acute exacerbation of chronic heart failure and idiopathic interstitial pneumonia caused by right-sided pneumonia . A nodular shadow in right upper lobe spread and consolidated into the airspace, and it failed to improve despite administration of meropenem trihydrate, vancomycin hydrochloride and clindamycin . A definitive diagnosis of Legionella micdadei pneumonia was made on the basis of this organism being isolated in culture from bronchial lavage fluid and subsequent identification of Legionella micdadei using DNA-DNA hybridization . The airspace consolidation gradually improved following treatment with intravenous erythromycin and minocycline hydrochloride.

Mil Med, 2004 Jun, 169(6), 417 - 20
Experience with directly observed prophylaxis using erythromycin in military trainees exposed to pertussis; Purcell BK et al.; Pertussis, once a serious respiratory disease in children, has recently been identified as a common cause of chronic cough in adults . Military personnel are known to be vulnerable to this disease . After a training barracks exposure to pertussis, routine arrangements for contact prophylaxis with erythromycin failed . This experience is reported here as well as that of our subsequent aggressive attempts using directly observed prophylaxis (DOP) with standard erythromycin regimens . No secondary cases occurred . However, many contacts (35%) could not finish a 14-day course despite DOP, mostly because of nausea (85%) or diarrhea (72%) . Seventeen (18%) soldiers missed classes because of erythromycin side effects; five required emergency department visits or hospital admission for the same . Sixteen (17%) soldiers were switched to azithromycin because of side effects; all were able to complete a 14-day course without symptoms . High adherence rates with erythromycin administration using DOP are attainable but may trigger unacceptable toxicities; alternative prophylactic regimens should be considered for active duty personnel.

J Nat Prod, 2004 Jul, 67(7), 1079 - 83
Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities; Usia T et al.; Three new sesquiterpenes, (2R,3S,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (1), (2R,3R,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (2), and (5R)-2,6,9-humulatrien-5-ol-8-one (3), and two new flavonol glycosides, kaempferol-3-O-(2,3-di-O-acetyl-alpha-l-rhamnopyranoside) (4) and kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5), were isolated from the EtOAc-soluble fraction of the water extract of Zingiber aromaticum, along with 13 known compounds (6-18) . The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses . The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using {N-methyl-(14)C}erythromycin or {O-methyl-(14)C}dextromethorphan as a substrate, respectively . Kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5) showed the most potent inhibitory activity (IC(50), 14.4 microM) on the metabolism mediated by CYP3A4, and kaempferol-3-O-methyl ether (14) inhibited CYP2D6 most potently (IC(50), 4.63 microM).

Commun Dis Public Health, 2004 Jun, 7(2), 128 - 31
Management of pertussis in a nurse at a special care baby unit; Wright EP et al.; A case of pertussis in a nurse at a special care baby unit prompted the identification of both neonates and healthcare staff with significant exposure to the index case . Respiratory tract samples were collected from all neonates involved and prophylactic erythromycin given . Only healthcare staff who developed symptoms were investigated and offered treatment . Though no secondary cases were identified in this instance, the importance of the early recognition of pertussis in adult healthcare workers is highlighted.

J Ind Microbiol Biotechnol, 2004 Aug, 31(7), 335 - 44 Epub 2004 Jul 15.
The erythromycin biosynthetic gene cluster of Aeromicrobium erythreum; Brikun IA et al.; The erythromycin-biosynthetic (ery) gene cluster of Aeromicrobium erythreum was cloned and characterized . The 55.4-kb cluster contains 25 ery genes . Homologues were found for each gene in the previously characterized ery gene cluster from Saccharopolyspora erythraea . In addition, four new predicted ery genes were identified . Two of the new predicted genes, coding for a phosphopantetheinyl transferase (eryP) and a type II thioesterase (eryTII), were internal to the ery cluster . The other two new genes, coding for a thymidine 5'-diphosphate-glucose synthase (eryDI) and a MarR-family transcriptional repressor (ery-ORF25), were found at the two ends of the ery cluster . A knockout in eryDI showed it to be essential for erythromycin biosynthesis . The gene order of the two ery clusters was conserved within a core region of 15 contiguous genes, with the exception of IS1136 which was not found in the A . erythreum cluster . Beyond the core region, gene shuffling had occurred between the two sides of the cluster . The flanking regions of the two ery clusters were not alike in the type of genes found.

Metab Eng, 2004 Jul, 6(3), 186 - 96
Reverse engineering of industrial pharmaceutical-producing actinomycete strains using DNA microarrays; Lum AM et al.; Transcript levels in production cultures of wildtype and classically improved strains of the actinomycete bacteria Saccharopolyspora erythraea and Streptomyces fradiae were monitored using microarrays of the sequenced actinomycete S . coelicolor . Sac . erythraea and S . fradiae synthesize the polyketide antibiotics erythromycin and tylosin, respectively, and the classically improved strains contain unknown overproduction mutations . The Sac . erythraea overproducer was found to express the entire 56-kb erythromycin gene cluster several days longer than the wildtype strain . In contrast, the S . fradiae wildtype and overproducer strains expressed the 85-kb tylosin biosynthetic gene cluster similarly, while they expressed several tens of other S . fradiae genes and S . coelicolor homologs differently, including the acyl-CoA dehydrogenase gene aco and the S . coelicolor isobutyryl-CoA mutase homolog icmA . These observations indicated that overproduction mechanisms in classically improved strains can affect both the timing and rate of antibiotic synthesis, and alter the regulation of antibiotic biosynthetic enzymes and enzymes involved in precursor metabolism.

Curr Treat Options Gastroenterol, 2004 Aug, 7(4), 317 - 325
Chronic Intestinal Pseudoobstruction; Lyford G et al.; Patients with chronic intestinal pseudoobstruction (CIP) experience a constellation of symptoms including abdominal pain, nausea, fullness, and malaise which fluctuates in severity and invariably result in a diminished quality of life . Though surgical resection or transplantation may be an option for some, there currently is no cure for CIP . Thus, management strategies utilize pharmacologic, intravenous, endoscopic, and surgical techniques to promote transit, minimize painful bloating, reduce complications of stasis, and improve quality of life . Prokinetic agents such as erythromycin, metoclopramide, cisapride, neostigmine, and tegaserod may be effective for acute exacerbations . Octreotide may reduce symptoms of bacterial overgrowth and bloating by stimulating migrating motor complexes . Enteral tubes for venting and nutritional support may reduce hospitalizations . Total parenteral nutrition (TPN), fraught with well-known complications, may be the only tolerated source for nutrients and fluid . Advanced disease may magnify nutritional problems, difficulties of long term intravenous and intestinal access, and poor symptom control . Because the initial process may manifest in other intestinal regions following surgery, resection of involved segments should be performed with caution . Small intestinal transplantation is a high-risk surgery performed in persons unable to tolerate intravenous (IV) nutrition . Optimal management for persons with CIP should not only provide nutritional and symptom focused care but should be part of a supportive network which links patients to their appropriate healthcare needs.

Curr Treat Options Gastroenterol, 2004 Aug, 7(4), 259 - 264
Delayed Gastric Emptying in Functional Dyspepsia; Stanghellini V et al.; Functional dyspepsia is a complex syndrome with a poorly defined pathophysiology, resulting in uncertainties in its therapeutic approach . Abnormalities in gastrointestinal motility and sensitivity alone or combined seem to play a role in a substantial subgroup of patients . Drugs capable of prokinetic effects, such as antidopaminergics (eg, metoclopramide, domperidone, levosulpiride) and serotonin 5-HT4 receptor agonists (eg, tegaserod) can be potentially used in the treatment of dyspeptic patients . Furthermore, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone which may also contribute to improved symptoms in subsets of patients . Alosetron, a 5-HT3 receptor antagonist, has been investigated mainly in irritable bowel syndrome, and the few studies performed in functional dyspepsia have provided conflicting results . Erythromycin and related derivatives, the motilides, represent another class of prokinetic compounds able to accelerate gastric emptying and potentially indicated in functional dyspepsia . The stimulatory effect on fundic tone and the occurrence of tachyphilaxis hamper the efficacy of these drugs in the long-term treatment . kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but there are few available results and most are inconclusive . Results are also needed to prove efficacy of antidepressants (tricyclic agents and 5-HT reuptake inhibitors) . Future clinical trials should be performed so that the formal structure required by good clinical practice can be adapted to detect significant effects in subgroups of patients with functional dyspepsia . Therapy should be ideally targeted to the different pathophysiologic abnormalities of these subgroups . The identification of the mechanisms leading to symptom generation should facilitate the development of newer and more effective therapeutic strategies in functional dyspepsia.

Pharmacol Res, 2004 Sep, 50(3), 237 - 46
PXR and the regulation of apoA1 and HDL-cholesterol in rodents; Bachmann K et al.; Orphan nuclear receptors (ONRs) have been implicated in the regulation of lipids . Several clinical studies conducted either prospectively or epidemiologically have pointed to a link between the regulation of hepatic CYP enzymes and HDL-cholesterol (HDL-C) and/or apolipoprotein A1 (apoA1) . The treatment of rats with a series of imidazole inducers of CYP3A yielded correlations between in vitro CYP3A activity measured as erythromycin demethylase activity and plasma HDL-C and hepatic apoA1 mRNA . Similarly, a correlation was established between in vivo CYP3A activity, measured as ethosuximide clearance, and plasma HDL-C and hepatic apoA1 mRNA . The treatment of wild-type (WT) mice with PXR agonists elicited increases in serum HDL-C and serum apoA1 levels . On the other hand, the treatment of PXR-knockout mice (PXR-KOs) with the same PXR agonists failed to elicit increases in either serum HDL-C or serum apoA1 levels . Superposition of the structures of three imidazoles known to be active CYP3A inducers in rats with the human PXR pharmacophore demonstrated a partial fit and predicted EC(50) values typical of weak-moderate hPXR inducers in humans . These imidazoles have been shown to increase apoA1 and HDL-C in rats and mice . Taken together, these data suggest that PXR plays an important role in the regulation of apoA1 and HDL-C in rodents.

Nucleic Acids Res, 2004 Jul 1, 32(Web Server issue), W405 - 13
NRPS-PKS: a knowledge-based resource for analysis of NRPS/PKS megasynthases; Ansari MZ et al.; NRPS-PKS is web-based software for analysing large multi-enzymatic, multi-domain megasynthases that are involved in the biosynthesis of pharmaceutically important natural products such as cyclosporin, rifamycin and erythromycin . NRPS-PKS has been developed based on a comprehensive analysis of the sequence and structural features of several experimentally characterized biosynthetic gene clusters . The results of these analyses have been organized as four integrated searchable databases for elucidating domain organization and substrate specificity of nonribosomal peptide synthetases and three types of polyketide synthases . These databases work as the backend of NRPS-PKS and provide the knowledge base for predicting domain organization and substrate specificity of uncharacterized NRPS/PKS clusters . Benchmarking on a large set of biosynthetic gene clusters has demonstrated that, apart from correct identification of NRPS and PKS domains, NRPS-PKS can also predict specificities of adenylation and acyltransferase domains with reasonably high accuracy . These features of NRPS-PKS make it a valuable resource for identification of natural products biosynthesized by NRPS/PKS gene clusters found in newly sequenced genomes . The training and test sets of gene clusters included in NRPS-PKS correlate information on 307 open reading frames, 2223 functional protein domains, 68 starter/extender precursors and their specific recognition motifs, and also the chemical structure of 101 natural products from four different families . NRPS-PKS is a unique resource which provides a user-friendly interface for correlating chemical structures of natural products with the domains and modules in the corresponding nonribosomal peptide synthetases or polyketide synthases . It also provides guidelines for domain/module swapping as well as site-directed mutagenesis experiments to engineer biosynthesis of novel natural products . NRPS-PKS can be accessed at http://www.nii.res.in/nrps-pks.html.

Eur Rev Med Pharmacol Sci, 2004 Jan-Feb, 8(1), 55 - 8
Breath tests with stable isotopes: have they a role in liver transplantation?
Festi D, Capodicasa S, Vestito A, Mazzella G, Roda E, Vitacolonna E, Petrolati A, Angelico M, Colecchia A.
Evaluation of liver function is crucial in the overall management of patients with liver disease . In particular, patients with end-stage liver disease need accurate prognostic indicators to plan liver transplantation, and in this case, to manage their presence in the waiting list . Availability of predictors of clinical outcome is further essential after liver transplant, mainly to correctly diagnose and adequately treat complications, such as acute rejection, drug toxicity, liver dysfunction . Breath tests using labelled substrates selectively metabolized within the liver may represent an accurate diagnostic and prognostic tool in these clinical conditions, possibly with an adjuntive role to the most commonly used prognostic models (Child-Pugh and MELD scores) . Promising results have been in fact recently obtained by the use of different substrates (aminopyrine, methacetin, erythromycin, methionine) which explore different metabolic function of the hepatocyte . The usefulness of breath tests has been documented in liver disease patients both before and after liver transplantation, in the early as well as in the late phase.

Eur Rev Med Pharmacol Sci, 2004 Jan-Feb, 8(1), 33 - 46
13C-breath tests in the study of microsomal liver function; Nista EC et al.; Conventional liver tests can be used to estimate a mixture of injury and function but none of these may be regarded as a reliable marker either to quantify functional hepatic reserve or to reflect life-threatening complications of acute and chronic liver diseases . To overcome this limit, many dynamic tests have been developed in order to evaluate the "hepatic functional mass" . Among these tests we can include breath tests with 13C-labeled substrates undergoing different metabolic pathways . As concerning the evaluation of microsomal function, two main categories of breath tests have been developed based on the limiting step in the different substrates metabolism . The first group include aminopyrine, caffeine and diazepam, all substrates with a metabolism independent from hepatic blood flow and dependent almost exclusively from the enzymatic activity of different cytochromes P450 . The other group is composed of substrates with flow dependent metabolism like methacetin, phenacetin, erythromycin . The aim of this review is to describe the clinical applications of microsomal liver breath tests in different hepatic diseases.

Xenobiotica, 2004 Mar, 34(3), 215 - 28
Prediction of in vivo drug interactions with eplerenone in man from in vitro metabolic inhibition data; Cook CS et al.; 1: The inhibition kinetics of eplerenone (EP) 6beta-hydroxylation by 10 drugs were determined in vitro using human liver microsomes . Inhibition factors were calculated from in vitro inhibition constant (Ki) and three different inhibitor Cmax values (liver Cmax of total and unbound inhibitor, and maximum influx concentration of inhibitor into the liver) . Subsequently, the inhibition factors were compared with available pharmacokinetic data derived from clinical interaction trials conducted by Pfizer involving EP and these drugs . EP was also evaluated for its effect on the metabolism of 10 drugs in vitro, and again the in vitro data were compared with results from the clinical trials . 2: The Ki values for the inhibition of EP 6beta-hydroxylation by cisapride, cyclosporine, digoxin, erythromycin, fluconazole, ketoconazole, midazolam, saquinavir, simvastatin and verapamil were 2.90, 1.24,>75.0, 9.50, 59.0, 0.160, 8.10, 0.546, 6.23 and 13.3 microM, respectively . Among the three methods, inhibition factors (Rb) calculated using the Ki and estimated liver Cmax values of the unbound drug were best correlated with the in vivo area under the curve-fold increases of EP in humans . The Rb values for the drugs listed above were 1.04, 1.69, 1.00, 2.17, 2.24, 4.90, 1.00, 1.82, 1.01 and 1.04, respectively, and the in vivo area under the curve-fold increases of EP by these drugs were 1.04, 1.16, 0.930, 2.87, 2.24, 5.39, 1.00, 2.07, 1.03 and 1.98, respectively . 3: EP did not have any significant effects on the drugs tested in vitro or in the clinic . 4: Using in vitro metabolic interaction data, human in vivo pharmacokinetic interactions involving EP could be predicted nearly quantitatively . The lack of effects of EP on the pharmacokinetics of other drugs in man was also suggested in the in vitro data .

Am J Physiol Gastrointest Liver Physiol, 2004 Nov, 287(5), G1028 - 34 Epub 2004 Jun 10.
Stimulation of small intestinal burst activity in the postprandial state differentially affects lipid and glucose absorption in healthy adult humans; Bryant LK et al.; Small intestinal motor activity is important for the optimal digestion and absorption of nutrients . These motor responses to feeding are frequently abnormal during critical illness, with the persistence of migrating bursts of contractions during enteral feeding . Whether this disturbance influences nutrient absorption is not known . In this study, the effects of small intestinal burst activity on lipid and glucose absorption were evaluated in 10 healthy human adults (6 males, 4 females, 19-47 yr) . Upper gastrointestinal manometry was recorded for 6 h during and shortly after a 20-min intravenous infusion of either erythromycin (1 mg/kg), to stimulate burst activity, or saline (0.9%) in a double-blind randomized fashion . Simultaneously with the start of the intravenous infusion, 60 ml liquid feed mixed with 200 microl 13C-triolein and 2 g 3-O-methylglucose (3-OMG) was infused intraduodenally for 30 min . Absorption of lipid and glucose was assessed using the {13C}triolein breath test and plasma concentrations of 3-OMG, respectively . Infusion of erythromycin was followed by a more rapid onset of burst activity following commencement of the duodenal infusion compared with saline (30 +/- 6.1 vs . 58 +/- 10.7 min; P < 0.05) . Erythromycin was associated with a slower recovery of 13CO2 (P < 0.01) . A positive correlation existed between the time to onset of burst activity and 13CO2 recovery (P < 0.001) . Erythromycin had no effect on 3-OMG absorption . In conclusion, stimulation of small intestinal burst activity reduces the rate of lipid absorption but not glucose absorption in healthy human adults.

Free Radic Biol Med, 2004 Jul 1, 37(1), 10 - 22
Kupffer cells and reactive oxygen species partially mediate lipopolysaccharide-induced downregulation of nuclear receptor pregnane x receptor and its target gene CYP3a in mouse liver; Xu DX et al.; Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates target gene transcription in a ligand-dependent manner . The in vivo effects of lipopolysaccharide (LPS) on expression of PXR and its target gene cytochrome P450 3A (CYP3A) in mouse liver were investigated in this study . Mice were injected intraperitoneally with different doses of LPS (0.1-5.0 mg/kg) . PXR and CYP3A11 mRNA levels were measured using reverse transcription polymerase chain reaction . Results indicate that LPS significantly inhibits the expression of PXR mRNA in a dose-dependent manner, followed by suppression of CYP3A11 mRNA in mouse liver . LPS also represses the upregulation of CYP3A11 mRNA levels and erythromycin N-demethylase (ERND) catalytic activity in mice pretreated with PXR ligands dexamethasone, rifampicin, mifepristone, and phenobarbital . LPS-induced downregulation of PXR and CYP3A11 mRNA in liver was significantly attenuated in mice pretreated with gadolinium chloride, a selective Kupffer cell toxicant . Pretreatment with a single dose of gadolinium chloride (10 mg/kg) also significantly attenuated LPS-induced downregulation of dexamethasone-, rifampicim-, mifepristone-, and phenobarbital-inducible, CYP3A11 mRNA expression and ERND activity in mouse liver . Furthermore, LPS-induced downregulation of PXR and CYP3A11 mRNA was significantly attenuated in mice pretreated with allopurinol, an inhibitor of xanthine oxidase, and diphenyleneiodonium chloride, an inhibitor of NADPH oxidase . Allopurinol and diphenyleneiodonium chloride pretreatment also attenuated the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver . However, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, has no effect on LPS-induced downregulation of PXR and CYP3A11 mRNA . Finally, LPS-induced downregulation of PXR and CYP3A11 mRNA was prevented in mice pretreated with either N-acetylcysteine or ascorbic acid . These antioxidants also prevented the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver . These results indicate that Kupffer cells contribute to LPS-induced downregulation of PXR and CYP3A in mouse liver . Reactive oxygen species, produced possibly by NADPH oxidase and perhaps by xanthine oxidase, are involved in LPS-induced downregulation of nuclear receptor PXR and its target gene CYP3A in mouse liver .

J Pharmacol Exp Ther, 2004 Oct, 311(1), 246 - 55 Epub 2004 Jun 02.
Pharmacokinetics of erythromycin in rabbit corneas after single-dose infusion: role of P-glycoprotein as a barrier to in vivo ocular drug absorption; Dey S et al.; Efflux pump like P-glycoprotein (P-gp) is known to be a major barrier to drug delivery . Functional P-glycoprotein has been recently identified in cornea and corneal cell lines . Thus, it is probable that P-glycoprotein may restrict in vivo ocular drug absorption, resulting in low ocular bioavailability . Experiments were designed using New Zealand albino (New Zealand White) rabbits to assess inhibitors of P-gp efflux to increase drug absorption . Anesthetized rabbits were given constant topical infusions of {(14)C}erythromycin in the presence and absence of inhibitors . Testosterone, verapamil, quinidine, and cyclosporine A were selected as P-gp inhibitors . Transport experiments were conducted in Madin-Darby canine kidney cells transfected with the human mdr1 gene (MDCK-MDR1) . Erythromycin exhibited significant efflux out of MDCK-MDR1 cells, suggesting that erythromycin is a good substrate for P-gp . Ocular pharmacokinetic studies were conducted using a topical single-dose infusion method . Maximum inhibition of P-gp mediated efflux was observed with 500 microM testosterone . Area under the curve (AUC)(0- infinity ) of erythromycin with 500 microM testosterone was almost 4 times higher than AUC(0- infinity ) without any inhibitor . Rate of elimination (k(10)) for erythromycin and those with inhibitors was found to be similar (141 +/- 23 min), suggesting that elimination pathways were not altered . All the inhibitors were found to be nontoxic . Verapamil also inhibited the efflux pump with moderate change in AUC(0- infinity ) and C(max) compared with control . Thus, P-gp is found to be active in vivo, and it restricts topical erythromycin absorption across the cornea, which can be inhibited by known P-gp inhibitors . Therefore, ocular bioavailability of P-gp substrates can be significantly enhanced by proper selection of P-gp inhibitors.

Antimicrob Agents Chemother, 2004 Jun, 48(6), 2298 - 301
Genetic basis of erythromycin resistance in oral bacteria; Villedieu A et al.; We determined the prevalence of erythromycin-resistant bacteria in the oral cavity and identified mef and erm(B) as the most common resistance determinants . In addition, we demonstrate the genetic linkage, on various Tn1545-like conjugative transposons, between erythromycin and tetracycline resistance in a number of isolates.

Antimicrob Agents Chemother, 2004 Jun, 48(6), 1989 - 92
Reactivity of platelia Aspergillus galactomannan antigen with piperacillin-tazobactam: clinical implications based on achievable concentrations in serum; Singh N et al.; The possible reactivities of commonly used antibiotics of fungal, nonfungal, and nonmicrobial or synthetic sources with the Platelia Aspergillus galactomannan assay were assessed . For drugs that tested positive, the minimal concentration of the antibiotic in serum that yielded a positive test (index, >0.5) was determined . At undiluted concentrations, piperacillin and multiple lots of piperacillin-tazobactam tested positive, whereas amoxicillin, ampicillin-sulbactam, nafcillin, cefazolin, ceftazidime, erythromycin, gentamicin, and levofloxacin tested negative . All three lots of piperacillin-tazobactam and all bags within each lot tested positive, with a mean index value of 5.168 . At achievable concentrations in serum, however, only one of three lots of piperacillin-tazobactam yielded a positive test . Concentrations of 75, 150, and 300 microg/ml of serum tested positive with the Platelia Aspergillus enzyme immunoassay, whereas lower concentrations, mimicking the trough levels, tested negative . Thus, while achievable serum piperacillin-tazobactam concentrations may potentially result in a positive test for galactomannan, the timing of the collection of serum samples from patients may influence the test results, with reactivity being less likely in samples collected at trough levels or prior to the administration of a dose of the antibiotic.

J Org Chem, 2004 May 28, 69(11), 3907 - 11
Synthesis of erythromycin derivatives via the olefin cross-metathesis reaction; Hsu MC et al.; Olefin cross metathesis (CM) was applied to the synthesis of 6-O-substituted erythromycin derivatives . The reactions were catalyzed by transition metal alkylidene complexes, particularly bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (Grubbs' first-generation catalyst) . This approach allowed for the elaboration of the 6-O-allyl group of highly functionalized macrolides at various stages of the synthetic sequence, affording 6-O-3-aryl-propenyl products with excellent E-selectivity . Little or no self-dimerization of the reacting components was found in the crude mixtures . Preliminary kinetic data accounts for the observed cross-selectivity based on substrate reactivity and steric factors.

Am Fam Physician, 2004 May 1, 69(9), 2123 - 30
Diagnosis and treatment of acne; Feldman S et al.; Acne can cause significant embarrassment and anxiety in affected patients . It is important for family physicians to educate patients about available treatment options and their expected outcomes . Topical retinoids, benzoyl peroxide, sulfacetamide, and azelaic acid are effective in patients with mild or moderate comedones . Topical erythromycin or clindamycin can be added in patients with mild to moderate inflammatory acne or mixed acne . A six-month course of oral erythromycin, doxycycline, tetracycline, or minocycline can be used in patients with moderate to severe inflammatory acne . A low-androgen oral contraceptive pill is effective in women with moderate to severe acne . Isotretinoin is reserved for use in the treatment of the most severe or refractory cases of inflammatory acne . Because of its poor side effect profile and teratogenicity, isotretinoin (Accutane) must by prescribed by a physician who is a registered member of the manufacturer's System to Manage Accutane-Related Teratogenicity program.

Int J Pharm, 2004 Mar 1, 271(1-2), 63 - 76
A kinetic study on the degradation of erythromycin A in aqueous solution; Kim YH et al.; The pH is a critical factor determining the rate of the degradation of erythromycin A in aqueous solutions . However, the kinetics of the acid- and base-catalyzed degradation is still uncertain . This study used a sensitive coulometric detection method to determine concentrations of erythromycin A and its degradation products . To determine the buffer-independent rate constants, sodium acetate (0.05-0.2 M) and Tris-HCl (0.1-0.5 M) were used in a pH range of 3.5-5.5 and 7.0-9.0, respectively . In acidic conditions, anhydroerythromycin A appeared to be produced directly through an internal dehydration of erythromycin A-6,9-hemiketal which simultaneously established an equilibrium with erythromycin A enol ether on the other hand . In weakly alkaline conditions, hydroxide ion appeared to catalyze the hydrolysis of the lactonyl ester bond of erythromycin A-6,9-hemiketal by the pseudo-first-order kinetics, and the C13 --> C11 translactonization and internal dehydration reactions subsequently occurred to form pseudoerythromycin A enol ether . We suggest here a predictive model for reasonable interpretation of the kinetics of erythromycin A degradation in aqueous solutions, in which the observed rate constant was expressed by the sum of the partial reaction rate constants for the acid- and base-catalyzed degradation of erythromycin A-6,9-hemiketal as a function of pH in a range of 3.0-10.0.

J Clin Gastroenterol, 2004 Mar, 38(3), 237 - 42
Erythromycin in the short- and long-term control of dyspepsia symptoms in patients with gastroparesis; Dhir R et al.; BACKGROUND: Few prokinetic drugs are available to treat gastroparesis . Data are limited on short-term and long-term efficacy of erythromycin as a prokinetic drug . GOALS: Assess efficacy of low-dose erythromycin suspension to treat gastroparesis . STUDY: Patients with dyspepsia and gastroparesis by gastric emptying study were treated with low-bulk diet and low-dose (50-100 mg 3 times a day and at bedtime) oral erythromycin suspension . Data were collected by retrospective chart review and telephone questionnaire for short- and long-term follow-up, respectively . RESULTS: Of 25 patients, 18 had short-term follow-up, 18 had longterm follow-up, and 14 had both . On short-term follow-up, 15 patients (83%) experienced some or dramatic improvement, while 3 (17%) experienced worsening or no change in symptoms (P = 0.005) . Mean duration of long-term use was 11 +/- 7 months . On long-term followup, 12 (67%) patients noticed some or dramatic improvement, while 6 (33%) experienced worsening or no change in symptoms (P = 0.16) . Correlation (0.7) between short- and long-term response was significant (P < 0.005) . Of the 3 patients with poor short-term response, none did well long term . Of the 11 patients with some or dramatic response in short-term, 7 continued to have some response long term . There was no relation between gastric emptying time and response to erythromycin suspension . CONCLUSIONS: Treatment of gastroparesis with low-dose erythromycin and low-bulk diet results in a dramatic short-term improvement in the majority of patients . Short-term response predicts long-term response . This response may not be as great, possibly due to tachyphylaxis.

World J Gastroenterol, 2004 May 1, 10(9), 1325 - 8
Modulation of Kupffer cells on hepatic drug metabolism; Ding H et al.; AIM: To observe the effects of Kupffer cells on hepatic drug metabolic enzymes . METHODS: Kunming mice were i.p . injected with GdCl310, 20, 40 mg/kg to decrease the number and block the function of kupffer cells selectively . The contents of drug metabolic enzymes, cytochrome P450, NADPH-cytochrom C redutase (NADPH-C), aniline hydroxylase (ANH), aminopyrine N-demethylase (AMD), erythromycin N-demethylase (EMD), and glutathione s-transferase (mGST) in hepatic microsome and S9-GSTpi, S9-GST in supernatant of 9 000 g were accessed 1 d after the injection . The time course of alteration of drug metabolic enzymes was observed on d 1, 3, and 6 treated with a single dose GdCl3 . Mice were treated with Angelica sinensis polysaccharides (ASP) of 30, 60, 120 mg/kg, i.g., qd x 6 d, respectively and the same assays were performed . RESULTS: P450 content and NADPH-C, ANH, AMD, and EMD activities were obviously reduced 1 d after Kupffer cell blockade . However, mGST and S9-GST activities were significantly increased . But no relationship was observed between GdCl3 dosage and enzyme activities . With single dose GdCl3 treatment, P450 content, NADPH-C, and ANH activities were further decreased following Kupffer cell blockade lasted for 6 d, by 35.7%, 50.3%, 36.5% after 3 d, and 57.9%, 57.9%, 63.2% after 6 d, respectively . On the contrary, AMD, EMD, mGST, and S9-GST activities were raised by 36.5%, 71.9%, 23.1%, 35.7% after 3 d, and 155%, 182%, 21.5%, 33.7% after 6 d, respectively . Furthermore, the activities of drug metabolic enzymes were markedly increased after 30 mg/kg ASP treatment, and decreased significantly after 120 mg/kg ASP treatment . No change in activity of S9-GSTpi was observed in the present study . CONCLUSION: Kupffer cells play an important role in the modulation of drug metabolic enzymes . The changes of drug metabolic enzyme activities depend on the time of kupffer cell blockade and on the degree of Kupffer cells activated . A low concentration of ASP increases the activities of drug metabolic enzymes, but a high concentration of ASP decreases the activities of drug metabolic enzymes.

Am J Clin Dermatol, 2004, 5(2), 85 - 95
Prurigo: diagnosis and management; Wallengren J; Prurigo is a condition of nodular cutaneous lesions that itch (pruire) intensely . Although the acute form can be caused by insect stings, most of the subacute and chronic forms appear to be idiopathic . Toxic agents deposited in the skin by exogenous factors such as parasites, bacteria, or topically or orally administered drugs can induce itch . In susceptible individuals, physical mechanisms such as UV light can induce changes in epidermal innervation that result both in itch generally and in prurigo lesions . Prurigo is sometimes associated with atopy, pregnancy, internal diseases, malabsorption, or malignancy . Some forms of prurigo may be secondary to scratching . Emotional factors can also influence the perception of itch and induce prurigo by provoking scratching . These are the various specialized forms of prurigo, and there are certain others, such as prurigo pigmentosa, that have some ethnic preference . Topical treatments by corticosteroids, coal tar, bath photochemotherapy, UVB, cryotherapy, or capsaicin, as well as systemic regimens involving use of psoralen + UVA (PUVA), erythromycin, arotinoid acid, cyclosporine, chloroquine, dapsone, minocycline, naltrexone, azathioprine or thalidomide are used for the treatment of this condition . Psychotherapeutic agents to treat problems of mood that deteriorate prurigo are also prescribed . Combined sequential treatments for generalized, therapy-resistant cases need to be tailored to the exacerbations that occur and to provide maintenance treatment in order to enable the patient to withstand the intolerable itch.

Vet Surg, 2004 May-Jun, 33(3), 279 - 85
Survey of prokinetic use in horses with gastrointestinal injury; Van Hoogmoed LM et al.; OBJECTIVE: To report prokinetic strategies used to manage horses after gastrointestinal surgery . DESIGN: Electronic questionnaire . SAMPLE POPULATION: Diplomates of the American College of Veterinary Surgeons (ACVS) who perform equine intestinal surgery . PROCEDURE: A survey (21 questions) designed to determine use of prokinetic agents was sent electronically to 112 ACVS Diplomates known to perform equine intestinal surgery . Several clinical scenarios were also described to determine which, if any, prokinetic agent respondents would select . RESULTS: Responses were obtained from 58 (52%) surgeons from 44 clinics . Selection of prokinetic agent for specific gastrointestinal conditions was relatively uniform whereas there was considerable variation in dose administered . For postoperative ileus (POI) associated with most intestinal lesions, 2% lidocaine was most commonly selected . Other prokinetics in decreasing frequency of use were erythromycin lactobionate, metoclopramide, and cisapride . Prokinetic agents were more commonly administered after small intestine strangulating obstructions and less commonly for large intestinal lesions . No novel agents were identified by respondents . CONCLUSIONS: Prokinetic drugs are commonly used for the management and/or attenuation of POI in horses, but dosages and routes of administration are variable . CLINICAL RELEVANCE: Although prokinetics are commonly used for management of POI in horses there is clearly a need for more controlled studies to define efficacious dosing and a need to develop new prokinetic drugs.

Drug Metab Dispos, 2004 May, 32(5), 536 - 44
Comparative hepatic and extrahepatic enantioselective sulfoxidation of albendazole and fenbendazole in sheep and cattle; Virkel G et al.; The enantioselective sulfoxidation of the prochiral anthelmintic compounds albendazole (ABZ) and fenbendazole (FBZ) was investigated in liver, lung and small intestinal microsomes obtained from healthy sheep and cattle . The microsomal fractions were incubated with a 40 microM concentration of either ABZ or FBZ . Inhibition of the flavin-containing monooxygenase (FMO) system was carried out by preincubation with 100 microM methimazole (MTZ) either with or without heat pretreatment (2 min at 50 degrees C) . ABZ and FBZ were metabolized to the (+) and (-) enantiomers of their sulfoxide metabolites, named albendazole sulfoxide (ABZSO) and oxfendazole (OFZ), respectively . ABZ sulfoxidation rates were higher (p < 0.001) than those observed for FBZ . The FMO-mediated liver sulfoxidation of ABZ was enantioselective (100%) toward the (+) ABZSO production in both species . Liver sulfoxidation of FBZ by FMO was also enantioselective toward (+) OFZ (sheep = 65%; cattle = 79%) . Cytochrome P450 was found to be mainly involved in the production of (-) ABZSO in the liver . MTZ did not affect the sulfoxidation of ABZ by lung microsomes, which may indicate that FMO is not involved in the production of ABZSO in this tissue . A significant (p < 0.05) inhibition of (-) ABZSO production by liver microsomes was observed after ABZ incubation in the presence of erythromycin (cattle = 21%) and ketoconazole (sheep = 36%) . Both CYP3A substrates induced a reduction in the production of (-) ABZSO (sheep = 67-78%, cattle = 50-78%) by lung microsomes . Overall, the results reported here contribute to the identification of the metabolic pathways involved in the biotransformation of benzimidazole anthelmintics extensively used for parasite control in ruminants.

J Pharm Pharmacol, 2004 Apr, 56(4), 477 - 83
Influence of intravenous methylprednisolone pulse treatment on the disposition of ciclosporin and hepatic CYP3A activity in rats; Konishi H et al.; We examined the effects of high-dose methylprednisolone (MP) on the disposition of ciclosporin (CsA) and hepatic microsomal CYP3A activity using rats . Methylprednisolone sodium succinate (MPS), a prodrug of MP, was intravenously administered as repeated doses (66.3 mg kg(-1)) for 3 days or as a single dose . In MP-treated rats, a significant increase was observed in the total body clearance (CL(tot)) and elimination rate constant (Ke) of intravenously administered CsA . The enzyme activities of triazolam hydroxylations and erythromycin N-demethylation in hepatic microsomes were also enhanced by about 50% by MP treatment, suggesting that the alteration in the CsA pharmacokinetics was due to significant induction of the hepatic CYP3A responsible for the metabolic conversion of CsA . In contrast, no significant changes in the values of CL(tot) and Ke were found following a single treatment with MP . On the other hand, MP inhibited the CYP3A-mediated triazolam hydroxylations in a concentration-dependent manner . The difference between the in-vivo and in-vitro inhibitory behaviours of MP was attributed to the rapid elimination of MP after biotransformation from MPS because the plasma MP concentration decreased with a half-life of 15 min immediately after reaching a level close to the inhibition constant for the triazolam 4-hydroxylation reaction (32.4 microM) . Although there is a general consideration that MP cannot act as an enzyme inducer at maintenance doses, the present results strongly suggest that high-dose MP is likely to interact pharmacokinetically with CsA by inducing hepatic CYP3A . These results may provide basic explanations for the clinical experience that blood CsA levels are reduced during MP pulse therapy.

Neurourol Urodyn, 2004, 23(3), 273 - 9
Direct inhibition of rat detrusor muscle contraction by erythromycin; England RC et al.; PURPOSE: Detrusor instability is a common problem in the elderly, which is usually treated with anti-cholinergic medication . This study investigates the effect of erythromycin on rat detrusor muscle contractile response to characterise its potential as an alternative inhibitor of bladder muscle contraction . MATERIALS AND METHODS: Strips of rat detrusor muscle were suspended in a perfusion organ bath . The contractile response to direct muscle stimulation, electrical field stimulation (EFS, 0.5-60 Hz), carbachol (10(-5) M), and potassium (10-80 x 10(-3) M) were determined before and after the addition of erythromycin (10(-4)-10(-3) M) . The contractile response to carbachol (10(-5) M) in the presence of nifedipine (10(-8) or 10(-6) M) or in calcium-free Kreb's solution was also determined in the absence and presence of erythromycin . RESULTS: Erythromycin 5 x 10(-4) M inhibited the maximum contractile response to EFS, carbachol, and potassium by 38% (P < 0.01), 62% (P < 0.001), and 17% (P < 0.05), respectively, but did not significantly reduce the response to direct muscle stimulation . The atropine-resistant component of EFS-evoked contraction was inhibited by 19.5% (P < 0.01) in the presence of erythromycin . In calcium-free Krebs solution, the maximum contractile response to carbachol was reduced by 42% of control (P < 0.0001) and nifedipine 10(-8) M had no additional effect . When erythromycin 5 x 10(-4) M was added together with nifedipine 10(-8) M, the response to carbachol was inhibited by a further 25% (P < 0.005) . CONCLUSIONS: Erythromycin inhibits rat detrusor muscle contraction through the inhibition of calcium influx and the modulation of intracellular calcium movement .

J Cataract Refract Surg, 2004 Apr, 30(4), 918 - 20
Orbital cellulitis after phacoemulsification and intraocular lens implantation; Kumar V et al.; We report a case of orbital cellulitis after uneventful phacoemulsification and intraocular lens implantation under peribulbar injection . The eyelid skin was prepared with chlorhexidine gluconate before the peribulbar injection, and the eyelid and conjunctival cul-de-sac were prepared with povidone-iodine before phacoemulsification . Five days postoperatively, the patient presented with reduced visual acuity and lid swelling . Ocular examination showed signs of orbital cellulitis, which was confirmed by a computed tomography scan . Oral erythromycin and metronidazole were given, after which the symptoms improved with successful outcomes.

Ann Pharmacother, 2004 Jun, 38(6), 982 - 5 Epub 2004 Apr 14.
Enhanced hypoprothrombinemia with warfarin due to azithromycin; Rao KB et al.; OBJECTIVE: To report a case of probable azithromycin-warfarin drug interaction with enhanced hypoprothrombinemic effect of warfarin . CASE SUMMARY: An 83-year-old African American man stabilized on warfarin therapy (10 mg on Wednesdays, 7.5 mg on other days) developed a prolonged prothrombin time one day after starting azithromycin 500 mg . The elevated prothrombin time normalized 3 days after azithromycin was discontinued . After the initial increase in the international normalized ratio, the absence of any significant confounding factors affecting the anticoagulant effect of warfarin in our patient and the numerous reports of such interactions indicate that an interaction between azithromycin and warfarin may have been responsible for the elevated prothrombin time seen in this patient . An objective causality assessment revealed that the adverse event was probably related to the combination of these drugs . DISCUSSION: Azithromycin, unlike erythromycin and clarithromycin, is not known to inhibit the cytochrome P450 enzyme system and is presumed to be the macrolide of choice in patients already on warfarin . However, previously reported cases of azithromycin-warfarin interactions support the possibility that azithromycin does interact with warfarin, although the exact mechanism is not understood . CONCLUSIONS: Azithromycin may interact with warfarin and enhance its hypoprothrombinemic effects . This effect may be delayed for 4-8 days after a course of azithromycin has been completed . Periodic monitoring of the prothrombin time is recommended when using azithromycin in patients taking warfarin.

Aquat Toxicol, 2004 May 12, 67(4), 387 - 96
Effects of erythromycin, tetracycline and ibuprofen on the growth of Synechocystis sp . and Lemna minor; Pomati F et al.; Pharmaceutically active substances have recently been recognised as an emerging environmental problem . Human and veterinarian therapeutic agents can contaminate aquatic ecosystems via sewage discharges (human and animal excretion), improper disposal or industrial waste . Very little is known on the effects of pharmaceutical pollutants on aquatic photosynthetic organisms . In this study the effects of erythromycin, tetracycline and ibuprofen on the growth of the cyanobacterium Synechocystis sp . PCC6803 and the duckweed Lemna minor FBR006 were studied at concentrations of 1-1000 microg l(-1) . At dosage of 1 mg l(-1), erythromycin affected the growth of both Synechocystis and Lemna with a maximum inhibition of 70 and 20%, respectively . Tetracycline had inhibitory effects (20-22% reduction in growth) on Synechocystis at intermediate dosages . The same aminoglycoside antibiotic promoted growth in Lemna by 26% at 10 microg l(-1), while frond development was reduced at 1 mg l(-1) (tetracycline) . The anti-inflammatory ibuprofen strongly stimulated the growth of Synechocystis at all concentrations tested (72% increase at 10 microg l(-1)) although inhibited Lemna in a linear dose-dependent manner with a 25% reduction over control levels at a dosage of 1 mg l(-1) . The 7 days effective concentration (EC(50)) calculated for Lemna were 5.6, 1 and 4 g l(-1), respectively, for erythromycin, tetracycline and ibuprofen . Moreover, exposure to the three pharmaceuticals resulted in the production of the stress hormone, abscisic acid (ABA), in Lemna . Erythromycin and tetracycline were more effective in promoting ABA synthesis compared to ibuprofen . The effects shown by the three therapeutic drugs on Synechocystis and Lemna growth may have potential implications in the assessments of residual environmental risks associated with the presence of pharmaceuticals in freshwater ecosystems . Promotion of ABA synthesis in Lemna by the two antibiotics and by copper suggests that the plant hormone could be a suitable (additional) indicator for future evaluation of phytotoxicity that results in plant senescence.

J Toxicol Clin Toxicol, 2004, 42(1), 73 - 7
Evaluation of promotility agents to limit the gut bioavailability of extended-release acetaminophen; Amato CS et al.; BACKGROUND: Erythromycin and neostigmine have both been shown to act as gastrointestinal promotility agents . OBJECTIVES: The purpose of this study was to determine whether either erythromycin or neostigmine, administered parenterally, would result in lower serum levels of a recently ingested drug, when compared with placebo . METHODS: Ten volunteers ingested 1300 mg of extended-release acetaminophen on each of three occasions . They were then given an intravenous dose of erythromycin (200 mg), neostigmine (2 mg), or placebo . Each volunteer received all three treatments in a counterbalanced fashion, each separated from the next by at least two weeks . Blood for serum acetaminophen concentration was drawn at 1, 2, 4, 6 and 8 h after treatment, and the serum acetaminophen elimination curves were compared for the three treatments . RESULTS: The elimination phase of the curves did not differ among the treatments as a result of administration of the prokinetic agents . CONCLUSIONS: Under the present conditions, administration of erythromycin and neostigmine as prokinetic agents failed to alter the kinetics of an ingested dose of sustained-release acetaminophen.

Curr Opin Crit Care, 2004 Apr, 10(2), 156 - 61
Establishment of enteral nutrition: prokinetic agents and small bowel feeding tubes; Davies AR et al.; PURPOSE OF REVIEW: Nutritional support is vital to improving the clinical outcomes in patients in the intensive care unit . Enteral nutrition should be administered early and aggressively, thereby reducing the need for parenteral nutrition . Because nasogastric feeding is often associated with gastrointestinal intolerance, recent research has focused on the use of prokinetic agents or small bowel feeding tubes to enhance the successful establishment and maintenance of enteral nutrition . RECENT FINDINGS: Prokinetic agents (such as metoclopramide and erythromycin) improve markers of gastric emptying and appear to improve tolerance of enteral nutrition, although their effects on clinical outcomes are not as well established . In comparison with nasogastric feeding, small bowel feeding allows the dysfunctional stomach of the critically ill to be bypassed, thereby reducing the rate of gastrointestinal complications and probably the risk of pneumonia . Small bowel tubes are more difficult to place than nasogastric tubes, although the new Tiger tube appears very promising . SUMMARY: Nasogastric feeding is preferred for almost all patients in the intensive care unit . Metoclopramide is the preferred prokinetic agent, although whether it or erythromycin should be administered to all patients in the intensive care unit or only those with gastrointestinal intolerance remains unknown . Small bowel feeding is not currently recommended for all patients in the intensive care unit because the benefits do not appear to outweigh the logistic and cost considerations . Nevertheless, when gastrointestinal intolerance develops in a nasogastrically fed patient, a small bowel feeding tube should be inserted at the earliest opportunity.

Pharmacoepidemiol Drug Saf, 1997 Jan, 6(1), 13 - 9
Erythromycin prolongs the QTc interval among patients with pneumonia; Freeman J et al.; Erythromycin is commonly used to treat simple community-acquired pneumonia . We measured the prolongation in QT(c) intervals in EKGs associated with intravenous erythromycin administration among patients hospitalized for simple pneumonia (DRGs 89 and 90) . We reviewed the medical records of 50 patients who received at least 5 days of intravenous erythromycin, and found 15 with readable paired EKGs, at least one taken during the period of erythromycin administration and at least one other obtained when the patient had no erythromycin . The mean QT(c) interval in lead II for EKGs taken without erythromycin was 0.422 s and the average prolongation of the QT(c) interval associated with erythromycin administration was 0.046 s (P<0.01) . The administration of erythromycin was thus associated with an increase in QT(c) intervals to a mean of 0.468 s, a value considered to be abnormally prolonged . We conclude that erythromycin prolongs the QT(c) interval among patients hospitalized with pneumonia in the same manner previously reported for healthy volunteers in an experimental setting . The magnitude of this erythromycin-induced QT(c) prolongation raises QT(c) intervals into the abnormal range . Although no patient in this small study suffered an adverse effect from the QT(c) prolongation, the magnitude of this effect is sufficiently large to raise clinical concerns .

J Pediatr Surg, 2004 Apr, 39(4), 565 - 9
A multicenter, randomized, double-blind, placebo-controlled trial of the prokinetic agent erythromycin in the postoperative recovery of infants with gastroschisis; Curry JI et al.; BACKGROUND/PURPOSE: The recovery of gut function after repair of gastroschisis is frequently prolonged, and these infants are prone to complications associated with parenteral nutrition . This trial was designed to investigate the effect of the prokinetic agent, erythromycin, on the attainment of full enteral feeding in infants after primary repair of uncomplicated gastroschisis . METHODS: A multicenter, randomized, double-blind, placebo-controlled trial was used to investigate the effect of enteral erythromycin (3 mg/kg/dose 4 times daily) compared with placebo on the attainment of full enteral feeding tolerance after primary repair of uncomplicated gastroschisis . Eleven neonatal surgical units in the United Kingdom participated in the study . The primary end-point was the time taken to achieve continuous enteral feeding at 150 mL/kg/24 hours sustained for 48 hours . RESULTS: Of 70 eligible infants, 62 were recruited and randomly divided . There were 30 patients in group I (placebo) and 32 in group II (erythromycin) . The groups were comparable in terms of mean gestational age, mean birth weight, extent of evisceration, and degree of intestinal peel . There was no statistically significant difference between the 2 groups in the time taken to achieve full enteral feeding (27.2 v 28.7 days; P =.75) . Similarly, no significant differences were found in the incidence of catheter-related sepsis, duration of parenteral nutrition, or time to discharge between the 2 groups . CONCLUSIONS: Enterally administered erythromycin at a dose of 3 mg/kg 4 times daily conferred no advantage in the time taken to achieve full enteral feeding after primary repair of uncomplicated gastroschisis.

J Am Dent Assoc, 2004 Mar, 135(3), 298 - 311
Drug interactions in dentistry: the importance of knowing your CYPs; Hersh EV et al.; BACKGROUND . The hepatic and intestinal cytochrome, or CY, P450 enzyme system is responsible for the biotransformation of a multitude of drugs . Certain medications used in dentistry can act as substrates, inducers or inhibitors of this system . METHODS . The authors conducted a MEDLINE search of articles appearing between 1976 and the present using the keywords "drug interactions" and "cytochrome P450," and reviewed reports involving dental therapeutic agents using PubMed links from an Indiana University CYP450 drug interaction table on the World Wide Web . RESULTS . The antibiotics erythromycin and clarithromycin are potent inhibitors of CYP3A4 and can increase blood levels and toxicity of CYP3A4 substrates . Likewise, quinolone antibiotics such as ciprofloxacin inhibit the metabolism of CYP1A2 substrates . Other dental therapeutic agents are substrates for CYP2C9 (celecoxib, ibuprofen and naproxen), CYP2D6 (codeine and tramadol), CYP3A4 (methylprednisolone) and CYP2E1 (acetaminophen) . Because codeine and tramadol are prodrugs, inhibition of their metabolism can lead to a diminution of their analgesic effects . While inducers of acetaminophen metabolism, including alcohol, theoretically can increase the proportion of it that is biotransformed into a potentially hepatotoxic metabolite, recent research suggests that concomitant alcohol intake does not increase the hepatotoxic potential of therapeutic doses of acetaminophen . CONCLUSIONS: A number of clinically significant drug interactions can arise with dental therapeutic agents that act as substrates or inhibitors of the CYP450 system . Clinical Implications . As polypharmacy continues to increase, the likelihood of adverse drug interactions in dentistry will increase as well . Ensuring that patients' medical histories are up to date and acquiring knowledge of the various substrates, inducers and inhibitors of the CYP450 system will help practitioners avoid potentially serious adverse drug interactions.

J Pharmacol Exp Ther, 2004 Aug, 310(2), 703 - 9 Epub 2004 Mar 31.
Preclinical pharmacokinetic properties of the p-glycoprotein inhibitor GF120918A (HCl salt of GF120918, 9,10-dihydro-5-methoxy-9-oxo-N-{4-{2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl}phenyl}-4-acridine-carboxamide) in the mouse, rat, dog, and monkey; Ward KW et al.; GF120918A, the HCl salt of GF120918 (9,10-dihydro-5-methoxy-9-oxo-N-{4-{2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl) ethyl}phenyl}-4-acridine-carboxamide), has been used both in vitro and in vivo as a tool inhibitor of P-glycoprotein (Pgp) to investigate the role of transporters in the disposition of various test molecules . However, to date, a detailed description of the preclinical pharmacokinetic properties of GF120918A has not been published . This investigation was performed to evaluate in vitro and in vivo pharmacokinetic properties of GF120918A in the mouse, rat, dog, and monkey and to evaluate the in vivo efficacy of GF120918A in modulating absorption and systemic exposure in the monkey . GF120918A demonstrated reasonable absorption and systemic exposure in each of the species studied, however, in rodents, administration of 300 mg/kg afforded a substantially less than linear increase in systemic exposure compared with 30 mg/kg . In accordance with its intestinal and hepatic exposure and potency against P-glycoprotein, GF120918A demonstrated marked modulation of erythromycin systemic exposure in the monkey, with no effect on propranolol, a negative control molecule . In vitro, GF120918A demonstrated high plasma protein binding across species, although a definitive protein binding evaluation was precluded by poor recovery, particularly in buffer and in mouse, rat, and dog plasma . GF120918A did not demonstrate potent inhibition of several human cytochrome P450 enzymes evaluated in vitro, with IC(50) values well above concentrations anticipated to be achieved in vivo . Together, these data confirm the utility of GF120918A as a tool P-glycoprotein inhibitor in preclinical species and offer additional guidance on preclinical dose regimens likely to produce P-glycoprotein-mediated effects.

Anal Sci, 2004 Feb, 20(2), 291 - 5
Effect of the size of molecularly imprinted polymers sensing materials on piezoelectric quartz crystal sensor performance; Zhang Z et al.; The effect of the size of the molecularly imprinted polymers (MIPs) on the piezoelectric quartz crystal (PQC) sensor performance was investigated . Erythromycin imprinted polymers microspheres with different sizes were synthesized by precipitation polymerization . The size of the MIPs was characterized by using transmission electron microscope (TEM) analysis . Being coated with a poly(vinyl chloride) (PVC) membrane containing MIPs, the proposed PQC sensor can selectively adsorb the template molecule . Investigation of the performance of sensors modified with different sizes of MIPs showed that PQC sensor modified with smaller size MIPs exhibited better performance and excellent selectivity . Other influencing factors on sensor functions modified with different sizes MIPs were also investigated.

Antimicrob Agents Chemother, 2004 Apr, 48(4), 1347 - 9
Mutations in a 23S rRNA gene of Chlamydia trachomatis associated with resistance to macrolides; Misyurina OY et al.; For six clinical isolates of Chlamydia trachomatis, in vitro susceptibility to erythromycin, azithromycin, and josamycin has been determined . Four isolates were resistant to all the antibiotics and had the mutations A2058C and T2611C (Escherichia coli numbering) in the 23S rRNA gene . All the isolates had mixed populations of bacteria that did and did not carry 23S rRNA gene mutations.

Antimicrob Agents Chemother, 2004 Apr, 48(4), 1096 - 104
Interaction of the new ketolide ABT-773 (cethromycin) with human polymorphonuclear neutrophils and the phagocytic cell line PLB-985 in vitro; Labro MT et al.; A classical velocity centrifugation technique was used to study the in vitro uptake of the new ketolide ABT-773 by human polymorphonuclear neutrophils (PMNs) and a myelomonoblastic cell line, PLB-985, which can be differentiated into PMNs under certain culture conditions, compared to that of HMR 3004 . ABT-773 was rapidly taken up by PMNs (cellular concentration to extracellular concentration ratio {C/E}, about 34 at 30 s and up to 207 at 5 min), and uptake plateaued from 30 to 180 min (C/E, about 300) . ABT-773 was accumulated significantly better than HMR 3004 from 5 to 180 min . Nondifferentiated PLB-985 cells (ND-PLB) accumulated significantly less ABT-773 and HMR 3004 than PMNs and PLB-985 cells differentiated into PMNs (D-PLB) . Whatever the cell type and in contrast to the results obtained with HMR 3004, ABT-773 was mainly located in the cytosol (about 75%) and was rapidly released from loaded cells (about 40% at 5 min), followed by a plateau, likely owing to avid reuptake . Verapamil and H89, an inhibitor of protein kinase A, increased drug efflux . Uptake was sensitive to external pH, and the activation energy was moderate (about 50 kJ/mol) . The existence of an active transport system on the PMN membrane was suggested by the following findings: concentration-dependent and saturable uptake (V(max), about 10,000 ng/2.5 x 10(6) PMNs/5 min; K(m), about 60 microg/ml) the inhibitory effects of PMN activators or inhibitors (phorbol myristate acetate, verapamil, Ni(2+)) and the significantly decreased levels of accumulation by killed cells and cells treated at low temperatures . In addition, various macrolides impaired ABT-773 uptake, contrary to the findings for the quinolone levofloxacin . ND- and D-PLB also presented saturation kinetics that defined an active transport system (V(max) and K(m) values were similar to those obtained with PMNs), but the activation pathway of the carrier system did not seem to be fully functional in ND-PLB . As has been observed with other erythromycin A derivatives, ABT-773 impaired oxidant production by phagocytes in a time- and concentration-dependent manner . These data extend our previous results on the existence of an active transport system common to all macrolides and ketolides, at least in PMNs.

Zhonghua Er Bi Yan Hou Ke Za Zhi, 2003 Dec, 38(6), 451 - 4
{Effect of erythromycin on the expression of apoptotic gene on eosinophils in nasal polyps in vitro}; Tang J et al.; OBJECTIVE: To study the expression of apoptotic gene in nasal polyps and the possible effect of erythromycin on it . METHODS: Total 40 nasal polyps biopsies were detected the expression of Bcl-2, Bax, Bcl-xL as well as Fas protein on eosinophils by immunohistochemistry . The expression of Bax, Bcl-xL, Fas on eosinophils in 15 nasal polyps explants which cultured with or without erythromycin were detected also . RESULTS: In nasal polyps, the expression of Bcl-2, Bax, Bcl-xL and Fas protein on eosinophils are 5% (2/10), 65% (26/40), 40% (16/40) and 90% (36/40) respectively . As compared with inferior turbinate, there were significant difference in expression of Bax and Fas protein between two tissues (P < 0.05) . After cultured with erythromycin, the expression of Bax protein increased (P < 0.05), but the expression of Bcl-xL and Fas protein had not changed . CONCLUSION: Bax may be the most significant gene which control the apoptosis of eosinophils in nasal polyps . And a possible mechaism which erythromycin promote the apoptosis of eosinophils is increase the expression of Bax.

An Pediatr (Barc), 2004 Apr, 60(4), 349 - 53
{Respiratory infection due to Chlamydia trachomatis in infants . Clinical presentation and outcome in 18 patients}; Marin Gabriel MA et al.; BACKGROUND: Among other diseases, Chlamydia trachomatis causes epididymitis and prostatitis in men and urethritis, cervicitis and pelvic inflammatory disease in women . In children, it most usually causes conjunctivitis and is also responsible for lower respiratory tract disease, occasionally requiring hospital admission . OBJECTIVE: To draw attention to this disease, which is usually overlooked and which can be potentially serious . METHODS: We retrospectively reviewed the medical records of infants aged less than 6 months with symptoms of lower respiratory tract disease in whom C . trachomatis antigen was detected by enzyme immunoassay . RESULTS: We identified 18 patients with C . trachomatis between 1993 and 2002 . Of these, 17 patients required hospital admission and five required monitoring in the pediatric intensive care unit . The mean length of hospital stay was 9.6 days . Three patients were immigrants . The mean age at admission was 6.6 weeks . Apnea occurred in five infants . Chest x-ray showed interstitial infiltrates in five infants . Sixteen patients were treated with erythromycin and all made a complete recovery . CONCLUSIONS: Although lower respiratory tract disease caused by C . trachomatis is usually managed on an outpatient basis, it sometimes requires hospital admission or even management in the intensive care unit . Therefore, C . trachomatis infection should be ruled out in infants aged less than 6 months with clinical symptoms of lower respiratory tract disease for which no other pathogen can be found.

Basic Clin Pharmacol Toxicol, 2004 Mar, 94(3), 144 - 50
The influence of amphotericin B and neomycin on the effect of human relaxin-2 on foetal membranes and isolated myometrium; Vogel I et al.; In vitro studies have documented effects of relaxin on utero-placental tissues . Previously unpublished experiments indicate that neomycin and amphotericin B in vitro influences the effect of human relaxin-2 on the strength of human foetal membranes . The aim of the current study was to investigate the interaction between neomycin and amphotericin B and human relaxin-2 using human foetal membranes, human myometrium and rat myometrium . Chloramphenicol, erythromycin and penicillin were also examined . Human foetal membranes were stretched until rupture in a materials-testing machine while the contractility of rat and human myometrium were examined by myography . Human relaxin-2 (hrlx-2, 10(-9) M) induced a decreased strength in human foetal membranes, although this effect of hrlx-2 was inhibited after co-incubation with neomycin and amphotericin B . Hrlx-2 (10(-9) M) in combination with chloramphenicol induced a decreased strength of human foetal membranes . Hrlx-2 (10(-9) M) decreased myometrial contractility on amplitude and frequency in the rat myometrium, but had no effect on baseline tension . After exposure to amphotericin B, hrlx-2 induced a more pronounced decrease in amplitude, increased baseline tension and increased the frequency of contractions of the rat myometrium . Hrlx-2 (10(-9) M) had no effect on the human myometrium . However, after exposure to amphotericin B or neomycin+amphotericin B, hrlx-2 induced an increase in baseline tension and a decrease in amplitude . Amphotericin B and neomycin+amphotericin B increased the frequency of contractions and this effect was further enhanced by the addition of hrlx-2 . We therefore conclude that amphotericin B and neomycin + amphotericin B may have an influence on relaxin's effect on isolated foetal membranes and myometrium.

Aliment Pharmacol Ther, 2004 Mar 15, 19(6), 687 - 94
Erythromycin for the treatment of chronic intestinal pseudo-obstruction: description of six cases with a positive response; Emmanuel AV et al.; BACKGROUND: Chronic intestinal pseudo-obstruction, due to intestinal myopathy or neuropathy, is characterized by the signs and symptoms of intestinal obstruction in the absence of true obstruction . Episodes are resistant to medical therapy . AIM: To determine the value of erythromycin treatment in chronic intestinal pseudo-obstruction . METHODS: All patients with proven chronic intestinal pseudo-obstruction treated with erythromycin were reviewed . Patients with symptomatic benefit are described in detail . Responders were compared with non-responders to identify the factors associated with benefit . RESULTS: Fifteen consecutive patients (nine females; median age, 37 years; median follow-up, 41 months) were treated with oral erythromycin, 1.5-2.0 g/day . Six patients (three primary visceral myopathy, two normal histology on light microscopy, one visceral myopathy secondary to scleroderma) responded, with decreased pain and vomiting, normalized bowel dysfunction and decreased episodes of ileus . Five of the six patients (83%) who responded to erythromycin were male, compared with two of the nine non-responders (22%) (P = 0.04) . Four of the six responders (67%) had histological or immunohistological visceral myopathy, compared with three of the nine patients (33%) who failed to respond . Responders were less likely than non-responders to be taking long-term opiates . CONCLUSIONS: Erythromycin is effective for acute episodes of ileus and chronic symptoms in some patients with chronic intestinal pseudo-obstruction.

J Pharm Biomed Anal, 2004 Mar 10, 34(5), 861 - 70
Investigating the potential of erythromycin and derivatives as chiral selector in capillary electrophoresis; Thanh Ha PT et al.; Macrocyclic antibiotics are present in an increasing number of chiral separation applications . In this study, erythromycin and some derivatives, belonging to the group of macrolide antibiotics, were investigated for their potential as chiral selector . Erythromycin A itself and five related substances namely erythromycin A N-oxide, anhydroerythromycin A, anhydroerythromycin A N-oxide, erythralosamine and erythralosamine N-oxide were included . Twenty-one chiral compounds with a wide difference in physico-chemical properties were used to test the chiral activity of the erythromycins . The chiral compounds were analysed using capillary zone electrophoresis with the erythromycins dissolved in the running buffer at different concentrations ranging from 0.1 to 10mM, with three different BGEs: sodium phosphate pHs 3.0 and 7.0 and sodium borate pH 9.2 . The erythromycins showed more interactions with the acidic compounds (as observed with leucovorin, dopa, carbidopa, ketoprofen, indoprofen and warfarin) than with the neutral or weakly basic ones, especially in acidic medium . Unfortunately, no chiral separations were obtained for any of the 21 racemic mixtures . The complexation constants were calculated for the compounds showing interaction, based on the variation of electrophoretic mobility of the compounds in the presence of different concentrations of erythromycins . Finally, the size of erythromycin A was calculated using computational modelling . It was shown that the aglycone ring is only half as big as the beta-cyclodextrin cavity, giving a possible explanation for the negative response of erythromycin in this study.

Ned Tijdschr Geneeskd, 2004 Feb 14, 148(7), 332 - 6
{Bronchocentric granulomatosis and mycoplasmal pneumonia}; Keijzer A et al.; A 61-year-old man presented with dyspnoea, chest pain, high fever and rigour . Chest X-ray revealed a combination of alveolar consolidations and abnormal nodular and interstitial markings . His clinical condition deteriorated despite treatment with antibiotics prescribed on a working diagnosis of pneumonia with an atypical pathogen . Finally, an open-lung biopsy specimen showed the characteristic picture of bronchocentric granulomatosis . Serological testing supported a primary infection with Mycoplasma pneumoniae . The patient responded well to treatment with prednisolone and erythromycin and five months after discharge, no radiological abnormalities were found . The combination of bronchocentric granulomatosis and mycoplasmal pneumonia has never been described in the literature and a causal relation can only be suggested . This case-report illustrates the importance of invasive diagnostic procedures if a patient with a clinical pneumonia fails to respond to adequate treatment.

Clin Neurol Neurosurg, 2004 Mar, 106(2), 129 - 31
Mycoplasma pneumoniae causing nervous system lesion and SIADH in the absence of pneumonia; Coelho M et al.; A patient was admitted for fever and acute respiratory failure (ARF), rapidly progressive tetraparesis, delirium, behavioral abnormalities, and diplopia . Leukocytosis and a rise in C-reactive protein were present . A syndrome of inappropriate anti-diuretic hormone secretion (SIADH) was also diagnosed . Lumbar puncture yielded colorless CFS with mononuclear pleocytosis and protein rise . Electrodiagnosis revealed demyelinating polyneuropathy and axonal degeneration . Serum IgG and IgM for mycoplasma pneumoniae (MP) was consistent with acute infection, and erythromycin was started with rapid resolution of symptoms . Contrarily to most reports, an associated respiratory disease was not present and SIADH in association with MP has been reported only once, in a patient without direct central nervous system (CNS) involvement . Differential diagnosis and possible pathogenic mechanisms are discussed.

Pharmacol Res, 2004 May, 49(5), 481 - 6
Protective role of tetrahydrocurcumin against erythromycin estolate-induced hepatotoxicity; Pari L et al.; Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, was investigated for its possible hepatoprotective effect in Wistar rats against erythromycin estolate-induced toxicity . Oral administration of THC significantly prevented the occurrence of erythromycin estolate-induced liver damage . The increased level of serum enzymes (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP)), bilirubin, cholesterol, triglycerides, phospholipids, free fatty acids and plasma thiobarbituric acid reactive substances (TBARS) and hydroperoxides observed in rats treated with erythromycin estolate were very much reduced in rats treated with THC and erythromycin estolate . This biochemical observation were supplemented by histopathological examination of liver section . Results of this study revealed that THC could afford a significant protection against erthromycin estolate-induced hepatocellular damage . Tetrahydrocurcumin had a better protective effect when compared with Silymarin, a reference drug.

J Rheumatol, 2004 Mar, 31(3), 436 - 41
Erythromycin suppresses the expression of cyclooxygenase-2 in rheumatoid synovial cells; Fumimori T et al.; OBJECTIVE: To investigate whether erythromycin (EM) can suppress the expression of cyclooxygenase-2 (COX-2) in rheumatoid synovial cells, and determine the mechanisms involved . Methods . Synovial tissues were obtained from 25 patients with rheumatoid arthritis (RA) . Rheumatoid synovial cells were cultured with or without EM (0.1-1000 nM) in the presence of interleukin 1beta (IL-1beta) for various times . Protein expression of COX-2, and phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) were detected by Western blot . COX-2 messenger RNA (mRNA) was detected by RT-PCR . DNA binding activity of nuclear factor kappa B (NF-kB) was detected by ELISA . Results . IL-1beta-stimulated synovial cells expressed COX-2 protein . EM suppressed the IL-1beta-induced COX-2 protein expression in a dose-dependent manner and inhibited IL-1beta-induced p38 MAPK phosphorylation, which was correlated with COX-2 expression in synovial cells . In contrast, EM had no effect on DNA binding activity of NF-kB and ERK1/2 expression . CONCLUSION: Our results indicated that EM downregulated COX-2 expression by inhibiting the p38 MAPK cascade, but had no effect on NF-kB or ERK1/2, in rheumatoid synovial cells.

J Infect Chemother, 2004 Feb, 10(1), 42 - 5
Longterm azithromycin therapy for three patients with chronic lower respiratory tract infections; Kasahara K et al.; Longterm macrolide therapy has been reported to be effective in treating chronic lower respiratory tract infections (CLRTIs) . In this context, erythromycin and clarithromycin are usually used for this purpose . However, refractory cases are occasionally encountered, thereby indicating a major problem pending . In the present study, we administered azithromycin to three patients with CLRTIs whose clinical course had been unsatisfactory with longterm therapy of either erythromycin or clarithromycin . Following longterm therapy with azithromycin, both the incidence of acute exacerbations and the sputum volume were decreased . A significant change in the sputum flora was observed, without obvious side effects; however, no improvement was evidenced in the findings on flow volume curve tests and arterial blood gas analysis . In advanced disease, longterm azithromycin therapy may be as effective as that with erythromycin or clarithromycin; in our view, however, its efficacy may be limited, and large-scale clinical trials are required to determine the most suitable macrolide for the treatment of CLRTIs.

Antimicrob Agents Chemother, 2004 Mar, 48(3), 1021 - 3
Ribosomal mutations in Arcanobacterium pyogenes confer a unique spectrum of macrolide resistance; Jost BH et al.; Four macrolide-resistant Arcanobacterium pyogenes isolates contained A2058T, A2058G, or C2611G (Escherichia coli numbering) mutations in their 23S rRNA genes . While these mutations conferred resistance to erythromycin, oleandomycin, and spiramycin, they did not confer resistance to tylosin.

J Laryngol Otol, 2004 Feb, 118(2), 97 - 101
Anti-inflammatory effect of erythromycin on histamine-induced otitis media with effusion in guinea pigs; Aktan B et al.; In this study, the anti-inflammatory effect of erythromycin was investigated in a model of histamine-induced otitis media with effusion (OME) . OME was induced in guinea pigs by the transtympanic injection of histamine solution into the middle-ear cavity . Guinea pigs were randomly assigned to one of three groups: control, erythromycin treatment, or methylprednisolone treatment . After histamine injection, the animals were treated with intraperitoneal medication for five days consecutively . Afterwards, the animals were sacrificed and the temporal bones were removed . The samples were examined stereologically . In the erythromycin-treated group, it was observed that neutrophil infiltration was significantly inhibited when compared to the control group . This result shows that erythromycin may produce a significant anti-inflammatory effect in this model of OME.

J Colloid Interface Sci, 2004 Mar 15, 271(2), 336 - 41
Preparation and characterization of biodegradable poly(l-lactide)/poly(ethylene glycol) microcapsules containing erythromycin by emulsion solvent evaporation technique; Park SJ et al.; In this work, the producing of a biodegradable poly(l-lactide) (PLA)/poly(ethylene glycol) (PEG) microcapsule by emulsion solvent evaporation method was investigated . The effect of PEG segments added to the PLA microcapsules on the degradation, size distribution, and release behavior was studied . According to the results, PLA/PEG copolymer was more hydrophilic than PLA homopolymer, and with lower glass transition temperature . The surface of PLA/PEG microcapsules was not as smooth as that of PLA microcapsules, the mean diameters of prepared PLA and PLA/PEG microcapsules were 40 and 57 microm, respectively . And spherical forms were observed by the image analyzer and the scanning electron microscope (SEM) . Drug release from microcapsules was affected by the properties of PLA/PEG copolymers determined by UV-vis spectra . It was found that the drug release rates of the microcapsules were significantly increased with adding of PEG, which explained by increasing hydrophilic groups.

J Med Chem, 2004 Feb 26, 47(5), 1085 - 97
Nonpeptide luteinizing hormone-releasing hormone antagonists derived from erythromycin A: design, synthesis, and biological activity of cladinose replacement analogues; Randolph JT et al.; The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described . The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for the design of more potent antagonists . Medicinal chemistry efforts to find a replacement for cladinose at position 3 of the erythronolide core provided a series of oxazolidinone carbamates that were equally as active as the cladinose-containing parent macrolides . The descladinose LHRH antagonist 14 has 1-2 nM affinity for both rat and human LHRH receptors and is a potent inhibitor of LH release (pA2 = 8.76) in vitro . In vivo, 14 was found to produce a dose-dependent suppression of LH in male castrate rats via both i.v . and p.o . dosing.

Eur J Dermatol, 2004 Jan-Feb, 14(1), 71 - 2
Treatment of an infantile acne with oral isotretinoin; Sarazin F et al.; We report the case of a little girl who presented with a nodulocystic acne which had its onset at the age of 20 months . She had no clinical or biological features of endocrinopathy . The lesions did not respond to conventional antibiotics so she was started on oral isotretinoin . A seven-month treatment period was necessary to achieve remission . The onset of infantile acne is usually around 6 to 16 months and there is a male predominance . The onset is later in females . Oral erythromycin is the first line treatment when topical therapies are inefficacious . Some cystic lesions do not respond to oral antibiotics . In these cases, oral isotretinoin may be effective and the treatment is similar to that of an adult . Clinical and biological tolerance is good with no growth retardation . Lesions may relapse after the withdrawal of isotretinoin but they are less important and easily controlled with topical treatments . Isotretinoin can be used for nodulocystic acne to reduce the risk of scarring . Copyright John Libbey Eurotext 2003.

J Environ Qual, 2004 Jan-Feb, 33(1), 257 - 64
Adsorption and clay-catalyzed degradation of erythromycin A on homoionic clays; Kim YH et al.; Erythromycin has been widely used in food-producing animals and in humans, and is frequently detected as an organic pollutant in U.S . streams . In batch experiments with homoionic clays, the Freundlich isotherms were determined at 10 and 25 degrees C . The adsorption of erythromycin A was strongly influenced by clay type, exchanged cations, the pH of the bulk solutions, and the acidity of clay surfaces . The formation of clay-erythromycin A complexes was thermodynamically favorable except for K+- and Fe3+-exchanged montmorillonites, since the reactions were exothermic (deltaH(o) > 0) and the systems became stable (deltaS(o) > 0) . Clays catalyzed the erythromycin A degradation by the hydrolysis of the neutral sugar and the multiple dehydrations . The surface acidity of clay surface enhanced the rate of clay-catalyzed degradation of erythromycin A . In addition, the Fe3+-exchanged clay minerals seemed to have an electrostatic interaction with the erythromycin A molecule, by which the hydrolysis of the neutral sugar was influenced.

Pharmacogenomics J, 2004, 4(2), 91 - 101
CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11; Anakk S et al.; This study reports that Cyp3a41 gene contains 13 exons and is localized on the chromosome 5 . CYP3A41 is a female-specific isoform that is predominantly expressed in the liver . Estrogen signaling is not responsible for its female specificity . CYP3A41 expression in kidney and brain is observed only in 50% of mice examined . PXR mediates dexamethasone-dependent suppression of CYP3A41 . In contrast to CYP3A11, CYP3A41 expression is not induced by pregnenolone-16alpha-carbonitrile (PCN) in wild-type mice, but is significantly suppressed by PCN in PXR(-/-) mice . Phenobarbital and TCPOBOP induce CYP3A11 expression only in the presence of CAR, but have no effect on CYP3A41 expression . Immunoblot and erythromycin demethylase activity analysis reveal robust CYP3A induction after PCN treatment, which is poorly correlated to CYP3A41 . These findings suggest a differential role for CAR/PXR in regulating individual CYP3A isoforms by previously characterized CYP3A inducers.

Chest, 2004 Feb, 125(2), 587 - 91
Transpyloric feeding tube placement in critically ill patients using electromyogram and erythromycin infusion; Levy H et al.; STUDY OBJECTIVES: Transpyloric feeding is desirable in critically ill patients who often have gastroparesis; however, correct placement is difficult, requiring fluoroscopy, endoscopy, or time-consuming blind attempts . This study evaluated the success rate and time required to place transpyloric tubes using erythromycin infusion and GI electromyogram (EMG) signal . DESIGN: Observational trial . SETTING: University hospital medical ICU . PATIENTS: Thirty-nine patients receiving mechanical ventilation for respiratory failure (n = 13), pancreatitis (n = 9), ARDS (n = 8), neurologic disease (n = 4), major surgery (n = 3), and GI disease (n = 2) were enrolled (25 men and 14 women; mean age, 48.4 years; range, 21 to 82 years) . INTERVENTIONS: Unweighted Flexiflo 10F feeding tubes were modified by the placement of an electrode 4 to 8 cm from the tip to record electromyogram (EMG) signals (Ross Products Division; Columbus, OH) . Gastric signals are high amplitude with a frequency of 3 cycles per minute, while the duodenum and jejunum are low amplitude and 11 to 13 cycles per minute . Erythromycin was infused at a dose of 3 mg/kg to enhance gastric motor activity and emptying . The transpyloric tube was placed in the stomach, and its position was confirmed by EMG, then slowly advanced until duodenal EMG was detected . Tube position was determined by abdominal radiography . Measurements and results: Thirty-one of 39 placements were immediately successful (initial success rate, 80%), 23 jejunal and 8 duodenal, requiring an average 7.8 min (range, 3 to 31 min) . Six attempts in five patients were initial failures but were repeated, reaching the duodenum in one patient and the jejunum in four patients . CONCLUSION: Erythromycin infusion and EMG guidance can facilitate rapid transpyloric feeding tube placement in critically ill patients at the bedside.

Neurogastroenterol Motil, 2004 Feb, 16(1), 13 - 21
Neural regulation of tone in the oesophageal body: in vivo barostat assessment of volume-pressure relationships in the feline oesophagus; Zhang X et al.; Recent combined manometric-barostat studies demonstrated that the oesophageal body exhibits both peristaltic contractions and tone . This study further characterized the neural modulation of tone in the feline oesophageal body . Simultaneous oesophageal barostat and manometry were performed in 20 adult cats under ketamine sedation . Oesophageal tone and peristalsis were assessed in the distal smooth muscle oesophagus . Cholinergic modulation was studied using neostigmine, erythromycin, atropine and vagotomy . Nitrergic regulation was assessed using sildenafil to increase cellular cyclic guanosine monophosphate and the nitric oxide synthase blocker Nomega-nitro-l-arginine (l-NNA) . The presence of a tonic contractile activity in the distal oesophageal body was confirmed . Peristaltic contractions proceeded along the oesophageal body over the background tonic contraction . Neostigmine and erythromycin enhanced (20-30%) whereas bilateral vagotomy and atropine strongly decreased oesophageal tone (50-60%) . However, l-NNA increased (40%) and sildenafil decreased oesophageal tone (30%) . Therefore, tonic contractile activity in the oesophageal body is mainly caused by a continuous cholinergic excitatory input . A nitric oxide inhibitory mechanism may have a complementary role in the regulation of oesophageal tone.

Biotechnol Prog, 2004 Jan-Feb, 20(1), 215 - 22
Principal component analysis of nonlinear chromatography; Pate ME et al.; Principal component analysis (PCA) has been used for the modeling of nonlinear chromatography under overload conditions . A 10-fold range of crude erythromycin samples were loaded onto columns with different stationary-phase chemistries (2 polystyrene, 1 methacrylate) in direct proportion to the bed volumes . The elution profiles indicated slightly concave isotherms for the polystyrene supports and a convex Langmuirian isotherm for the methacrylic support used . The principal component models accounted for over 98% of the original variance in the data for all three columns and were able to give excellent models of complete chromatograms in the absence of first-principle models or physicochemical data . Correlations between sample mass and the principal component scores were made for each that were consistent for the column types despite the different geometries and stationary phases . Linear relationships with high correlation coefficients were observed when the scores of the same principal component were compared between columns . Such correlations offer considerable potential for modeling of nonlinear chromatography.

Mol Microbiol, 2004 Jan, 51(2), 471 - 81
A CDP-choline pathway for phosphatidylcholine biosynthesis in Treponema denticola; Kent C et al.; The genomes of Treponema denticola and Treponema pallidum contain a gene, licCA, which is predicted to encode a fusion protein containing choline kinase and CTP:phosphocholine cytidylyltransferase activities . Because both organisms have been reported to contain phosphatidylcholine, this raises the possibility that they use a CDP-choline pathway for the biosynthesis of phosphatidylcholine . This report shows that phosphatidylcholine is a major phospholipid in T . denticola, accounting for 35-40% of total phospholipid . This organism readily incorporated {14C}choline into phosphatidylcholine, indicating the presence of a choline-dependent biosynthetic pathway . The licCA gene was cloned, and recombinant LicCA had choline kinase and CTP:phosphocholine cytidylyltransferase activity . The licCA gene was disrupted in T . denticola by erythromycin cassette mutagenesis, resulting in a viable mutant . This disruption completely blocked incorporation of either {14C}choline or 32Pi into phosphatidylcholine . The rate of production of another phospholipid in T . denticola, phosphatidylethanolamine, was elevated considerably in the licCA mutant, suggesting that the elevated level of this lipid compensated for the loss of phosphatidylcholine in the membranes . Thus it appears that T . denticola does contain a licCA-dependent CDP-choline pathway for phosphatidylcholine biosynthesis.

Am J Health Syst Pharm, 2004 Jan 15, 61(2), 160 - 73; quiz 175-6
Diabetic neuropathy: an intensive review; Duby JJ et al.; PURPOSE: The epidemiology, classification, pathology, and treatment of diabetic neuropathy are reviewed . SUMMARY: Diabetic peripheral neuropathy is a common complication of diabetes that can cause significant morbidity and mortality . Some 30% of hospitalized and 20% of community-dwelling diabetes patients have peripheral neuropathy; the annual incidence rate is approximately 2% . The primary risk factor is hyperglycemia . Sensorimotor neuropathy is marked by pain, paresthesia, and sensory loss . Cardiac autonomic neuropathy (CAN) may contribute to myocardial infarction, malignant arrhythmia, and sudden death . Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy . Genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder . The pathology of diabetic neuropathy involves oxidative stress, advanced glycation end products, polyol pathway flux, and protein kinase C activation; all contribute to microvascular disease and nerve dysfunction . For symptom management current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications . Citalopram, nonsteroidal antiinflammatory drugs, and opioid analgesics may be used as adjuvant agents . Lamotrigine, oxcarbazepine, paroxetine, levodopa, and alpha-lipoic acid are alternative considerations . Evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal . Complementary therapies have also shown efficacy . The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, and beta-blockers . Gastroparesis may be treated with metoclopramide or erythromycin . The most promising disease-modifying therapy is ruboxistaurin, which is in Phase III trials . Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment . CONCLUSION: Diabetic neuropathy is a many-faceted complication of diabetes that can be managed symptomatically with an array of drugs.

Drug Metab Dispos, 2004 Feb, 32(2), 172 - 7
Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics . II . Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey; Ward KW et al.; The effect of P-glycoprotein (Pgp) and/or CYP3A on the disposition of xenobiotics has been extensively investigated and is often of interest during drug discovery lead optimization . We have previously described a monkey pharmacokinetic screen to rapidly estimate absorption and first-pass extraction . In the present work, this monkey screen has been expanded to include an assessment of Pgp/CYP3A effects on absorption and first-pass extraction, using ketoconazole as a prototypic dual Pgp/CYP3A inhibitor . To generate a ketoconazole dosing regimen, the pharmacokinetics of ketoconazole were first determined in the monkey and were found to be consistent with that previously described in the rat, dog, and human . Dose-ranging experiments demonstrated that a single 10-mg/kg intraduodenal ketoconazole dose would provide an appropriate exposure; this dose was used throughout subsequent interaction experiments . Next, erythromycin and propranolol were explored as positive and negative control substrates for Pgp/CYP3A interactions, respectively . As anticipated, ketoconazole produced no change in the absorption or first-pass extraction of propranolol but resulted in a substantial increase in absorption and decrease in first-pass extraction of erythromycin . Finally, this ketoconazole-based monkey screen was deployed in a drug discovery setting, and examples of such use are presented . These experiments have allowed a more complete characterization of ketoconazole as a prototypic dual Pgp/CYP3A inhibitor and its use as a tool in a preclinical setting and further demonstrate the use of the monkey to investigate the role of Pgp/CYP3A in limiting the oral bioavailability of new drug candidates.

Eur J Drug Metab Pharmacokinet, 2003 Oct-Dec, 28(4), 309 - 13
Effect of P-glycoprotein inhibitors erythromycin and cyclosporin A on brain pharmacokinetics of nimodipine in rats; Liu XD et al.; Effect of P-glycoprotein (P-gp) inhibitors erythromycin (Ery) and cyclosporin A(CsA) on brain pharmacokinetics of nimodipine (NMD) in rats was studied . NMD concentrations in rat plasma and brain were determined after iv 2 mg/kg NMD alone, co-administration with Ery and CsA, respectively . It was found that concentrations of NMD in plasma of the three groups had a little difference, but brain concentrations of NMD in rats co-administrated with Ery and CsA were significantly higher than those in rats NMD alone . Significances of NMD in rat brain were found at 20, 40, 60 and 90 min after iv NMD . The brain T(1/2) in rat treated with ery(75.0 min) and CsA(79.0 min) were larger than that (44.2 min) in rats NMD alone . The results indicated that P-gp inhibitors Ery and CsA may increase concentration in rat brain by inhibiting elimination of NMD from brain.

Life Sci, 2004 Feb 20, 74(14), 1723 - 37
Selective suppression of cytochrome P450 gene expression by the medicinal herb, Thonningia sanguinea in rat liver; Gyamfi MA et al.; The effect of the administration of Thonningia sanguinea (T . S.) on the abundance of individual components of the cytochrome P450 monooxygenase enzyme was examined using Western blotting and competitive reverse-transcriptase-polymerase chain reaction (RT-PCR) . We also investigated the time-course of inhibition of T . S . on drug metabolizing enzymes . A single intraperitoneal dose of T . S . extract (5 ml/kg) suppressed CYP, cytochrome b5 and NADPH-CYP reductase activity by 45%, 34% and 22% respectively 24 h after T . S . administration . While T . S . did not have any significant effect on microsomal glutathione S-transferase activity, it inhibited p-nitrophenol hydroxylase (PNPH, CYP2E1) and 7-methoxyresorufin O-demethylase (MROD, CYP 1A2) activities by 37% and 32% respectively at 12 h post-T . S . administration . PNPH, erythromycin N-demethylase (ERDM, CYP 3A1/2) and MROD activities were inhibited by 28-36% 24 h after T . S . injection . Consistent with these observations, the levels of CYP2E1, CYP1A2 and CYP3A2 proteins were also suppressed 24 h post-T . S . administration . While CYP2E1 mRNA was unaffected by T . S . administration, CYP1A2 and CYP3A2 mRNAs were decreased by T . S . Cytosolic glutathione S-transferase activity was increased by 30%, 6 h after T . S injection . These data demonstrate that administration of T . S . differentially affect CYP isoforms in the liver of rats and that T . S . selectively suppresses CYP3A2 and CYP1A2 gene expression.

Analyst, 2004 Jan, 129(1), 15 - 9 Epub 2003 Dec 05.
Analysis of erythromycin and tylosin in bovine muscle using disposable screen printed electrodes; Ammida NH et al.; A disposable electrochemical enzyme-linked immunosorbent assay (ELISA) for the detection of two macrolides (erythromycin and tylosin) in bovine muscle was developed using a screen printed electrode (SPE) system as a differential pulse voltammetry (DPV) transducer with mouse anti-erythromycin (and anti-tylosin) monoclonal antibodies (MAb) serving as molecular recognition elements . The immunochemical system makes use of the competition assay principle, and employs an erythromycin (or tylosin)-BSA conjugate as coating molecule . After competition between free and coated analyte for the antibodies, the activity of the alkaline phosphatase labelled antiglobulins was measured electrochemically using 1-naphthylphosphate as substrate . Using standard solutions of erythromycin and tylosin, the detection limit of the assay was 0.2 ng mL(-1) determined to be for erythromycin and 2.0 ng mL(-1) for tylosin, while the sensitivity (25% inhibition concentration) was 1.0 ng mL(-1) for erythromycin and 3.0 ng mL(-1) for tylosin . The suitability of the assay for quantification of erythromycin and tylosin in bovine muscle was also studied . Spiked and real samples were analysed using the immunosensor system developed here . The ELISA showed precision values (relative standard deviation, RSD%) ranging from 4 to 9% for erythromycin and from 8 to 15% for tylosin; the accuracy (relative error, RE%) ranged from -11 to 6% and from -4 to 12% for erythromycin and tylosin, respectively . Results obtained on real samples were confirmed by micro-liquid chromatography coupled on line with tandem mass spectrometry (micro-LC-MS-MS), using an atmospheric pressure ionisation (API) source and an ionspray (IS) interface . The latter provides unequivocal identification and quantification of the analytes at the level of interest.

J Antimicrob Chemother, 2004 Feb, 53(2), 367 - 70 Epub 2004 Jan 16.
Modification of phagocytosis and cytokine production in peritoneal and splenic murine cells by erythromycin A, azithromycin and josamycin; Ortega E et al.; OBJECTIVES: The aim of this study was to determine whether pre-incubation of peritoneal or splenic cells with different doses of the macrolides erythromycin A (14-membered ring), azithromycin (15-membered ring) and josamycin (16-membered ring) affects their phagocytic activity or cytokine production . METHODS: Peritoneal and splenic cells from BALB/c mice were pre-incubated with different concentrations of these antibiotics, those similar to serum levels attained with the treatment schedules used in human therapy . RESULTS: From our observations of phagocytic activity and IL-12 production by peritoneal cells, these macrolide antibiotics seem to act mainly as immunosuppressive agents, although they induce peritoneal cells to increase IL-18 production and splenic cells IL-4 production . CONCLUSIONS: Macrolide antibiotics can interfere with the Th1 cell-amplifying activity of IL-18 in conjunction with IL-12 and, in contrast, may induce a Th2 cell response in an IL-4-dependent manner . These results could improve their therapeutic use especially in immunosuppressed patients.

Am J Cardiovasc Drugs, 2003, 3(2), 117 - 38
Cilostazol: a review of its use in intermittent claudication; Chapman TM et al.; Cilostazol (Pletal((R))) is a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties . It also exhibits antiproliferative effects on smooth muscle cells and has beneficial effects on high density lipoprotein-cholesterol and triglyceride levels.Randomized, double-blind, placebo-controlled 12- to 24-week trials in >2000 patients with moderate to severe intermittent claudication demonstrated that cilostazol generally significantly increased walking distances and improved quality of life compared with placebo . Additionally, a large comparative 24-week trial showed that cilostazol 100mg twice daily was significantly more effective than pentoxifylline 400mg three times daily (pentoxifylline was not significantly different from placebo) . Cilostazol was generally well tolerated . Adverse events reported significantly more often with cilostazol than with placebo included headache, diarrhea, abnormal stools, infection, rhinitis and peripheral edema and in comparison with pentoxifylline were headache, diarrhea, abnormal stools and palpitations . Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal . Significant drug interactions are observed when cilostazol is coadministered with other agents that inhibit cytochrome P450 (CYP) 3A4 (e.g . erythromycin or diltiazem) or CYP2C19 (e.g . omeprazole) . As a result, in Europe cilostazol is contraindicated in patients receiving CYP3A4 or CYP2C19 inhibitors and in the US it is recommended that dosage reduction for cilostazol be considered during coadministration of cilostazol and CYP3A4 or CYP2C19 inhibitors . Conversely, cilostazol itself does not appear to inhibit CYP3A4 . Coadministration of cilostazol with aspirin or warfarin did not result in any clinically significant changes to coagulation parameters, bleeding time or platelet aggregation . CONCLUSION: In six of eight well designed clinical trials, cilostazol was significantly more effective than placebo in increasing walking distances and improving the quality of life of patients with moderate to severe intermittent claudication . In addition, limited comparative data have shown that cilostazol has superior efficacy compared with pentoxifylline . Cilostazol is also generally well tolerated . Additional comparative trials are required to confirm these results, to determine the place of cilostazol in relation to other agents or exercise therapy and risk factor reduction alone, and to establish the effects of long-term treatment with cilostazol in patients with intermittent claudication . Cilostazol is contraindicated in several subpopulations of patients, particularly those with congestive heart failure and severe hepatic or renal impairment . Nonetheless, current data support the choice of cilostazol as a promising therapy amongst the limited options available for patients with intermittent claudication.

Am Fam Physician, 2004 Jan 1, 69(1), 87 - 91
Pityriasis rosea; Stulberg DL et al.; Pityriasis rosea is a common, acute exanthem of uncertain etiology . Viral and bacterial causes have been sought, but convincing answers have not yet been found . Pityriasis rosea typically affects children and young adults . It is characterized by an initial herald patch, followed by the development of a diffuse papulosquamous rash . The herald patch often is misdiagnosed as eczema . Pityriasis rosea is difficult to identify until the appearance of characteristic smaller secondary lesions that follow Langer's lines (cleavage lines) . Several medications can cause a rash similar to pityriasis rosea, and several diseases, including secondary syphilis, are included in the differential diagnosis . One small controlled trial reported faster clearing of the exanthem with the use of erythromycin, but the mechanism of effect is unknown . Resolution of the rash may be hastened by ultraviolet light therapy but not without the risk of hyperpigmentation . Topical or systemic steroids and antihistamines often are used to relieve itching.

Endoscopy, 2004 Jan, 36(1), 52 - 8
Nonvariceal upper gastrointestinal bleeding; Rollhauser C et al.; Although the incidence of nonvariceal upper gastrointestinal bleeding (NVUGIB) may be decreasing, the case fatality associated with it remains unchanged . What do the most recent studies tell us about medical and endoscopic therapy? Erythromycin is a potentially useful adjunct to endoscopy, and further data are needed to establish its role in the management of patients with NVUGIB . The use of proton-pump inhibitors in addition to combination endoscopic therapy appears to reduce the rebleeding rate consistently across different studies; the route of administration, dosage, and duration of treatment require further definition . Although two controlled studies suggest improved outcomes with clot removal and endoscopic therapy, the exact role of endoscopic treatment in the setting of overlying clots remains controversial . Hemoclips have not been found, in general, to be superior to the available endoscopic techniques . Currently, other hemostatic techniques such as injection and thermocoagulation - and in particular, combination therapy using both methods - are preferable . No major "breakthrough" endoscopic treatment has emerged . Newer endoscopic therapies such as cryotherapy are interesting, but have not had widespread application . Endoscopic suturing techniques, as used in the treatment of esophageal reflux and obesity, have not been adapted to the management of gastrointestinal bleeding.

J Mol Model (Online), 2004 Apr, 10(2), 94 - 101 Epub 2004 Jan 13.
A computational approach to the synthesis of dirithromycin; Duran D et al.; Dirithromycin is a macrolide antibiotic derived from erythromycin A . Dirithromycin is synthesized by the condensation of 9( S)-erythromycylamine with 2-(2-methoxyethoxy)-acetaldehyde . To gain insight into the synthesis, the condensation mechanism has been analyzed computationally by the AM1 method in the gas phase . First, the formation of the Schiff bases of dirithromycin and epidirithromycin from 9( S)-erythromycylamine and 2-(2-methoxyethoxy)-acetaldehyde were modeled . Then, the tautomerization of the Schiff bases to dirithromycin and epidirithromycin were considered . Finally, the epimerization of the Schiff base of epidirithromycin to the Schiff base of dirithromycin was investigated . Our results show that, even though carbinolamine forms faster for epidirithromycin than the corresponding structure for dirithromycin, dirithromycin is the major product of the synthesis.FIGURE Synthesis of dirithromycin

Contraception, 2004 Jan, 69(1), 47 - 9
Use of erythromycin for nonsurgical female sterilization in West Bengal, India: a study of 790 cases; Bairagy NR et al.; OBJECTIVE: Determine if erythromycin is an effective agent for achieving occlusion of the Fallopian tube for nonsurgical female sterilization . METHODS: Two studies of 100 healthy volunteers requesting sterilization were planned, one in Julpia Andhermanik and the other in Kolkata (Calcutta) . A readily available marketed tablet preparation containing 500 mg of the estolate salt of erythromycin was used for the trial . In one study (Bishnupur), the tablet was crushed before placing in a copper-T IUD inserter for placement at the fundus . In the other study (Kolkata), crushed tablets were processed into 50 mg pellets of the same diameter as standard quinacrine pellets and 10 pellets were inserted at the fundus using aseptic precautions . Procedures in each study were repeated at 30 days . Oral contraceptives were prescribed for three cycles following first insertion . No incentive was offered for participation in the trial . Follow-up treatment, including first-trimester abortion for pregnancy due to failure of the sterilization procedure, was assured without charge . Due to extraordinary patient demand, one study (Bishnupur) was expanded to 690 cases for reasons of compassion . RESULTS: At 12 months of use, the failure rate of the sterilization procedure for the crushed 500 mg tablets was 35.8% (SE = 1.8) with 417 women at risk . At 12 months of use, the failure rate for the erythromycin pellets was 28.6% (SE = 5.0) with 43 women at risk . There were no serious complications reported in either trial . All pregnancies resulting from failure of the sterilization procedure were terminated by menstrual regulation within 10 weeks gestation . CONCLUSIONS: The failure rate in this study is unacceptably high for erythromycin to be used as a sterilization method.

Zhonghua Jie He He Hu Xi Za Zhi, 2003 Dec, 26(12), 750 - 5
{An experimental study on airway inflammation and remodeling in a rat model of chronic bronchitis and emphysema}; Zhong XN et al.; OBJECTIVE: To study the pathological features of airway inflammation and remodeling in rats with chronic bronchitis (CB) and emphysema and to evaluate the protective and therapeutic effects of erythromycin (EM) . METHODS: Forty-three Wistar rats were assigned to eight groups: normal control group (A group, n = 5), normal saline solution group (P group, n = 5), CB group (L group, n = 6), CB and emphysema group (S group, n = 6), low-dose EM-treatment group (E(1) group, n = 5), high-dose EM-treatment group (E(2) group, n = 6), low-dose EM-prevention group (E(10) group, n = 5) and high-dose EM-prevention group (E(20) group, n = 5) . The rat model of CB and emphysema was established by intratracheal instillation of lipopolysaccharide (LPS) and daily exposure to cigarette smog . After four weeks, total and differential cell counts in bronchoalveolar lavage fluid (BALF) were observed, and the pathomorphological changes in the lung were analyzed . The thickness of the smooth muscles and collagen in the bronchial wall were measured . Expression and localization of transforming growth factor beta(1) (TGF-beta(1)) were observed in the bronchi and lung tissues by immunohistochemistry . The levels of hyaluronic acid (HA) and procollagen type III (PCIII) in the serum and BALF were determined by the radioimmunoassay (RIA) . RESULTS: (1) Compared with A group {(0.9 +/- 0.7) x 10(5)/ml}, absolute neutrophil count in BALF from S group {(17.1 +/- 10.8) x 10(5)/ml} were significantly higher (P < 0.01) . (2) Both the pathologic scores obtained from the S group (329 +/- 114) and P group (67 +/- 25), and the thickness of smooth muscles and collagen from S group {(9.6 +/- 2.6)%} and A group {(6.1 +/- 1.8)%} were statistically different (P < 0.01, P < 0.05, respectively) . Expression of TGF-beta(1) in the lung of S group was significantly higher than that in A group . (3) The levels of HA {(152.5 +/- 36.3) micro g/ml} and PCIII {(40 +/- 8) micro g/ml} in serum and the levels of HA {(94 +/- 35) micro g/ml} and PCIII {(39 +/- 7) micro g/ml} in BALF in S group were higher than those in A group (P < 0.01) . (4) After treatment with 100 mg/kg EM, absolute neutrophil count in BALF, the pathologic scores, the thickness of smooth muscles and collagen in the bronchi, the levels of PCIII and HA in serum and the levels of PCIII and HA in BALF were reduced to (2.1 +/- 1.4) x 10(5)/ml, 187 +/- 61, (6.0 +/- 2.3)%, (9.69 +/- 5.61) micro g/ml, (63.0 +/- 11.6) micro g/ml, (16 +/- 6) micro g/ml, (52 +/- 12) micro g/ml, respectively . Statistical analysis revealed that there were significant differences as compared to those of group S (P < 0.05) . CONCLUSIONS: Many inflammatory cells especially neutrophils and alveolar macrophages might play an important role in the airway inflammation of CB and emphysema . Thickening of smooth muscles and collagen in the bronchi and the excessive depositions of extracellular matrix (ECM) constitute the fundamental pathological characteristic of airway remodeling in CB and emphysema . EM may prevent airway inflammation and remodeling to some degree.

J Clin Psychopharmacol, 2004 Feb, 24(1), 4 - 10
Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers; DeVane CL et al.; An antidepressant for use in the patient receiving concomitant drug treatment, over-the-counter medications, or herbal products should lack cytochrome P-450 (CYP) 3A4 inductive or inhibitory activity to provide the least likelihood of a drug-drug interaction . This study addresses the potential of 4 diverse antidepressants (venlafaxine, nefazodone, sertraline, and fluoxetine) to inhibit or induce CYP3A4 . In a 4-way crossover design, 16 subjects received clinically relevant doses of venlafaxine, nefazodone, or sertraline for 8 days or fluoxetine for 11 days . Treatments were separated by a 7- to 14-day washout period and fluoxetine was always the last antidepressant taken . CYP3A4 activity was evaluated for each subject at baseline and following each antidepressant using the erythromycin breath test (EBT) and by the pharmacokinetics of alprazolam (ALPZ) after 2-mg dose of oral ALPZ . Compared to baseline, venlafaxine, sertraline, and fluoxetine caused no apparent inhibition or induction of erythromycin metabolism (P > 0.05) . For nefazodone, a statistically significant inhibition was observed (P < 0.0005) . Nefazodone was also the only antidepressant that caused a significant change in ALPZ disposition, decreasing its area under the concentration-versus-time curve (AUC; P < 0.01), and increasing its elimination half-life (16.4 vs . 12.3 hours; P < 0.05) compared with values at baseline . No significant differences were found in the pharmacokinetics of ALPZ with any of the other antidepressants tested . These results demonstrate in vivo that, unlike nefazodone, venlafaxine, sertraline, and fluoxetine do not possess significant metabolic inductive or inhibitory effects on CYP3A4.

Circulation, 2004 Jan 20, 109(2), 166 - 71 Epub 2004 Jan 05.
Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance; Lau WC et al.; BACKGROUND: Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described . Additionally, aspirin resistance and clopidogrel resistance occur in some individuals . Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity . METHODS AND RESULTS: Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers . The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers . Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer) . Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 micromol/L)-induced platelet aggregation of <10%, 10% to 29%, and > or =30%, respectively . Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders . Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders . Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (r=-0.6, P=0.003) . Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin . CONCLUSIONS: Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity . Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy.

Am J Ophthalmol, 2004 Jan, 137(1), 138 - 44
Ocular rosacea in childhood; Nazir SA et al.; PURPOSE: To describe the clinical characteristics and treatment response of ocular rosacea in the pediatric population . DESIGN: Retrospective case series . METHODS: The clinic charts of consecutive pediatric cases of ocular rosacea were evaluated over a 34-month period . Minimal diagnostic inclusion criteria were the presence of posterior eyelid inflammation including meibomian gland inspissation and lid margin telangiectasis, in conjunction with conjunctival injection or episcleritis . RESULTS: Six patients ranged from 3 to 12 years of age at presentation . All shared a long history of ocular irritation and photophobia . Five patients (83%) were female and had bilateral involvement . Eyelid telangiectases and meibomian gland disease were present in all cases . Three patients (50%) had sterile corneal ulcers . Only two patients (33%) had cutaneous involvement at the time of diagnosis . All patients experienced significant improvement with a combination of oral antibiotics (doxycycline or erythromycin), with or without topical antibiotics (erythromycin or bacitracin) or topical steroids (fluorometholone) . CONCLUSION: Ocular rosacea in children may be misdiagnosed as viral or bacterial infections . Unlike in adults, associated cutaneous changes are uncommon . Most disease is bilateral, although involvement may be asymmetric . Response to conventional treatment is excellent, although long-term treatment may be necessary to prevent relapses.

Gastroenterology, 2004 Jan, 126(1), 49 - 56
Mechanoreceptors of the proximal stomach: Role in triggering transient lower esophageal sphincter relaxation; Penagini R et al.; BACKGROUND AND AIMS: The role of fundic tension and stretch mechanoreceptors in triggering transient lower esophageal sphincter (LES) relaxation is still unknown . This information would be useful for the development of effective pharmacologic strategies . To elucidate this topic, gastric contractile activity was modified during isovolumetric gastric distention at 2 different volumes . METHODS: LES (Dentsleeve) and gastric (barostat) motility were recorded in 21 healthy subjects during studies comprising two 30-minute isovolumetric gastric distentions (placebo and glucagon or erythromycin) . Glucagon (bolus of 4.8 microg/kg plus infusion of 9.6 microg x kg(-1) x h(-1)) was administered at high intragastric volume (i.e., 75% of the threshold volume for discomfort; n = 7) and erythromycin (3 mg/kg) at high (n = 7) and low intragastric volume (i.e., at perception threshold; n = 7) . RESULTS: Glucagon decreased (P < 0.05) baseline intragastric pressure and abolished gastric contractions (0 vs . 16.7 +/- 2.3), whereas erythromycin increased (P < 0.05) baseline pressure and doubled (P < 0.05) the rate of gastric contractions at both volumes . Neither drug affected the rate of transient LES relaxations . Low intragastric volume induced a lower rate of transient LES relaxations (1.7 +/- 0.3 vs . 5.7 +/- 1.1; P < 0.01) and gastric contractions (11.8 +/- 2.5 vs . 20.5 +/- 3.1; P < 0.05) compared with high volume but similar baseline intragastric pressure (10.6 +/- 0.6 vs . 11.9 +/- 0.9 mm Hg) . CONCLUSIONS: Stretch receptors (gastric volume) seem to be more relevant than tension receptors in triggering transient LES relaxation.

Chembiochem, 2004 Jan 3, 5(1), 116 - 25
Identification of a phosphopantetheinyl transferase for erythromycin biosynthesis in Saccharopolyspora erythraea; Weissman KJ et al.; Phosphopantetheinyl transferases (PPTases) catalyze the essential post-translational activation of carrier proteins (CPs) from fatty acid synthases (FASs) (primary metabolism), polyketide synthases (PKSs), and non-ribosomal polypeptide synthetases (NRPSs) (secondary metabolism) . Bacteria typically harbor one PPTase specific for CPs of primary metabolism ("ACPS-type" PPTases) and at least one capable of modifying carrier proteins involved in secondary metabolism ("Sfp-type" PPTases) . In order to identify the PPTase(s) associated with erythromycin biosynthesis in Saccharopolyspora erythraea, we have used the genome sequence of this organism to identify, clone, and express (in Escherichia coli) three candidate PPTases: an ACPS-type PPTase (S . erythraea ACPS) and two Sfp-type PPTases (a discrete enzyme (SePptII) and another that is integrated into a modular PKS subunit (SePptI)) . In vitro analysis of these recombinant PPTases, with an acyl carrier protein-thioesterase (ACP-TE) didomain from the erythromycin PKS as substrate, revealed that only SePptII is active in phosphopantetheinyl transfer with this substrate . SePptII was also shown to provide complete modification of ACP-TE and of an entire multienzyme subunit from the erythromycin PKS in E . coli . The efficiency of the SePptII in phosphopantetheinyl transfer in E . coli makes it an attractive alternative to other Sfp-type PPTases for co-expression experiments with PKS proteins.

Antimicrob Agents Chemother, 2004 Jan, 48(1), 143 - 50
Molecular basis of intrinsic macrolide resistance in the Mycobacterium tuberculosis complex; Buriankova K et al.; The intrinsic resistance of the Mycobacterium tuberculosis complex (MTC) to most antibiotics, including macrolides, is generally attributed to the low permeability of the mycobacterial cell wall . However, nontuberculous mycobacteria (NTM) are much more sensitive to macrolides than members of the MTC . A search for macrolide resistance determinants within the genome of M . tuberculosis revealed the presence of a sequence encoding a putative rRNA methyltransferase . The deduced protein is similar to Erm methyltransferases, which confer macrolide-lincosamide-streptogramin (MLS) resistance by methylation of 23S rRNA, and was named ErmMT . The corresponding gene, ermMT (erm37), is present in all members of the MTC but is absent in NTM species . Part of ermMT is deleted in some vaccine strains of Mycobacterium bovis BCG, such as the Pasteur strain, which lack the RD2 region . The Pasteur strain was susceptible to MLS antibiotics, whereas MTC species harboring the RD2 region were resistant to them . The expression of ermMT in the macrolide-sensitive Mycobacterium smegmatis and BCG Pasteur conferred MLS resistance . The resistance patterns and ribosomal affinity for erythromycin of Mycobacterium host strains expressing ermMT, srmA (monomethyltransferase from Streptomyces ambofaciens), and ermE (dimethyltransferase from Saccharopolyspora erythraea) were compared, and the ones conferred by ErmMT were similar to those conferred by SrmA, corresponding to the MLS type I phenotype . These results suggest that ermMT plays a major role in the intrinsic macrolide resistance of members of the MTC and could be the first example of a gene conferring resistance by target modification in mycobacteria.

Eur J Dermatol, 2003 Sep-Oct, 13(5), 493 - 6
Febrile ulceronecrotic Mucha-Habermann disease with extensive skin necrosis in intertriginous areas; Yang CC et al.; Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a severe variant of pityriasis lichenoides et varioliformis acuta characterized by high fever and papulonecrotic skin lesions . Here we report a case of a 14-year-old boy with typical features of FUMHD and unusual manifestation of extensive skin necrosis in intertriginous regions including axillae, neck, inguinal and antecubital areas . Systemic administration of corticosteroid and erythromycin led to rapid healing of ulcerations without residual scar formation . Review of the literature showed male-predominance and favorable outcome in pediatric cases of FUMHD.

Zhonghua Nan Ke Xue, 2003 Nov, 9(8), 599 - 600, 603
{Prevalence and drug tolerance of mycoplasma in patients with urogenital inflammation}; Yan ZH et al.; OBJECTIVE: To observe the prevalence and drug tolerance of mycoplasma(Ureaplasma urealyticum and Mycoplasma hominis) in patients with urogenital inflammation . METHODS: Three thousand and fifty-five patients with urogenital inflammation such as non-gonococcal urethritis(NGU), chronic prostatitis or pelvic inflammation from 1999 to 2003 were included . The results of mycoplasma culture and drug sensitivity test were analyzed . RESULTS: A total of 992(32.5%) cases were mycoplasma positive in the 3,055 patients, and there was no significant difference in the yearly positive percentage in the 5 years (P < 0.05) . Among them, 701(70.7%) were infected with Ureaplasma urealyticum, 44(4.4%) with Mycoplasma hominis, and 247(24.9%) with both Ureaplasma urealyticum and Mycoplasma hominis, the Ureaplasma urealyticum infection rate being much higher than that of Mycoplasma hominis and mixed infection (P < 0.01) . The high colony counting(> or = 10(4) cfu/ml) in Ureaplasma urealyticum infection patients accounted for 76.7%, while Mycoplasma hominis infection represented only 18.2% . The results of drug tolerance test showed a higher sensitivity to doxycycline, pristinamycin, jiaomycin and testracycline (94.3%, 96.6%, 86.5% and 97.4% respectively), and a lower sensitivity to erythromycin and ofloxacin (54.8% and 29.4% respectively) . CONCLUSIONS: Ureaplasma urealyticum and Mycoplasma hominis should be detected simultaneously and the drug tolerance test is needed for the selection of appropriate antibiotics.

Org Biomol Chem, 2003 Dec 7, 1(23), 4144 - 7 Epub 2003 Oct 29.
Heterologous expression in Saccharopolyspora erythraea of a pentaketide synthase derived from the spinosyn polyketide synthase; Martin CJ et al.; A truncated version of the spinosyn polyketide synthase comprising the loading module and the first four extension modules fused to the erythromycin thioesterase domain was expressed in Saccharopolyspora erythraea . A novel pentaketide lactone product was isolated, identifying cryptic steps of spinosyn biosynthesis and indicating the potential of this approach for the biosynthetic engineering of spinosyn analogues . A pathway for the formation of the tetracyclic spinosyn aglycone is proposed.

Therapie, 2003 Sep-Oct, 58(5), 439 - 43
Protective effect of Sesbania grandiflora against erythromycin estolate-induced hepatotoxicity; Pari L et al.; Sesbania grandiflora, commonly known as 'sesbania', is widely used in Indian folk medicine for the treatment of liver disorders . Oral administration of an ethanolic extract of S . grandiflora leaves (200 mg/kg/day) for 15 days produced significant hepatoprotection against erythromycin estolate (800 mg/kg/day)-induced hepatotoxicity in rats . The increased level of serum enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase), bilirubin, cholesterol, triglycerides, phospholipids, free fatty acids, plasma thiobarbituric acid reactive substances and hydroperoxides observed in rats treated with erythromycin estolate were significantly decreased in rats treated concomitantly with sesbania extract and erythromycin estolate . The sesbania extract also restored the depressed levels of antioxidants to near normal . The results of the study reveal that sesbania could afford a significant protective effect against erythromycin estolate-induced hepatotoxicity . The effect of sesbania was compared with that of silymarin, a reference hepatoprotective drug.

FEMS Microbiol Lett, 2003 Dec 12, 229(2), 195 - 202
Allelic exchange in Francisella tularensis using PCR products; Lauriano CM et al.; We describe here a technique for allelic exchange in Francisella tularensis subsp . novicida utilizing polymerase chain reaction (PCR) products . Linear PCR fragments containing gene deletions with an erythromycin resistance cassette insertion were transformed into F . tularensis . The subsequent ErmR progeny were found to have undergone allelic exchange at the correct location in the genome; the minimum flanking homology necessary was 500 bp . This technique was used to create mglA, iglC, bla, and tul4 mutants in F . tularensis subsp . novicida strains . The mglA and iglC mutants were defective for intramacrophage growth, and the tul4 mutant lacked detectable Tul4 by Western immunoblot, as expected . Interestingly, the bla mutant maintained resistance to ampicillin, indicating the presence of multiple ampicillin resistance genes in F . tularensis.

Expert Opin Pharmacother, 2004 Jan, 5(1), 5 - 13
Medical treatment of rosacea with emphasis on topical therapies; Del Rosso JQ; Due to the development and release of newer topical formulations, the diagnosis and treatment of rosacea has received renewed attention over the past 3-5 years both in the literature and at medical symposia . Rosacea is a very common facial dermatosis . In the US, rosacea is estimated to affect > 14 million people, predominantly adults with approximately 60% of cases diagnosed before the age of 50 . A frustrating aspect of the disease is its inherent chronicity punctuated with periods of exacerbation and relative remission . A variety of subtypes have been identified which correlate with clinical presentation . Although the pathogenesis of rosacea is poorly understood, multiple topical agents are available . The efficacy of topical therapy for rosacea relates primarily to reduction in inflammatory lesions (papules, pustules), decreased intensity of erythema, a reduction in the number and intensity of flares and amelioration of symptoms, which may include stinging, pruritus and burning . The list of main topical agents utilised for the treatment of rosacea include metronidazole, sulfacetamide-sulfur, azelaic acid and topical antibiotics (clindamycin, erythromycin) . Depending on the severity at initial presentation, topical therapy may be combined with systemic antibiotic therapy (e.g., oral tetracycline derivative) . Newer therapeutic choices primarily involve improved vehicle formulations, which demonstrate favourable skin tolerability and cosmetic elegance.

Br J Clin Pharmacol, 2004 Jan, 57(1), 44 - 53
Population pharmacokinetics of weekly docetaxel in patients with advanced cancer; Slaviero KA et al.; AIMS: Previous pharmacokinetic studies of the 3-weekly regimen (100 mg m(-2) every 3 weeks) of docetaxel have shown that docetaxel clearance is affected by liver function, body surface area, age, serum alpha1-acid glycoprotein and cytochrome P450 3A4 (CYP3A4) activity . However, the pharmacokinetics of a weekly docetaxel (40 mg m(-2) week(-1)) schedule are not well characterized . The aims of this study were (a) to investigate the pharmacokinetics of docetaxel (40 mg m(-2) week(-1)) using sparse concentration-time data collected from patients with advanced cancer and (b) to utilize a population pharmacokinetic approach to identify patient covariates that significantly influence the clearance of docetaxel when administered according to this regimen . METHODS: A two-compartment pharmacokinetic model was used to describe the docetaxel concentration-time data from 54 patients with advanced cancer . The mean population and individual posterior Bayesian estimates of docetaxel clearance were estimated using P-PHARM . The relationships between docetaxel clearance and 21 covariates were investigated . This included estimates of CYP3A4 function in each patient using the erythromycin breath test (1/tmax) . Significant covariates were included into the final population pharmacokinetic model . Pharmacokinetic models were validated using a data splitting approach with a dataset consisting of 16 patients . RESULTS: Significant relationships were found between docetaxel clearance and 1/tmax (erythromycin breath test parameter) and several of the liver function enzymes and CL was best described by the equation; CL = 21.51 + 217 (1/tmax) - 0.13 (ALT) . This final population pharmacokinetic model provided both precise and unbiased predictions of docetaxel concentrations in a validation group of patients and an estimate of the population mean (95% confidence interval) clearance of docetaxel was 30.13 l h(-1) (12.54, 46.04 l h(-1)) with an intersubject variability 30% . CONCLUSIONS: A population pharmacokinetic model has been developed and validated for weekly docetaxel (40 mg m(-2)) in patients with advanced cancer . These results indicate that CYP3A4 activity and hepatic function have an impact on the pharmacokinetics of docetaxel when administered weekly.

Mol Cell Biochem, 2003 Dec, 254(1-2), 1 - 7
Characterization of the inhibitory effects of erythromycin and clarithromycin on the HERG potassium channel; Stanat SJ et al.; Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans, however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current (IKr) encoded by HERG (the human ether-a-go-go-related gene) at drug concentrations, temperature and ionic conditions mimicking those occurring in human subjects . Potassium currents in HEK 293 cells stably transfected with HERG were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the HERG encoded potassium current in a concentration dependent manner with an IC50 of 38.9 +/- 1.2 microM and Hill Slope factor of 0.4 +/- 0.1 . Clarithromycin produced a similar concentration-dependent block with an IC50 of 45.7 +/- 1.1 microM and Hill Slope factor of 1.0 +/- 0.1 . Erythromycin (25-250 microM) and clarithromycin (5 or 25 microM) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the HERG potassium current at clinically relevant concentrations.

Nihon Kokyuki Gakkai Zasshi, 2003 Nov, 41(11), 840 - 5
{A case of severe Chlamydia pneumoniae pneumonia requiring mechanical ventilation and complicated with disseminated intravascular coagulation}; Yanagi S et al.; A previously healthy 48-year-old man presented to his primary care physician with high fever, dry cough and dyspnea . Pneumonia was diagnosed and intravenous administration of imipenem/cilastatin was begun, but his respiratory condition worsened and he was admitted to our hospital with severe hypoxia . A chest radiograph showed reticular opacity and consolidation in both lung fields . The case was complicated with disseminated intravascular coagulation . Analysis of the bronchoalveolar lavage fluid showed increases in the total cell counts and an elevated percentage of lymphocytes . Sputum, blood and bronchoalveolar lavage examinations failed to reveal etiology to explain his severe respiratory illness . Treatment consisted of mechanical ventilation and administration of steroid pulse-therapy and gabexate mesilate . On the basis of his clinical course, we suspected possible atypical pneumonia, and began therapy with intravenous minocyclin and oral erythromycin administration . On the third hospital day, the arterial blood gas data improved and the bilateral pulmonary infiltration on the chest radiographs disappeared . Using paired sera, we detected increases of 1.35 in ID for anti-Chlamydia pneumoniae IgG antibodies by ELISA, and arrived at a diagnosis of Chlamydia pneumoniae pneumonia.

J Gene Med, 2003 Dec, 5(12), 1067 - 79
Novel macrolide-adjustable bidirectional expression modules for coordinated expression of two different transgenes in mice; Fux C et al.; BACKGROUND: Precise control of transgene expression is essential for a variety of applications ranging from gene-function analysis, biopharmaceutical manufacturing to next-generation molecular interventions in gene therapy and tissue engineering . The regulation of gene expression is currently a key issue for clinical implementation of gene-therapy-based treatments since desired transgene expression may need to be maintained within a narrow therapeutic window for successful treatment of a particular human disease . METHODS: We have designed a novel bidirectional expression module that enables adjustable coregulation of two different transgenes in response to clinical doses of macrolide antibiotics . A bidirectional macrolide-responsive promoter consisting of a central operator module (ETR) specific for the macrolide-dependent transactivator (ET1) is flanked by two minimal promoters (P(hCMVmin); P(hsp70min)) which drive expression of two divergently oriented transgenes . Macrolide antibiotics modulate the binding affinity of ET1 to ETR and adjust expression of both transgenes to desired levels . RESULTS: Bidirectional expression configurations enabled excellent macrolide-adjustable coregulation profiles of two secreted reporter genes or one-vector-based autoregulated fine-tuning of a single transgene in various transgenic rodent and human cell lines . Following implantation of microencapsulated CHO-K1 cell derivatives transgenic for macrolide-controlled bidirectional expression of erythropoietin (EPO) and the human secreted alkaline phosphatase (SEAP) intraperitoneally into mice, serum EPO and SEAP levels could be coadjusted to desired levels by administration of different erythromycin doses . CONCLUSIONS: Based on their in vivo compatibility, the versatile bidirectional and macrolide-responsive expression modules represent an important advancement on the way to implementing targeted and conditional molecular interventions into a clinical reality .

J Orthop Res, 2004 Jan, 22(1), 21 - 9
Erythromycin inhibits wear debris-induced osteoclastogenesis by modulation of murine macrophage NF-kappaB activity; Ren W et al.; Activation of nuclear factor kappa B (NF-kappaB) signaling in response to cell stimulation by wear debris may be critical in the pathogenesis of aseptic loosening . Erythromycin (EM), a macrolide antibiotic, has been shown to effectively suppress some types of inflammatory reactions . In this study, we examined the effect of EM on wear debris-induced osteoclastic bone resorption in vitro . EM inhibited Ca+ release from neonatal calvaria co-cultured with conditioned medium from mouse RAW264.7 macrophages activated by wear debris . Inhibition of Ca+ release was associated with a decreased number of tartrate-resistant acid phosphatase (TRAP)-positive cells in cultured bones . To investigate the mechanism whereby EM inhibits bone-resorption, RAW cells were incubated with wear debris in the presence EM . Real time RT-CR analysis revealed that EM (5 microg/ml) significantly inhibited mRNA expression of NF-kappaB, cathepsin K (CPK), IL-1beta and TNFalpha, but not RANK in RAW cells stimulated with wear debris . Furthermore, electrophoretic mobility-shift assay showed that EM (0.2 microg-5 microg/ml) could reduce DNA-binding activity of NF-kappaB in RAW cells stimulated with wear debris . The inhibition of inflammatory osteoclastogenesis by EM treatment was further confirmed by an osteoclast (OC) formation assay using primary cultures of mouse bone marrow progenitor cells stimulated with macrophage colony-stimulating factor and RANK ligand (RANKL) . EM treatment (5 microg/ml) resulted in more than 70% reduction in multinucleated OC formation and 50% reduction of TRAP+ cells by bone marrow progenitor cells . Our findings support that EM suppresses wear debris-induced osteoclastic bone resorption by, at least, down-regulation of NF-kappaB signaling pathway . It appears that EM represents a potential therapeutic candidate for the treatment and prevention of aseptic loosening.

Mol Cells, 2003 Oct 31, 16(2), 187 - 93
Renaturation of recombinant ErmSF and its refolding behavior; Lee HJ et al.; ErmSF is one of four gene products responsible for the resistance of Streptomyces fradiae to the autogenous antibiotic, tylosin . It catalyzes the methylation of a single adenine residue (A2058) of 23S rRNA to produce dimethyl adenine from monomethyl adenine or unmodified adenine . This reduces the affinity of macrolide-lincosamide-streptogramin B (MLS) antibiotics for the peptidyltransferase circle and confers resistance to these antibiotics . We earlier cloned ermSF from Streptomyces fradiae, ligated it into pET23b with a T7 promoter and transformed it into E . coli . The transformants were resistant to erythromycin, but most of the expressed protein was present as an inclusion body . In the present work, the protein was extracted from the inclusion bodies, solubilized with 6 M guanidine-HCl, and purified by metal ion (Ni2+) affinity chromatography yielding 171 mg of denatured protein per liter of culture . Renaturation of the protein was achieved by step-wise removal of the guanidine-HCl . Most of the refolded protein appeared to assume the natural conformation, as judged by circular dichroism spectroscopy . The yield of refolded protein increased as the protein concentration in the renaturation medium was lowered, but the activity of the renatured protein tended to increase with protein concentration . The highest yield of renatured protein, 107 mg/L of culture had 55% of the activity of the naturally folded protein . Refolding was also carried out by removing denaturant by a simple two-step dilution-dialysis method . With that method, the yield of the refolded protein was lower and the activity higher than with step-wise refolding . The yields and activities did not seem to be affected by the concentration of denaturant, suggesting that renaturation under the conditions employed occurred spontaneously with a strong tendency to fold to the native state, even though ErmSF contains two domains.

Biochemistry, 2003 Dec 9, 42(48), 14342 - 8
6-Deoxyerythronolide B analogue production in Escherichia coli through metabolic pathway engineering; Kennedy J et al.; The erythromycin precursor polyketide 6-deoxyerythronolide B (6-dEB) is produced from one propionyl-CoA starter unit and six (2S)-methylmalonyl-CoA extender units . In vitro studies have previously demonstrated that the loading module of 6-deoxyerythronolide B synthase (DEBS) exhibits relaxed substrate specificity and is able to accept butyryl-CoA, leading to the production of polyketides with butyrate starter units . We have shown that we can produce butyryl-CoA at levels of up to 50% of the total CoA pool in Escherichia coli cells that overexpress the acetoacetyl-CoA:acetyl-CoA transferase, AtoAD (EC 2.8.3.8), in media supplemented with butyrate . The DEBS polyketide synthase (PKS) used butyryl-CoA and methylmalonyl-CoA supplied in vivo by the AtoAD and methylmalonyl-CoA mutase pathways, respectively, to produce 15-methyl-6-dEB . Priming DEBS with endogenous butyryl-CoA affords an alternative and more direct route to 15-Me-6-dEB than that provided by the chemobiosynthesis method {Jacobsen, J . R., et al . (1997) Science 277, 367-369}, which relies on priming a mutant DEBS with an exogenously fed diketide thioester . The approach described here demonstrates the utility of metabolic engineering in E . coli to introduce precursor pathways for the production of novel polyketides.

Vet Rec, 2003 Nov 8, 153(19), 588 - 91
Evaluation of tetracycline, erythromycin, penicillin and streptomycin for decontaminating koala semen contaminated in vitro with chlamydiae; Bodetti TJ et al.; Semen from seven koalas was extended in a tris-citrate glucose diluent containing one of four antibiotics at different concentrations and then contaminated with a standard concentration of chlamydiae . These semen preparations were then tested for residual chlamydial viability by an in vitro cell culture assay, and any detrimental effect of the antibiotics on the motility and viability of the sperm was assessed . Penicillin at 25 iu/ml or more, erythromycin at 1000 microg/ml or more and tetracycline at 200 microg/ml or more were highly effective at rendering the chlamydiae non-viable, but streptomycin showed no antichlamydial activity . There was a significant reduction of the motility of spermatozoa extended in diluents containing erythromycin (P < 0.05), but spermatozoa incubated with tetracycline up to concentrations of 200 microg/ml were not affected.

Br J Clin Pharmacol, 2003 Dec, 56(6), 639 - 52
Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability; Kerbusch T et al.; AIMS: A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies . The relationships between explanatory covariates and pharmacokinetic parameters were explored . METHODS: Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33 darifenacin/metabolite observations per healthy subject), and one Phase 2 study (median 7/7 darifenacin/metabolite observations per subject) encompassing one intravenous and five different oral formulations (1-45 mg) . RESULTS: Non-linear Mixed Effects Models (NONMEM Version VI) described both the population pharmacokinetics of darifenacin and its hydroxylated metabolite with a two-compartment disposition model with first order absorption . The values (mean +/- standard error of the mean) for clearance (CL) and volume of distribution of the central compartment were 40.2 +/- 2.0 l h-1 and 34.7 +/- 4.6 l h-1, respectively, in a typical male CYP2D6 homozygote-extensive metabolizer (Hom-EM) . The absolute bioavailability (F) of darifenacin in a Hom-EM after doses of 7.5, 15 or 30 mg extended release formulation (CR) was 15, 19 and 25%, respectively . Factors influencing F were formulation (70-110% higher for CR compared with immediate release following equivalent daily doses), CYP2D6 genotype {heterozygote-extensive metabolizers (Het-EM) and poor metabolizers (PM) experienced 40 and 90%, respectively, higher exposure than Hom-EM irrespective of dose administered} and saturable first-pass metabolism (dose nonlinearity 1.05-1.43-fold) . Race affected F, which was 56% lower in Japanese males . The CYP3A4 inhibitors ketoconazole and erythromycin increased F to approximately 100% and ketoconazole decreased CL by 67.5% . CL was 31% lower in females and 10% lower at night . Formulation affected the metabolite absorption/formation rate . Ketoconazole and erythromycin administration resulted in a decrease of 61.2 and 28.8% in exposure to the metabolite, respectively . The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin . CONCLUSIONS: The pooled analysis provided a descriptive integration of all characteristics and covariates of the pharmacokinetics of darifenacin and its metabolite, enabling interpolation and extrapolation of these key factors.

Br J Clin Pharmacol, 2003 Dec, 56 Suppl 1, 30 - 6
No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers; Purkins L et al.; AIMS: The antibiotic erythromycin is a potent inhibitor of cytochrome P450 CYP3A4 metabolism . As CYP isozymes, including CYP3A4, are involved in the metabolism of the new triazole voriconazole, this study investigated the effects of multiple-dose erythromycin or azithromycin on the steady-state pharmacokinetics of voriconazole in healthy male subjects . METHODS: In an open, randomized, parallel-group, single-centre study, 30 healthy male subjects aged 20-41 years received oral voriconazole 200 mg twice daily for 14 days plus either erythromycin (1 g twice daily on days 8-14), azithromycin (500 mg once daily on days 12-14) or placebo (twice daily on days 8-14) . Only morning doses were administered on day 14 . Plasma concentrations of voriconazole were measured up to 12 h postdose on days 7 and 14, and plasma pharmacokinetic parameters were calculated . Adverse events and standard laboratory test results were recorded before and throughout the study . RESULTS: Comparison of the voriconazole Cmax day 14/day 7 ratio for the voriconazole + erythromycin group with that of the voriconazole + placebo group yielded a ratio of 107.7%{90% confidence interval (CI) 90.6, 128.0}; for the voriconazole + azithromycin group, the ratio was 117.5% (90% CI 98.8, 139.7) . Comparison of the voriconazole AUCtau day 14/day 7 ratios of the voriconazole + erythromycin and voriconazole + azithromycin groups with that of the voriconazole + placebo group showed ratios of 101.2% (90% CI 89.1, 114.8) and 107.9% (90% CI 95.1, 122.4), respectively . For voriconazole tmax, the differences between the day 14-day 7 calculations for the voriconazole + erythromycin or the voriconazole + azithromycin groups and that of the voriconazole + placebo group were - 0.2 h (90% CI - 0.8, 0.3) and - 0.1 h (90% CI - 0.7, 0.5), respectively . None of these changes was considered clinically relevant . The study drugs were well tolerated by subjects in all groups; the most common study drug-related adverse events were visual disturbances, reported in all groups, and abdominal pain, present in the voriconazole + erythromycin group . CONCLUSIONS: Coadministration of erythromycin or azithromycin does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner in healthy male subjects.

Intensive Care Med, 2004 Jan, 30(1), 103 - 7 Epub 2003 Nov 13.
A novel method for insertion of post-pyloric feeding tubes at the bedside without endoscopic or fluoroscopic assistance: a prospective study; Slagt C et al.; OBJECTIVE: To assess a novel method, adapted from already published literature, for bedside placement of nasojejunal feeding tubes using erythromycin, air insufflation of the stomach and continuous ECG guidance . DESIGN AND SETTING: Prospective study in a tertiary teaching hospital . PATIENTS AND PARTICIPANTS: 40 consecutive patients who required enteral nutrition and mechanical ventilation for at least 48 h . INTERVENTIONS: Erythromycin (200 mg) was administered intravenously 30 min prior to the insertion of the feeding tube . The post-pyloric feeding tube was then inserted into the stomach and 500 ml air insufflated . Stomach ECG was performed, and during further insertion of the tube the QRS complex was continuously monitored for a change in polarity, suggesting passage across the midline through the pylorus . At the end of the procedure aspirate was obtained from the feeding tube and checked for alkaline pH . Exact tube position was determined by abdominal radiography . MEASUREMENTS AND RESULTS: In 88% of cases the feeding tubes were post-pyloric, with a median time to insertion of 15 min (range 7-75) . No major complications were seen in 52 attempts . Change in QRS polarity had 94% sensitivity in predicting post-pyloric tip placement . Of the 32 alkaline pH aspirates 31 were post-pyloric . CONCLUSIONS: This procedure is safe, effective and could be performed in a short time period within the confines of the intensive care unit without endoscopic assistance.

J Clin Pharmacol, 2003 Dec, 43(12), 1377 - 81
Effect of influenza immunization on CYP3A4 activity in vivo; Hayney MS et al.; Many reports of interactions between drugs metabolized by CYP3A4 and influenza vaccine have been made . The authors hypothesized that changes in CYP3A4 activity following influenza immunization would correlate with cytokine production or age . Twenty-four subjects had an erythromycin breath test (ERMBT) and blood draw for lymphocyte culture prior to and on day 7 following influenza immunization . Cytokine production by lymphocytes cultured with influenza antigen was measured by ELISA . Eight men and sixteen women ranging in age from 20 to 66 years (mean = 38.7 years; SE = 2.9) participated in the study . Interferon gamma (IFNgamma) production inversely correlated with change in ERMBT (correlation coefficient = -0.614; p < 0.02), although the overall change in ERMBT was not statistically significant (mean = -4%; p = 0.28) . The IFNgamma production correlates with change in ERMBT . This correlation supports in vitro findings of decreased CYP3A4 expression and activity with IFNgamma exposure.

Arch Pharm Res, 2003 Oct, 26(10), 800 - 4
Effects of a new neuroprotective agent KR-31378 on liver cytochrome P450s in male Sprague Dawley rats; Jeong TC et al.; The effects of KR-31378, a neuroprotective agent for ischemia-reperfusion damage, on liver microsomal cytochrome P450s (CYPs) were investigated in male Sprague Dawley rats . When rats were treated orally with KR-31378 for 7 consecutive days, CYP3A-selective erythromycin N-demethylase (ERDM) activity was significantly induced in a dose-dependent manner . In Western immunoblotting, CYP 3A proteins were clearly induced by treatment with KR-31378 . Within 24 h after treatment with 80 mg/kg of KR-31378, ERDM activity was induced in liver microsomes in accompanied by induction of the level of CYP 3A proteins . The present results suggest that KR-31378 might modulate the expression of CYP 3A enzymes in humans.

J Org Chem, 2003 Nov 14, 68(23), 8847 - 52
Allylation of erythromycin derivatives: introduction of allyl substituents into highly hindered alcohols; Stoner EJ et al.; Functionalized erythromycin 9-oxime derivatives are 6-O-allylated under mild conditions using substituted allyl tert-butyl carbonates under palladium(0) catalysis . This allylation works well where traditional ether-forming protocols function poorly . Allyl tert-butyl carbonates provide higher yields in this reaction than lesser substituted carbonates such as ethyl or isopropyl . Aryl-substituted allyl carbonates or carbamates may be employed as well and, when used, produce trans-olefinic products.

Int J Antimicrob Agents, 2003 Nov, 22(5), 532 - 6
Correlation between susceptibility and BRO type enzyme of Moraxella catarrhalis strains; Kadry AA et al.; Clinical isolates of Moraxella catarrhalis (76 isolates) were screened for beta-lactamase production and antibiotic susceptibility . beta-Lactamases (detected in 90.8% of isolates) were typed using isoelectric focusing to BRO-1 (87%) and BRO-2 (13%) . Minor variations in electrofocusing patterns between the two types were seen . Isolates expressing BRO type enzymes showed solid resistance to penicillin, ampicillin and cephalothin, in particular BRO-1 producers . BRO-1 isolates were less susceptible to cephems and to beta-lactamase inhibitors than BRO-2 isolates . Isolates harbouring BRO-1 enzymes have more enzymatic activity than those expressed by BRO-2 isolates . Apart from resistance to tetracycline (14.5%), all isolates were consistently susceptible to erythromycin, chloramphenicol, ciprofloxacin and gentamicin . The conjugal transfer of BRO beta-lactamase gene(s) between M . catarrhalis isolates occurred with a frequency of 10(-5) to 10(-7)/donor cell . The data emphasize the importance of M . catarrhalis as an etiological agent spreading beta-lactamases that may inhibit some beta-lactams and lead to failure in treatment of mixed infections.

Med Hypotheses, 2003 Nov-Dec, 61(5-6), 617 - 22
Virtual elimination of necrotising enterocolitis for 5 years - reasons?
Patole S, McGlone L, Muller R.
A standardised feeding regimen was adopted in 1997 for guiding enteral feeding of neonates <32 weeks' gestation during clinical trials (18 months each) involving erythromycin (n=73) as a prokinetic and carboxymethylcellulose (n=70) as a laxative as well as for during 2 years (n=155) without any trials . Most aspects of the feeding regimen (e.g., milk increments-total volume/day, use of breast milk by choice, etc) were not significantly different from current practices . RESULTS: 298 neonates <32 weeks' gestation (<28 weeks; n=78) were enterally fed during the 5 years . Their demographic characteristics and median (interquartile) age in days at starting (AST) and days to reach full enteral feeds (FFT) of 150 ml/kg/day were not significantly different during these 5 years: {AST: 5 (3-7.5)}, {FFT: 4 (3-7)} Only one case of definite NEC (> or =Stage II) occurred during the 5 years . The time to reach full feeds was also reduced by over 54% (including for neonates <28 weeks gestation) compared with a historical cohort . CONCLUSION: Sustained reduction in the time to reach full feeds with virtual elimination of > or =Stage II NEC for 5 years indicates continued benefits of a standardised feeding regimen as a simple preventive strategy to prevent NEC . Whether our specific policy of no enteral feeds in presence of hemodynamic instability associated with PDA requiring indomethacin, and/or sepsis played a role in achieving the significant results needs controlled trials.

Ned Tijdschr Geneeskd, 2003 Oct 11, 147(41), 2029 - 32
{Chickenpox in pregnancy with serious consequences for both mother and child}; Manten GT et al.; A 41-year-old woman with chickenpox in the third trimester of her pregnancy was admitted to the Intensive Care Unit of our hospital for ventilatory support . She was treated with aciclovir, amoxicillin-clavulanic acid and erythromycin . Her baby was delivered by forceps following placental abruption . After delivery, both mother and child recovered slowly but could eventually leave the hospital in good condition . If a pregnant woman without a prior history of varicella-zoster infection is exposed to a child that has chickenpox, passive immunisation with varicella-zoster immunoglobulin should be administered . This reduces the risk of maternal complications and may prevent a fetal varicella syndrome . If the mother has already developed chickenpox and there are serious complications, she should be treated with intravenous aciclovir . If possible, delivery should be delayed until 5 days after the onset of maternal chickenpox.

Rapid Commun Mass Spectrom, 2003, 17(21), 2439 - 49
Increasing sensitivity and decreasing spot size using an inexpensive, removable hydrophobic coating for matrix-assisted laser desorption/ionisation plates; Owen SJ et al.; Spot size reduction and increased detection sensitivity in matrix-assisted laser desorption/ionisation (MALDI) of small molecules are accomplished by using an inexpensive and removable hydrophobic coating for MALDI targets, based on 3M Scotch Gard surface treatment . Several variations in sample preparation were explored, such as surface coating technique, identity of the matrix, solvent composition, and the type of metal support plate used . These were investigated on both uncoated and coated surfaces and their impact on spot size, crystal coverage, and sensitivity is presented here . Additionally, crystallisation behaviour obtained on coated plates is compared with that on uncoated plates using scanning electron microscope analysis . To demonstrate the potential of the new coating technique, erythromycin A and valinomycin are studied to determine the increase in detection sensitivity of coated plates in comparison to uncoated plates, and to reveal the suitability of the plates for application in combined high-performance liquid chromatography/MALDI (HPLC/MALDI), where widely varying solvent compositions and droplet volumes are observed . It is shown that enhancements in detection sensitivities correlate very well with the achieved spot size reduction . The versatility of the coated plates is also exhibited by the ease of removing the surface layer, after which the plates can be rigorously cleaned without worry about damaging the hydrophobic surface, followed by a quick reapplication of new hydrophobic coating material . This makes the non-polar coating superior to more expensive commercial hydrophobic-coated targets, which are much more delicate to clean . Furthermore, cleaning and reapplication eliminate potential carry-over effects and the easy application procedure also makes the fabrication of inexpensive, disposable MALDI targets readily possible .

Cochrane Database Syst Rev . 2003;(4):CD003744.
Erythromycin for the prevention of chronic lung disease in intubated preterm infants at risk for, or colonized or infected with Ureaplasma urealyticum; Mabanta CG et al.; BACKGROUND: Controversy exists over whether or not Ureaplasma urealyticum colonization or infection of the respiratory tract contributes to the severity of chronic lung disease (CLD), a major cause of morbidity and mortality in preterm infants . OBJECTIVES: To evaluate the efficacy and safety of prophylactic or therapeutic erythromycin in preventing chronic lung disease in intubated preterm infants with unknown U . urealyticum status or proven positivity . SEARCH STRATEGY: Searches were done of MEDLINE (1966-June 9, 2003), EMBASE (1980-May 5, 2003), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2002), previous reviews including cross-references, and abstracts of conference proceedings (Pediatric Academic Societies 2000-2003, American Thoracic Society 2001-2003) . There were no language restrictions . Expert informants were contacted . SELECTION CRITERIA: Randomized or quasi-randomized studies comparing either prophylactic or therapeutic administration of oral or intravenous erythromycin (regardless of dose and duration) versus no treatment or placebo among intubated preterm infants <37 weeks and <2500 grams with either unknown U . urealyticum status or proven positivity by culture or polymerase chain reaction . DATA COLLECTION AND ANALYSIS: Data were extracted by all of the authors independently and differences were resolved by consensus . Treatment effects for categorical outcomes were expressed as relative risk, with 95% confidence intervals . MAIN RESULTS: Two small controlled studies, both involving intubated babies <30 weeks gestation, were eligible for inclusion . Lyon 1998 tested prophylactic erythromycin in babies whose U . urealyticum status was unknown at the time of initiation of treatment . Jonsson 1998 tested erythromycin in babies known to be culture positive for U . urealyticum . Neither trial showed a statistically significant effect of erythromycin on CLD, death or the combined outcome CLD or death . Because the two studies differed importantly in their design, the results were not combined in meta-analyses . No adverse effects of a 7-10 day course of erythromycin were reported in either study . REVIEWER'S CONCLUSIONS: Current evidence does not demonstrate a reduction in CLD/death when intubated preterm infants are treated with erythromycin prophylactically before U . urealyticum culture/PCR results are known or when Ureaplasma colonized, intubated preterm infants are treated with erythromycin . However, a true benefit could easily have been missed with the small sample sizes in the two eligible studies . The studies were greatly underpowered to detect uncommon adverse effects such as pyloric stenosis . Additional controlled trials are required to determine whether antibiotic therapy of Ureaplasma reduces CLD and/or death in intubated preterm infants.

Mol Cell Biol, 1982 Jun, 2(6), 694 - 700
Nuclear inheritance of erythromycin resistance in human cells: new class of mitochondrial protein synthesis mutants; Doersen CJ et al.; The characterization of two new erythromycin-resistant mutants of HeLa cells is described . The strains ERY2305 and ERY2309 both exhibited resistance to erythromycin in growth assays and cell-free mitochondrial protein synthesis assays . The erythromycin resistance phenotype could not be transferred by cybridization . The mutation appeared to be encoded in the nucleus and inherited as a recessive trait . These two mutants, therefore, represent a new class of erythromycin-resistant mutants in human cells that is distinct from the cytoplasmically inherited mutation in strain ERY2301 described previously.

J Pediatr Gastroenterol Nutr, 2003 Nov, 37(5), 554 - 8
Establishing enteral feeding in preterm infants with feeding intolerance: a randomized controlled study of low-dose erythromycin; Ng SC et al.; OBJECTIVE: A prospective, double-blind, randomized, controlled trial was conducted to evaluate the effect of low-dose erythromycin on the time taken to attain full enteral feedings in preterm infants with very low birth weight and feeding intolerance . METHODS: Two groups of preterm infants (birth weight </= 1500 g) with feeding intolerance were randomized to either low-dose erythromycin (5 mg/kg every 8 hours) or 5% dextrose placebo, both of which were discontinued 1 week after full enteral feedings were tolerated . The primary outcome variable was the time taken to attain full enteral feedings of at least 130 mL/kg/d . RESULTS: The gestational age at birth was similar in the two groups (erythromycin, 27.1 +/- 1.9 weeks; placebo, 27.5 +/- 2.9 weeks) . The mean birth weight of the erythromycin group was lower (806.3 +/- 215.6 g) than the placebo group (981.4 +/- 285.4 g; P = 0.18), and included more infants who were small for gestational age (4/13 = 31% versus 1/11 = 9%; P = 0.224) . There was no difference between the two groups with regard to the volume of feedings they were receiving at the time of enrollment . Reduction in symptoms of gastroesophageal reflux was similar in the two groups . 3 of 13 in the erythromycin group and 4 of 11 in the placebo group improved during the study (P = 0.565) . The mean time to attain full enteral feedings after enrollment was 24.9 + 2.9 days in the erythromycin group and 30.8 +/- 4.1 days in the placebo group, a difference that did not reach statistical significance (P = 0.17) . CONCLUSIONS: Low-dose erythromycin did not reduce the time taken to attain full enteral feedings in preterm infants with very low birth weight and feeding intolerance . Gastroesophageal reflux decreased as a consequence of maturation of the gastrointestinal tract and not because of erythromycin . These preliminary results justify verification in larger multicenter trials.

Yi Chuan Xue Bao, 2003 Jul, 30(7), 646 - 52
{Analysis of dominant-recessive mutated character of nfr genes of Chlamydomonas reinhardtii and its mutual interaction with the chloroplastic psbA gene}; Mijit G et al.; Phenotypic analysis of the nfr/Nfr diplontic hybrids has demonstrated the recessive mutated character of the nfr genes, and the norflurazon resistant character of the Nfr-4 And Nfr-5 mutants were resulted in by the different nuclear genes nfr-1 and nfr-2 respectively . From the tetrad analysis result of hybridizations of psbA mutant with wild strains CC-124 and nfr mutant, it have been demonstrated that the sensitivity of psbA mutated strain to norflurazon under photoautotrophic condition is due to its multiple effect whereas the chloroplast genome under the mixotrophic situation also gives some effect for resistance to norflurazon . From the titration results of cross-resistant character for antibiotics of norflurazon resistant strains, we had found that, the Nfr-3 mutant has some cross-resistance to erythromycin and streptomycin; based on this phenomenon it would be expected that this mutant having resistant character to suppressor of phytoene desaturase also give some effect for construction of chloroplastic protein.

Z Rheumatol, 2003 Oct, 62(5), 450 - 8
{Epidemiology and therapy of Lyme arthritis and other manifestations of Lyme borreliosis in Germany: results of a nation-wide survey}; Priem S et al.; AIM OF THE STUDY: Only little is known about the epidemiology of Lyme borreliosis in Germany . As an example, it is still unclear if there are regional differences in the incidence of Lyme disease in general or of certain clinical manifestations like Lyme arthritis . Moreover, standardization of diagnostic or therapeutic procedures does not exist . Therefore, a Germany-wide questionnaire-based survey was conducted in order to achieve more epidemiological data and to obtain more information about the diagnostic and therapeutic approaches of general practitioners and specialists . METHODS: A self-designed questionnaire was distributed along with two editions of the journal "Deutsches Arzteblatt" (which is delivered to every physician in Germany) and additionally by a pharmaceutical company . During the collection period from March 1, 1998 to February 28, 1999, patients with Lyme disease were reported and information was given about site of infection, diagnostic procedures, clinical symptoms, treatment, and outcome . RESULTS: Altogether 3935 patients were reported . Their mean age was 43.4 years with the peak incidences around the ages of 10 and 60 years . 37.3% of the questionnaires were sent in by general practitioners, 17.6% by dermatologists, 15.7% by pediatricians, 9.7% by internists, and 2.7% by neurologists . 83% of the patients did not have a special infecion risk . The most frequent clinical Lyme manifestation was erythema migrans (EM), which occurred in 50.9% of the patients . 21.3% suffered from general symptoms . Of special interest, 24.5% of the patients had Lyme arthritis (14.7% mon- or oligoarthritis, 9.8% polyarthritis) . Therefore, arthritis was more frequently reported than neuroborreliosis (18.4%) . Only 16% of the neuroborreliosis patients and 32% of the arthritis patients remembered having had an EM . 189 patients (4.8%) with lymphadenosis cutis benigna and 100 patients (2.5%) with acrodermatitis chronica atrophicans were reported . In 80.4% of the patients, positive Lyme serology was detected . In a few cases, the diagnosis was established by isolation of borreliae, PCR or histology . 3754 patients were treated by antibiotics . The most frequently used compounds were doxycycline (50.4%), followed by ceftriaxone (22.4%), amoxicillin (13.6%), penicillin (7%), and erythromycin (4.2%) with differences depending on clinical manifestations and specialization of the prescribing physician . In less than 10% of the cases, not evaluated or recommended therapeutic procedures were performed . DISCUSSION: Lyme disease is endemic throughuot Germany . The most frequent manifestations are EM, followed by Lyme arthritis and neuroborreliosis . Less than one third of patients suffering from disseminated or chronic Lyme disease remembered an EM . Most of the physicians taking part in this survey follow treatment recommendations concerning choice of antibiotics and treatment durations.

J Chromatogr A, 2003 Oct 10, 1015(1-2), 129 - 41
Determination of selected human pharmaceutical compounds in effluent and surface water samples by high-performance liquid chromatography-electrospray tandem mass spectrometry; Hilton MJ et al.; A simple method is presented for the analysis of 13 pharmaceutical and pharmaceutical metabolite compounds in sewage effluents and surface waters . The pharmaceutical compounds were extracted using a genetic solid-phase extraction (SPE) procedure using Phenomenex Strata X as a stationary phase . Extracts were quantitatively analysed by four separate reversed-phase high-performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS) techniques and quantified by comparison with an internal standard ({13C}-phenacetin) . Recoveries and limits of detection (LOD) for sulfamethoxazole (120%, 50 ng l(-1)), acetyl-sulfamethoxazole (56%, 50 ng l(-1)), trimethoprim (123%, 10 ng l(-1)), erythromycin (73%, 10 ng l(-1)), paracetamol (75%, 50 ng l(-1)), ibuprofen (117%, 20 ng l(-1)), clofibric acid (83%, 50 ng l(-1)), mefenamic acid (24%, 50 ng l(-1)), diclofenac (62%, 20 ng l(-1)), propranolol (45%, 10 ng l(-1)), dextropropoxyphene (63%, 20 ng l(-1)) and tamoxifen (42%, 10 ng l(-1)) were all acceptable . The recovery of lofepramine (4%) was too low to be of use in a monitoring programme . Application of the method to samples collected from UK sewage effluents and surface waters showed detectable concentrations of mefenamic acid, diclofenac, propranolol, erythromycin, trimethoprim and acetyl-sulfamethoxazole in both matrices . Ibuprofen and dextropropoxyphene were detected in sewage effluents alone . All other pharmaceutical compounds were below the methods limits of detection.

Neth J Med, 2003 Jul, 61(7), 266 - 7
Acute pancreatitis after a course of clarithromycin; Schouwenberg BJ et al.; We present a case of acute pancreatitis after a course of clarithromycin . An 84-year-old woman died of suspected pneumonia and cardiac failure . Autopsy surprisingly revealed acute pancreatitis . Except for the use of clarithromycin no other cause for her acute pancreatitis was obvious . Pancreatitis induced by clarithromycin has been reported twice in the English literature so far . There are, however, a few reports on acute pancreatitis associated with other macrolide antibiotics, such as erythromycin and roxithromycin.

J Perinatol, 2003 Oct, 23(7), 541 - 4
The value of Ureaplasma urealyticum tracheal culture and treatment in premature infants following an acute respiratory deterioration; Mhanna MJ et al.; OBJECTIVE: To determine if treatment of Ureaplasma urealyticum (Uu), found at the time of an acute respiratory deterioration, decreases the incidence of chronic lung disease (CLD) in very low birth weight infants (VLBW) . STUDY DESIGN: Between 1996 and 1999, medical records of all mechanically ventilated VLBW infants, who had an acute respiratory deterioration, were reviewed for gestational age (GA), birth weight (BW), gender, presence of CLD, Uu tracheal cultures, and erythromycin treatment . RESULTS: A total of 100 patients met our inclusion criteria (GA: 26.2+/-1.7 weeks, BW: 737+/-167.1 g (mean+/-SD)) . Uu was present in 46.3% (38/82) of patients with CLD versus 50% (9/18) of patients without CLD (odds ratio 0.86 (CI: 0.31 to 2.39); p=0.77) . Erythromycin treatment was not found to be protective against the development of CLD (odds ratio: 1.46 (CI: 0.25 to 8.31); p=0.66) . CONCLUSION: Following an acute respiratory deterioration, tracheal isolation, and treatment of Uu may not decrease the incidence of CLD in VLBW infants.

Anal Bioanal Chem, 2004 Feb, 378(4), 955 - 63 Epub 2003 Oct 16.
Liquid chromatography with triple-quadrupole or quadrupole-time of flight mass spectrometry for screening and confirmation of residues of pharmaceuticals in water; Stolker AA et al.; LC-MS-MS has been performed with triple-quadrupole (QqQ) and quadrupole-time of flight (Q-ToF) instruments and has been used for screening and confirmation of pharmaceuticals in surface, drinking, and ground water . Screening was based on monitoring of one specific MS-MS ion of the target compounds . Confirmation of the identity of the pharmaceuticals was based either on the monitoring of two specific MS-MS ions and calculation of the ratio of their intensities, or on the exact masses of MS-MS product ions obtained for a molecular ion by use of LC-Q-ToF MS . The set of pharmaceuticals included four analgesics (acetylsalicylic acid, diclofenac, ibuprofen, and paracetamol), three antibiotics (sulfamethoxazole, erythromycin, and chloramphenicol), five blood-lipid regulators and beta-blockers (fenofibrate, bezafibrate, clofibric acid, bisoprolol, and metoprolol), and the anti-epileptic drug carbamazepine . Limits of quantification ranged from 5 to 25 ng L(-1) . Fifty-six samples were analysed and residues of the pharmaceuticals were detected in almost all surface and groundwater and in some drinking water samples . The identity of the compounds could be confirmed by use of both QqQ- and Q-ToF-based LC-MS-MS . However, the latter technique has the distinct advantage that a large number of pharmaceuticals can be screened and confirmed at low concentrations (1-100 ng L(-1)) in one run.

Am J Respir Cell Mol Biol, 2004 Apr, 30(4), 569 - 75 Epub 2003 Oct 09.
Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating granulocyte macrophage colony-stimulating factor release; Yamasawa H et al.; Macrolides have been shown to be effective in treating diffuse panbronchiolitis (DPB), although the precise modes of action remain unclear . At sites of airway inflammation, respiratory epithelium is considered an active participant in regulating neutrophil survival . We therefore examined the effect of erythromycin, clarithromycin, azithromycin, and josamycin on both neutrophil survival and on epithelial-derived factors, which influence neutrophil longevity . Media conditioned with transiently tumor necrosis factor (TNF)-alpha-stimulated A549 human airway epithelial cells prolonged neutrophil survival compared with control media . The presence of dexamethasone during neutrophil culture led to further prolongation of neutrophil survival . In contrast, none of the tested macrolides modulated neutrophil survival, suggesting a lack of direct effect of these drugs . On the other hand, pretreatment of TNF-alpha-stimulated A549 cells by erythromycin, clarithromycin, azithromycin, or dexamethasone, but not josamycin, decreased the neutrophil survival-enhancing effects in a dose-dependent manner . Neutralizing antibodies to granulocyte macrophage colony-stimulating factor (GM-CSF) dampened the prolonged neutrophil survival observed in TNF-alpha-stimulated A549 conditioned media . Erythromycin, clarithromycin, azithromycin, and dexamethasone inhibited TNF-alpha-induced GM-CSF expression in A549 cells at both the protein and messenger RNA levels . These results suggest that macrolides inhibit epithelial cell-mediated neutrophil survival by modulating GM-CSF release, which may, at least in part, explain the effectiveness of this family of drugs on DPB.

CNS Drugs, 2003, 17(13), 947 - 63
Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists; Bentue-Ferrer D et al.; Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer's disease . These drugs are also being used off label to treat severe cases of Alzheimer's disease or vascular dementia and other disorders . The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations . The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors . The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance . The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms) . The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin . It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions . Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g . bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors . A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics . Possible interactions involving other often coprescribed antidementia agents (e.g . memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use.

Clin Pharmacokinet, 2003, 42(13), 1141 - 60
Clinical pharmacokinetics of atorvastatin; Lennernas H; Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease . Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase . The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose . The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form . Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration . However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14% . The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98% . Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine . In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter . The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours . The renal route is of minor importance (<1%) for the elimination of atorvastatin acid . In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin . Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3 . Atorvastatin can be given either in the morning or in the evening . Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration . Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose . Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated . An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation . A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs . Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.

Pharmacogenetics, 2003 Oct, 13(10), 595 - 606
Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women; Floyd MD et al.; CYP3A activity in adults varies between individuals and it has been suggested that this has a genetic basis, possibly related to variant alleles in CYP3A4 and CYP3A5 genes . Accordingly, genotype-phenotype associations were investigated under constitutive and induced conditions . Midazolam's systemic and oral clearances, and the erythromycin breath test (ERBT) were determined in 57 healthy subjects: 23 (11 men, 12 women) European- and 34 (14 men, 20 women) African-Americans . Studies were undertaken in the basal state and after 14-15 days pretreatment with rifampin . DNA was characterized for the common polymorphisms CYP3A4*1B, CYP3A5*3, CYP3A5*6 and CYP3A5*7 by direct sequencing, and for exon 21 and exon 26 variants of MDR1 by allele-specific, real-time polymerase chain reaction . In 95% of subjects, the basal systemic clearance of midazolam was unimodally distributed and variability was less than four-fold whereas, in 98% of the study population, oral clearance varied five-fold . No population or sex-related differences were apparent . Similar findings were observed with the ERBT . Rifampin pretreatment markedly increased the systemic (two-fold) and oral clearance (16-fold) of midazolam, and the ERBT (two-fold) but the variabilities were unchanged . No associations were noted between these phenotypic measures and any of the studied genotypes, except for oral clearance and its fold-increase after rifampin . These were related to the presence of CYP3A4*1B and the inversely linked CYP3A5*3 polymorphism, with the extent of induction being approximately 50% greater in CYP3A5*3 homozygotes compared to wild-type subjects . In most healthy subjects, variability in intestinal and hepatic CYP3A activity, using midazolam as an in-vivo probe, is modest and common polymorphisms in CYP3A4 and CYP3A5 do not appear to have important functional significance.

Neurogastroenterol Motil, 2003 Oct, 15(5), 467 - 73
Electrogastrography as a diagnostic tool for delayed gastric emptying in functional dyspepsia and irritable bowel syndrome; van der Voort IR et al.; Several pathophysiological mechanisms have been proposed in functional gastrointestinal (GI) disorders, e.g . altered GI motility and sensitivity . The aim of this study was to investigate gastric electrical activity (GEA) in patients with functional dyspepsia (FD) or irritable bowel syndrome (IBS) compared with healthy controls (HC), and to assess if abdominal symptoms and delayed gastric emptying are associated with alterations in GEA, as determined by electrogastrography (EGG) . Forty patients with FD, IBS or both were compared with 22 HC . EGG was performed before and after a standard meal . Frequencies and amplitudes pre- and post-prandially were analysed . Furthermore, gastric emptying and symptom scores were assessed . Eight of 40 patients (20%; three FD, three IBS, two FD and IBS) had delayed gastric emptying . Disturbed gastric emptying and lack of a postprandial increase in the EGG amplitude were significantly correlated (r = 0.8; P < 0.005) . No differences between controls and patients were observed in the distribution of EGG frequencies . Treatment with the prokinetically active macrolide erythromycin improved gastric emptying, GEA and symptoms (n = 4) . The data suggest that EGG could be useful as a diagnostic tool in patients with FD and IBS to identify a subgroup of patients with delayed gastric emptying.

Antimicrob Agents Chemother, 2003 Oct, 47(10), 3326 - 31
Erythromycin esterase gene ere(A) is located in a functional gene cassette in an unusual class 2 integron; Biskri L et al.; The gene ere(A) of the plasmid pIP1100 is larger than originally reported and is organized as an integron gene cassette . The ere(A) gene cassette carries its own promoter and is propagated by a class 2 integron with an insertion sequence element, IS1, inserted upstream of the intI2 gene . The mobility of the ere(A) cassette has been demonstrated.

Bioprocess Biosyst Eng, 2003 Nov, 26(1), 49 - 55 Epub 2003 Sep 19.
Modelling the adsorption kinetics of erythromycin onto neutral and anionic resins; Ribeiro MH et al.; In this study the selective adsorption method was chosen to enable the recovery of erythromycin . The following sorbents were tested: neutral resins (XAD-4, XAD-7 and XAD-16) and an anionic resin (IRA-410) . A mathematical kinetic model for the adsorption of erythromycin against time, on XAD-4, XAD-7 and XAD-16 resins, is proposed . Both Freundlich and Langmuir models showed a good fit for the sorbents XAD-7 and IRA-410 resins . The highest adsorption efficiency was observed when synthetic neutral resin, XAD-7 and XAD-16, were used . The estimated affinity and concentration factors show that the neutral resins tested are adequate for the selective adsorption of erythromycin . The estimated values of enthalpy and free energy of adsorption, lower than 12 kJ mol(-1) and -2 kJ mol(-1), respectively, indicate that a physiosorption process occurred.

Br J Pharmacol, 2003 Nov, 140(5), 948 - 54 Epub 2003 Sep 22.
The rabbit motilin receptor: molecular characterisation and pharmacology; Dass NB et al.; Following identification of the human motilin receptor, we isolated the rabbit orthologue by PCR amplification and found this to be 85% identical to the open reading frame of the human receptor . The protein encoded was 84% identical to the human polypeptide . In HEK293T cells transfected with the rabbit receptor, motilin concentration-dependently increased intracellular calcium mobilisation (pEC50=9.25) . After transfection with Go1alpha, motilin similarly stimulated {35S}GTPgammaS binding (pEC50=8.87) . Using both systems, similar values were obtained with the human receptor, with rank-order potencies of motilin={Nle13}-motilin>erythromycin; ghrelin was ineffective . In circular muscle preparations of rabbit gastric antrum, {Nle13}-motilin 0.1-30 nM concentration-dependently increased the amplitude of electrically-evoked, neuronally-mediated contractions (pEC50=8.3); higher concentrations increased the muscle tension (30-3000 nM) . Both responses to {Nle13}-motilin faded rapidly during its continual presence . Rat or human ghrelin 0.01-10 microM were without activity . Erythromycin 30-3000 nM and 10 microM, respectively, increased neuronal activity and muscle tension in rabbit stomach . Unlike {Nle13}-motilin, the increase in neuronal activity did not fade during continual presence of submaximally-effective concentrations of erythromycin; some fade was observed at higher concentrations . We conclude that the pharmacology of the rabbit motilin receptor is similar to the human orthologue and, when expressed as a recombinant, comparable to the native receptor . However, in terms of their ability to increase neuronal activity in rabbit stomach, {Nle13}-motilin and erythromycin are distinguished by different response kinetics, reflecting different rates of ligand degradation and/or interaction with the receptor.

Eur J Intern Med, 2003 Aug, 14(5), 329 - 331
Fulminant Mycoplasma pneumoniae infection with multi-organ involvement: a case report; Kountouras D et al.; A 50-year-old man with no medical history was admitted because of progressive respiratory distress, aseptic meningitis, disseminated intravascular coagulation, cholestatic hepatitis, and renal failure . Mycoplasma pneumoniae infection was confirmed serologically . The patient was treated with erythromycin and showed a favorable recovery . Although M . pneumoniae infection is usually a benign, self-limited acute respiratory disease, on rare occasions it can manifest itself with a fulminant course and multi-organ involvement, even in normal healthy individuals.

Dig Liver Dis, 2003 Jul, 35 Suppl 3, S17 - 9
Factors affecting gallbladder motility: drugs; Marzio L; Various drugs and medications that inhibit or stimulate gallbladder contraction and basal tone in humans are described . Active gallbladder contraction may be achieved using synthetic hormones such as cholecystokinin, caerulein and motilin, cholinomimetic drugs such as bethanecol, prostigmine, and erythromycin due to its motilin-like effect . Furthermore, cisapride and cholestyramine, may have some excitatory activity on the gallbladder muscle . Intravenous amino acids also induce gallbladder contraction through the release of cholecystokinin . Inhibition of gallbladder contraction induced by a meal, or reduction of the basal fasting tone may be achieved by using atropine and other cholinergics, and by inhibitory hormones such as somatostatin, the nitric acid releaser arginine, the calcium channel antagonist nifedipine, and progesterone . Other drugs such as trimebutine, loperamide and ondansetron may negatively affect gallbladder contraction.

Biotechnol Lett, 2003 Jul, 25(14), 1175 - 8
Characterization and regulation of NADP+-isocitrate dehydrogenase from Saccharopolyspora erythraea; Alvarado A et al.; NADP+-Isocitrate dehydrogenase (ICDH) activity was detected in cell-free extracts of Saccharopolyspora erythraea CA340, an erythromycin producer . Apparent Km values for DL-isocitrate and NADP+ were 0.14 microM and 0.026 microM, respectively . ATP, ADP, GTP, citric acid, oxaloacetate, alpha-ketoglutarate, glyoxalate and glyoxalate plus oxaloacetate, each at 1 mM concentration, caused 50, 20 10, 50, 25, 60, 20 and 50% inhibition of ICDH activity, respectively . Phosphoenolpyruvate, fructose 1,6-diphosphate and pyruvate had no effect . ICDH specific activity profile was growth-associated and activity with dextrose or fructose as sole carbon source, was twice of that obtained with lactose.

Zh Mikrobiol Epidemiol Immunobiol, 2003 Jul-Aug, (4), 81 - 5
{Drug sensitivity of Ureaplasma urealyticum, persisting in patients with chronic inflammatory diseases of the urogenital tract}; Gamova NA; A total of 65 U . urealyticum cultures isolated from patients with chronic inflammatory diseases of the urogenital tract after their prolonged persistence of in the human body, were studied for sensitivity to medicinal preparations of different groups: tetracyclines (tetracycline and doxycycline), macrolids (erythomycin, clarithromycin, midecamycin, josamycin), quinolon (pefloxacin), amino glycoside (gentamicin), lincoamides (lincomycin, clindamycin) . The majority of isolated U . urealyticun were highly sensitive to josamycin, clacide, doxycycline (89.2, 84.6, 76/9% respectively), and somewhat lesser number of these organisms were highly sensitive to midecamycin and pefloxacin (51.3 and 44.4% respectively) . Among U . urealyticum strains circulating in the Moscow region some strains which persisted in patients with chronic inflammatory diseases of the urogenital tract for a long time were found to be resistant to erythromycin (23.1%), tetracycline (19.5%), and in very rare cases (1.6%) they were found to multiple drug resistance to all preparations under study . In view of the varying sensitivity of the clinical isolates of U . urealyticum to medicines and the presence of resistant forms in their population, the sensitivity of the isolated U . urealyticum should be determined in vitro prior to drug therapy.

Internist (Berl), 2003 May, 44(5), 519 - 28, 530-2
{Acute upper gastrointestinal hemorrhage . Diagnosis and management}; Nietsch H et al.; Upper gastrointestinal hemorrhage calls for a team approach . Early endotracheal intubation of unconscious patients helps to prevent aspiration . Erythromycin i.v . 20 min . before emergency endoscopy improves the diagnostic yield . Patients without increased risk of rebleeding may be treated on an outpatient basis . Band ligation is the gold standard for acute variceal bleeding . Terlipressin, somatostatin and octreotide are equally effective but require additional measures for prevention of late recurrence . Somatostatin and analogues used as adjunct to ligation slightly reduce the risk of rebleeding but not of death . Three to seven days of prophylactic antibiotics decrease the risk of uncontrolled or recurrent bleeding . Therapeutic failures are rescued by transjugular intrahepatic portosystemic shunting (TIPS) . Patients with nonvaricose bleeding should only be treated when active hemorrhage or a "visible vessel" is found . First line treatment is endoscopic injection of diluted adrenalin or isotonic saline . Thermal coagulation is an alternative . Tissue-destructing sclerosants should be avoided . Clipping and injection of fibrin glue are second and third line measures . Proton pump inhibitors improve endoscopic hemostasis, however, it is unclear whether high i.v . doses are required . H . pylori must be eradicated to prevent late recurrence . Rebleeding is treated endoscopically with angiographic intervention or surgery as rescue measures.

J Fish Dis, 2003 May, 26(5), 277 - 85
Uptake of erythromycin by first-feeding sockeye salmon, Oncorhynchus nerka (Walbaum), fed live or freeze-dried enriched adult Artemia or medicated pellets; Cook MA et al.; The potential to use adult Artemia to deliver erythromycin to first-feeding sockeye salmon, Oncorhynchus nerka (Walbaum), was investigated in three trials . In the first trial, first-feeding sockeye were fed live erythromycin enriched adult Artemia or pellets containing equal amounts of erythromycin for 35 days . At the end of the trial, tissue erythromycin concentration of the fish fed the live Artemia was significantly greater (P < 0.05, 25.52 +/- 1.29 microg mL(-1); mean +/- SEM), than the tissue concentration of the fish fed the pellets (0.72 +/- 0.01 microg mL(-1)) . In the second trial, first-feeding sockeye were fed either live or freeze-dried bioencapsulated erythromycin (adult Artemia) or pellets containing erythromycin daily for 21 days . Mean daily erythromycin concentration in fish fed the freeze-dried Artemia, live Artemia, or pellets did not differ significantly . In the third trial, apparent erythromycin digestibility was determined . Significantly more (P < 0.05) erythromycin was retained by juvenile sockeye fed freeze-dried bioencapsulated erythromycin (98.3 +/- 1.0%) compared with medicated pellets (89.2 +/- 1.7%) . Uptake of bioencapsulated erythromycin from adult Artemia (live or freeze-dried) appears to be greater than uptake from pellets . Freeze-dried and live Artemia were equally effective at delivery suggesting enriched freeze-dried adult Artemia could be produced into a highly palatable, consistent, off-the-shelf product.

J Pediatr Gastroenterol Nutr, 2003 Sep, 37(3), 281 - 6
Erythromycin fails to improve feeding outcome in feeding-intolerant preterm infants; ElHennawy AA et al.; OBJECTIVE: Approximately half of extremely low birth weight infants have feeding intolerance, which delays their achievement of full enteral feedings . Erythromycin, a motilin receptor agonist, triggers migrating motor complexes and accelerates gastric emptying in adults with feeding intolerance . Few studies have assessed the efficacy of this drug in preterm infants with established feeding intolerance . This study was designed to assess the efficacy of erythromycin in feeding-intolerant infants, as measured by gastric emptying, maturation of gastrointestinal motor patterns, and time to achieve full enteral feedings . METHODS: Subjects were 27 preterm infants who were admitted to the neonatal intensive care unit and who did not achieve full enteral feeding volumes (150 mL/kg/day) within 8 days of the initiation of feedings . In a controlled, randomized, double-blinded clinical trial, infants received intragastric erythromycin or placebo for 8 days without crossover . At study entry, the authors recorded motor activity in the antrum and the duodenum during fasting, in response to intragastric erythromycin (1.5 mg/kg) or placebo, and in response to feeding . Gastric emptying at 20 minutes and transit time from duodenum to anus were determined . Each infant then received erythromycin or placebo for 8 days, and feeding characteristics were prospectively tracked . RESULTS: Gastric emptying and characteristics of antroduodenal motor contractions were similar in the two groups, as were the transit times from duodenum to anus . Feeding outcomes were comparable in the two groups . CONCLUSION: Intragastric erythromycin does not improve feeding tolerance in preterm infants with established feeding intolerance because it fails to improve gastrointestinal function in the short or long term.

Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai), 2003 Sep, 35(9), 811 - 5
Involvement of dopamine D3 and neuropeptide Y Y5 receptors in diabetic gastroparetic rats without response to erythromycin; Qin XY et al.; Erythromycin may accelerate gastric emptying in animals and human probably as an motilin agonist, but its prokinetic effects show obvious individual disparity . This study was to find the mechanism of this phenomenon . Microarray analysis was used to screen genes that might be involved in the response of diabetic gastroparesis rats to erythromycin . It was found that erythromycin accelerated gastric emptying of diabetic rats with great individual disparity . Through microarray analysis we screened differential expression genes that might be involved in the effect of erythromycin . Among 10 genes screened out, dopamine D3 receptor (DRD3) and neuropeptide Y Y5 receptor (NPYY5) genes were submitted to RT-PCR quantification and showed consistent results with microarray . It can be concluded that erythromycin promote gastric emptying of gastroparetic rats; DRD3 and NPYY5 may be involved in prokinetic action of erythromycin; and targets other than motilin receptor of erythromycin might exist as prokinetics.

FASEB J, 2003 Sep, 17(12), 1736 - 8 Epub 2003 Jul 03.
Genomic characterization and regulation of CYP3a13: role of xenobiotics and nuclear receptors; Anakk S et al.; We report that CYP3a13 gene, located on mouse chromosome 5, spans 27.5 Kb and contains 13 exons . The transcription start site is 35 bp upstream of the coding region and results in a 109 bp 5' untranslated region . CYP3a13 promoter shows putative binding sites for retinoid X receptor, pregnane X receptor, and estrogen receptor . CYP3a13 shows a broad tissue distribution with predominant expression in liver . Although CYP3a13 shares 92% nucleotide identity with the female-specific rat CYP3A9, its expression does not exhibit sexual dimorphism . Ligand activation of peroxisomal proliferator-activated receptor-gamma and retinoid X receptor inhibit expression of CYP3a13 at the transcription level in a tissue-specific manner . Another novel finding is hepatic induction of CYP3a13 by dexamethasone occurring only in pregnane X receptor null mice . We also report that pregnane X receptor is essential to maintain robust in vivo basal levels of CYP3a13 in contrast to CYP3a11 . CYP3a13 protein expressed in vitro can metabolize clinically active drugs ethylmorphine and erythromycin, as well as benzphetamine . We conclude that CYP3a13 is regulated differentially by various nuclear receptors . In humans this may lead to altered drug metabolism, as many of the newly synthesized ligands/drugs targeted toward these nuclear receptors could influence CYP3A gene expression.

Acta Pharmacol Sin, 2003 Sep, 24(9), 903 - 6
P-glycoprotein restricted transport of nimodipine across blood-brain barrier; Zhang L et al.; AIM: To examine whether the transport of nimodipine (NMD) from the circulating blood into the brain is restricted by P-glycoprotein (P-gp) in rat brain capillary endothelial cells (BCEC) . METHODS: When cells reached confluence, a time course of NMD uptake was recorded by incubation with a medium containing NMD 10 mg/L at 37 degrees C . Effects of various agents in the steady-state uptake of NMD were tested by co-administration with NMD and each compound to cells at 37 degrees C for 90 min . The uptake of NMD was measured for 90 min . Effects of P-gp inhibitors on the efflux of NMD from primary cultured BCEC were studied by administration of erythromycin, clarithromycin, cyclosporin A (CsA), and Hanks' solution after the accumulation of NMD by BCEC at 37 degrees C for 90 min . RESULTS: The uptake of NMD by primary cultured rat BCEC was time-dependent, and the steady-state uptake of NMD was increased in the presence of several substrates of P-gp in BCEC . The steady-state uptake was also significantly increased (P<0.01) when cellular ATP was depleted by treatment with sodium azide . Furthermore, efflux of NMD from BCEC was inhibited by erythromycin,clarithromycin, and CsA . CONCLUSION: The permeability of NMD into the brain is restricted by P-gp and increased by co-administration with P-gp inhibitors.

J Pharm Pharmacol, 2003 Aug, 55(8), 1163 - 7
Effects of the aqueous extract from Salvia miltiorrhiza Bge on the pharmacokinetics of diazepam and on liver microsomal cytochrome P450 enzyme activity in rats; Jinping Q et al.; The aim of this study was to determine the effects of the aqueous extract of Salvia miltiorrhiza Bge (danshen in Chinese) on the pharmacokinetics of diazepam and on liver microsomal cytochrome P450 enzyme activity in rats . Rats (n = 5) were pretreated with danshen extract (100 mg kg(-1) per day, p.o.) for 15 consecutive days . Control rats (n = 5) received saline at the same time . Each rat was then administered a single oral dose of 15 mg kg(-1) diazepam . The pharmacokinetic parameters of diazepam were significantly different between the two groups . In the danshen pretreated group, the maximum concentration of diazepam and the area under the plasma concentration-time curve were reduced to about 72.7% and 44.4%, respectively, while the total body clearance was markedly increased by 2-fold . To help explain the results, liver microsomal suspensions were obtained from rats that were randomly divided into the control group (n = 10), and the low- (20 mg kg(-1) for 15 days, p.o., n = 10) and high-dose groups (100 mg kg(-1) for 15 days, p.o., n = 10) pretreated with danshen extract . Compared with the control rats, the microsomal protein content, cytochrome P450 enzyme level and erythromycin N-demethylase activity of pretreated rats were significantly increased . These results indicate that danshen extract can stimulate the activity of cytochrome P450 isoforms, and changes in the pharmacokinetics of diazepam resulting from danshen extract are related to an increase in metabolic activity of cytochrome P450.

BMC Pediatr . 2003 Sep 04;3(1):10.
Failure of erythromycin to eliminate airway colonization with ureaplasma urealyticum in very low birth weight infants; Baier RJ et al.; BACKGROUND: Airway colonization of mechanically ventilated very low birth weight infants (birth weight < 1500 grams) by Ureaplasma urealyticum (Uu) is associated with an increased risk of bronchopulmonary dysplasia (BPD) . While Uu is sensitive to erythromycin in vitro, the efficacy of intravenous (IV) erythromycin to eliminate Uu from the airways has not been studied . METHODS: 17 very low birth weight infants with Uu positive tracheal aspirate (TA) cultures were randomized to either 5 (8 infants) or 10 days (9 infants) of IV erythromycin lactobionate (40 mg/kg/day in 3 divided doses) . Tracheal aspirate cultures for Uu were performed on days 0, 5, 10 and 15 . RESULTS: Intravenous erythromycin failed to eliminate airway colonization in a large proportion of infants regardless of whether they received 5 or 10 days of treatment . Ureaplasma urealyticum was isolated from 4/15 (27%) of TAs obtained at 5 days, 5/12 TAs (42%) obtained at 10 days and 6/11(55%) TAs obtained at 15 days (combined group data) . CONCLUSIONS: Erythromycin administered IV does not eliminate Uu from the airways in a large proportion of infants . Failure of erythromycin to eliminate Uu from the airways may contribute to the lack of efficacy of this drug in reducing the incidence of BPD in very low birth weight infants.

J Chromatogr B Analyt Technol Biomed Life Sci, 2003 Sep 5, 794(2), 293 - 302
Analysis of erythromycin and benzoylperoxide in topical gels by liquid chromatography; Dehouck P et al.; Gels containing a combination of erythromycin and benzoylperoxide are frequently used in the treatment of acne vulgaris . A method was developed to determine the content of both erythromycin and benzoylperoxide in these gels . Erythromycin was extracted from the gel in conditions where the oxidative power of benzoylperoxide was neutralised by addition of ascorbic acid and this extract was analysed on an Xterra RP(18) column, with a mobile phase containing acetonitrile-0.2 M K2HPO4-water (35:5:60, v/v/v) . The detection wavelength was 215 nm . A second extraction procedure was developed for the analysis of benzoylperoxide . The extraction solution was analysed on a Hypersil C(18) BDS column and a mobile phase containing acetonitrile-water (58:42, v/v) . Detection was performed at 254 nm . The flow rate was 1.0 ml/min in both methods . The selectivity, repeatability, linearity and recovery of both methods were examined . Special attention was given to determination of the recovery and the uncertainty on the recovery . This allowed evaluation of the bias of the extraction method . The method developed was used to examine the stability of a gel for topical use.

Eur J Pharmacol, 2003 Aug 15, 475(1-3), 93 - 7
Electrophysiological effects of erythromycin, but lack of mechanical effects, in airway smooth muscle; Janssen LJ et al.; The antibiotic erythromycin has been shown to modulate a variety of electrophysiological and mechanical responses in many cell types . We investigated whether it did so in airway smooth muscle using standard patch clamp, fura-2 fluorimetric and organ bath techniques . Erythromycin (10(-4) M) evoked a small transient inward current with reversal potential and time-course similar to that of the Ca2+-dependent Cl- currents seen in these cells . Unlike its effects in other cell types, however, it did not alter basal {Ca2+}i, voltage-dependent Ca2+ currents, nor mechanical tone at rest, nor the corresponding responses to cholinergic stimulation (membrane currents; release of internally sequestered Ca2+, nor contractions evoked by neural stimulation or exogenously added cholinergic agonist) . In conclusion, erythromycin does exert interesting electrophysiological actions in airway smooth muscle, but does not alter mechanical activity as it has been shown to do elsewhere.

J Clin Pharmacol, 2003 Aug, 43(8), 831 - 9
Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice; Veronese ML et al.; Consumption of typical quantities of grapefruit juice (GFJ) increases the oral bioavailability of several CYP3A4 substrates without affecting their elimination, consistent with selective inhibition of intestinal but not hepatic CYP3A4 . However, increases in the AUCs of CYP3A4 substrates recently associated with the consumption of large amounts of GFJ were similar to those observed with potent inhibitors of hepatic CYP3A4 . The current study compared the effects of consuming large quantities and more typical amounts of GFJ on the activity of hepatic and intestinal cytochrome P450 3A4 in vivo, employing the erythromycin breath test (EBT) and oral midazolam pharmacokinetics . This was a two-phase, randomized, placebo-controlled crossover study, with each phase conducted with a separate panel of subjects . In Phase I, 8 male volunteers were randomized to the order of receiving one glass (240 mL) of water (placebo) or double-strength (DS) GFJ tid for 2 days and then 90, 60, and 30 minutes prior to administration of probe drugs on the 3rd day . In Phase II, 16 male volunteers were randomized to the order of receiving one glass of (1) single-strength (SS) GFJ, (2) DS GFJ, and (3) water (placebo) . All treatments were administered in a fasted state . There was at least a 7-day washout period between treatments . Probe drugs, administered 30 minutes or 1 hour following each treatment in Phase I or II, respectively, consisted of oral midazolam (2 mg) coadministered with IV {14G N-methyl} erythromycin (0.03 mg) . The EBT was performed 20 minutes following erythromycin administration . Blood was collected during the 24 hours following probe drug administration for the analysis of midazolam pharmacokinetics . In Phase I, consumption of one glass of DS GFJ tid for 3 days increased the Cmax of midazolam 3-fold, the AUC 6-fold, and the t1/2 2-fold and decreased the amount of exhaled 14CO2 in all 8 subjects, with a mean decrease in EBT of 18% . In Phase II, consumption of one glass of DS GFJ significantly increased the AUC and Cmax of midazolam approximately 2-fold without a significant effect on the t1/2 of midazolam or the EBT . The effects of consuming one glass of SS GFJ on midazolam pharmacokinetics and the EBT were not significantly different from those of one glass of DS GFJ . It was concluded that consumption of one glass of DS GFJ tid for 3 days significantly increased the AUC, Cmax, and t1/2 of midazolam and reduced EBT values, reflecting inhibition of both hepatic and intestinal CYP3A4 . In contrast, consumption of one glass of SS or DS GFJ increased midazolam AUC and Cmax, with little effect on the midazolam t1/2 and EBT values, reflecting preferential inhibition of intestinal CYP3A4 . Alterations of midazolam AUC and Cmax induced by nine glasses of DS GFJ were significantly greater than those produced by one glass of SS or DS GFJ . These data suggest that GFJ inhibits intestinal and hepatic CYP3A4 in an exposure-dependent fashion and that patients taking medications that are CYP3A4 substrates are at risk for developing drug-related adverse events if they consume large amounts of grapefruit juice.

Digestion, 2003, 68(1), 41 - 8 Epub 2003 Aug 29.
Inhibition of cytochrome P450 3A: relevant drug interactions in gastroenterology; Sagir A et al.; Cytochrome P450 3A (CYP3A) is involved in biotransformation of more than half of all drugs currently available . Drug interactions by inhibition of CYP3A are of major interest in patients receiving combinations of drugs . Some interactions with CYP3A inhibitors also involve inhibition of the multidrug export pump, P-glycoprotein . An increasing number of adverse drug reactions might be avoided on the basis of knowledge about CYP3A substrates and inhibitors . This article summarizes some examples of such interactions relevant to gastroenterologists . Serious cases by coadministration of CYP3A inhibitors resulting in acute hepatitis, hypotension, rhabdomyolyis, torsade de pointes, sedation, or ergotism are presented: interactions with azole antifungals (ketoconazole, itraconazole, fluconazole), HIV protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir), macrolide antibiotics (clarithromycin, erythromycin), and grapefruit juice . In addition, 1 case is reported who presented the highest trough levels of the CYP3A substrate budesonide in serum ever measured . Practitioners have to be aware of the high potential of metabolic drug interactions when they prescribe a CYP3A inhibitor . It is wise to check carefully comedication in patients complaining of side effects with substrates of CYP3A .

Dev Med Child Neurol, 2003 Sep, 45(9), 634 - 7
Acute bilateral thalamic necrosis in a child with Mycoplasma pneumoniae; Ashtekar CS et al.; A previously neurodevelopmentally intact 5-year-old male was admitted to hospital with a right lower lobe pneumonia with pleural effusion, subsequently confirmed to be a Mycoplasma pneumoniae infection . On the seventh day of the illness he had a prolonged generalized tonic or tonic-clonic convulsion, requiring intubation and ventilation . He was slow to regain consciousness (Child's Glasgow Coma Score 7-10 over 6 days) and brain imaging with CT and then MRI demonstrated bilateral thalamic lesions with oedema and central haemorrhage suggestive of acute bilateral thalamic necrosis, without striatal or white-matter involvement . He was treated with a 2-week course of erythromycin, and as an autoimmune process was considered possible, 5 days of intravenous methylprednisolone (20 mg/kg/day) followed by a 4-week oral prednisolone taper . He made a slow recovery over the next few weeks with almost complete neurological recovery by 2 months but with significant dysarthria, drooling, and a mild left hemiparesis . At 9 months, significant dystonia continued to affect his speech and, together with tremor, his upper-limb fine motor function bilaterally . His gait, personality, and higher cognitive functions appeared to have recovered fully . Although acute striatal necrosis, acute disseminated encephalomyelitis, and encephalitis have been reported with Mycoplasma pneumoniae and a similar picture of acute bilateral thalamic necrosis with influenza-A ('acute necrotizing encephalopathy'), this is the first reported case of Mycoplasma pneumoniae-associated isolated acute bilateral thalamic necrosis.

Sichuan Da Xue Xue Bao Yi Xue Ban, 2003 Apr, 34(2), 322 - 4
{An experimental study of gastric pacing on postsurgical gastric dynamic dysfunction}; Li F et al.; OBJECTIVE: To probe the feasibility and curative effect of gastric pacing on postsurgical gastric dynamic dysfunction . METHODS: Thirty-two rabbits were divided into four groups . The gastric dynamic indices of applying gastric pacing to the experimental animal model of acute post-vagotomy gastroparesis were compared with those of the groups treated with erythromycin (1 mg/kg) . RESULTS: The measurements of "gastroduodenal pressure at different sites" of the gastric pacing group and erythromycin group were higher than those of the before pacing group respectively (P < 0.001) . The gastric pressure of the gastric pacing group was higher than that of the erythromycin group (P < 0.001) . No significant difference in the duodenal pressure was observed between the above two groups (P > 0.05) . The measurements of pressure at different sites (gastric fundus; gastric corpus; gastric antrum) after stopping pacing were higher than those of the erythromycin group, respectively (P < 0.01, P < 0.05, P < 0.05) . The "pressure gradient between gastric antrum and duodenum" of the gastric pacing group was higher than that of the erythromycin group (P < 0.01) . The gastric emptying rate of the gastric pacing group (64.41% +/- 6.66%) was significantly higher than that of the erythromycin group (53.73% +/- 7.09%) (P < 0.01) . CONCLUSION: Applying higher frequency gastric pacing can markedly enhance the gastric pressure, the pressure gradient between gastric antrum and duodenum, and the gastric emptying rate.

Drugs Today (Barc), 2003 Jun, 39(6), 451 - 68
Rupatadine: a new selective histamine H1 receptor and platelet-activating factor (PAF) antagonist . A review of pharmacological profile and clinical management of allergic rhinitis; Izquierdo I et al.; Rupatadine is a new agent for the management of diseases with allergic inflammatory conditions, such as seasonal and perennial rhinitis . The pharmacological profile of rupatadine offers particular benefits in terms of a strong antagonist activity towards both histamine H1 receptors and platelet-activating factor (PAF) receptors . Rupatadine has a rapid onset of action, and its long-lasting effect (>24 h) permits once-daily dosing . Rupatadine should not be used in combination with the cytochrome P450 inhibitors, such as erythromycin or ketoconazole, due to an increase in AUC and Cmax for rupatadine, although no clinically relevant adverse events have been reported . In addition, rupatadine, at the recommended dose of 10 mg, has been shown to be free of sedative effects and not to cause significant changes in the corrected QT interval in special populations, including the elderly, nor when coadministered with erythromycin or ketoconazole . Preclinical data have also shown that rupatadine and its main active metabolites did not interfere with cloned human HERG channel and did not affect in vitro isolated dog Purkinje fibers at concentrations at least 2000 times greater than those obtained with therapeutic doses in humans . Rupatadine is clinically effective in relieving symptoms in patients with seasonal and perennial allergic rhinitis . Newly published data on its efficacy and safety suggest that this compound may improve the nasal and non-nasal symptoms in comparison to other currently available second generation H1 receptor antihistamines . 2003 Prous Science . All rights reserved.

Toxicol Sci, 2003 Nov, 76(1), 220 - 8 Epub 2003 Aug 27.
Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats; Kostrubsky VE et al.; Inhibition of canalicular bile acid efflux by medications is associated with clinical liver toxicity, sometimes in the absence of major liver effects in experimental species . To predict the hepatotoxic potential of compounds in vitro and in vivo, we investigated the effect of clinical cholestatic agents on {3H}taurocholic acid transport in regular and collagen-sandwich cultured human hepatocytes . Hepatocytes established a well-developed canalicular network with bile acid accumulating in the canalicular lumen within 15 min of addition to cells . Removing Ca2+ and Mg2+ from the incubation buffer destroyed canalicular junctions, resulting in bile acid efflux into the incubation buffer . Canalicular transport was calculated based on the difference between the amount of bile acid effluxed into the Ca/Mg2+-free and regular buffers with linear efflux up to 10 min . Hepatocytes cultured in the nonsandwich configuration also transported taurocholic acid, but at 50% the rate in sandwiched cultures . Cyclosporin A, bosentan, CI-1034, glyburide, erythromycin estolate, and troleandomycin inhibited efflux in a concentration-dependent manner . In contrast, new generation macrolide antibiotics with lower incidence of clinical hepatotoxicity were much less potent inhibitors of efflux . An in vivo study was conducted whereby glyburide or CI-1034, administered iv to male rats, produced a 2.4-fold increase in rat total serum bile acids . A synergistic 6.8-fold increase in serum total bile acids was found when both drugs were delivered together . These results provide methods to evaluate inhibitory effects of potentially cholestatic compounds on bile-acid transport, and to rank compounds according to their hepatotoxic potential.

Br J Gen Pract, 2003 Jun, 53(491), 480 - 7
A systematic review and meta-analysis of treatments for impetigo; George A et al.; BACKGROUND: Impetigo is a common clinical problem seen in general practice . Uncertainty exists as to the most effective treatment, or indeed if treatment is necessary . AIM: To determine the most effective treatment for impetigo in a systemically well patient . DESIGN OF STUDY: Systematic review and meta-analysis . METHOD: Databases were searched for relevant studies . The Cochrane highly sensitive randomised controlled trial (RCT) search string was employed and combined with the word 'impetigo' as the MeSH term and keyword . The bibliographies of relevant articles were searched for additional references . RCTs that were either double- or observer-blind, and involved systemically well patients of any age in either primary or secondary care settings, were included . Studies that selected patients on the basis of skin swab results were excluded, as were studies that were not in English . Cure or improvement of impetigo reported at seven to 14 days from start of treatment was the primary outcome measure . Meta-analysis was performed on homogeneous studies . RESULTS: Three hundred and fifty-nine studies were identified, of which 16 met the inclusion criteria . Meta-analysis demonstrated that topical antibiotics are more effective than placebo (odds ratio {OR} = 2.69, 95% confidence interval {CI} = 1.49 to 4.86) . There is weak evidence for the superiority of topical antibiotics over some oral antibiotics, such as erythromycin (OR = 0.48, 95% CI = 0.23 to 1.00) . There is no significant difference between the effects of mupirocin and fusidic acid (OR = 1.76, 95% CI = 0.77 to 4.03) . CONCLUSION: This review found limited high-quality evidence to inform the treatment of impetigo . From that which is available, we would recommend the use of a topical antibiotic for a period of seven days in a systemically well patient with limited disease . Further research is needed on the role of flucloxacillin and non-antibiotic treatments for impetigo.

J Antibiot (Tokyo), 2003 Jun, 56(6), 543 - 51
A novel erythromycin, 6-desmethyl erythromycin D, made by substituting an acyltransferase domain of the erythromycin polyketide synthase; Petkovic H et al.; The acyltransferase (AT) domain in module 4 of the erythromycin polyketide synthase (PKS) was substituted with an AT domain from the rapamycin PKS module 2 in order to alter the substrate specificity from methylmalonyl-CoA to malonyl-CoA . The resulting strain produced 6-desmethyl erythromycin D as the predominant product . This AT domain swap completes the library of malonyl-CoA AT swaps on the erythromycin PKS and reinforces PKS engineering as a robust and generic tool.

Genetics, 2003 Aug, 164(4), 1345 - 53
Molecular markers for rapidly identifying candidate genes in Chlamydomonas reinhardtii . Ery1 and ery2 encode chloroplast ribosomal proteins; Bowers AK et al.; To take advantage of available expressed sequence tags and genomic sequence, we have developed 64 PCR-based molecular markers in Chlamydomonas reinhardtii that map to the 17 linkage groups . These markers will allow the rapid association of a candidate gene sequence with previously identified mutations . As proof of principle, we have identified the genes encoded by the ERY1 and ERY2 loci . Mendelian mutations that confer resistance to erythromycin define three unlinked nuclear loci in C . reinhardtii . Candidate genes ribosomal protein L4 (RPL4) and L22 (RPL22) are tightly linked to the ERY1 locus and ERY2 locus, respectively . Genomic DNA for RPL4 from wild type and five mutant ery1 alleles was amplified and sequenced and three different point mutations were found . Two different glycine residues (G(102) and G(112)) are replaced by aspartic acid and both are in the unstructured region of RPL4 that lines the peptide exit tunnel of the chloroplast ribosome . The other two alleles change a splice site acceptor site . Genomic DNA for RPL22 from wild type and three mutant ery2 alleles was amplified and sequenced and revealed three different point mutations . Two alleles have premature stop codons and one allele changes a splice site acceptor site.

Auris Nasus Larynx, 2003 Aug, 30(3), 247 - 51
Modulation of neutrophil adhesion to vascular endothelial cells in rat experimental otitis media treated with a macrolide; Enomoto F et al.; OBJECT: We previously reported that erythromycin (EM) affected the adhesion molecules that interact with neutrophils and inhibited neutrophil infiltration in a rat experimental otitis media model . PURPOSE: The purpose of the present study was to examine whether EM affects the adhesion of rat neutrophils to endothelial cells . METHODS: The adhesion of neutrophils to WK-5 endothelial cells was evaluated . One group of rats was given EM for 2 weeks, while the other group received no treatment . The adhesion of peripheral-blood neutrophils and neutrophils accumulated in the middle ear from these two groups were compared . RESULTS: Two-week EM pretreatment inhibited adhesion of neutrophils to WK-5 cells . The adhesion of neutrophils accumulated in the middle ear cavity to WK-5 cells was significantly higher than that of peripheral-blood neutrophils from control rats . CONCLUSION: The results suggest that EM affects the adhesion of neutrophils to endothelial cells.

Acta Chir Belg, 2003 Jun, 103(3), 338 - 9
Delayed gastric emptying after pancreatoduodenectomy; Closset J et al.; With pylorus-preserving pancreatoduodenectomy (PPPD) the goal is to reduce long-term morbidities such as gastric dumping, marginal ulceration or bile-reflux gastritis . Compared with te classical Whipple procedure, PPPD is affected by an equal postoperative morbidity but is known to induce delayed gastric emptying (DGE) . It is difficult to evaluate the true incidence of DGE after PPPD (from 5 to 50% according to the literature) . Early and low doses of erythromycin in the postoperative period could prevent the onset of DGE and the administration of cisapride 15 mg/day improves gastric emptying up to 6 months after PPPD.

Gut, 2003 Sep, 52(9), 1271 - 7
Assessment of meal induced gastric accommodation by a satiety drinking test in health and in severe functional dyspepsia; Tack J et al.; AIMS: Impaired gastric accommodation is a major pathophysiological mechanism in functional dyspepsia . The aim of the present work was to assess a satiety drinking test in the evaluation of accommodation in health and dyspepsia . METHODS: Twenty five controls and 37 severely dyspeptic patients seen at a tertiary care centre completed a dyspepsia questionnaire, and gastric emptying and gastric barostat studies . The amount of liquid meal ingested at maximum satiety during a slow satiety drinking test was determined . In controls, we studied the influence of caloric density and of pharmacological agents that influence accommodation . RESULTS: In patients, satiety scores were higher and maximum satiety occurred at lower calories (542 (50) v 1508 (53) kcal; p<0.0001) . Six patients had required nutritional support, but excluding these did not alter the correlations . With increasing severity of early satiety, less calories were ingested at maximum satiety . In multivariate analysis, the amount of calories was significantly correlated to accommodation but not to gastric emptying or sensitivity . Sensitivity and specificity of the satiety test in predicting impaired accommodation reached 92% and 86%, respectively . At different caloric densities, ingested volume rather than caloric load determined maximum satiety . Pharmacological agents (sumatriptan, cisapride, erythromycin) affected the satiety test according to their effect on accommodation . CONCLUSION: A slow caloric drinking test can be used to evaluate accommodation and early satiety . It provides a non-invasive method of predicting impaired accommodation and quantifying pharmacological influences on accommodation.

Vet Res, 2003 Jul-Aug, 34(4), 405 - 11
In vitro formation of metabolic-intermediate cytochrome P450 complexes in rabbit liver microsomes by tiamulin and various macrolides; Carletti M et al.; Tiamulin and a number of macrolides were evaluated as to their ability in forming metabolic-intermediate (MI) complexes with cytochrome P450 in liver microsomes from rabbits bred for meat production . Complex formation, which occurred only in preparations where the expression of P450 3A was increased as the result of rifampicin pre-treatment and with different kinetics, was in the order tiamulin > erythromycin > TAO approximately roxithromycin approximately tylosin and did not take place with tilmicosin and spiramycin . Most of the tested compounds underwent an oxidative N-dealkylation and a good relationship could be found between the rate of N-dealkylase activity in induced preparations and the aptitude in generating MI complexes . Although the results from in vitro studies should be interpreted with caution, it is suggested that the potential for in vivo drug interactions also exists in the rabbit for tiamulin and for four out of the six tested macrolides.

J Pharm Pharmacol, 2003 Jul, 55(7), 995 - 1002
Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide; Hanada E et al.; Disopyramide, a class Ia antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent . In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide . We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study . Action potentials and membrane potassium currents, including delayed rectifier current (I(K)) and transient outward current (I(to)), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells . Erythromycin and disopyramide prolonged APD in a concentration-dependent manner . Disopyramide (10-100 microM) and erythromycin (100 microM) led to increases in the APD at 90% repolarization level . Disopyramide reduced I(K) (IC50 = 37.2 +/- 0.17 microM) and I(to) (IC50 = 20.9 +/- 0.13 microM) while erythromycin reduced I(K) (IC50 = 60.1 +/- 0.29 microM) but not I(to) . The observed prolongation of APD might be ascribed to the inhibition of potassium currents . Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells . The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions . However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions . Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.

Pediatr Res, 2003 Oct, 54(4), 441 - 5 Epub 2003 Aug 06.
Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain; Hanko E et al.; P-glycoprotein (P-gp) is an ATP-dependent integral plasma membrane efflux pump, expressed in abundance in brain capillary endothelial cells and astrocytes . P-gp contributes to the blood-brain barrier in limiting the influx and retention of a variety of lipophilic compounds, including unconjugated bilirubin . Several drugs block P-gp function and thereby enhance intracellular accumulation of P-gp substrates . In this study we proposed that pretreatment with drugs known to inhibit P-gp function in clinically relevant doses would alter the uptake of bilirubin in the brain of 32- to 36-d-old rats . In the first arm of the study, the animals received pretreatment with an i.v . infusion of either propanolol, erythromycin, verapamil, ceftriaxone, rifampin, or saline, 10 min before an i.v . bolus of 50 mg/kg bilirubin was given . Except for the erythromycin-treated rats, all treatment groups had significantly higher brain-to-serum bilirubin ratios than control animals (p < 0.05, Welch's t test) . In the second arm of the study, treatment with either ceftriaxone or rifampin or saline i.v . preceded a 50 mg/kg i.v . bolus of radioactive bilirubin . Analysis of seven different brain regions by scintillation counting showed that the distribution patterns differed significantly between the study groups (p < 0.001, ANOVA), however, not in accordance with a kernicteric staining pattern . Because of limited knowledge of expression and function of P-gp and other membrane transport proteins in the newborn, the implications of this study remain to be seen . We speculate that drugs known to inhibit P-gp function may increase the risk of bilirubin encephalopathy in the hyperbilirubinemic infant.

Microbiology, 2003 Aug, 149(Pt 8), 2213 - 25
A specific role of the Saccharopolyspora erythraea thioesterase II gene in the function of modular polyketide synthases; Hu Z et al.; Bacterial modular polyketide synthase (PKS) genes are commonly associated with another gene that encodes a thioesterase II (TEII) believed to remove aberrantly loaded substrates from the PKS . Co-expression of the Saccharopolyspora erythraea ery-ORF5 TEII and eryA genes encoding 6-deoxyerythronolide B synthase (DEBS) in Streptomyces hosts eliminated or significantly lowered production of 8,8'-deoxyoleandolide {15-nor-6-deoxyerythronolide B (15-nor-6dEB)}, which arises from an acetate instead of a propionate starter unit . Disruption of the TEII gene in an industrial Sac . erythraea strain caused a notable amount of 15-norerythromycins to be produced by utilization of an acetate instead of a propionate starter unit and also resulted in moderately lowered production of erythromycin compared with the amount produced by the parental strain . A similar behaviour of the TEII gene was observed in Escherichia coli strains that produce 6dEB and 15-methyl-6dEB . Direct biochemical analysis showed that the ery-ORF5 TEII enzyme favours hydrolysis of acetyl groups bound to the loading acyl carrier protein domain (ACP(L)) of DEBS . These results point to a clear role of the TEII enzyme, i.e . removal of a specific type of acyl group from the ACP(L) domain of the DEBS1 loading module.

Adv Neonatal Care, 2002 Feb, 2(1), 27 - 36
A matched cohort study of feeding practice guidelines for infants weighing less than 1,500 g; Premji SS et al.; PURPOSE: To evaluate the efficacy and safety of clinical practice guidelines (CPG) for the nutritional management of infants weighing < 1,500 g . SUBJECTS: Infants weighing < 1,500 g (n = 200) admitted to the NICU who had no major congenital anomalies were enrolled . DESIGN AND METHODS: A before-and-after matched cohort study was conducted during 1996/1997 and 1998/1999 enrolling infants in a Standard Practice (SP) group and CPG group, respectively . Weight-stratified CPG were introduced between these 2 study periods . Data on the first 100 babies who could be matched for birth weight and gestational age were analyzed . Data collection continued until full feedings were established and tolerated for 48 hours or the infant was discharged from the hospital, whichever came first . PRIMARY OUTCOME MEASURE: Of the 200 infants in the study (median gestational age 28 weeks), 142 infants attained full feedings . The median time to full feedings was 15 days in both groups, and a paired sample t test showed no significant difference between the 2 groups (P = 0.35) . PRINCIPAL RESULTS: No statistically significant differences in the age of feeding commencement, number of feeding interruptions, days on total parenteral nutrition, days to regain birth weight, age at discharge, incidence of sepsis, necrotizing enterocolitis, or use of erythromycin were found . CONCLUSIONS: The CPG was a safe alternative to standardize nutritional practices in the NICU . The lack of differences between groups shown in this study is likely related to gut immaturity limiting the infant's response to changes in feeding practices, inconsistent use of the guidelines, confounding factors, the small sample size, or the similarity between SP and the CPG.

Zhonghua Jie He He Hu Xi Za Zhi, 2003 Apr, 26(4), 206 - 9
{The effects of erythromycin on the secretion of tumor necrosis factor-alpha and transforming growth factor-beta1 and expression of connexin 43 in human pleural mesothelial cells}; Huang JQ et al.; OBJECTIVES: To investigate the effects of erythromycin on secretion of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(1) (TGF-beta(1)), and the level of connexin 43 in human pleural mesothelial cells (HPMC), and to explore the mechanism of pleurodesis . METHODS: HPMC was incubated with erythromycin at concentrations of 100 mg/L or 25 mg/L . The levels of TNF-alpha and TGF-beta(1) in the supernatants were measured by ELISA method, and levels of connexin 43 were detected by Western blot . RESULTS: The secretion of TNF-alpha by HMPC increased after incubation with 100 mg/L erythromycin for 3 or 5 days, and the secretion of TGF-beta(1) increased markedly after incubation with lower or higher concentrations of erythromycin . The levels of connexin 43 in HPMC decreased after stimulation with 100 mg/L erythromycin, but no relationship was observed between the levels and the stimulation time . CONCLUSIONS: HPMC incubated with erythromycin showed increased secretion of TNF-alpha and TGF-beta(1), which may be one of the mechanisms for erythromycin pleurodesis . Erythromycin decreased the level of connexin 43 in HPMC, and this effect may be a response of the cells to the stimulus . A high concentration of erythromycin is suggested for clinical pleurodesis based on the results from this study.

Biotechnol Bioeng, 2003 Sep 30, 83(7), 810 - 20
Artificial regulatory networks and cascades for discrete multilevel transgene control in mammalian cells; Kramer BP et al.; Prototype drug-adjustable heterologous transcription control systems designed for gene therapy applications typically show sigmoid dose-response characteristics and enable fine-tuning of therapeutic transgenes only within a narrow inducer concentration range of a few nanograms . However, the design of clinical dosing regimes which achieve tissue-specific concentrations with nanogram precision is yet a "mission impossible." Therefore, most of today's transcription control systems operate as ON/OFF switches and not in a true adjustable mode . The availability of robust transcription control configurations which lock expression of a single therapeutic transgene at desired levels in response to fixed clinical doses of different inducers rather than minute concentration changes of a single inducer would be highly desirable . Based on in silico predictions, we have constructed a variety of mammalian artificial regulatory networks by interconnecting the tetracycline- (TET(OFF)), streptogramin- (PIP(OFF)), and macrolide- (E(OFF)) repressible gene regulation systems as linear (auto)regulatory cascades . These networks enable multilevel expression control of several transgenes in response to different antibiotics or allow titration of a single transgene to four discrete expression levels by clinical dosing of a single antibiotic: 1) high expression in the absence of any antibiotic (+++), 2) medium level expression following addition of tetracycline (++), 3) low level expression in response to the macrolide erythromycin (+), and 4) complete repression by streptogramins such as pristinamycin (-) . The first-generation artificial regulatory networks exemplify modular interconnections of different heterologous gene regulations systems to achieve multigene expression, fine-tuning, or to design novel control networks with unprecedented transgene regulation properties . Such higher-level transcription control modalities will lead the way towards composite artificial regulatory networks able to effect complex therapeutic interventions in future gene therapy and tissue engineering scenarios .

Transplantation, 2003 Jul 27, 76(2), 358 - 63
Relationship between postoperative erythromycin breath test and early morbidity in liver transplant recipients; Schmidt LE et al.; BACKGROUND: Interindividual variability in dosage requirements of the calcineurin inhibitor immunosuppressive agents cyclosporine and tacrolimus after liver transplantation may result from differences in the CYP3A activity of the liver graft . Early postoperative erythromycin breath test (ERMBT) is an in vivo measure of graft CYP3A activity . This study evaluates the usefulness of an early postoperative ERMBT in predicting early morbidity in liver transplant recipients . METHODS: In 26 liver transplant recipients, ERMBT was performed within 2 hr after transplantation . Main end points were the occurrence of cyclosporine and tacrolimus nephrotoxicity, episodes of early graft rejection, early graft function, and graft survival . RESULTS: Cyclosporine and tacrolimus nephrotoxicity were associated with low postoperative ERMBT values (mean 0.63%+/-0.25% 14C/hr vs . 1.35%+/-0.84% 14C/hr, P=0.02) . No significant association between early graft rejection and ERMBT values was demonstrated . There was a significant inverse correlation between postoperative ERMBT values and the time to normalization of international normalized ratio as a measure of early graft function (r=-0.78, P<0.001) . Graft loss was associated with low postoperative ERMBT values (0.21%+/-0.15% 14C/hr vs . 1.09%+/-0.72% 14C/hr, P=0.002) . CONCLUSION: An early postoperative ERMBT may be useful in predicting the development of cyclosporine and tacrolimus nephrotoxicity, severe graft dysfunction, or even graft loss in liver transplant recipients when calcineurin inhibitors are administered according to protocols . Whether ERMBT results may be used to individualize dosage of calcineurin inhibitors needs to be explored.

Toxicol Sci, 2003 Oct, 75(2), 378 - 92 Epub 2003 Jul 25.
Use of a low-density microarray for studying gene expression patterns induced by hepatotoxicants on primary cultures of rat hepatocytes; de Longueville F et al.; In the field of gene expression analysis, DNA microarray technology is having a major impact on many different areas including toxicology . For instance, a number of studies have shown that transcription profiling can generate the information needed to assign a compound to a mode-of-action class . In this study, we investigated whether compounds inducing similar toxicological endpoints produce similar changes in gene expression . In vitro primary rat hepatocytes were exposed to 11 different hepatotoxicants: acetaminophen, amiodarone, clofibrate, erythromycin estolate, isoniazid, alpha-naphtylylisothiocyanate, beta-naphtoflavone, 4-pentenoic acid, phenobarbital, tetracycline, and zileuton . These molecules were selected on the basis of their variety of hepatocellular effects observed such as necrosis, cholestasis, steatosis, and induction of CYP P450 enzymes . We used a low-density DNA microarray containing 59 genes chosen as relevant toxic and metabolic markers . The in vitro gene expression data generated in this study were generally in good agreement with the literature, which mainly concerns in vivo data . Furthermore, gene expression profiles observed in this study have been confirmed for several genes by real-time PCR assays . All the tested drugs generated a specific gene expression profile . Our results show that even with a relatively limited gene set, gene expression profiling allows a certain degree of classification of compounds with similar hepatocellular toxicities such as cholestasis, necrosis . The clustering analysis revealed that the compounds known to cause steatosis were linked, suggesting that they functionally regulate similar genes and possibly act through the same mechanisms of action . On the other hand, the drugs inducing necrosis and cholestasis were pooled in the same cluster . The drugs arbitrarily classified as the CYP450 inducers formed individual clusters . In conclusion, this study suggests that low-density microarrays could be useful in toxicological studies.

AAPS PharmSci . 2003;5(2):E12.
Influence of solvents on the variety of crystalline forms of erythromycin; Mirza S et al.; The influence of the organic solvents widely used in the pharmaceutical industry (acetone, methylethylketone, ethanol, and isopropanol) both in the presence and in the absence of water on the crystallization behavior of erythromycin (Em), a clinically relevant antibiotic of the macrolide group, was investigated . It was observed that despite a high preference for water as a guest molecule, Em rather easily forms solvates with the organic solvents studied . Consequently, 4 distinct solvates of Em have been isolated by recrystallization: acetonate, methylethylketonate, ethanolate, and isopropanolate . It was established that in a pure organic solvent, or 1:9 or 1:1 water-organic solvent mixtures, the corresponding solvate is always crystallized . However, the recrystallization of erythromycin from 2:1 water-organic solvent (excluding methylethylketone) mixture results in the formation of a crystal hydrate form . X-ray powder diffraction revealed the isostructurality of the solvates with acetone and methylethylketone . Thermogravimetric analysis showed that the loss of volatiles by all of the solvated crystals is nonstoichiometric . The desolvation behavior of the solvates with the organic solvents studied by means of variable-temperature x-ray powder diffraction indicates that in contrast to erythromycin dihydrate, they belong to a different class of solvates--those that produce an amorphous material upon desolvation.

J Mol Biol, 2003 Jul 25, 330(5), 1005 - 14
The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome; Tenson T et al.; The macrolide-lincosamide-streptogramin B class (MLS) of antibiotics contains structurally different but functionally similar drugs, that all bind to the 50S ribosomal subunit . It has been suggested that these compounds block the path by which nascent peptides exit the ribosome . We have studied the mechanisms of action of four macrolides (erythromycin, josamycin, spiramycin and telithromycin), one lincosamide (clindamycin) and one streptogramin B (pristinamycin IA) . All these MLS drugs cause dissociation of peptidyl-tRNA from the ribosome . Josamycin, spiramycin and clindamycin, that extend to the peptidyl transferase center, cause dissociation of peptidyl-tRNAs containing two, three or four amino acid residues . Erythromycin, which does not reach the peptidyl transferase center, induces dissociation of peptidyl-tRNAs containing six, seven or eight amino acid residues . Pristinamycin IA causes dissociation of peptidyl-tRNAs with six amino acid residues and telithromycin allows polymerisation of nine or ten amino acid residues before peptidyl-tRNA dissociates . Our data, in combination with previous structural information, suggest a common mode of action for all MLS antibiotics, which is modulated by the space available between the peptidyl transferase center and the drug.

Toxicol Sci, 2003 Sep, 75(1), 25 - 30 Epub 2003 Jul 11.
Hyperforin contributes to the hepatic CYP3A-inducing effect of Hypericum perforatum extract in the mouse; Cantoni L et al.; This study in mice investigated whether hyperforin accounts for the inductive effects on cytochrome P4503A enzymes of St . John's wort extracts (SJW; Hypericum perforatum), one of the most popular herbal preparations because of its alleged activity in mild to moderate depression . A hydroalcoholic extract containing 4.5% hyperforin was given at a dose of 300 mg/kg, bis in die (b.i.d.), for 4 and 12 days . Hyperforin, its main phloroglucinol component, was given as dicyclohexylammonium (DCHA) salt (18.1 mg/kg, b.i.d.) on the basis of its content in the extract, to ensure comparable exposure to hyperforin . The extract increased hepatic erythromycin-N-demethylase (ERND) activity, which is cytochrome P450 enzyme (CYP) 3A-dependent, about 2.2-fold after 4 days of dosing, with only slightly greater effect after 12 days (2.8 times controls) . Hyperforin too increased ERND activity within 4 days, much to the same extent as the extract (1.8 times the activity of controls), suggesting that it behaves qualitatively and quantitatively like the extract as regards induction of CYP3A activity . This effect was confirmed by Western blot analysis of hepatic CYP3A expression . Exposure to hyperforin at the end of the 4-day treatment was still similar to that with SJW extract, although it was variable and lower than after the first dose in both cases, further suggesting that hyperforin plays a key role in CYP3A induction by the SJW extract in the mouse . Standardization of the extracts based on the hyperforin content can be proposed for further evaluation of their potential action on first-pass metabolism and clearance of coadministered CYP3A substrates.

Pol J Pharmacol, 2003 Jan-Feb, 55(1), 57 - 62
Effect of erythromycin on contractile response of uterine smooth muscle strips in non-pregnant rats; Liu H et al.; OBJECTIVE: Erythromycin stimulates stomach smooth muscle contraction via action on motilin receptors, but the effects of erythromycin on non-pregnant uterine smooth muscle are unknown . The purpose of this study was to assess the effect of erythromycin on non-pregnant uterine smooth muscle and to examine the possible mechanism of its action . STUDY DESIGN: Uterine smooth muscle strips from rats were suspended in organ baths containing Krebs solution, and then isometric tension was measured . The response to erythromycin and the effect of hexamethonium, indomethacin, phentolamine, diphenhydramine, atropine, metoclopramide and verapamil on erythromycin-induced contraction were also assessed . RESULTS: The present study showed for the first time that erythromycin dose-dependently increased contractile frequency, and at a dose of 1.55 x 10(-3) mol/l it also increased contractile tension in non-pregnant uterine smooth muscle strips in rats . These actions were not affected by pretreatment with hexamethonium, indomethacin, phentolamine, atropine and metoclopramide, but histamine H1 receptor blocker diphenhydramine and calcium channel blocker verapamil inhibited both responses induced by erythromycin . CONCLUSION: Our results suggest that erythromycin could increase contractile frequency and tension of non-pregnant uterine smooth muscle via histamine H1 receptor and calcium channel.

Respir Med, 2003 Jul, 97(7), 844 - 50
Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis; Kadota J et al.; Diffuse panbronchiolitis (DPB) can now be cured with long-term erythromycin treatment . Our group conducted a prospective open trial of long-term treatment with a macrolide antibiotic, clarithromycin . We studied ten patients who were treated for 4 years with oral clarithromycin (200 mg once a day) . Pulmonary function test, blood gas analysis, comprehensive improvement score, and bacterial culture of sputum were examined at 3, 6, 12 months, and at 2, 3, 4 years after the initiation of the therapy . Pulmonary function improved in most of the patients within 6 months: the forced expiratory volume in one second showed a maximal increase from a mean (SE) value of 1.74 (0.12) l at baseline to 2.31 (0.22) l at 6 months (P < 0.01) and the volume (l) of forced vital capacity also showed a maximal increase within 6 months . The partial pressure of arterial oxygen at rest significantly increased at 3-6 months . The comprehensive improvement score also reached maximum within 6 months in nine of the patients . The majority of patients have developed sputum culture in which bacteria were negative within 6 months after the therapy . All of the patients maintained a stable condition with continued therapy, and no side effects of clarithromycin were observed during the study . This prospective study demonstrated that 6-month treatment with clarithromycin might be necessary to improve the clinical conditions of patients with DPB and the drug could be safely used for a long term.

Solid State Nucl Magn Reson, 2003 Aug, 24(1), 23 - 38
Ring-chain tautomerism in solid-phase erythromycin A: evidence by solid-state NMR; Iuliucci RJ et al.; Chemical shift modeling, utilizing the DFT B3LYP/D95** method, provides the spectral assignment of the 35 visible 13C resonances from the solid-phase erythromycin A dihydrate . A new resonance at 110.8ppm is observed in the high-resolution 13C CP/MAS spectrum upon the application of heat or sample desiccation . With the use of the dipolar-dephasing spectral editing technique, this resonance is identified as a hemiketal carbon and the alternative hypothesis, a conformational change to the anomeric carbon of the desosamine sugar, is ruled out . Hence, the formation of a cyclic hemiketal in erythromycin A while in the solid phase is proven by solid-state NMR . The principal components of the 13C chemical-shift tensor corresponding to this hemiketal are reported . This is the first measurement of hemiketal 13C principal values . The delta11 and delta22 components are unique compared to anomeric carbon values reported in the literature.

Crit Care Med, 2003 Jul, 31(7), 1952 - 8
Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients; de Wildt SN et al.; OBJECTIVE: To determine the pharmacokinetics and metabolism of midazolam in pediatric intensive care patients . DESIGN: Prospective population pharmacokinetic study . SETTING: Pediatric intensive care unit . PATIENTS: Twenty-one pediatric intensive care patients aged between 2 days and 17 yrs . INTERVENTIONS: The pharmacokinetics of midazolam and metabolites were determined during and after a continuous infusion of midazolam (0.05-0.4 mg/kg/hr) for 3.8 hrs to 25 days administered for conscious sedation . MEASUREMENTS AND MAIN RESULTS: Blood samples were taken at different times during and after midazolam infusion for determination of midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations via high-performance liquid chromatography-ultraviolet detection . A population analysis was conducted via a two-compartment pharmacokinetic model by the NPEM program . The final population model was used to generate individual Bayesian posterior pharmacokinetic parameter estimates . Total body clearance, apparent volume distribution in terminal phase, and plasma elimination half-life were (mean +/- sd, n = 18): 5.0 +/- 3.9 mL/kg/min, 1.7 +/- 1.1 L/kg, and 5.5 +/- 3.5 hrs, respectively . The mean 1-OH-midazolam/midazolam ratio and (1-OH-midazolam + 1-OH-midazolam-glucuronide)/midazolam ratio were 0.14 +/- 0.21 and 1.4 +/- 1.1, respectively . Data from three patients with renal failure, hepatic failure, and concomitant erythromycin-fentanyl therapy were excluded from the final pharmacokinetic analysis . CONCLUSIONS: We describe population and individual midazolam pharmacokinetic parameter estimates in pediatric intensive care patients by using a population modeling approach . Lower midazolam elimination was observed in comparison to other studies in pediatric intensive care patients, probably as a result of differences in study design and patient differences such as age and disease state . Covariates such as renal failure, hepatic failure, and concomitant administration of CYP3A inhibitors are important predictors of altered midazolam and metabolite pharmacokinetics in pediatric intensive care patients . The derived population model can be useful for future dose optimization and Bayesian individualization.

Curr Treat Options Gastroenterol, 2003 Aug, 6(4), 299 - 309
Idiopathic and Diabetic Gastroparesis; O'Donovan D et al.; The management of both diabetic and idiopathic gastroparesis often represents a substantial clinical challenge . In formulating recommendations for therapy, it should be recognized that these are based on less than optimal evidence; in particular, there are substantial deficiencies in current knowledge relating to the pathophysiology of gastroparesis, as well as the natural history of gastrointestinal symptoms, and the majority of pharmacologic trials have been short term and associated with methodologic limitations . Although the etiologic factors differ, the overall management principles are similar in the two conditions . Maintenance of adequate nutrition is pivotal, and parenteral nutrition may be required in severe cases associated with malnutrition . In patients with diabetes, rigorous attempts should be made to optimize glycemic control--hyperglycemia slows gastric emptying and may exacerbate symptoms and attenuate the effects of prokinetic drugs . Despite the relatively poor predictive value of symptoms, it is reasonable to suggest a trial of prokinetic therapy for about 4 weeks, rather than initially establishing the diagnosis by measurement of gastric emptying . However, it should be recognized that there is a substantial placebo response, a lack of evidence to support the cost effectiveness of such an approach, and that most patients will require prolonged therapy . In type 1 diabetic patients, prokinetic therapy may potentially benefit glycemic control, and this forms an additional rationale (albeit not established) for therapy . Some patients with diabetes and idiopathic gastroparesis with severe vomiting are unable to tolerate oral medication; in such cases subcutaneous metoclopramide may prove useful . Patients with intractable symptoms should be hospitalized and given intravenous erythromycin . The repertoire of prokinetic agents available in the United States is limited and includes metoclopramide, erythromycin, and cisapride (available by special program from its manufacturer); all of these drugs are associated with side effects . The use of metoclopramide may represent the first choice for chronic oral therapy, although it has been studied less comprehensively than cisapride . Combination therapy may be potentially more efficacious than the use of single agents . Dehydration and metabolic derangements should be corrected . The choice of chronic medical therapy should be individualized, taking factors such as age, presence of diabetes, concurrent medications, and comorbidities into account . In a small number of patients in whom medical treatment fails, surgery should be considered, and, if performed, done in a specialized center . A number of novel therapies, including gastric electrical stimulation, are currently being evaluated.

J Clin Endocrinol Metab, 2003 Jul, 88(7), 3113 - 6
Troglitazone induces CYP3A4 activity leading to falsely abnormal dexamethasone suppression test; Dimaraki EV et al.; After evaluating a patient who appeared to have a falsely abnormal response to the dexamethasone suppression test while taking troglitazone, we examined the effects of troglitazone on the activity of hepatic CYP3A4 and the screening tests for Cushing's syndrome . We studied five healthy women and three healthy men, aged 25 +/- 2 yr, before and after treatment with troglitazone (600 mg daily) for 28 d . Baseline 0800 h cortisol and corticosterone were similar before and after troglitazone treatment . Before troglitazone treatment, all subjects suppressed 0800 h cortisol below 1.8 micro g/dl (mean, 0.66 +/- 0.08 micro g/dl) during the 1-mg overnight dexamethasone suppression test (DST), whereas during troglitazone treatment none of the subjects suppressed 0800 h cortisol below 1.8 micro g/dl (mean, 9.0 +/- 1.8 micro g/dl) . Serum dexamethasone levels decreased by 66 +/- 4%, and the erythromycin breath test measurements increased by 27 +/- 8%, indicating increased CYP3A4 activity during troglitazone treatment . The hydrocortisone suppression test (HST) was performed by administering 50 mg hydrocortisone at 2300 h . Using the criterion of suppression of 0800 h plasma corticosterone by more than 50%, the specificity of the HST was 100% both before and after troglitazone treatment . In conclusion, troglitazone induced the activity of CYP3A4 leading to falsely abnormal DST . HST is a useful alternative to the DST in patients taking medications that increase the activity of CYP3A4.

Food Chem Toxicol, 2003 Aug, 41(8), 1141 - 7
Hepatic and intestinal cytochrome P450 and conjugase activities in rats treated with black tea theafulvins and theaflavins; Catterall F et al.; Theaflavins and theafulvins, a fraction of thearubigins, were isolated from aqueous infusions of black tea, and their effects on the hepatic and intestinal cytochrome P450 system, and on the glutathione S-transferase, epoxide hydrolase, glucuronosyl transferase and sulphotransferase enzyme systems were investigated in rats following oral intake for four weeks . Neither theafulvins nor theaflavins influenced cytochrome P450 activity in the liver as exemplified by the O-dealkylations of methoxy-, ethoxy- and pentoxyresorufin, the hydroxylations of lauric acid and p-nitrophenol, and the N-demethylation of erythromycin; similarly, hepatic xenobiotic conjugation systems were unaffected . In the intestine, both polyphenolic fractions markedly suppressed the O-deethylation of ethoxyresorufin and this was accompanied by a decrease in the CYP1A1 apoprotein levels . Probing intestinal microsomes with antibodies to CYP2E1 revealed the presence of a single band in the cytochrome P450 region whose intensity was lower in the polyphenol-treated animals . Immunoblot analysis utilising antibodies to CYP3A showed that the treatment with theafulvins and theaflavins reduced the apoprotein levels . A single band in the cytochrome P450 region was evident when the intestinal microsomes were probed with antibodies to CYP4A1 but the level of expression was not affected by the treatment with the black tea polyphenols . Finally, treatment of the rats with theaflavins had no effect on any of the intestinal conjugating enzymes studied, but treatment with theafulvins led to inhibition of glucuronosyl transferase activity.

Nihon Kokyuki Gakkai Zasshi, 2003 Jun, 41(6), 421 - 5
{Hypogammaglobulinemia associated with thymoma (Good syndrome) similar to diffuse panbronchiolitis}; Tsuburai T et al.; A 65-year-old woman complained of dyspnea and a productive cough after surgical treatment and irradiation therapy for thymoma . Chest radiography and high-resolution computed tomography showed small nodules in centrilobular lesions in all of both lung fields, but predominantly in the lower fields . In addition, blood tests showed hypogammaglobulinemia . Chronic sinusitis, mild hypoxemia, severe obstructive impairment and the pathological findings of bronchiolitis led to a diagnosis of sinobronchial syndrome caused by Good syndrome . Treatment with oral erythromycin 600 mg/day was started . After 6 months, the patient improved both clinically and radiologically . Low-dose, long-term treatment with erythromycin was effective against sinobronchial syndrome caused by Good syndrome.

J Public Health Med, 2002 Sep, 24(3), 200 - 6
UK guidelines for use of erythromycin chemoprophylaxis in persons exposed to pertussis; Dodhia H et al.; Pertussis is well controlled in the UK as a result of an effective vaccination programme . Nevertheless, the disease has not been eliminated, and cases still occur in the most vulnerable group of young infants . Erythromycin chemoprophylaxis has been advocated for use in contacts to prevent secondary cases but the evidence for its use is weak . These guidelines are based on a review of the evidence and aim to help clinicians make more rational decisions on the use of erythromycin chemoprophylaxis for pertussis . Erythromycin has well-established side effects and so its use should be limited to situations where it is likely to be of greatest benefit . If a clinically suspected or confirmed case of pertussis is identified who is also in household contact with someone at greatest risk from pertussis--young infants, especially neonates--then erythromycin chemoprophylaxis should be considered . The aim is to protect those at greatest risk from pertussis by offering chemoprophylaxis to them, to all their household contacts who are unimmunized and to contacts who are 5 years or older if they did not receive a pre-school pertussis booster (not given to those born before 1996 in the United Kingdom) . There is no evidence of any benefit from chemoprophylaxis given more than 21 days from the date of onset of the primary case . Unimmunized or partially immunized cases and contacts should complete their course of vaccine.

Viral Immunol, 2003, 16(2), 99 - 109
Rhinovirus and asthma; Yamaya M et al.; Rhinoviruses (RVs) cause the majority of common colds, which often provoke wheezing in patients with asthma . The precise mechanisms responsible for the RV infection-induced exacerbations of bronchial asthma are still uncertain . However, several reports reveal airway hyperresponsiveness, increases in chemical mediators in airway secretions such as kinin and histamine, and airway inflammation in patients with bronchial asthma after RV infection . RV infection induces an accumulation of inflammatory cells in airway mucosa and submucosa including neutrophils, lymphocytes and eosinophils . RV affects the barrier function of airway epithelial cells, and activates the airway epithelial cells and other cells in the lung to produce pro-inflammatory cytokines, including various kinds of interleukins, GM-CSF and RANTES, and histamine . RV also stimulates the expression of intercellular adhesion molecule-1 (ICAM-1) and low-density lipoprotein receptors in the airway epithelium, receptors for major and minor RVs . On the other hand, RV infection is inhibited by treatment with soluble ICAM-1, and by reduction of ICAM-1 expression in the airway epithelial cells after treatment with erythromycin . Both soluble ICAM-1 and erythromycin were reported to reduce the frequency of common colds . Here, we review the pathogenesis and management of RV infection-induced exacerbation of bronchial asthma.

Drugs, 2003, 63(13), 1339 - 58
Current concepts in diabetic gastroparesis; Smith DS et al.; Diabetic gastroparesis is a common and debilitating condition affecting millions of patients with diabetes mellitus worldwide . Although gastroparesis in diabetes has been known clinically for more than 50 years, treatment options remain very limited . Until recently, the scientific literature has offered few clues regarding the precise aetiology of gastric dysfunction in diabetes.Up to 50% of patients with diabetes may experience postprandial abdominal pain, nausea, vomiting and bloating secondary to gastric dysfunction . There is no clear association between length of disease and the onset of delayed gastric emptying . Gastroparesis affects both type 1 (insulin dependent) and type 2 (non- insulin dependent) forms of diabetes . Diagnosis requires identifying the proper symptom complex, while excluding other entities (peptic ulcer disease, rheumatological diseases, medication effects) . The diagnosis of gastroparesis may be confirmed by demonstrating gastric emptying delay during a 4-hour scintigraphic study . Treatment options are limited and rely on dietary modifications, judicious use of available pharmacological agents, and occasionally surgical or endoscopic placement of gastrostomies or jejunostomies . Gastric pacing offers promise for patients with medically refractory gastroparesis but awaits further investigation . Current pharmacological agents for treating gastroparesis include metoclopramide, erythromycin, cisapride (only available via a company-sponsored programme) and domperidone (not US FDA approved) . All of these drugs act as promotility agents that increase the number or the intensity of gastric contractions . These medications are not uniformly effective and all have adverse effects that limit their use . Cisapride has been removed from the open market as a result of over 200 reported cases of cardiac toxicity attributed to its use . Unfortunately, there is a paucity of clinical studies that clearly define the efficacy of these agents in diabetic gastroparesis and there are no studies that compare these drugs to each other . The molecular pathophysiology of diabetic gastroparesis is unknown, limiting the development of rational therapies . New studies, primarily in animals, point to a defect in the enteric nervous system as a major molecular cause of abnormal gastric motility in diabetes . This defect is characterised by a loss of nitric oxide signals from nerves to muscles in the gut resulting in delayed gastric emptying . Novel therapies designed to augment nitric oxide signalling are being studied.

Herz, 2003 Jun, 28(4), 284 - 90
{Sex, erectile dysfunction, and the heart: a growing problem}; Gorge G et al.; BACKGROUND: Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance . ED may also be an early sign of cardiovascular disease . The main risk factors for coronary heart disease (high LDL, smoking, hypertension, diabetes) and ED are the same . ED after the diagnosis of coronary artery disease or myocardial infarction is also common . CARDIOVASCULAR EFFECTS AND RISK OF SEXUAL ACTIVITY: Cardiac and metabolic expenditures during sexual intercourse will vary depending on the type of sexual activity . When oxygen uptake was measured in men, an average metabolic expenditure during stimulation and orgasm of 2.5 metabolic equivalents (METs) was found for woman-on-top coitus, and of 3.3 METs for man-on-top coitus (range 2.0-5.4 METs) . However, coital death is rare, encompassing only 0.6% of all sudden death cases . A retrospective case-crossover study has shown that although sexual activity can trigger the onset of myocardial infarction, the relative risk in the 2 h after sexual activity was low (2.5; 95% confidence interval {CI} 1.7-3.7) . Sexual activity was a likely contributor to the onset of myocardial infarction only 0.9% of the time . Regular exercise appears to prevent triggering . It has to be cautioned that these reassuring data should not be extrapolated to patients taking sildenafil, if they perform at higher cardiac and metabolic expenditures during coitus . The hemodynamic changes associated with sexual activity may be far greater with an unfamiliar partner, in unfamiliar settings, and after excessive eating and drinking . The Princeton Consensus Table for estimation of cardiovascular risk during sexual intercourse gives a first orientation regarding the question which patients can perform sex safely and which subgroup needs further diagnosis and treatment . PHOSPHODIESTERASE-5 INHIBITORS FOR ED TREATMENT: The introduction of sildenafil has been a valuable contribution to the treatment of ED . Sildenafil acts as a selective inhibitor of cyclic guanosine monophosphate-(cGMP-)specific phosphodiesterase type 5 (PDE 5), resulting in smooth muscle relaxation, vasodilation, and enhanced penile erection . Reported cardiovascular side effects in healthy males are headache, flushing, and < 10% decreases in systolic and diastolic blood pressures . Significant hypotension can be found in patients who are concurrently taking nitrates . On the basis of the pharmacokinetic profile of sildenafil, the co-administration of a nitrate within the first 24 h is likely to produce a severe, potentially lifethreatening hypotensive response and is therefore contraindicated . The risk of precipitating a cardiotoxic, hypotensive, or hemorrhagic event secondary to combining sildenafil (a PDE 5 inhibitor) with specific PDE 3 inhibitors such as milrinone and enoximone or with nonspecific PDE inhibitors such as theophylline and pentoxifylline is unlikely . Sildenafil is predominantly metabolized by both the P450 2C9 pathway and the P450 3A4 pathway . Thus, potent inhibitors of the P450 3A4 pathway may increase the plasma concentrations of sildenafil, like cimetidine, erythromycin, digitoxin, and CSE inhibitors (simvastatin, atorvastatin, etc.) . A creatinine clearance < 30 ml/min also increases plasma levels of sildenafil . SAFETY PROFILE OF SILDENAFIL: Sildenafil is safe in healthy subjects . In a postmarketing study on 6,527 males, no increase of cardiovascular events was found . However, in older males with coronary heart disease, the risk of sildenafil and the risk of physical exercise during sexual intercourse contribute both to fatal outcomes . Of 69 cases reported to the FDA, 46 patients might have had a cardiovascular event, and in twelve a possible interaction with nitrate use has been reported . Sildenafil is absolutely contraindicated in patients taking long-acting nitrates, those with severe aortic stenosis, and patients with hypertrophic obstructive cardiomyopathy (HOCM) . No nitrates should be used within 24 h of sildenafil use . Caution is necessary in patients with a combination of antihypertensive medications, and in patients with cardiac insufficiency . A "pre-Viagra" treadmill test to assess for the presence of stress-induced ischemia can be helpful for both the patient and the physician . If the patient can achieve > or = 5 METs without demonstrating ischemia, the risk of ischemia during coitus is low . MANAGEMENT OF SEVERE ADVERSE EVENTS: If severe hypotension occurs, aggressive fluid resuscitation is the first step, followed by administration of vasoactive drugs and, if necessary, by intraaortic balloon counterpulsation . If unstable angina or myocardial infarctions occurs after the use of sildenafil, the patient is treated according to the guidelines, but without nitrates . CONCLUSION: Sexual activity is a cornerstone of quality of life . However, giving the incidence of "occult" cardiovascular disease in patients with ED and the indications and contraindications of PDE 5 inhibitors in patients with cardiovascular diseases, all patients with ED must be evaluated by a cardiovascular specialist.

Jpn J Infect Dis, 2003 Apr, 56(2), 62 - 4
Characterization of the first Korean isolate of a Chlamydia pneumoniae strain; Lee SJ et al.; Chlamydia pneumoniae is a common pathogen that causes upper and lower respiratory tract infections and is difficult to isolate from clinical specimens . Recently, we succeeded in isolating the first C . pneumoniae strain in Korea . This study characterizes the morphology, infectivity, and drug sensitivity of the Korean strain, designated LKK-1 . Electron microscopy was performed for thin sections, and the infectivity over time was tested by counting the inclusion-forming units every 12 h . The minimum inhibitory concentrations of doxycycline, erythromycin, clarithromycin, ciprofloxacin, and levofloxacin were determined following the standard Japanese method . The elementary bodies of LKK-1 were round, like those in Japanese strain KKpn-1, whereas those of TW-183 have wavy cell membranes and are pear-shaped . The infectivity curve and drug sensitivities of LKK-1 were nearly the same as those of KKpn-1 . In conclusion, LKK-1, the first strain from Korea, is similar to the Japanese strain KKpn-1 in terms of morphology, growth, and drug sensitivities, and shows a distinct difference in morphology compared with TW-183 . Further studies are needed to elucidate the morphological differences between round strains and classical pear-shaped strains of C . pneumoniae.

J Antibiot (Tokyo), 2003 Apr, 56(4), 392 - 8
Novel 12-membered ring macrolides with activity against erythromycin-resistant organisms; Nemoto PA et al.; A series of novel 12-membered ring macrolides was designed based on available information on structure-activity relationships and macrolide-ribosome interactions . Compounds with the desosamine and the anchor group properly attached to the 12-membered lactone ring exhibited improved activity against erythromycin-resistant organisms.

Drug Metab Dispos, 2003 Jul, 31(7), 945 - 54
Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes; Ito K et al.; Clinical studies have revealed that plasma concentrations of midazolam after oral administration are greatly increased by coadministration of erythromycin and clarithromycin, whereas azithromycin has little effect on midazolam concentrations . Several macrolide antibiotics are known to be mechanism-based inhibitors of CYP3A, a cytochrome P450 isoform responsible for midazolam hydroxylation . The aim of the present study was to quantitatively predict in vivo drug interactions in humans involving macrolide antibiotics with different inhibitory potencies based on in vitro studies . alpha- and 4-Hydroxylation of midazolam by human liver microsomes were evaluated as CYP3A-mediated metabolic reactions, and the effect of preincubation with macrolides was examined . The hydroxylation of midazolam was inhibited in a time- and concentration-dependent manner following preincubation with macrolides in the presence of NADPH, whereas almost no inhibition was observed without preincubation . The kinetic parameters for enzyme inactivation (K'app and kinact) involved in midazolam alpha-hydroxylation were 12.6 microM and 0.0240 min-1, respectively, for erythromycin, 41.4 microM and 0.0423 min-1, respectively, for clarithromycin, and 623 microM and 0.0158 min-1, respectively, for azithromycin . Similar results were obtained for the 4-hydroxylation pathway . These parameters and the reported pharmacokinetic parameters of midazolam and macrolides were then used to simulate in vivo interactions based on a physiological flow model . The area under the concentration-time curve (AUC) of midazolam after oral administration was predicted to increase 2.9- or 3.0-fold following pretreatment with erythromycin (500 mg t.i.d . for 5 or 6 days, respectively) and 2.1- or 2.5-fold by clarithromycin (250 mg b.i.d . for 5 days or 500 mg b.i.d . for 7 days, respectively), whereas azithromycin (500 mg o.d . for 3 days) was predicted to have little effect on midazolam AUC . These results agreed well with the reported in vivo observations.

Drug Metab Dispos, 2003 Jul, 31(7), 861 - 9
Eletriptan metabolism by human hepatic CYP450 enzymes and transport by human P-glycoprotein; Evans DC et al.; "Reaction phenotyping" studies were performed with eletriptan (ETT) to determine its propensity to interact with coadministered medications . Its ability to serve as a substrate for human P-glycoprotein (P-gp) was also investigated since a central mechanism of action has been proposed for this "triptan" class of drug . In studies with a characterized bank of human liver microsome preparations, a good correlation (r2 = 0.932) was obtained between formation of N-desmethyl eletriptan (DETT) and CYP3A4-catalyzed testosterone 6 beta-hydroxylation . DETT was selected to be monitored in our studies since it represents a significant ETT metabolite in humans, circulating at concentrations 10 to 20% of those observed for parent drug . ETT was metabolized to DETT by recombinant CYP2D6 (rCYP2D6) and rCYP3A4, and to a lesser extent by rCYP2C9 and rCYP2C19 . The metabolism of ETT to DETT in human liver microsomes was markedly inhibited by troleandomycin, erythromycin, miconazole, and an inhibitory antibody to CYP3A4, but not by inhibitors of other major P450 enzymes . ETT had little inhibitory effect on any of the P450 enzymes investigated . ETT was determined to be a good substrate for human P-gp in vitro . In bidirectional transport studies across LLC-MDR1 and LLC-Mdr1a cell monolayers, ETT had a BA/AB transport ratio in the range 9 to 11 . This finding had significance in vivo since brain exposure to ETT was reduced 40-fold in Mdr1a+/+ relative to Mdr1a-/- mice . ETT metabolism to DETT is therefore catalyzed primarily by CYP3A4, and plasma concentrations are expected to be increased when coadministered with inhibitors of CYP3A4 and P-gp activity.

Fundam Clin Pharmacol, 2003 Jun, 17(3), 349 - 53
The {14C-N-methyl}-erythromycin breath test dosimetry complies with the French regulations for radiation safety; Salvat C et al.; The {14C-N-methyl}-erythromycin breath test (14C-ERMBT) is one of the most valuable probes for liver cytochrome P450-3A4 activity in humans . In order to extend the use of this test in France, we herein provide safety data regarding either patient dosimetry or worker exposure to {14C-N-methyl}-erythromycin . In order to determine the maximum radiation exposure for patient and nuclear medicine technician following one intravenous 14C-ERMBT {111 kiloBequerel (kBq)}, we have used the dosimetric data gathered in animal studies and extrapolated to humans using a weight-based method, approximate data provided by the French Society of Radioprotection and erythromycin pharmacokinetics in humans, considering always the worst conditions for the patient and worker exposure determination . The radioactivity administered to a patient after one 14C-ERMBT was equal to 108.8 kBq (i.e . 98% of the total radioactivity in the 14C-erythromycin vial) leading to a patient effective dose of 20 microsievert (microSv) and a maximum effective dose after 14CO2 inhalation by the exposed worker of 16 microSv compared with a mean individual annual effective dose from natural and artificial radioactivity exposure of 3500 microSv in France . The 14C-ERMBT is safe and complies with the European regulations regarding the administration of 14C-labelled compounds in humans . It can therefore be used in clinical research in France without any particular safety requirement.

ANZ J Surg, 2003 Jun, 73(6), 400 - 3
Duodenogastric reflux after biliary surgery: scintigraphic quantification and improvement with erythromycin; Fountos A et al.; BACKGROUND: Persistence of dyspeptic symptoms after cholecystectomy or choledochoduodenostomy is common . There is -evidence that at least some of these symptoms may be attributed to duodenogastric reflux (DGR) . The aim of the study was to quantify DGR before and after cholecystectomy, with or without choledochoduodenostomy, and endoscopic sphincterotomy for common bile duct stones, and to assess the effect of erythromycin on the increased DGR . METHODS: Forty-seven patients before and after cholecystectomy, 26 after cholecystectomy and choledochoduodenostomy and nine after sphincterotomy had postprandial (300 mL of fresh milk, 4% fat) duodenogastric reflux measured by 99mTc-hepatic imino diacetic acid scintigraphy . Patients with a DGR index (DGRi) >20% were considered as having pathological DGR that justifies symptoms, and their DGRi was reassessed after administration of 200 mg of erythromycin intravenously . RESULTS: Twenty-seven patients before cholecystectomy (57%) showed a normal DGRi <7% . In five cases DGRi was greater than 20% . After cholecystectomy, duodenogastric refluxes increased, so that only 16 patients (32%) showed a normal DGRi, while a DGRi >20% was observed in 10 cases . Only eight patients after cholecystectomy and choledochoduodenostomy (23%) presented with a DGRi within the normal range . The remaining 18 had a DGRi >7% . Five of them exhibited a DGRi >20% . Of the nine patients with sphincterotomy, three showed a DGRi >20% . Erythromycin almost completely normalized DGRi in all 18 patients with pathological DGR (P < 0.0001) . CONCLUSIONS: Duodenogastric reflux is common after biliary surgery, including endoscopic sphincterotomy . Erythromycin appears to decrease duodenogastric reflux to normal levels.

Surgery, 2003 Jun, 133(6), 647 - 55
Erythromycin induces pyloric relaxation accompanied by a contraction of the gastric body after pylorus-preserving gastrectomy; Nakabayashi T et al.; BACKGROUND: Pylorus-preserving gastrectomy (PPG) is a function-preserving surgery; however, long-term retention of food in the residual stomach is a frequent complication during the early postoperative period . We reported that gastric stasis after PPG was attributable to the delayed recovery of gastric phase III, in which pyloric relaxation accompanied a contraction of the gastric body . The objective of the present study is to determine whether erythromycin can induce phase III with pyloric relaxation after PPG . METHODS: We studied gastrointestinal motility in dogs after PPG by using strain gauge force transducer . After randomized administration of either erythromycin or saline, interdigestive gastropyloroduodenal motility was recorded . RESULTS: Erythromycin induced phase III with pyloric relaxation in the early postoperative period . Pyloric relaxation accompanied a contraction of the gastric body . Compared with the saline group (body: 87.2 +/- 16.7 mmHg x min, antrum: 69.7 +/- 13.7 mmHg x min, pylorus: 91.7 +/- 22.1 mmHg x min), the erythromycin group showed significantly increased gastropyloric motility indexes (body: 506.2 +/- 33.5 mmHg x min, antrum: 430.9 +/- 53.7 mmHg x min, pylorus: 589.5 +/- 59.5 mmHg x min) . CONCLUSIONS: Erythromycin can induce phase III, in which pyloric relaxation accompanied a contraction of the gastric body in the early postoperative period after PPG . Erythromycin might be used as a prokinetic agent for the treatment of early gastric stasis after PPG.

Arch Pediatr Adolesc Med, 2003 Jun, 157(6), 565 - 71
Oral erythromycin prophylaxis vs watchful waiting in caring for newborns exposed to Chlamydia trachomatis; Rosenman MB et al.; BACKGROUND: Chlamydia trachomatis exposure at birth may cause conjunctivitis or pneumonia . Until recently, a course of oral erythromycin prophylaxis was recommended for C trachomatis-exposed neonates . However, recognition of an association between erythromycin and pyloric stenosis prompted a change to a watchful waiting recommendation under which only infants who develop symptomatic C trachomatis infection are treated with oral erythromycin . OBJECTIVE: To compare erythromycin prophylaxis with watchful waiting for a hypothetical cohort of 100 000 neonates exposed to C trachomatis . METHODS: In a decision tree, potential outcomes were C trachomatis conjunctivitis, C trachomatis pneumonia (which could require inpatient or outpatient therapy), no clinical disease, and pyloric stenosis . Published data were reviewed to derive probability point estimates and ranges . Estimated charges served as outcome measures . RESULTS: Watchful waiting is less expensive than erythromycin prophylaxis ($15.1 million vs $28.3 million); prophylaxis prevents 5986 cases of C trachomatis pneumonia, including 1197 hospital admissions, but causes 3284 pyloric stenosis cases . (For every 30 infants given oral erythromycin prophylaxis, one additional case of pyloric stenosis would be expected to occur, and approximately 1.8 cases of C trachomatis pneumonia would be prevented.) In sensitivity analyses, if more than 3.4% of exposed neonates are hospitalized for C trachomatis pneumonia, prophylaxis becomes favored . CONCLUSIONS: This study supports the watchful waiting recommendation for asymptomatic C trachomatis-exposed neonates . However, there are wide plausible ranges for pyloric stenosis risk after erythromycin administration and for the incidence of C trachomatis pneumonia severe enough to require hospitalization; under some combinations of these rates, prophylaxis could be favored.

Afr Health Sci, 2001 Dec, 1(2), 90 - 6
Bioavailability and stability of erythromycin delayed release tablets; Ogwal S et al.; BACKGROUND: Erythromycin is available as the free base, ethylsuccinate, estolate, stearate, gluceptate, and lactobionate derivatives . When given orally erythromycin and its derivatives except the estolate are inactivated to some extent by the gastric acid and poor absorption may result . OBJECTIVES: To establish whether delayed release erythromycin tablets meet the bioequivalent requirement for the market . METHODS: Sectrophotometric analysis was used to determine the dissolution percentage of the tablets in vitro . High performance liquid chromatography and IBM/XT microcomputer was used to determine the bioavailability and pharmacokinetic parameters in vivo . RESULTS: Dissolution percentage in thirty minutes reached 28.9% and in sixty minutes erythromycin was completely released . The parameters of the delayed release tablets were Tlag 2.3 hr, Tmax.4.5 hr, and Cmax 2.123 g/ml Ka 0.38048 hr(-1) T (1/2) 1.8 hr, V*C/F 49.721 AUC 12.9155 . The relative bioavailability of erythromycin delayed release tablet to erythromycin capsules was 105.31% CONCLUSION: The content, appearance, and dissolution bioavailability of delayed release erythromycin tablets conforms to the United States pharmacopoeia standards . The tablets should be stored in a cool and dry place in airtight containers and the shelf life is temporarily assigned two years.

Yao Xue Xue Bao, 2003 Feb, 38(2), 108 - 12
{Prognosticating the region-selectivity in the O-methylation reaction of erythromycins by conformational search model}; Xu J et al.; AIM: In order to find a way to prognosticate the region-selectivity in the O-methylation reaction of erythromycin and its derivatives, conformation search model of Hyperchem Pro 6.0 used in personal computer was used to establish it . METHODS: The results of O-methylation reaction of compound 1, 2 and 3 showed the difference between 6-OH and 11-OH . Using the conformational search model of hyperchem, 1,000 conformations of compound 4, 5 and 6 were found with the parameter of dihedral angle . The 14-membered lactone ring was defined as a "plane" . The position of carbonyl of 1- or 9- and hydroxyl of 6- or 11- is different, either "up-plane" or "down-plane" . A statistic analysis of low-energy conformation clusters was used to sort these clusters by the parameter of the dihedral angle . The data is in accord with the results of the experiments . RESULTS: Conformation numbers, energy minimum, energy average and position of the active groups of compounds 4, 5 and 6, the simplified structures of compound 1, 2 and 3, were given in Table 1 . by sorting the dihedral angle . CONCLUSION: The interaction of the hydroxyl and carbonyl were analysed and found that O-methylation reactions of erythromycin and its derivatives were impacted by the space factor . The clusters of energy minimum, maximum number and "outside" were discussed . The selectivity of the O-methylation reaction of erythromycin and its derivatives can be prognosticated by analysing the parameter of the dihedral angle.

J Dermatolog Treat, 2003 Jun, 14(2), 124 - 7
Severe erythema nodosum due to Behçet's disease responsive to erythromycin; Kaya TI et al.; A patient with severe erythema nodosum due to Behcet's disease is reported on here . Erythema nodosum lesions did not respond to classical treatments; however, they cleared after erythromycin treatment, which was prescribed for the treatment of coincidental erythrasma . Erythromycin treatment appears to be an effective treatment option in erythema nodosum . The hypothetical anti-inflammatory effects of erythromycin, besides its antibiotic properties, are reviewed and discussed to explain such a clinical improvement.

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