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 correspondi