Zhonghua Liu Xing Bing Xue Za Zhi, 2001 Aug, 22(4), 293 - 5 {Clinic intervention study on urogenital mycoplasma infection of pregnant women}; Ye Y et al.; OBJECTIVE: To explore the hypothesis of pathogenic relationship between urogenital mycoplasma infection and adverse perinatal outcomes . METHODS: Four hundred and eighty-eight mycoplasma-positive pregnant women detected by culture method were randomly divided into erythromycine-intervention group and non-intervention group . Comparison was made on rate of reverse sero-conversion, of vertical transmission to mycoplasma and adverse perinatal outcomes incidence between groups . RESULTS: Ureaplasma urealyticum sero-conversion rate and rate of vertical-transmission in intervention group were significantly lower than in non-intervention group (P < 0.05) . The incidences rates of preturm labor, post partum fever, puerperal infection and neonate pneumonia in intervention group were significantly lower than in non-intervention group (P < 0.05) . CONCLUSION: Erythromycin is effective in control of ureaplasma urealyticum infection among pregnant women through cutting off vertical transmission passway and lowering adverse perinatal outcomes against ureaplasma urealyticum. Hautarzt, 2001 Oct, 52(10 Pt 2), 980 - 4 {Acute generalized cat scratch disease in myelodysplastic syndrome}; von Kobyletzki G et al.; In patients with normal immunity, cat scratch disease typically develop a papule at the portal of entry and no other cutaneous features . A 73 year old male patient with a myelodysplastic syndrome developed generalized petechial, papular and, vasculitic skin lesions in association with cat scratch disease . After the diagnosis was established by identifying the causative organism in a lymph node biopsy, the patient was treated with erythromycin for three weeks resulting in progressive clearance of the skin lesions . Apart from the soluble IL-2 receptor, no other serologic inflammatory parameters were elevated . IgG antibodies against Bartonella henselae and Bartonella quintana increased only slightly during acute exacerbation of the disease, but significantly increased some months later . The diagnosis was established by the positive staining of the lymph node biopsy using the Warthin-Starry stain. Cardiovasc Drugs Ther, 2001, 15(3), 211 - 8 Safety of HMG-CoA reductase inhibitors: focus on atorvastatin; Bernini F et al.; Statins effectively lower LDL-cholesterol and some members of this class have been shown to reduce the risk of major cardiovascular events and total mortality in patients with or at risk for coronary heart disease . Statins are in general well tolerated . Withdrawal rates related to adverse events are low (< or =3%) . The most common adverse events are mild gastrointestinal symptoms . Elevated serum transaminase levels occur infrequently (< or = 1.5%) . These are generally asymptomatic, reversible and rarely require drug withdrawal . Statins do not cause adverse endocrine effects, do not alter glycemic control in diabetic patients, and do not increase cancer risk . Dose-related myopathy and/or rhabdomyolysis also occurs very rarely, although the risk is increased by concomitant administration of cyclosporine, niacin, fibrates, or by CYP3A4 isoenzyme inhibitors (e.g . erythromycin, systemic azole antifungal agents etc.) with statins metabolized by this isoenzyme . The pharmacokinetics of the individual statin should be considered in patients receiving polypharmacological treatments, to minimize the risk of unfavorable drug interactions . Atorvastatin is well tolerated in long-term treatment of dyslipidemia and is characterized by a safety profile similar to the other available statins. Int J Antimicrob Agents, 2001 Nov, 18(5), 427 - 31 Tolerability of 3-day, once-daily azithromycin suspension versus standard treatments for community-acquired paediatric infectious diseases; Treadway G et al.; Tolerability of azithromycin oral suspension, 10 mg/kg once daily for 3 days, was assessed in paediatric patients (< or = 18 years) with respiratory or skin and soft-tissue infections . Of 2425 patients evaluated, 1213 received azithromycin and 1212 received standard regimens of amoxycillin/clavulanic acid, cefaclor, cefixime, ceftriaxone, clarithromycin, erythromycin, or penicillin V . The incidence of treatment-related adverse events was significantly lower in patients receiving azithromycin than comparators (7.9 vs . 11.5%, P=0.003), while discontinuation rates were similar (1.0 and 1.1%, respectively) . Significantly fewer gastrointestinal events were recorded for azithromycin than comparators (6.5 vs . 9.9%, P=0.002), and their duration was significantly shorter (mean 2.3 vs . 5.0 days, P=0.0001) . Azithromycin paediatric oral suspension is well tolerated and associated with significantly fewer adverse events than comparators. Antimicrob Agents Chemother, 2001 Dec, 45(12), 3644 - 6 Newer macrolides as empiric treatment for acute Q fever infection; Gikas A et al.; The effectiveness of newer macrolides in acute Q fever for 113 patients was recorded . The mean times to defervescence were 2.9 days for doxycycline and 3.3, 3.9, 3.9, and 6.4 days for clarithromycin, roxithromycin, erythromycin, and beta-lactams, respectively (P < 0.01 for macrolides versus beta-lactams) . We conclude that macrolides may be an adequate empirical antibiotic therapy for acute Q fever. Drugs, 2001, 61(13), 1893 - 9 Role of erythromycin for treatment of incipient chronic lung disease in preterm infants colonised with Ureaplasma urealyticum; Buhrer C et al.; Ureaplasma urealyticum is frequently isolated from tracheal aspirates of very low birthweight infants who go on to develop chronic lung disease . The use of erythromycin has been advocated in ventilated very low birthweight infants who are colonised with U . urealyticum, although the association between U . urealyticum and chronic lung disease remains controversial . There are only two randomised, controlled trials involving a total of 37 U . urealyticum-positive very low birthweight infants . Both trials failed to demonstrate a reduction in the incidence of chronic lung disease after 7 or 10 days of erythromycin . On the other hand, there are reports of rare but serious adverse effects of erythromycin in newborn infants including sudden cardiovascular compromise and hypertrophic pyloric stenosis . We conclude that, at present, there is insufficient evidence to support the use of erythromycin for the treatment of incipient chronic lung disease in very low birthweight infants colonised with U . urealyticum. Pacing Clin Electrophysiol, 2001 Oct, 24(10), 1575 - 6 Risk of torsades de pointes from oral erythromycin with concomitant carbimazole (methimazole) administration; Koh TW; There are many reports of intravenous erythromycin causing QT prolongation and torsades de pointes, but this complication is seldom ascribed to orally administered erythromycin, which is by far the most commonly prescribed route . This report describes a case of torsades de pointes associated with oral erythromycin as a result of a previously undescribed interaction with carbimazole, an antithyroid drug that is metabolized to the active drug methimazole, and the potential pharmacokinetic and pharmacodynamic mechanisms are highlighted. Can J Physiol Pharmacol, 2001 Oct, 79(10), 848 - 53 Differential effects of phenobarbital on the constitutive and inducible expression of P450 2B and 3A subfamilies in sheep tissues; Dupuy J et al.; The activity and expression of cytochromes P450 were determined in liver, kidneys, lungs, duodenum, jejunum, ileum, and caecum of adult Lacaune sheep . High expression of total P450, benzphetamine and erythromycin demethylase activities, and P450 2B isoforms, as two distinct proteins that were detected and called P4502 Bm and P4502 Bx, was found in the lungs (in addition to liver) . By contrast, the P450 3A subfamily was only expressed in liver and duodenal mucosa of untreated sheep . Phenobarbital (PB) treatment led to significant increases in all measured hepatic parameters and in total P450 of each investigated organ with the exception of ileum and caecum . Benzphetamine demethylase activity increased in liver and kidneys, correlating with the expression of the two P450 2B proteins, which were also induced in duodenum and ileum . By contrast, benzphetamine demethylase activity and expression of the P450 2B isoforms in lungs were unchanged by PB treatment . Erythromycin demethylation activity and P450 3A subfamily expression was increased only in liver of PB-treated sheep. J Biotechnol, 2002 Jan 18, 92(3), 217 - 28 Saccharopolyspora erythraea-catalyzed bioconversion of 6-deoxyerythronolide B analogs for production of novel erythromycins; Carreras C et al.; A method was developed for the large-scale bioconversion of novel 6-deoxyerythronolide B (6-dEB) analogs into erythromycin analogs . Erythromycin biosynthesis in Saccharopolyspora erythraea proceeds via the formation of a polyketide aglycone, 6-dEB, which is subsequently glycosylated, hydroxylated and methylated to yield the antibiotic erythromycin A . A modular polyketide synthase (PKS) directs 6-dEB synthesis using a dedicated set of active sites for the condensation of each of seven propionate units . Strategies based on genetic manipulation and precursor feeding are available for the efficient generation of novel 6-dEB analogs using a plasmid-based system in Streptomyces coelicolor . 6-dEB and 13-substituted 6-dEB analogs produced in this manner were fed to S . erythraea mutants which could not produce 6-dEB, yet retained their 6-dEB modification systems, and resulted in the generation of erythromycin A and 13-substituted erythromycin A analogs . Erythromycin B, C and D analogs were observed as intermediates of the process . Dissolved oxygen, temperature, the specific aglycone feed concentration, and pH were found to be important for obtaining a high yield of erythromycin A analogs . Cultivation conditions were identified which resulted in the efficient bioconversion of 6-dEB analogs into erythromycin A analogs, which this process demonstrated at the 100 l scale. Intern Med, 2001 Oct, 40(10), 1064 - 7 Legionnaires' disease associated with habitual drinking of hot spring water; Tominaga M et al.; A 57-year-old man presented with pneumonia, respiratory distress, and myelodysplastic syndrome . A diagnosis of Legionnaires' disease due to Legionella pneumophila (L . pneumophila) was established . The patient had long been drinking tap water via a conduit from a hot spring resource, from which L . pneumophila was also isolated . Both the patient's strain and the water strain of L . pneumophila were identified as serogroup 1, and the genetic relatedness between the two strains as seen by pulsed-field gel electrophoresis was 87% . The patient was successfully treated with erythromycin, fluoroquinolone, and rifampicin . This case raises an important issue on public health represented by legionellosis in Japan. Vutr Boles, 2000, 32(4), 13 - 7 {Macrolides: pharmacology and clinical use}; Draganov V et al.; Members of macrolides are Erythromycin, Oleandomycin, Spiramycin, Roxithromycin, Josamycin, Midecamycin, Clarithromycin, Azithromycin and Dirithromycin . This review present mechanism of action, pharmacokinetic, adverse drug reactions and main clinical uses of the macrolides. Ann Surg, 2001 Nov, 234(5), 668 - 74 Low-dose erythromycin reduces delayed gastric emptying and improves gastric motility after Billroth I pylorus-preserving pancreaticoduodenectomy; Ohwada S et al.; OBJECTIVE: To test the hypothesis that early and low doses of erythromycin reduce the incidence of early delayed gastric emptying (DGE) and induce phase 3 of the migratory motor complex in the stomach after Billroth I pylorus-preserving pancreaticoduodenectomy (PPPD) . SUMMARY BACKGROUND DATA: Delayed gastric emptying is a leading cause of complications after PPPD, occurring in up to 50% of patients . High doses of erythromycin (200 mg) accelerate gastric emptying after pancreaticoduodenectomy and reduce the incidence of DGE, although they induce strong contractions that do not migrate to the duodenum . METHODS: Thirty-one patients were randomly assigned to either the erythromycin or control groups . The patients received erythromycin lactobionate (1 mg/kg) every 8 hours, or H2-receptor antagonists and gastrokinetic drugs from days 1 to 14 after surgery . On postoperative day 30, gastroduodenal motility was recorded in 14 patients . RESULTS: Preoperative, intraoperative, and postoperative factors were comparable in the erythromycin and control groups . The erythromycin group had a shorter duration of nasogastric drainage, earlier resumption of eating, and a 75% reduction in the incidence of DGE . Erythromycin was an independent influence on nasogastric tube removal, and preservation of the right gastric vessels was a significant covariate . Low doses of erythromycin induced phase 3 of the migratory motor complex and phase 3-like activity, with the same characteristics as spontaneous phase 3, in 86% of patients: two had quiescent stomachs and the others had spontaneous phase 3 or phase 3-like activity . CONCLUSIONS: Low doses of erythromycin reduced the incidence of DGE by 75% and induced phase 3 of the migratory motor complex after Billroth I PPPD . Low doses of erythromycin are preferable to high doses in the unfed period after PPPD. Am J Physiol Gastrointest Liver Physiol, 2001 Nov, 281(5), G1214 - 20 Pressure-geometry relationship in the antroduodenal region in humans; Faas H et al.; Understanding of the control mechanisms underlying gastric motor function is still limited . The aim of the present study was to evaluate antral pressure-geometry relationships during gastric emptying slowed by intraduodenal nutrient infusion and enhanced by erythromycin . In seven healthy subjects, antral contractile activity was assessed by combined dynamic magnetic resonance imaging and antroduodenal high-resolution manometry . After intragastric administration of a 20% glucose solution (750 ml), gastric motility and emptying were recorded during intraduodenal nutrient infusion alone and, subsequently, combined with intravenous erythromycin . Before erythromycin, contraction waves were antegrade (propagation speed: 2.7 +/- 1.7 mm/s; lumen occlusion: 47 +/- 14%) . Eighty-two percent (51/62) of contraction waves were detected manometrically . Fifty-four percent of contractile events (254/473) were associated with a detectable pressure event . Pressure and the degree of lumen occlusion were only weakly correlated (r(2) = 0.02; P = 0.026) . After erythromycin, episodes of strong antroduodenal contractions were observed . In conclusion, antral contractions alone do not reliably predict gastric emptying . Erythromycin induces strong antroduodenal contractions not necessarily associated with fast emptying . Finally, manometry reliably detects ~80% of contraction waves, but conclusions from manometry regarding actual contractile activity must be made with care. Early Hum Dev, 2001 Dec, 65(2), 91 - 6 The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants; Costalos C et al.; The aim of the study was to determine the effect of a low oral dose of erythromycin on whole gastrointestinal transit time {WGTT} . Erythromycin {EM} {1.5 mg/kg, 6 hourly} or placebo was given first over 7 days in a double blind randomized crossover study of 21 preterm infants with feed intolerance . Median {range} birth weight was 1420 {690, 2200} g and postconceptual age 32 . 5 {20, 36.4} weeks . WGTT was assessed on day 3 of each treatment, by timing the transit of carmine red through the gut . Treatments were compared using Student's paired t test . RESULTS: WGTT was significantly shorter following EM treatment as compared to placebo: mean {SD} 10.16 {4.6} h vs . 15 . 9 {7.2} h, p<0.01 . CONCLUSION: Oral low-dose EM significantly shortens WGTT of feed-intolerant preterm infants. Chem Biol Interact, 2001 Oct 25, 138(1), 85 - 106 alpha-Naphthoflavone acts as activator and reversible or irreversible inhibitor of rabbit microsomal CYP3A6; Boek-Dohalska L et al.; This report describes the effect of alpha-naphthoflavone (alpha-NF), a known substrate, inhibitor and activator of several cytochromes P450 (CYP), on rabbit CYP3A6 . Hepatic microsomes of rabbit pretreated with rifampicine (RIF), enriched with CYP3A6, as well as purified CYP3A6 reconstituted with isolated NADPH:CYP reductase were used as enzymatic systems in this study . The data from difference spectroscopy experiments showed that alpha-NF does yield a type I binding spectrum . This compound is oxidized by microsomal CYP3A6 into two metabolites (5,6-epoxide and trans-7,8-dihydrodiol) . While alpha-NF is a substrate of CYP3A6, it also acts as an enzyme modulator . Under the conditions used, stimulation of 17beta-estradiol 2-hydroxylation by alpha-NF was observed . In contrast, this compound reversibly inhibited N-demethylation of erythromycin and tamoxifen, competitively with respect to these substrates, having the K(i) values of 51.5 and 18.0 microM, respectively . Moreover, alpha-NF was found to be an effective inactivator of progesterone and testosterone 6beta-hydroxylation catalyzed by CYP3A6 in RIF-microsomes . In addition, time- and concentration-dependent inactivation of human CYP3A4-mediated 6beta-hydroxylation of testosterone by alpha-NF, was determined . The inactivation of CYP3A6 followed pseudo-first-order kinetics and was dependent on both NADPH and alpha-NF . The concentrations required for half-maximal inactivation (K(i)) were 80.1 and 108.5 microM and the times required for half of the enzyme to be inactivated were 10.0 and 11.9 min for 6beta-hydroxylation of progesterone and testosterone, respectively . The loss of the enzyme activity was not recovered following dialysis, while 90% of the ability to form a reduced CO complex remained . This indicates the binding of alpha-NF to a CYP apoprotein molecule rather than to a heme moiety . Protection from inactivation was seen in the presence of all tested CYP3A substrates . Progesterone and testosterone protected CYP3A6 against inactivation competitively with respect to inactivator, erythromycin non-competitively and 17beta-estradiol showed a mixed type of protection . Here, we described for the first time that alpha-NF is capable of irreversible inhibition of microsomal rabbit CYP3A6 and human CYP3A4 . The obtained results strongly suggest that the CYP3A active center contains at least two and probably three distinct binding sites for substrates. Kansenshogaku Zasshi, 2001 Sep, 75(9), 808 - 11 {Two patients with Bartonella henselae infection from a dog}; Murano I et al.; Two patients were reported as having been infected with Bartonella henselae after having contact with a dog . Both of the patients owned a dog, but had no contact with cats . One patient was a 10-year-old boy who had experienced a fever of 38-39 degrees C for 11 days, as well as having bilateral cervical lymphadenopathy . The boy's serum IgM antibodies to B . henselae were negative on the 6th and 16th day of his illness, whereas his IgG value, using indirect fluorescence antibody (IFA) method, was found to be elevated from 1:256 to 1:1,024 . B . henselae DNA was detected, by PCR method, in swabs from the gingiva and buccal membrane of the dog with which the boy had been in contact . The boy was first treated with cefdinir (300 mg daily) for 6 days without beneficial effect . He responded, however, to minocycline (100 mg daily) with symptom resolution in four days . The other patient was a 64-year-old man who had experienced a fever of 38-39 degrees C for 27 days, as well as having right inguinal lymphadenopathy . The man's serum IgM antibody to B . henselae was negative, although his IgG value, determined by IFA, was 1:1,024 . In addition, B . henselae DNA was detected, by PCR method, in parafin-embedded tissue obtained from the biopsied inguinal lymph nodes . The man was treated with cefazolin (2 g daily) . His fever resolved, but his lymph nodes remained swollen . After a regimen of erythromycin (1,200 mg daily), the swelling in his inguinal lymphnodes gradually disappeared . Careful review of suspected CSD victims' history of contact with animals is important in making a prompt diagnosis of B . henselae infection. Pharmacotherapy, 2001 Oct, 21(10), 1192 - 5 Effects of metronidazole on hepatic CYP3A4 activity; Haas CE et al.; STUDY OBJECTIVE: To evaluate the effect of a short course of oral metronidazole, commonly used for bowel-preparation regimens, on hepatic cytochrome P450 (CYP) 3A4 activity, as measured by the {14C N-methyl}-erythromycin breath test (ERMBT) in healthy volunteers . DESIGN: Prospective, nonrandomized, interventional study SETTING: University-affiliated, community, teaching hospital . SUBJECTS: Five healthy male volunteers . INTERVENTION: Subjects underwent a baseline ERMBT in the morning before receiving three oral doses of metronidazole 500 mg administered at 3 P.M., 7 P.M., and 11 P.M . Repeat ERMBTs were performed at 24, 72, and 96 hours after the initial ERMBT . Changes in ERMBT values were compared with baseline results using Freidman's repeated-measures analysis of variance on ranks . MEASUREMENTS AND MAIN RESULTS: The ERMBT values did not change significantly compared with baseline (p=0.82) . Median (range) ERMBT values expressed as a percentage of baseline at 24, 72, and 96 hours were 110.3 (96.2-136.9), 101.3 (99.3-115.0), and 101.8 (95.5-116.3), respectively CONCLUSION: A short course of oral metronidazole does not result in a significant change in hepatic CYP3A4 activity as measured by the ERMBT. Ned Tijdschr Geneeskd, 2001 Sep 22, 145(38), 1828 - 31 {Erythromycin for premature rupture of membranes is beneficial for infant}; Buitendijk SE; In the 'Overview of the role of antibiotics in curtailing labour and early delivery' (ORACLE I)-trial in women with premature rupture of membranes, the use of erythromycin was found to be associated with a decrease in the primary composite outcome (neonatal death, chronic lung disease or major cerebral abnormality on ultrasound; p = 0.08) and in single adverse neonatal outcomes (p = 0.02) when compared to placebo . The positive results were more significant in the singleton group (p = 0.02 for the composite outcome), while no effects were found in twin pregnancies . The combination of amoxycillin and clavulanic acid, with or without erythromycin, was associated with some improvements in outcome, but was also accompanied by a higher rate of neonatal necrotising enterocolitis . Another trial (ORACLE II) found no effects of antibiotic use in women with premature labour with intact membranes . Although both trials were of good quality, the stratification into singleton and twin pregnancies should have been done more consistently . Because premature rupture of membranes in singleton pregnancies is more likely to be associated with a pre-existing infection than in multiple pregnancies, the potential benefit of treatment with antibiotics is larger in singleton pregnancies. Microbiol Immunol, 2001, 45(8), 617 - 20 Characteristics of macrolide-resistant Mycoplasma pneumoniae strains isolated from patients and induced with erythromycin in vitro; Okazaki N et al.; Some patients with Mycoplasma pneumoniae infection are clinically resistant to antibiotics such as erythromycin, clarithromycin, or clindamycin . We isolated M . pneumoniae from such patients and found that one of three isolates showed a point mutation in the 23S rRNA gene . Furthermore, 141 EM-sensitive clinical isolates of M . pneumoniae were cultured in broth medium containing 100 microg/ml of erythromycin (EM) . Among 11 EM-resistant strains that grew in the medium, point mutations in the 23S rRNA were found in 3 strains at A2063G, 5 strains at A2064G and 3 strains at A2064C . The relationship between the point mutation pattern of these EM-resistant strains and their resistance phenotypes to several macrolide antibiotics was investigated. N Z Med J, 2001 Aug 24, 114(1138), 374 - 7 Treatment practices for chlamydial infection in New Zealand; Bennett S et al.; AIMS: To identify prescribing and treatment practices for chlamydial infection in New Zealand . METHODS: Postal survey to doctors and nurses at all sexual health, family planning, student and youth health centres, and randomly selected general practitioners . RESULTS: There was considerable variation in treatment regimes used for chlamydial infection with few respondents treating in accordance with international guidelines regarding dose, frequency, and duration of treatment . Doxycycline (88.4%) was most commonly used to treat uncomplicated chlamydial infection in non-pregnant patients . Most respondents (70.2%) stipulated doxycycline for longer durations than the seven day regimen international guidelines recommend, with doxycycline 100 mg twice a day for ten days most frequently specified . Among the 259 respondents who would treat pregnant women with erythromycin, 51 different treatment regimens were specified, and 51.7% recorded regimens less than that recommended by international guidelines . When treating a patient presumptively, the majority of respondents tested for chlamydial infection . In contrast to other respondents, sexual health clinic staff rarely provide patients with a prescription for a patient's partner without seeing the partner . CONCLUSIONS: Standardised treatment guidelines are required for patients diagnosed with chlamydial infection . Guidelines should include recommendations for the treatment of partners, and encourage the laboratory confirmation of diagnosis. Crit Care Med, 2001 Oct, 29(10), 1916 - 9 Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill; Boivin MA et al.; OBJECTIVE: To determine whether adding erythromycin to a gastric feeding regimen could render it as effective in meeting nutritional needs as transpyloric feeding . DESIGN: Randomized, controlled study . SETTING: University hospital medical, surgical, and neurologic care intensive care units . PATIENTS: Critically ill patients, requiring a projected 96 hrs of enteral feeding, who had no specific indication for tube location (gastric or transpyloric) . Eighty patients were randomized . INTERVENTIONS: Patients were randomized to gastric feeding with erythromycin (200 mg iv) given every 8 hrs or feeding through a transpylorically placed feeding tube . Goal rate and feeding advancement were determined by protocol . MEASUREMENTS AND MAIN RESULTS: During the 96-hr period, the gastric group received 74% of their goal calories and the transpyloric group received 67% . The only day on which gastric feedings were superior was the first study day, where the gastric group attained 55% of their goal, compared with 44% in the transpyloric group . This 1-day difference was the result of an initial failure of tube placement in some subjects . Exclusion of these patients did not change overall results . Nutritional indexes, length of stay in the intensive care unit, ventilator dependence, and survival were not different between the two groups . CONCLUSIONS: Gastric feeding with erythromycin as a prokinetic is equivalent to transpyloric feeding in meeting the nutritional goals of the critically ill. Int J Antimicrob Agents, 2001, 18 Suppl 1, S71 - 6 Comparative safety of the different macrolides; Rubinstein E; The macrolides are generally well tolerated when used for the treatment of acute infections . Even when given long term for prophylaxis, there are few discontinuations due to side-effects . There are isolated reports of QT(c) prolongation in patients treated with erythromycin and other 14-membered-ring macrolides . Since the 14-membered-ring macrolides are metabolized by P450 isoenzymes, there is the potential for interaction with other therapeutic agents also metabolized in this way . Pharmacokinetic studies have demonstrated interactions between either erythromycin or clarithromycin and cyclosporin, cisapride, pimozide, disopyramide, astemizole, carbamazepine, midazolam, digoxin, hydroxymethylglutaryl-coenzyme A reductase inhibitors (i.e . 'statins') and warfarin . In patients receiving such concurrent therapy, azithromycin may be superior to erythromycin and clarithromycin. Br J Anaesth, 2001 Jun, 86(6), 869 - 71 Gastric residual volume in children: a study comparing efficiency of erythromycin and metoclopramide as prokinetic agents; Zatman TF et al.; Metoclopramide may be used to stimulate gastric emptying when anaesthetizing children for emergency operations . Unfortunately, metoclopramide is associated with extrapyramidal side effects . Erythromycin, a motilin receptor agonist, is a prokinetic agent but its use has been little investigated in children . This randomized double-blind study compared the effects of premedication with oral metoclopramide 0.15 mg kg(-1) or erythromycin 1 mg kg(-1) on gastric emptying in 80 children undergoing tonsillectomy . Pre-operative fluids, premedication and anaesthetic technique were standardized and gastric volume was measured with an orogastric tube . Post-operative nausea and vomiting was recorded . Metoclopramide and erythromycin produced similar gastric volumes (0.29 and 0.24 ml kg(-1)) and there was no difference in post-operative vomiting . In the erythromycin group there were more patients with negative aspirates (45.9%) than in the metoclopramide group (35.1%), but the difference was not statistically significant . These results indicate that erythromycin may be as effective as metoclopramide as a prokinetic agent. Wien Klin Wochenschr, 2001 Aug 16, 113(15-16), 593 - 6 Efficacy of macrolides vs . metronidazole against Entamoeba histolytica clinical isolates; Georgopoulos A et al.; Current treatment of Entamoeba histolytica infection requires the use of several agents that are effective at different sites of the body . Commonly administered agents such as nitroimidazoles have a high rate of gastrointestinal side effects and their use is restricted during pregnancy . In order to offer new choices, four macrolide antibiotics (erythromycin, clarithromycin, azithromycin, josamycin) and metronidazole were tested for their in vitro activity against E . histolytica . Ten clinically isolated strains from an endemic area (Santo Domingo, Dominican Republic) were tested after polyxenical culture . Protozoan viability was significantly reduced by josamycin after 24 and 48 hours of incubation at a concentration of > or = 50 mg/l, which was slightly higher than that of metronidazole (25 mg/l) . No resistance to metronidazole was found . The antiamebic activity of azithromycin, clarithromycin and erythromycin was significant at drug concentrations > or = 100 mg/l . High doses of josamycin, which is a very well tolerated drug, may serve as a useful therapeutic agent in the presence of E . histolytica infection. Arch Intern Med, 2001 Sep 10, 161(16), 2021 - 6 Risk of cataract in patients treated with statins; Schlienger RG et al.; BACKGROUND: Studies in dogs showed that some hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are associated with cataract when administered in excessive doses . Clinical safety data of statins regarding cataract development in humans have been of limited value so far . OBJECTIVE: To determine whether long-term use of statins is associated with an increased risk of cataract . METHODS: We conducted a case-control analysis using data from the United Kingdom-based General Practice Research Database . The main outcome was a first-time diagnosis of cataract and/or cataract extraction in patients aged 40 to 79 years . Controls were matched to cases on age, sex, practice, calendar time, and duration of medical history in the database . Use of statins, fibrates, or other lipid-lowering drugs was compared with nonuse of any lipid-lowering drug, stratified by exposure duration and dose . RESULTS: We identified 7405 cases and 28 327 controls . Long-term use of statins (eg, > or =30 prescriptions) was not associated with an increased cataract risk (adjusted odds ratio {OR}, 0.9; 95% confidence interval {CI}, 0.5-1.6), nor was use of fibrates or of other lipid-lowering drugs (adjusted OR, 0.5; 95% CI, 0.3-1.1; and OR, 0.7; 95% CI, 0.1-5.6, respectively) . We found evidence that concomitant use of simvastatin and erythromycin, a potent inhibitor of simvastatin metabolism, is associated with an increased cataract risk (adjusted odds ratio, 2.2; 95% confidence interval, 1.2-4.1) . CONCLUSIONS: Our study provides evidence that long-term use of therapeutic statin doses does not increase the risk of developing cataract . Concomitant use of erythromycin and simvastatin may increase the cataract risk. Xenobiotica, 2001 Aug-Sep, 31(8-9), 469 - 97 Role of transport proteins in drug absorption, distribution and excretion; Ayrton A et al.; 1 . The molecular and functional characterization of transport proteins is emerging rapidly and significant numbers of drugs have been shown to be substrates or inhibitors . The purpose of this review is to highlight the in vivo preclinical and clinical evidence that supports a role for transport proteins in attenuating the absorption, distribution and excretion (ADE) of drugs . 2 . For absorption, a clear role has emerged for P-glycoprotein in limiting permeability across the gastrointestinal tract . As a result, a wide variety of drugs suffer from incomplete, variable and non-linear absorption . Similarly, at the blood-brain barrier a range of drugs has limited brain penetration due to P-glycoprotein-mediated efflux, which can limit therapeutic effectiveness of CNS agents . In the liver, transport proteins are present on the sinusoidal membrane that can be the rate-limiting step in hepatic clearance for some drugs . Mechanistic studies clearly suggest a key role and broad substrate specificity for the OATP family of sinusoidal transporters . Mainly ATP-dependent transport proteins such as P-glycoprotein and MRP2 govern active biliary excretion . 3 . Drug-drug interactions have been demonstrated involving inhibition or induction of transport proteins . Clinically significant interactions in the gastrointestinal tract and kidney have been observed with inhibitors such as ketoconazole, erythromycin, verapamil, quinidine, probenecid and cimetidine . Clinically significant inhibition at the blood-brain barrier is more difficult to demonstrate, relying on pharmacodynamic and toxicodynamic changes, but an example is quinidine increasing loperamide-induced central effects in humans . 4 . This review highlights the emerging role of transport proteins in ADE of drugs and suggests these need to be considered, in drug discovery and development, with respect to variability in drug disposition and response. Curr Opin Investig Drugs, 2001 Apr, 2(4), 555 - 7 GM-611 (Chugai Pharmaceutical); Peeters TL; GM-611 is an erythromycin derivative that acts as an agonist at the motilin receptor . It is being developed by Chugai as a potential treatment for gastric motility disorder {169036}, as well as reflux esophagitis, non-ulcer dyspepsia and diabetic gastroparesis {347963} . GM-611 is in phase II trials in the US for reflux esophagitis {322624}, {347955}, {399349} . GM-611 acts by a novel mechanism whereby it stimulates and promotes peristalsis in the stomach and other segments of the gastrointestinal tract {334994} . The drug was shown to produce a dose-dependent sustained depolarization of rabbit duodenal smooth muscle . Depolarization appeared to be associated with activation of monovalent cation-selective channels {273336} . In December 2000, Credit Suisse First Boston predicted that successful development of GM-611 could lead to sales over $500 million {400228}. Int J Clin Pharmacol Ther, 2001 Sep, 39(9), 369 - 82 Drug interactions of the statins and consequences for drug selection; Boger RH; Cholesterol-lowering drugs such as HMG-CoA reductase inhibitors ("statins") are increasingly used in hypercholesterolemic patients who suffer from multiple concomitant diseases, and are therefore taking multiple drugs . The statins do not differ in their mechanism of action (pharmacodynamics), but there are differences in the affinity to the target enzyme as well as differences in pharmacokinetic properties, which need to be considered when choosing a statin for a specific patient . The most critical side effect of statins is development of myopathy, which becomes evident as muscle pain, weakness, and elevation of serum creatine kinase activity . The incidence of myopathy is usually low . However, myopathy and rhabdomyolysis are more frequent when statins are combined with other drugs that inhibit cytochrome P450-dependent metabolism of statins in the liver (e.g., itraconazole, erythromycin) . Drug interactions can thus significantly increase the risk associated with statin therapy . Oral bioavailability of the statins varies considerably . Besides the absolute rate of oral bioavailability, it is important to know the relative difference between intestinal absorption rate and rate of oral bioavailability in order to assess the potential for drug-drug interactions . Statins that are not metabolized by a single cytochrome P450 isoenzyme, and have a high bioavailability, are the least prone to drug interactions. Curr Gastroenterol Rep, 2001 Oct, 3(5), 433 - 6 Update on acute colonic pseudo-obstruction; Eaker EY; Acute colonic pseudo-obstruction is characterized by distention of the colon in the absence of mechanical obstruction . This presentation is typically related to recent surgery, severe illness, or medication . Nasogastric and rectal tube decompression and correction of electrolyte abnormalities are the standard of care . Colonoscopic decompression, performed in a number of these cases, was felt to be unwarranted in many situations and is associated with a high recurrence rate . Medical management beyond conservative measures has been limited . Medical therapy with pharmacologic agents such as erythromycin, metoclopromide, and cisapride was of limited use . Recent findings confirm that an older agent, neostigmine, provides excellent results, including colonic decompression and clinical improvement after administration . This suggests a new standard of care. Kaohsiung J Med Sci, 2001 Jun, 17(6), 331 - 5 Legionnaires' disease in an immunocompetent young adult; Tsai HC et al.; Infection with Legionella pneumophila (LP) is a rare cause of pneumonia in previously healthy young adults . Pleural effusion is relatively common in Legionnaires' disease but is usually clinically insignificant . Herein we describe an immunocompetent, 19-year-old female with LP respiratory infection that presented with pleural effusion and mild interstitial infiltrates in the lower lungs . She received 3 weeks' treatment with erythromycin and rifampin and recovered completely . Diagnosis was based on serology testing with a four-fold rise of the antibody titer in the acute and convalescent phase . Legionnaires' disease should be considered in the differential diagnosis of culture-negative pleural effusion in immunocompetent young adults. Clin Pharmacol Ther, 2001 Sep, 70(3), 247 - 54 Population pharmacokinetics of everolimus in de novo renal transplant patients: impact of ethnicity and comedications; Kovarik JM et al.; BACKGROUND: Everolimus is a macrolide immunosuppressant intended for acute rejection prophylaxis after kidney transplantation . METHODS: A total of 5260 blood samples were collected in the context of two randomized, double-blind, multicenter efficacy trials in 673 patients over a 6-month period after kidney transplantation . The data were evaluated in a nonlinear mixed-effects model . The influence of demographic characteristics (age, weight, sex, and ethnicity) and of comedications on everolimus exposure was explored . RESULTS: For a reference 44-year-old, 71-kg Caucasian kidney allograft recipient receiving everolimus as part of a cyclosporine (INN, ciclosporin)-prednisone immunosuppressive regimen, the absorption rate constant was 6.07 h(-1) (standard error {SE}, 0.70 h(-1)), the apparent clearance was 8.8 L/h (SE, 0.2 L/h), and the apparent central distribution volume was 110 L (SE, 5 L) . There were no clinically relevant influences of age, weight, or sex on clearance . No significant difference in clearance was detected for Asian patients, whereas black patients had an average clearance that was 20% higher than that of nonblack patients . Patients concomitantly receiving erythromycin or azithromycin had an average 19% lower clearance . One patient receiving itraconazole had a 74% reduction in clearance . After we accounted for covariates, the remaining interindividual variability in clearance was 27% and the variability for distribution volume was 36% . The combined intraindividual and assay/measurement residual error in everolimus blood concentrations was 31% . CONCLUSIONS: Dose adjustment of everolimus on the basis of weight does not appear necessary . Black patients may need a higher dose to achieve exposure that is similar to that of nonblack patients . Concomitant administration of potent inhibitors of the cytochrome P450 isozyme CYP3A may reduce everolimus clearance and increase its blood concentrations. Clin Pharmacol Ther, 2001 Sep, 70(3), 228 - 36 Ethnic differences and relationships in the oral pharmacokinetics of nifedipine and erythromycin; Yu KS et al.; OBJECTIVE: Our objective was to investigate ethnic differences in the oral pharmacokinetics of nifedipine and erythromycin, both typical cytochrome P4503A (CYP3A) substrates, in Koreans and Caucasians and to identify the nature of any correlations between the pharmacokinetic parameters of the two drugs . METHODS: Twenty healthy male volunteers (10 Koreans and 10 Caucasians) received single oral doses of nifedipine (10 mg) or erythromycin (500 mg) in a randomized 2-way crossover study . Pharmacokinetic evaluations were performed, and parameters were compared for the two ethnic groups . During the nifedipine study period, hemodynamic measurements were conducted to determine the pharmacodynamic relevance of the pharmacokinetic differences . RESULTS: Koreans showed area under the concentration-time curves (AUCs) for both drugs that were 1.6 to 1.7 times higher than those of Caucasians . This difference decreased to 1.3 when normalized for body weight . Significant correlation between the AUCs of the two drugs was not evident . Hemodynamic changes after nifedipine administration paralleled those of the pharmacokinetic differences, with significantly greater decreases in blood pressure and total peripheral resistance noted in Koreans . CONCLUSIONS: Koreans showed significantly lower oral clearances of nifedipine and erythromycin, probably because of genetic differences attributed to the CYP3A enzymes. Antimicrob Agents Chemother, 2001 Oct, 45(10), 2798 - 806 Cellular uptake of two fluoroketolides, HMR 3562 and HMR 3787, by human polymorphonuclear neutrophils in vitro; Abdelghaffar H et al.; We analyzed the cellular accumulation of two new fluoroketolides, HMR 3562 and HMR 3787, by human polymorphonuclear neutrophils (PMN) in vitro . Both compounds were rapidly taken up by PMN, with a cellular-to-extracellular concentration ratio (C/E) of about 141 (HMR 3562) and 117 (HMR 3787) at 5 min, and this was followed by a plateau at 60 to 180 min, with a C/E of >300 at 180 min . Both ketolides were mainly located in PMN granules (about 75%) and egressed slowly from loaded cells (about 40% at 60 min), owing to avid reuptake . Uptake was moderately sensitive to external pH, and activation energy was also moderate (about 70 kJ/mol) . As with other macrolides and ketolides, the existence of an active transport system was suggested by (i) the strong interindividual variability in uptake kinetics, suggesting variability in the number or activity of a transport protein; (ii) the saturation kinetics characteristic of a carrier-mediated transport system (V(max), about 2,300 ng/2.5 x 10(6) PMN/5 min; K(m), about 50 microg/ml); (iii) the inhibitory effects of Ni(2+) (a blocker of the Na+-Ca(2+) exchanger), phorbol myristate acetate (a protein kinase C activator), and H89 (a protein kinase A inhibitor) . Although these two ketolides are more related to HMR 3647 (telithromycin), it is interesting that the presence of a fluoride gave these molecules a cellular pharmacokinetics more like those of HMR 3004 than those of HMR 3647 . The macrolide transport system has not been yet elucidated, but our data confirm that, despite variations in chemical structure, all erythromycin A derivatives share a transmembrane transport system. Chest, 2001 Sep, 120(3), 730 - 3 Erythromycin and common cold in COPD; Suzuki T et al.; STUDY OBJECTIVES: To investigate whether erythromycin therapy lowers the frequency of the common cold and subsequent exacerbation in patients with COPD . DESIGN: Prospective, randomized, controlled, but not blinded, trial . PATIENTS: One hundred nine patients with COPD were enrolled into the study . Patients were randomly assigned to erythromycin therapy or to no active treatment in September 1997 . Patients then were observed for 12 months, starting in October, during which time the risk and frequency of catching common colds and COPD exacerbations were investigated . Fifty-five patients received erythromycin at study entry (erythromycin group) . The remaining 54 patients received no active treatment (control group) . MEASUREMENTS AND RESULTS: The mean (+/- SE) number of common colds for 12 months was significantly lower in the erythromycin group than in the control group (1.24 +/- 0.07 vs 4.54 +/- 0.02, respectively, per person; p = 0.0002) . Forty-one patients (76%) in the control group experienced common colds more than once, compared to 7 patients (13%) in the erythromycin group . The relative risk of developing two or more common colds in the control group compared with that in the erythromycin group was 9.26 (95% confidence interval {CI}, 3.92 to 31.74; p = 0.0001) . Thirty patients (56%) in the control group and 6 patients (11%) in the erythromycin group had one or more exacerbations . The relative risk of experiencing an exacerbation in the control group compared with that in the erythromycin group was 4.71 (95% CI, 1.53 to 14.5; p = 0.007) . Significantly more patients were hospitalized due to exacerbations in the control group than in the erythromycin group (p = 0.0007) . CONCLUSION: Erythromycin therapy has beneficial effects on the prevention of exacerbations in COPD patients. Mol Microbiol, 2001 Sep, 41(5), 1091 - 9 The pleuromutilin drugs tiamulin and valnemulin bind to the RNA at the peptidyl transferase centre on the ribosome; Poulsen SM et al.; The pleuromutilin antibiotic derivatives, tiamulin and valnemulin, inhibit protein synthesis by binding to the 50S ribosomal subunit of bacteria . The action and binding site of tiamulin and valnemulin was further characterized on Escherichia coli ribosomes . It was revealed that these drugs are strong inhibitors of peptidyl transferase and interact with domain V of 23S RNA, giving clear chemical footprints at nucleotides A2058-9, U2506 and U2584-5 . Most of these nucleotides are highly conserved phylogenetically and functionally important, and all of them are at or near the peptidyl transferase centre and have been associated with binding of several antibiotics . Competitive footprinting shows that tiamulin and valnemulin can bind concurrently with the macrolide erythromycin but compete with the macrolide carbomycin, which is a peptidyl transferase inhibitor . We infer from these and previous results that tiamulin and valnemulin interact with the rRNA in the peptidyl transferase slot on the ribosomes in which they prevent the correct positioning of the CCA-ends of tRNAs for peptide transfer. J Vet Pharmacol Ther, 2001 Aug, 24(4), 251 - 9 Pharmacokinetics and microsomal oxidation of praziquantel and its effects on the P450 system in three-month-old lambs infested by Fasciola hepatica; Giorgi M et al.; Praziquantel (PZQ) is a broadly effective trematocide and cestocide, widely employed in veterinary and human medicine . In view of several differences in both its pharmacokinetic profile in different animal species and in the cytochrome P450-dependent system between ruminant and nonruminant species, the present study was undertaken to determine the pharmacokinetics of this drug, its effects on the P450 system and the involvement of cytochrome P450 in its metabolism in 3-month-old lambs infested by Fasciola hepatica . Following both oral and i.m . administration, PZQ disposition was best described by a linear one-compartment open model with a rapid absorption and elimination . Although the PZQ dose used by the i.m . route was only half of that used by the oral route, the mean PZQ plasma concentration was higher after i.m . than after oral treatment . Oral treatment with 30 mg/kg/day of PZQ did not modify the mono-oxygenase activities tested, whilst the administration of PZQ at a dose of 60 mg/kg/day for 2 days caused a significant decrease in the P450 3A-dependent erythromycin N-demethylase and 6beta testosterone hydroxylase activities . From the incubation of microsomes from lambs not treated with PZQ, a single metabolite (PZQ 11b-OH or PZQ 1-OH) was identified by GC/MS analysis . By selective inhibition of the 3A subfamily performed with triacetyloleandromycin, the production of this metabolite declined by about 90% suggesting a prominent role of P450 3A isoforms in this oxidation . These features indicate that agents or drugs which are able to modulate P450 3A-dependent catalysis may interfere with the metabolism, bioavailability and therapeutic effects of PZQ. J Chromatogr A, 2001 Aug 10, 926(1), 97 - 104 Confirmatory method for macrolide residues in bovine tissues by micro-liquid chromatography-tandem mass spectrometry; Draisci R et al.; A new confirmatory method for three macrolides (tylosin, tilmicosin and erythromycin) in bovine muscle, liver and kidney by micro-LC-MS-MS using an atmospheric pressure ionisation source and an ionspray interface has been developed . Roxithromycin was used as internal standard . The molecular related ions, {M+2H}2+, at m/z 435 for tilmicosin, and {M+H}+, at m/z 734 and 916 for erythromycin and tylosin, respectively, were the precursor ions for collision-induced-dissociation and two diagnostic product ions for each macrolide were identified for the unambiguous confirmation by selected reaction monitoring LC-MS-MS . Precision values (relative standard deviations) were all below 14.9%, whereas the overall accuracy (relative error) ranged from -17.7 to -9.8% for tylosin, from -17.5 to -10.7% for tilmicosin and from -19.6 to -13.7% for erythromycin, in all the investigated bovine tissues . The limits of quantification were 30 (muscle) or 40 (liver, kidney) microg kg(-1), 20 (muscle) or 150 (liver, kidney) microg kg(-1), 50 (muscle, liver) or 80 (kidney) microg kg(-1), 20 (muscle, liver) or 50 (kidney) microg kg(-1) for tylosin, tilmicosin, erytromycin and roxithromycin, respectively. J Toxicol Sci, 2001 Aug, 26(3), 141 - 50 Climbazole is a new potent inducer of rat hepatic cytochrome P450; Kobayashi Y et al.; We examined the effect of climbazole on the induction of rat hepatic microsomal cytochrome P450 (P450), and compared the induction potency with other N-substituted azole drugs such as clorimazole . We found that climbazole is found to be a potent inducer of rat hepatic microsomal P450 as clorimazole . Induced level of P450 by climbazole was almost similar in extent to clorimazole when compared with other imidazole drugs in a dose- and time-dependent manner . Parallel to the increase in P450, climbazole increased aminopyrine and erythromycin N-demethylase, ethoxycoumarin O-deethylase, and androstenedione 16 beta- and 15 alpha/6 beta hydroxylase activities; however, clorimazole did not induce aminopyrine N-demethylase activity irrespective of its marked increase in P450 content . Immunoblot analyses revealed that climbazole induced CYP2B1, 3A2 and 4A1 . The present findings indicate that climbazole is a new potent inducer of hepatic microsomal P450 and drug-metabolizing enzymes like clorimazole, but it may have some differential mechanism(s) for these enzymes' induction in rat liver. Biochem Biophys Res Commun, 2001 Sep 14, 287(1), 198 - 203 Gene expression profiles of human small airway epithelial cells treated with low doses of 14- and 16-membered macrolides; Yamanaka Y et al.; Although long-term treatment with low doses of 14-membered macrolides is widely applied in management of patients with chronic inflammatory diseases, e.g., diffuse panbronchiolitis, chronic bronchitis, or chronic lung damage in newborns, the physiological mechanisms underlying the action of macrolides in these conditions are unclear . To clarify the pathological basis of these diseases and also to aid in the design of novel drugs to treat them, we chose to investigate the molecular target(s) of macrolides . Our experiments involved long-term culture of human small airway epithelial cells (hSAEC) in media containing 14-membered macrolides erythromycin (EM) or clarithromycin (CAM), or a 16-membered macrolide, josamycin (JM), which lacks clinical anti-inflammatory effects . We then analyzed gene expression profiles in the treated cells using a cDNA microarray consisting of 18,432 genes . We identified nine genes whose expression was significantly altered during 22 days of culture with EM, and seven that were altered by CAM in that time . Four of those genes revealed similar behavior in cells treated with either of the 14-membered macrolides, but not JM . The products of these four genes may be candidates for mediating the ability of 14-membered macrolides to suppress chronic inflammation . Appl Microbiol Biotechnol, 2001 Aug, 56(3-4), 414 - 9 Disruption of a gene encoding a putative gamma-butyrolactone-binding protein in Streptomyces tendae affects nikkomycin production; Engel P et al.; A 2.6-kb BamHI fragment from the genome of the wild-type, nikkomycin-producing strain of Streptomyces tendae ATCC 31160 was cloned and sequenced . This 2.6-kb BamHI fragment corresponds to the DNA site where transposon Tn4560 had inserted to create a nikkomycin-nonproducing mutant . A possible ORF of 660 nucleotides was found in this 2.6-kb BamHI fragment, in which the third base of each codon was either G or C in 92% of the codons . The deduced amino acid sequence coded by this ORF (TarA, tendae autoregulator receptor) shows strong homology with several Gamma-butyrolactone-binding proteins that negatively regulate antibiotic production in other streptomycetes and have a helix-turn-helix DNA-binding motif . A portion (179 nucleotides) of tarA that encodes the helix-turn-helix motif was replaced with ermE, and wild-type S . tendae was transformed with this construct borne in pDH5, a gene-disruption vector . Southern hybridization indicated that ermE had inserted in the 2.6-kb BamHI region in one isolate that is erythromycin resistant . Northern hybridization indicated that tarA disruption significantly increased the amount of disrupted-tarA mRNA . This suggests that TarA negatively regulates its own synthesis . Nikkomycin production by the tarA disruptant was delayed but reached the wild-type level after longer incubation in production medium. Zh Mikrobiol Epidemiol Immunobiol, 2001 Mar-Apr, (2), 36 - 40 {Etiology, clinical manifestations, and epidemiology in community-acquired respiratory infection in children in the Khabarovsk region}; Kholodok GN et al.; Clinico-epidemiological analysis and etiological verification of the outbreak of respiratory infection among school children in a rural district of the Khabarovsk territory, registered in spring 1997, were made . According to clinical signs, one-third of the patients had whooping cough, while the rest of the children exhibited the signs of respiratory infection with the symptoms of longering bronchitis . A half of the children had not been vaccinated against whooping cough, as they had been given injections of adsorbed DT vaccine with reduced antigen content . Etiologically, the diagnosis of whooping cough was confirmed in 57% of the patients with 47.4% of them having Bordetella pertussis monoinfection and 52.6% having mixed infection, mainly in combination with chlamydiosis . Whooping cough took an abnormal course under these circumstances . Treatment with erythromycin produced a good effect. Cir Pediatr, 2001 Jul, 14(3), 98 - 102 {Anorexia nervosa or somatic disease}; Garcia Aroca J et al.; We have studied 18 patients with anorexia nervosa with antroduodenal manometry for 24 hours and also 24 hours oesophageal pH studies . After the first 12 hours of measurements we started treatment with Cisapride (n = 8) or Erythromycin (n = 10) in a blind study . The results of measurements reveal a severe gastroesophageal reflux in 4 patients . Antroduodenal manometry showed dysfunctions in gastric motility, without relation with weight loss or duration of the disease . Cisapride and more so Erythromycin favor gastrointestinal motility. J Infect, 2001 Apr, 42(3), 206 - 7 Legionella pneumonia and bacteraemia in association with protein-losing enteropathy after Fontan operation; Cheung YF et al.; A 20-year-old young man suffered from severe protein-losing enteropathy 4 years after Fontan operation . His postoperative haemodynamics were unfavourable in terms of poor myocardial contractility and moderate atrioventricular prosthetic paravalvar leakage . A 2-week trial of steroid therapy for protein-losing enteropathy was given without success . The clinical course was complicated by Legionella pneumophila pneumonia and bacteraemia, which respond to the combination therapy with intravenous erythromycin and ciprofloxacin . The vulnerability of the patient to infection was related to an immuno-deficiency state secondary to protein-losing enteropathy and steroid therapy . Steroids should be used with caution in the management of protein-losing enteropathy after Fontan operation . J Laryngol Otol, 2001 Aug, 115(8), 622 - 8 Reversible ototoxic effect of azithromycin and clarithromycin on transiently evoked otoacoustic emissions in guinea pigs; Uzun C et al.; The possible cochlear toxicity of systemically applied macrolides--erythromycin (ER), azithromycin (AZ) and clarithromycin(CL)--was investigated in guinea pigs by measuring transiently evoked otoacoustic emissions (TEOAEs) . A single dose of 125 mg/kg intravenous (i.v.) ER caused no change in TEOAEs in guinea pigs (p>0.05), whereas AZ (45 mg/kg orally) and CL (75 mg/kg i.v.) reversibly reduced the emission response (p<0.05) . The reversible reduction of TEOAE responses due to AZ and CL, which is in accordance with the clinical picture of AZ and CL ototoxicity, could likely be attributable to the transient dysfunction of outer hair cells . The present study reveals that at least one ototoxic effect of AZ and CL is on the inner ear . The results may also encourage planning clinical researches on TEOAE monitoring in patients receiving high doses of AZ or CL. J Antimicrob Chemother, 2001 Sep, 48(3), 403 - 5 In vitro activity of telithromycin, a new ketolide, against Chlamydia pneumoniae; Miyashita N et al.; The in vitro activity of telithromycin, a new ketolide, was compared with those of roxithromycin, azithromycin, clarithromycin and erythromycin A against 20 strains of Chlamydia pneumoniae . The MICs and minimal chlamydiacidal concentrations of telithromycin for the 20 C . pneumoniae strains both ranged between 0.031 and 0.25 mg/L . Telithromycin was twice as active as roxithromycin, azithromycin and erythromycin A, but less active than clarithromycin . These results appear to indicate that telithromycin is an effective antibiotic that should play some role in the treatment of respiratory tract infections caused by C . pneumoniae. Acta Obstet Gynecol Scand, 2001 Aug, 80(8), 697 - 701 Effects of erythromycin on stretch-induced contractile activity of isolated myometrium from pregnant women; Celik H et al.; BACKGROUND: Despite the fact that preterm labor and birth account for the vast majority of neonatal morbidity and mortality the currently available treatment options are still far from satisfactory . The aim of this study was to investigate the effects of erythromycin on stretch-induced contractions of pregnant human myometrial strips, obtained at cesarean section . METHOD: Myometrial strips were suspended in an organ bath under 3 g tension and the effects of erythromycin (0.1, 0.2, 0.5, 1.0 mM) on stretch-induced isometric contractions were evaluated . Results were statistically analyzed using Kruskal Wallis analysis of variance and Wilcoxon Rank tests where appropriate . RESULTS: Erythromycin caused a significant decrease in the peak amplitude, while causing an increase in frequency of stretch-induced myometrial contractions in a dose dependent manner in vitro . CONCLUSIONS: Results from this preliminary study suggest that erythromycin may have additional beneficial effects in infection related preterm labor cases, however, further studies are needed for clarifying the usefulness of erythromycin as a tocolytic agent. Nihon Kokyuki Gakkai Zasshi, 2001 Jun, 39(6), 446 - 51 {A case of Coxiella burnetii pneumonia in an adult}; Miyashita N et al.; A 49-year-old man visited our hospital complaining of a continuous high-grade fever and cough which had appeared during his stay in Indonesia . He was admitted on the same day because his laboratory data showed marked inflammatory changes and his chest radiograph revealed an infiltrative shadow in the right upper lung field . Initial treatment with beta-lactams was not effective and both his symptoms and his chest radiograph worsened . However, treatment with erythromycin clearly had an effect . Then, we carried out several tests for detection of atypical pathogens including Mycoplasma and Chlamydia . Finally, the case was diagnosed as one of Coxiella burnetii pneumonia because the DNA of C . burnetii was detected from his sera and seroconversion of C . burnetii--specific antibody was observed among paired serum samples . C . burnetii is one of the most commonly recognized pathogens among community-acquired pneumonias in Western countries, but in Japan, reports of community-acquired C . burnetii pneumonia have been rare . This difference may be due to the features of Q fever, in which there are large differences in frequency and form from country to country and among areas of the same country . Surveillance of C . burnetii pneumonia in Japan and different area will be required. Acta Paediatr, 2001 Aug, 90(8), 904 - 8 A placebo-controlled trial of low-dose erythromycin to promote feed tolerance in preterm infants; Oei J et al.; The aim of this study was to assess the efficacy of erythromycin, a motilin agonist, in promoting enteral feed tolerance in preterm infants of < or = 32 wk gestation . Eligible infants were randomized to receive either low-dose (2.5 mg kg(-1) per dose 6 hourly) oral erythromycin ethylsuccinate or placebo for 10 d from the time of the first oral feed . The data from 22 erythromycin and 21 placebo infants were analysed . Birthweights (erythromycin 1,216 +/- 380 g, placebo 1,355 +/- 228 g, p = 0.25), gestation (erythromycin 28.6 +/- 2.2 wk, placebo 29.3 +/- 1.7 wk, p = 0.24) and other clinical variables were not different between the groups . Almost all infants were fed expressed breast milk . Erythromycin infants had significantly fewer episodes of large residual gastric aspirates (>30% of the previous 6 h worth of feeds) over 10 d (erythromycin 1.1 +/- 1.9, placebo 3.6 +/- 2.2 episodes, p = 0.0007) . Infants in the erythromycin group achieved full oral feeds more quickly (6.0 +/- 2.3 vs 7.9 +/- 3.5 d, p = 0.04) . There were no significant differences between the groups with regard to the number of days on total parenteral nutrition or to the time needed to regain birthweight . One enrolled infant from each group died of necrotizing enterocolitis . CONCLUSION: Low-dose erythromycin promoted gastric emptying and feed tolerance in premature infants at a lower gestational age than previously reported . Increased exposure to broad-spectrum antibiotics may not be free of risk . Further studies are recommended to assess its efficacy in premature infants with established feed intolerance. Biopharm Drug Dispos, 2000 Nov, 21(8), 331 - 8 Effects of physostigmine on the pharmacokinetics of intravenous parathion in rats; Hurh E et al.; It was reported that the area under the plasma concentration-time curve from time zero to time infinity (AUC) of parathion was significantly smaller, and the time-averaged total body clearance (Cl) of parathion was significantly faster after intravenous administration of parathion to rats pretreated with dexamethasone than those in control rats . This was supported by significantly faster intrinsic clearance of parathion to form paraoxon in hepatic microsomal fraction of rats pretreated with dexamethasone . The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible hepatic cytochrome P450 (CYP) 3A in rats . The purpose of this study is to explain the protective effects of physostigmine against paraoxon toxicity by suppressing CYP3A, and hence, decreasing formation of a toxic metabolite, paraoxon . The pharmacokinetic changes of parathion and paraoxon were investigated after intravenous administration of parathion, 3 mg/kg, to control Sprague-Dawley rats, and the rats pretreated with physostigmine (100 microg/kg, intraperitoneal injection 30 min before parathion administration) . After a 1-min intravenous infusion of parathion to rats pretreated with physostigmine, the AUC of parathion (60.4 compared with 73.7 microg min/mL) was significantly greater, Cl of parathion (49.7 compared with 40.7 mL/min/kg) was significantly slower, and amount of paraoxon recovered from liver, mesentery and large intestine at 5 min was smaller than those in control rats . Based on in vitro rat hepatic microsomal studies, physostigmine inhibited significantly the erythromycin N-demethylase activity (1.03 compared with 0.924 nmol/mg protein/min), mainly mediated by hepatic cytochrome P450 3A in rats . The above data suggested that the formation of paraoxon was inhibited in rats pretreated with physostigmine by inhibiting CYP3A . J Agric Food Chem, 2001 Aug, 49(8), 3709 - 12 Procedure to evaluate the stability during processing and storage of a medicated premix and medicated farm feed: erythromycin thiocyanate; Bernabeu JA et al.; In this paper, a stability study of a medicated premix and medicated farm feed containing erythromycin thiocyanate was planned . No drug degradation was detected during the medicated farm feed processing . In the medicated premix stability study, significant drug degradation was detected only at 40 degrees C and 75% relative humidity . Because after 2 years of storage at 25 degrees C and 60% relative humidity no degradation of erythromycin thiocyanate was detected, this period of time is proposed as the premix shelf life . In the medicated farm feed stability study, drug degradation was detected under accelerated conditions, but it was not detected under long-term storage conditions for 3 months . Therefore, the proposed shelf life of the medicated farm feed is 3 months, as this is time enough to be consumed . The planned stability study-storage conditions, testing frequency, and proposed data evaluation-allowed an easy and reliable evaluation of veterinary medicine stability. Gut, 2001 Sep, 49(3), 395 - 401 Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial; Talley NJ et al.; INTRODUCTION: Erythromycin, a motilin agonist, is a potent prokinetic . ABT-229 is a specific motilin agonist that dose dependently accelerates gastric emptying . Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus . We aimed to evaluate the efficacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying . METHODS: Patients with type 1 diabetes and postprandial symptoms were randomised (n=270) . Based on a validated C(13) octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata . Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline . A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0-800 mm) from baseline to the final visit . RESULTS: The treatment arms were similar regarding baseline characteristics . There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline -169, -101, -155, -143, and -138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat) . The results were not significantly different in those with and without delayed gastric emptying . The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo . Overall, 63% of patients on placebo reported a good or excellent global response, and this was not different from the active treatment arms . CONCLUSIONS: The motilin agonist ABT-229 was not efficacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying. Mol Cell, 2001 Jul, 8(1), 181 - 8 The polypeptide tunnel system in the ribosome and its gating in erythromycin resistance mutants of L4 and L22; Gabashvili IS et al.; Variations in the inner ribosomal landscape determining the topology of nascent protein transport have been studied by three-dimensional cryo-electron microscopy of erythromycin-resistant Escherichia coli 70S ribosomes . Significant differences in the mouth of the 50S subunit tunnel system visualized in the present study support a simple steric-hindrance explanation for the action of the drug . Examination of ribosomes in different functional states suggests that opening and closing of the main tunnel are dynamic features of the large subunit, possibly accompanied by changes in the L7/L12 stalk region . The existence and dynamic behavior of side tunnels suggest that ribosomal proteins L4 and L22 might be involved in the regulation of a multiple exit system facilitating cotranslational processing (or folding or directing) of nascent proteins. Clin Pharmacokinet, 2001, 40(7), 501 - 7 Clinical pharmacokinetics of mizolastine; Lebrun-Vignes B et al.; Mizolastine is a new histamine H1 receptor antagonist . Mizolastine 10 mg/day is effective in allergic rhinitis and chronic idiopathic urticaria . In young healthy volunteers, absorption of mizolastine is rapid with time (tmax) to peak concentration (Cmax) of about 1 hour . The absolute bioavailability of mizolastine 10mg tablets is about 65% . Distribution is rapid with a mean distribution half-life of 1.5 to 1.9 hours . Mizolastine is >98% bound to serum albumin and the apparent volume of distribution is between I and 1.4 L/kg . Mizolastine is extensively metabolised by hepatic glucuronidation and sulphation, with no major active metabolite, and excreted in faeces . The terminal elimination half-life (t1/2beta) is 7.3 to 17.1 hours . The apparent oral clearance after a repeated oral dose of 10mg is 6.02 L/h, with steady state reached from day 3 and no accumulation between days 1 and 7 . Cmax and area under the concentration-time curve (AUC) are linearly related to dose . Mizolastine appears in vivo to be a relatively weak inhibitor of cytochrome P450 2E1, 2C9, 2D6 and 3A4 . In vivo, no interactions were observed between mizolastine and lorazepam or ethanol . A significant increase in Cmax and trough plasma concentration (Cmin) of digoxin occurred after coadministration with mizolastine, without change in AUC, tmax or clinical parameters . Significant increases in theophylline Cmin and AUC were observed after coadministration with mizolastine . Mizolastine Cmax and AUC were increased when coadministered with erythromycin, with no change in t1/2beta . Concomitant administration of mizolastine and ketoconazole increased mizolastine AUC values with no change in t1/2beta . In a population analysis of the pharmacokinetics of mizolastine in patients with allergies, parameter values were close to those in healthy volunteers, except for duration of absorption, which was almost doubled in the patients . Bodyweight and creatinine clearance were found to have little influence on oral clearance, and no influence of liver transaminases was found on clearance and distribution . Pharmacokinetic parameters of mizolastine in elderly individuals were similar to those observed in healthy young volunteers . In patients with chronic renal insufficiency, t1/2beta was prolonged by 47% compared with young healthy volunteers . In patients with cirrhosis, tmax was longer, Cmax was lower, distribution half-life was prolonged and AUC was 50% higher than in healthy volunteers . In pharmacodynamic-pharmacokinetic trials, the percentage of wheal and flare inhibition was found to correlate with mizolastine Cmin values . No direct relationship was found between drug concentrations in skin blister fluid and antihistamine activity. Mutat Res, 2001 Sep 1, 480-481, 171 - 8 Inhibitory effect of naringin on the micronuclei induced by ifosfamide in mouse, and evaluation of its modulatory effect on the Cyp3a subfamily; Alvarez-Gonzalez I et al.; Naringin (Nar) is a flavonone found in high amount in grapefruit . In in vitro studies to determine its antimutagenicity results have been both positive and negative . On the other hand, an increase in the bioavailability of some medicaments have been observed when these are ingested together with grapefruit . It has been suggested that the effect may be related to the inhibition of the human enzyme Cytochrome P450 (CYP) 3A4 by Nar, an enzyme with a high aminoacid sequence homology with the Cyp3a in mouse . The present study was designed for three main purposes: (1) to determine whether Nar has a genotoxic effect in mouse in vivo . This was evaluated by measuring the rate of micronucleated polychromatic erythrocytes (MNPE); (2) to determine its antigenotoxic and its anticytotoxic potential on the damage produced by ifosfamide (Ifos) . The first study was done by scoring the rate of MNPE, and the second one by establishing the index polychromatic erythrocytes/normochromatic erythrocytes (PE/NE); and (3) to explore whether its antigenotoxic mechanism of action is related to an inhibitory effect of Nar on the expression of the Cyp3a enzyme, an effect which could avoid the biotransformation of Ifos . A single oral administration was used for all groups in the experiment: three groups were given different doses of Nar (50, 250, and 500 mg/kg), other groups received the same doses of Nar plus an administration of Ifos (60 mg/kg), another group treated with distilled water and another with Ifos (60 mg/kg) were used as negative and positive controls, respectively . The micronuclei and the cell scoring were made in blood samples taken from the tail of the animals at 0, 24, 48, 72, and 96 h . The results showed that Nar was neither genotoxic nor cytotoxic with the doses tested, but Ifos produced an increase in the rate of MNPE at 24 and 48 h . The highest value was 24+/-1.57 MNPE per thousand cells at 48 h . The index PE/NE was significantly reduced by Ifos at 24 and 48 h . Concerning the antigenotoxic capacity of Nar, a significant decrease was observed in the MNPE produced by Ifos at the three tested doses . This effect was dose-dependent, showing the highest reduction in MNPE frequency (54.2%) at 48 h with 500 mg/kg of Nar . However, no protection on the cytotoxicity produced by Ifos was observed . Immunoblot analysis was used to assess the Cyp3a expression in liver and intestinal microsomes from mouse exposed orally to Nar . An induction in the Cyp3a protein was observed in both intestinal and hepatic microsomes from treated mice . This induction correlated with an increase in erythromycin N-demethylase activity . These data suggest that other mechanism(s) are involved in the antigenotoxic action of naringin. J Clin Pharmacol, 2001 Aug, 41(8), 852 - 60 The risk of liver damage associated with minocycline: a comparative study; Seaman HE et al.; Using the General Practice Research Database, the authors performed (1) a cohort analysis comparing the incidence of liver dysfunction in new users of minocycline with new users of oxytetracycline/tetracycline and (2) a case control study assessing antibiotic exposure in new cases of liver dysfunction and controls without liver dysfunction . In new users, the incidence of liver dysfunction in those exposed to minocycline was 1.04 cases/10,000 exposed person months (EPM) and 0.69 cases/10,000 EPM in those exposed to oxytetracycline/tetracycline (relative risk 1.51 {CI95: 0.63, 3.65}) . The risk in both groups was greatest in the first month of use . The adjusted odds ratio (ORadj) of liver dysfunction associated with exposure to minocycline compared with nonuse was 2.10 (CI95: 1.30, 3.40); for oxytetracycline/tetracycline, the ORadj was 1.46 (CI95: 0.81, 2.64); and for exposure to erythromycin, the ORadj was 1.64 (CI95: 0.71, 3.80) . The authors thus support a weak association between the use of oral antibiotics and liver dysfunction in patients with acne . The risk associated with exposure to minocycline appears to be very small . The cohort analysis demonstrated that any risk associated with minocycline was not significantly greater than that associated with oxytetracycline/tetracycline exposure. Prescrire Int . 2001 Feb;10(51):16. Erythromycin-induced pyloric stenosis in infants; Choosing a macrolide: drug interactions must be taken into account; (1) Some macrolides carry a strong risk of potentially severe drug interactions . (2) Erythromycin is the macrolide with the biggest risk of interactions . (3) Spiramycin is the macrolide with the smallest risk of interactions . Azithromycin and dirithromycin also seem to have a low risk of interactions, but they are far more recent and therefore less well known . (4) In first-line use, unless there are specific indications, a macrolide with a low risk of interactions should be used. Antimicrob Agents Chemother, 2001 Sep, 45(9), 2643 - 7 Stability and compatibility of ceftazidime administered by continuous infusion to intensive care patients; Servais H et al.; The stability and compatibility of ceftazidime have been examined in the context of its potential use in concentrated solutions for continuous infusion in patients suffering from severe nosocomial pneumonia and receiving other intravenous medications by the same route . Ceftazidime stability in 4 to 12% solutions was found satisfactory (<10% degradation) for 24 h if kept at a temperature of 25 degrees C (77 degrees F) maximum . Studies mimicking the simultaneous administration of ceftazidime and other drugs as done in clinics showed physical incompatibilities with vancomycin, nicardipine, midazolam, and propofol and a chemical incompatibility with N-acetylcystein . Concentrated solutions (50 mg/ml) of erythromycin or clarithromycin caused the appearance of a precipitate, whereas gentamicin, tobramycin, amikacin, isepamicin, fluconazole, ketamine, sufentanil, valproic acid, furosemide, uradipil, and a standard amino acid solution were physically and chemically compatible. Xenobiotica, 2001 May, 31(5), 265 - 75 Cooperativity of alpha-naphthoflavone in cytochrome P450 3A-dependent drug oxidation activities in hepatic and intestinal microsomes from mouse and human; Emoto C et al.; 1 . The effects of several CYP3A substrates (alpha-naphthoflavone (alphaNF), terfenadine, midazolam, erythromycin) on nifedipine oxidation and testosterone 6beta-hydroxylation activities were investigated in hepatic and intestinal microsomes from mouse and human . 2 . alphaNF (10 microM) and terfenadine (100 microM) inhibited nifedipine oxidation activities (at substrate concentration of 100 microM) in mouse hepatic microsomes to approximately 50%, but not in mouse intestinal microsomes . alphaNF (30 microM) stimulated nifedipine oxidation activities in mouse and human intestinal microsomes and in human hepatic microsomes to approximately 1.3-1.8-fold . Inhibitory potencies (50% inhibition concentration, IC50) of midazolam and erythromycin for nifedipine oxidations were calculated to be approximately 90 microM in human intestinal microsomes . In contrast, testosterone (100 microM) stimulated the nifedipine oxidation activities approximately 1.5-fold in hepatic and intestinal microsomes from mouse and human . 3 . alphaNF showed different effects on the kinetic parameters including the Hill coefficients of nifedipine oxidation and testosterone 6beta-hydroxylation catalysed by hepatic and intestinal microsomes from mouse and human . Cooperativity in nifedipine oxidation was increased by the addition of alphaNF to pooled human hepatic microsomes, but little effects of alphaNF could be observed in individual human intestinal microsomes . 4 . These results suggest that CYP3A enzymes in liver and intestine might have different characteristics and that observations from hepatic microsomes should not be directly applicable to intestine metabolism in some cases . Studies of drug-drug interactions of CYP3A substrates are recommended to be performed using intestinal samples. Ir J Med Sci, 2001 Apr-Jun, 170(2), 126 - 31 Electrogastrography: a non-invasive measurement of gastric function; Lawlor PM et al.; BACKGROUND: Electrogastrography (EGG) is the non-invasive measurement of gastric electrical activity . With the development of modern technology, improved recording and automated analysis, it is a reliable and accurate technique for the measurement of gastric myoelectrical activity providing information about the frequency and regularity of the gastric slow wave . AIM: The aim of this report is to evaluate its role in clinical practice . METHODS: The literature is reviewed and its role investigated . RESULTS: EGG has been successfully used in the investigation of gastroparesis, non-ulcer dyspepsia (NUD), gastric emptying (GE) disorders and diabetes mellitus (DM) . EGG also provides an insight into the effect of medications on gastric function, e.g . edrophonium, cisapride, erythromycin and proton-pump inhibitors (PPI) . CONCLUSIONS: EGG has a developing role in the assessment of gastric dysfunction and on the effect of medical treatment . The effect of surgery and anaesthesia on gastric myoelectric activity is less clear. Curr Treat Options Gastroenterol, 2001 Apr, 4(2), 179 - 191 Gastric Dysmotility and Gastroparesis; McCallum RW et al.; Nutrition support in gastroparesis begins with encouraging smaller volume, low-fat, low-fiber meals and, if necessary, liquid caloric supplements . There should be a low threshold for placing a jejunal feeding tube either by laparoscopy or mini-laparotomy . Parenteral nutrition should be used only briefly during hospitalization and not encouraged or sustained as an outpatient . Metoclopramide is now the prokinetic of choice for patients who can tolerate this agent; subcutaneous administration is an important method that allows for continued guaranteed absorption . Low-dosage erythromycin also has a prokinetic role alone or in combination with metoclopramide . Domperidone, a centrally acting antiemetic and prokinetic, is only be available to US citizens who can access sources in Canada or Mexico . Antiemetics should be used extensively because nausea is a very severe debilitating symptom, which is under-appreciated and under-treated by physicians . We recommend scopolamine patches to gain maximal absorption, in spite of vomiting and unpredictable oral intakes . The 5-hydroxytryptamine-3 (5-HT3) antagonists ondansetron and granisetron are the most powerful agents . Relief bands using the P6 acupuncture point are useful adjunct . Special vigilance should be paid to situations that can undermine medical therapy or result in breakthrough symptoms, such as hyperglycemic events in patients with diabetes, migraine headaches, cyclic nausea and vomiting, menstrual cycles, rumination syndrome (psychogenic vomiting), and elevated herpes simplex titers . Most excitingly, the era of gastric electrical stimulation has arrived for patients not responding to standard medical therapy . The dramatic improvement in nausea and vomiting, as well as a sustained evidence of improved quality of life, gastric emptying, nutritional status, and decreased hospitalizations by this device are documented by long-term follow-up of more than a year for patients in this country and world-wide. Am J Gastroenterol, 2001 Jul, 96(7), 2041 - 50 Effects of low doses of erythromycin on the 13C Spirulina platensis gastric emptying breath test and electrogastrogram: a controlled study in healthy volunteers; DiBaise JK et al.; OBJECTIVE: Electrogastrography and stable isotope gastric emptying breath tests (GEBTs) are relatively simple, noninvasive tests of gastric motor function that may be useful in monitoring the effects of therapeutic interventions . It was our primary objective to examine the effects of low dose i.v . erythromycin on the results of the 13C Spirulina platensis GEBT and electrogastrography . We were also interested in evaluating the reproducibility of these tests . METHODS: In 10 healthy subjects (five female, ages 23-37 yr), we simultaneously performed the GEBT, using a prepackaged meal (340 kcal), and electrogastrography on each of four different occasions separated by at least 1 wk . After performance of baseline studies, they were repeated in random order after the infusion of 50 mg of erythromycin (Er50), 100 mg erythromycin (Er100), and a placebo (saline) . Breath samples were obtained at baseline and at 75, 90, and 180 min after the meal and T1/2 and Tlag calculated . Electrogastrography recordings began 30 min before the test meal and continued for 2 h after the meal . RESULTS: Baseline and placebo T1/2 and Tlag were similar . Er50 resulted in a modest acceleration of gastric emptying (T1/2 Er50 vs baseline vs placebo = 104.0 vs 132.7 vs 125.5 min) and reduction in lag time (Tlag Er50 vs baseline vs placebo = 47.2 vs 61.5 vs 56.2 min) . A similar decrease was seen in response to Er100 . The baseline and placebo fasting and fed electrogastrography parameters were similar . After infusion of Er100, the percentage of normal slow waves in the first postprandial hour decreased relative to baseline and placebo (percent normogastria Er100 vs baseline vs placebo = 64.1+/-7.5 vs 82.4+/-6.4 vs 79.7+/-5.5) . This corresponded with an increase in percent tachygastria during the same period and an overall decrease in the mean dominant frequency . Similar but less striking changes were seen after administration of Er50 . Replicate GEBTs showed a high degree of reproducibility both within and between individuals for T1/2 and Tlag . In contrast, replicate electrogastrograms revealed moderate to high variability for all parameters except the dominant frequency . CONCLUSION: The stable isotope GEBT utilizing 13C S . platensis demonstrates responsiveness to the prokinetic effects of low dose i.v . erythromycin and good reproducibility. Pharm Res, 2001 May, 18(5), 652 - 5 Development of a generalized, quantitative physicochemical model of CYP3A4 inhibition for use in early drug discovery; Riley RJ et al.; PURPOSE: To examine the structure-activity relationships for the inhibition of the activity of recombinant human CYP3A4 and to establish a generalized, quantitative physicochemical model for use in early drug discovery . METHODS: Inhibition of the activity of recombinant human CYP3A4 (erythromycin N-demethylase) by 30 diverse chemicals was studied using enhanced throughput methodology . RESULTS: There was a general, strong correlation between the IC50 value determined against erythromycin N-demethylase activity and lipophilicity (LogD7.4) (r2 = 0.68, p <0.0001) . This relationship was strengthened further by subdividing the structures studied into two distinct subpopulations of chemistry within the dataset . These could be identified by the absence (r2 = 0.80, p <0.0001) or presence (r2 = 0.69, p <0.0001) of a sterically uninhindered N-containing heterocycle, more specifically a pyridine, imidazole, of triazole function . The presence of these structural motifs increased the potency of CYP3A4 inhibition by approximately 10-fold for a given lipophilicity (LogD7.4.value) . More detailed analyses of AstraZeneca compounds demonstrated that the inhibitory potency of the pyridine structure can be attenuated through direct steric effects or electronic substitution resulting in a modulation of the pKa of the pyridine nitrogen, thereby influencing its ability to interact with the CYP heme . CONCLUSIONS: A generalized, quantitative model is proposed for the inhibition of the major drug metabolizing enzyme, CYP3A4 . This model indicates the importance of lipophilicity and rationalizes increased potency arising through additional interactions with the heme iron . These general relationships were shown to be applicable to a selection of compounds of interest to several early research projects. J Am Chem Soc, 2001 Mar 21, 123(11), 2495 - 502 Precursor-directed biosynthesis of 16-membered macrolides by the erythromycin polyketide synthase; Kinoshita K et al.; Streptomyces coelicolor CH999/pJRJ2 harbors a plasmid encoding DEBS(KS1 degrees ), a mutant form of 6-deoxyerythronolide B synthase that is blocked in the formation of 6-deoxyerythronolide B (1, 6-dEB) due to a mutation in the active site of the ketosynthase (KS1) domain that normally catalyzes the first polyketide chain elongation step of 6-dEB biosynthesis . Administration of (2E,4S,5R)-2,4-dimethyl-5-hydroxy-2-heptenoic acid, N-acetylcysteamine thioester (6) an unsaturated triketide analogue of the natural triketide chain elongation intermediate to cultures of S . coelicolor CH999/pJRJ2 results in formation of a 16-membered macrolactone, which is isolated in the hemiketal form 33 . The formation of the octaketide 33 indicates that the triketide substrate has been processed by DEBS module 2 as if it were a diketide analogue . The substrate specificity of this novel reaction has been explored by the incubation of three additional analogues of the unsaturated triketide 6, compounds 18, 31, and 32, with S . coelicolor CH999/pJRJ2, resulting in the formation of the corresponding macrolactones 34, 35, and 36 . By contrast, the unsaturated triketide 10, lacking a methyl group at C-2, did not give rise to any detectable macrolactone product when incubated with S . coelicolor CH999/pJRJ2. Gut, 2001 Aug, 49(2), 203 - 8 Perception of changes in wall tension of the proximal stomach in humans; Piessevaux H et al.; BACKGROUND: Hypersensitivity to distension of the stomach is a frequent finding in functional dyspepsia . During gastric distension studies both wall tension and elongation are increased . AIM: We wished to distinguish changes in wall tension from changes in elongation in the genesis of perception of mechanical stimuli originating from the proximal stomach in healthy subjects . SUBJECTS AND METHODS: Twenty six volunteers were studied using gastric barostat and antroduodenal manometry . In 14 subjects, stepwise isobaric and isovolumetric distensions were performed before and during erythromycin infusion . In all volunteers, on a separate occasion, phasic contractions of the proximal stomach were detected as intraballoon pressure increases during fixed volume inflation . These contractions were matched with perception changes during two 10 minute periods, before and during administration of erythromycin . RESULTS: Erythromycin significantly lowered the perception and discomfort thresholds during stepwise gastric distension . During fixed volume inflation, erythromycin increased the number and amplitude of fundic contractions and enhanced their perception from 51.1 (7.4)% to 64.0 (4.7)% . The proportion of perception score increases coinciding with fundic contractions increased from 47.3 (0.7)% to 81.5 (0.5)% . The amplitude of correctly identified isolated fundic pressure waves was higher compared with non-identified waves . CONCLUSIONS: These results support the hypothesis that changes in gastric wall tension may be involved in the genesis of symptoms originating from the stomach. Chest, 2001 Jul, 120(1), 198 - 202 Centrilobular nodules correlate with air trapping in diffuse panbronchiolitis during erythromycin therapy; Yamada G et al.; BACKGROUND: Low-dose erythromycin therapy improves airflow limitation and airway inflammation in patients with diffuse panbronchiolitis (DPB) . However, to our knowledge there has been no study to determine whether physiologic improvement during erythromycin therapy correlates with radiologic findings . Study objective: To clarify whether improvement in pulmonary function correlates with specific changes on chest CT . DESIGN: The relationship between five CT findings and five pulmonary function parameters was evaluated before and 3 months after low-dose erythromycin therapy in 24 patients with DPB retrospectively . RESULTS: After erythromycin therapy, the predicted percentage of vital capacity (%VC; 87.0 +/- 3.07% vs 98.9 +/- 3.39%; p = 0.00006) and 50% of the maximum midexpiratory flow rate of FVC (1.41 +/- 0.26 L/s vs 1.61 +/- 0.27 L/s; p = 0.03) significantly increased, and the residual volume/total lung capacity ratio (RV/TLC%; 44.5 +/- 1.93% vs 40.7 +/- 1.83%; p = 0.0019) significantly decreased, but the FEV(1) to FVC ratio and 25% of the maximum expiratory flow rate of FVC did not . In five CT findings, centrilobular nodules (3.7 +/- 0.4 vs 1.5 +/- 0.3; p = 0.0001), peripheral bronchiolar wall thickness (3.8 +/- 0.3 vs 2.6 +/- 0.4; p = 0.0007), and peripheral bronchiolectasis (2.8 +/- 0.3 vs 2.2 +/- 0.4; p = 0.0058) had significantly improved, whereas low attenuation area and central bronchiectasis had not . There were positive correlations of improved scores of centrilobular nodules with improved %VC (r = 0.58, p = 0.0062) and RV/TLC% (r = 0.64, p = 0.0022) . CONCLUSIONS: Decreased air trapping in DPB correlates with an improvement of centrilobular nodules, which reflects the obstructive lesions of bronchioles during the erythromycin therapy. Allergol Immunopathol (Madr), 2001 Jan-Feb, 29(1), 31 - 2 Immediate reaction to clarithromycin; Gangemi S et al.; We present the case of bronchospastic reaction to clarithromycin had during a drug challenge test . Personal allergic history was negative for respiratory allergies and positive for adverse drug reactions to general and regional anesthesia and to ceftriaxone . After the administration of 1/4 of therapeutic dose of clarithromycin the patient showed dyspnea, cough and bronchospasm in all the lung fields . The positivity of the test was confirmed by the negativity to the administration of placebo . The quickness and the clinical characteristic of the adverse reaction suggest a pathogenic mechanism of immediate-type hypersensitivity . On reviewing the literature we have found no reports of bronchospastic reaction to clarithromycin . Macrolides are a class of antibiotics mainly used in the last years in place of beta-lactams because of a broad spectrum of action and a low allergic power . In fact, there are few reports on allergic reactions to these molecules . Clarithromycin is one of the latest macrolides, characterised by the presence of a 14-carbon-atom lactone ring as erythromycin, active on a wide spectrum of pathogens. Dermatol Surg, 2001 Jul, 27(7), 648 - 53; discussion 653-4 Artificial skin for closure and healing of wounds created by skin cancer excisions; Prystowsky JH et al.; BACKGROUND: A dermal regeneration template indicated for life-threatening third-degree burn injuries is a product with potential application to smaller wounds to aid in healing and closure of complex excision sites . OBJECTIVE: To assess the effectiveness of dermal regeneration template for closure of skin cancer excision sites that would have otherwise required complicated closures . METHODS: Five patients, 61-84 years old, with skin cancer surgery yielding a total of six wounds were treated with the dermal regeneration template to close and heal their wounds . RESULTS: Four of five patients had complete healing (five of six wounds) with cosmetically acceptable results . The one treatment failure was application of the dermal regeneration template over exposed skull where inadequate neodermis formed . Successful healing was observed in five complex skin cancer excision sites including two wounds in previously irradiated grafted skin, a large and deep temporal defect, a wide excision in the supraclavicular region, and an excision down to cartilage on the antihelix of the ear . No infections were noted, although in four of five patients prophylactic oral antibiotics (either erythromycin or cephalexin) were prescribed postoperatively for 1-2 weeks . CONCLUSION: The product simplified wound care, subjectively appeared to decrease pain and postoperative bleeding, and yielded cosmetically acceptable wound repair . Autografting was not necessary; wounds healed in 2-4 months by epithelialization over neodermis after removal of the silicone layer . Furthermore, the product was a convenient long-term dressing and healing device for wounds where complex repairs, autografts, and/or flaps would otherwise be considered for closure. J Am Chem Soc, 2001 Jul 11, 123(27), 6465 - 74 Assessing the balance between protein-protein interactions and enzyme-substrate interactions in the channeling of intermediates between polyketide synthase modules; Wu N et al.; 6-Deoxyerythronolide B synthase (DEBS) is the modular polyketide synthase (PKS) that catalyzes the biosynthesis of 6-deoxyerythronolide B (6-dEB), the aglycon precursor of the antibiotic erythromycin . The biosynthesis of 6-dEB exemplifies the extraordinary substrate- and stereo-selectivity of this family of multifunctional enzymes . Paradoxically, DEBS has been shown to be an attractive scaffold for combinatorial biosynthesis, indicating that its constituent modules are also very tolerant of unnatural substrates . By interrogating individual modules of DEBS with a panel of diketides activated as N-acetylcysteamine (NAC) thioesters, it was recently shown that individual modules have a marked ability to discriminate among certain diastereomeric diketides . However, since free NAC thioesters were used as substrates in these studies, the modules were primed by a diffusive process, which precluded involvement of the covalent, substrate-channeling mechanism by which enzyme-bound intermediates are directly transferred from one module to the next in a multimodular PKS . Recent evidence pointing to a pivotal role for protein-protein interactions in the substrate-channeling mechanism has prompted us to develop novel assays to reassess the steady-state kinetic parameters of individual DEBS modules when primed in a more "natural" channeling mode by the same panel of diketide substrates used earlier . Here we describe these assays and use them to quantify the kinetic benefit of linker-mediated substrate channeling in a modular PKS . This benefit can be substantial, especially for intrinsically poor substrates . Examples are presented where the k(cat) of a module for a given diketide substrate increases >100-fold when the substrate is presented to the module in a channeling mode as opposed to a diffusive mode . However, the substrate specificity profiles for individual modules are conserved regardless of the mode of presentation . By highlighting how substrate channeling can allow PKS modules to effectively accept and process intrinsically poor substrates, these studies provide a rational basis for examining the enormous untapped potential for combinatorial biosynthesis via module rearrangement. Ann Thorac Surg, 2001 Jun, 71(6), 1786 - 91 Bile exposure of the denervated stomach as an esophageal substitute; Gutschow CA et al.; BACKGROUND: Both the supine position and the existence of a gastric drainage procedure are suspected to promote reflux of duodenal juice into the denervated intrathoracic stomach . Erythromycin has been shown to weaken pyloric resistance to gastric outflow and to enhance antral motility, gastric emptying, and gallbladder contractility . METHODS: The presence of bile in the gastric transplant of 79 patients was monitored over a 24-hour period with use of the Bilitec 2000 optoelectronic device 3 to 195 months after subtotal esophagectomy . Ten patients were reinvestigated after a 3-year period . Five groups were studied: group I: n = 12, no gastric drainage, never given erythromycin, group 2: n = 40, gastric drainage, never given erythromycin, group 3: n = 7, no gastric drainage, given erythromycin, group 4: n = 13, gastric drainage, given erythromycin, and group 5: n = 7, no longer given erythromycin (with or without gastric drainage) . The percentage of time gastric bile absorbance was more than 0.25 was calculated for the total, supine, and upright periods of recording in reference to data from 25 healthy volunteers . RESULTS: The Bilitec test was pathologic in 9 of the 12 patients of group 1 whereas it was normal in three . Gastric exposure to bile was longer in group I patients than in controls for the total (p = 0.012) and supine (0.036) periods, but the difference did not reach statistical significance for the upright period (p = 0.080) . Bile exposure in group 4 did not significantly differ from controls (total: p = 0.701; supine: p = 0.124; upright: p = 0.712) . Bile exposure for the total period did not significantly differ whether patients were taking erythromycin or the drug had been discontinued at the time of the study (p = 0.234); and it tended to decrease with time in patients investigated twice (p = 0.046) . CONCLUSIONS: Gastric exposure to bile after truncal vagotomy and transposition of the stomach up to the neck is pathologic in three quarters of patients . It is more marked in the supine than in the upright position and tends to decrease with time . The addition of a gastric drainage procedure in combination with erythromycin therapy tends to normalize gastric exposure to bile . The effects of erythromycin may persist after discontinuation of the drug. Expert Opin Investig Drugs, 2001 Mar, 10(3), 547 - 60 Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug; Agrawal DK; Desloratadine is a biologically active metabolite of the second-generation antihistamine loratadine . Desloratadine is a highly selective peripheral H1 receptor antagonist that is significantly more potent than loratadine . Results of in vitro and in vivo studies have suggested that desloratadine has anti-allergic effects that are unrelated to its ability to antagonise the effects of histamine . Desloratadine inhibits the expression of cell adhesion molecules, inhibits the generation and release of inflammatory mediators and cytokines, attenuates eosinophil chemotaxis, adhesion and superoxide generation . Studies in animals indicate that desloratadine does not cross the blood-brain barrier and therefore does not cause sedation and does not impair cognition or psychomotor performance . Desloratadine has an excellent overall safety profile . It has no effect on QRS and QTc intervals and does not cause arrhythmias . Desloratadine is not associated with any significant changes in gastrointestinal function . In clinical studies, oral desloratadine is rapidly absorbed and bioavailability is not affected by ingestion with food or grapefruit juice . The half-life of desloratadine in humans is 27 h; the linear kinetic profile is unaltered by race or gender . Desloratadine is not a substrate for P-glycoprotein or organic anion transport polypeptide and the drug does not appear to be metabolised to a significant extent by the cytochrome P450 CYP3A4 pathway . It therefore may be safely administered with ketoconazole, erythromycin, fluoxetine, or azithromycin . Clinically, desloratadine effectively controls both nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR), including nasal congestion . Desloratadine also provides significant relief of SAR symptoms in patients with co-existing asthma and is effective in the treatment of chronic idiopathic urticaria . Desloratadine improves quality of life and is well-tolerated. Rev Mal Respir, 2001 Apr, 18(2), 193 - 6 {Sinobronchial syndrome}; Courbot A et al.; The sinobronchial syndrome consists of chronic sinusitis and chronic nonspecific inflammation of the lower airways, typically chronic bronchitis, bronchiectasis and diffuse panbronchiolitis . This airway disease of unknown etiology is not related to smoking . It is common in Japan and is poorly described in western countries . We report a case in a non-Asian patient . The known efficacy of long-term low-dose erythromycin therapy justifies careful diagnosis of sinobronchial syndrome in patients of non-Asian ethnic origin. Br J Clin Pharmacol, 2001 Jun, 51(6), 591 - 600 Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers; Khaliq Y et al.; AIMS: To evaluate the pharmacokinetic interaction between ritonavir and mefloquine . METHODS: Healthy volunteers participated in two separate, nonfasted, three-treatment, three-period, longitudinal pharmacokinetic studies . Study 1 (12 completed): ritonavir 200 mg twice daily for 7 days, 7 day washout, mefloquine 250 mg once daily for 3 days then once weekly for 4 weeks, ritonavir restarted for 7 days simultaneously with the last mefloquine dose . Study 2 (11 completed): ritonavir 200 mg single dose, mefloquine 250 mg once daily for 3 days then once weekly for 2 weeks, ritonavir single dose repeated 2 days after the last mefloquine dose . Erythromycin breath test (ERMBT) was administered with and without drug treatments in study 2 . RESULTS: Study 1: Ritonavir caused less than 7% changes with high precision (90% CIs: -12% to 11%) in overall plasma exposure (AUC(0,168 h)) and peak concentration (Cmax) of mefloquine, its two enantiomers, and carboxylic acid metabolite, and in the metabolite/mefloquine and enantiomeric AUC ratios . Mefloquine significantly decreased steady-state ritonavir plasma AUC(0,12 h) by 31%, Cmax by 36%, and predose levels by 43%, and did not affect ritonavir binding to plasma proteins . Study 2: Mefloquine did not alter single-dose ritonavir pharmacokinetics . Less than 8% changes in AUC and Cmax were observed with high variability (90%CIs: -26% to 45%) . Mefloquine had no effect on the ERMBT whereas ritonavir decreased activity by 98% . CONCLUSIONS: Ritonavir minimally affected mefloquine pharmacokinetics despite strong inhibition of CYP3A4 activity from a single 200 mg dose . Mefloquine had variable effects on ritonavir pharmacokinetics that were not explained by hepatic CYP3A4 activity or ritonavir protein binding. Eur J Clin Pharmacol, 2001 May, 57(2), 115 - 21 The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients; Grub S et al.; OBJECTIVE: The aim of this study was to compare the effect of ketoconazole, erythromycin and rifampicin on the pharmacokinetics of saquinavir soft-gelatin formulation (Fortovase; FTV) in healthy volunteers with that in HIV-infected patients at steady state after administration of 1200 mg three times daily . METHODS: In two open-labelled, randomised, crossover studies pharmacokinetic parameters were calculated in healthy volunteers who received on one occasion multiple doses of 1200 mg FTV three times daily alone and on the other occasion in combination with multiple doses of either 400 mg ketoconazole once daily or 600 mg rifampicin once daily . In another open-labelled, multicentre study, 33 HIV-infected patients underwent a pharmacokinetic assessment after 36-51 weeks of treatment with FTV and were then given additionally multiple doses of either 200 mg ketoconazole once daily, 250 mg erythromycin four times daily or 600 mg rifampicin once daily . Pharmacokinetic parameters of saquinavir were determined again at the end of the combination treatment . RESULTS: In healthy volunteers, coadministration of ketoconazole increased saquinavir area under the curve from time 0 to 8 h (AUC0-8 h) by 190% (95% CI: 90-343) whereas coadministration with rifampicin resulted in a decrease for AUC0-8 h by 70% (95% CI: 50-82) . In HIV-infected patients, coadministration of ketoconazole and erythromycin increased AUC0-8 h of saquinavir by 69% (95% CI: 14-150) and 99% (95% CI: 33-198), respectively . When saquinavir was given together with rifampicin, exposure of saquinavir in terms of AUC0-8 h was decreased by 46% (95% CI: 18-65) compared with the baseline assessment . CONCLUSION: Interactions of saquinavir with ketoconazole, erythromycin and rifampicin were observed in healthy volunteers as well as patients . The effects observed in patients, however, appear to be less pronounced . The enzyme induction caused by rifampicin might lead to subtherapeutic levels of saquinavir and this finding appears to be of clinical relevance. Respiration, 2001, 68(3), 319 - 22 Chronic bronchiolitis with associated eosinophilic lung disease (eosinophilic bronchiolitis); Takayanagi N et al.; We encountered an adult patient with dyspnea, eosinophilia and bronchiolitis . He was diagnosed as having diffuse panbronchiolitis, and was treated with erythromycin for 3 years, but his symptoms had gradually worsened . Bronchoalveol