Nucl Med Biol, 1998 Nov, 25(8), 705 - 9 Importance of metabolism in pharmacological studies: possible in vitro predictability; Delaforge M; Metabolic transformation of drug leads to the formation of a large number of secondary compounds . These metabolites may (a) participate to the elimination of the patent drug, (b) have similar or different therapeutic effects compared to the parent drug (c) exert toxic effects . Cytochromes P450 are the main enzymes involved in the biotransformation of exogenous drugs, leading to oxidized, reduced or peroxidized metabolites . Different isozymes of P450 are present in already all the organs and differ by their affinity for substrate families . P450 3A is the most abundant P450 protein in the adult human liver and is able to transform hundreds of substrates into either drugs or endogenous compounds such as testosterone . Its catalytic activities are regulated either by induction or by inhibition . Attempts to predict metabolic transformation of a given drug are based on the amount of P450 expressed in heterologous systems, induction, and inhibition experiments and by comparison to classical P450 substrates . Erythromycin metabolism and its P450 effects are used to illustrate the complexity and the consequences of metabolic transformation of a given drug. Gut, 1998 Sep, 43(3), 395 - 400 Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans; Coulie B et al.; BACKGROUND: During the interdigestive state in humans, erythromycin 40 mg induces a premature activity front that starts in the stomach, while erythromycin 200 mg induces a prolonged period of enhanced antral contractile activity . AIMS: To study the involvement of a cholinergic pathway in the motor effects of erythromycin using the muscarinic antagonist atropine and the neural 5-HT1 receptor agonist sumatriptan . METHODS: In 30 healthy volunteers, fasted antroduodenojejunal motor activity was studied by stationary manometry . Placebo (n = 10), atropine (15 micrograms/kg intravenous bolus plus 15 micrograms/kg/h over 30 minutes; n = 10), or sumatriptan (6 mg subcutaneously; n = 10) was administered, followed by infusion of erythromycin 40 mg or 200 mg . RESULTS: After placebo, erythromycin 40 mg induced a premature activity front with gastric onset after 19.1 (1.7) minutes in all volunteers . After atropine, erythromycin 40 mg failed to induce a premature activity front during a 60 minute period in all volunteers (p < 0.001), while sumatriptan prevented the induction of a premature activity front during a 60 minute period in all but one volunteer (p < 0.005) . The number of antral contractions and their mean amplitude in the 60 minutes after erythromycin 200 mg did not differ significantly after atropine or sumatriptan versus placebo . CONCLUSIONS: The antral motor effects of erythromycin in humans are mediated via different pathways . The induction of a premature activity front is mediated through activation of an intrinsic cholinergic pathway, while the induction of enhanced antral contractile activity may be mediated via a pathway potentially involving activation of a muscular receptor. Chem Biol, 1998 Dec, 5(12), 743 - 54 Evaluating precursor-directed biosynthesis towards novel erythromycins through in vitro studies on a bimodular polyketide synthase; Weissman KJ et al.; BACKGROUND: Modular polyketide synthases (PKSs) catalyse the biosynthesis of complex polyketides using a different set of enzymes for each successive cycle of chain extension . Directed biosynthesis starting from synthetic diketides is a potentially valuable route to novel polyketides . We have used a purified bimodular derivative of the erythromycin-producing polyketide synthase (DEBS 1-TE) to study chain extension starting from a variety of diketide analogues and, in some cases, from the alternative acyl-CoA thioester substrates . RESULTS: Chain initiation in vitro by DEBS 1-TE module 2 using a synthetic diketide analogue as a substrate was tolerant of significant structural variation in the starter unit of the synthetic diketide, but other changes completely abolished activity . Interestingly, a racemic beta-keto diketide was found to be reduced in situ on the PKS and utilised in place of its more complex hydroxy analogue as a substrate for chain extension . The presence of a diketide analogue strongly inhibited chain initiation via the loading module . Significantly higher concentrations of diketide N-acetylcysteamine analogues than their corresponding acyl-CoA thioesters are required to achieve comparable yields of triketide lactones . CONCLUSIONS: Although a broad range of variation in the starter residue is acceptable, the substrate specificity of module 2 of a typical modular PKS in vitro is relatively intolerant of changes at C-2 and C-3 . This will restrict the usefulness of approaches to synthesise novel erythromycins using synthetic diketides in vivo . The use of synthetic beta-keto diketides in vivo deserves to be explored. Kansenshogaku Zasshi, 1998 Oct, 72(10), 1076 - 9 {Legionella longbeachae pneumonia in a gardener}; Okazaki M et al.; A 52-year-old male gardener, who traveled to Guam Island several days ago, was admitted to our hospital with fever, cough and dyspnea . His chest X-ray showed bilateral infiltration and he was severely hypoxic and hypotensive on admission . He died of multiple organ failure in spite of intensive treatment with mechanical ventilation antibiotics including erythromycin . Legionella longbeachae serotype 1 was isolated from his sputum and was regarded as the etiologic agent . Legionella longbeachae was not isolated from the same type of leaf mold that he used as potting soil . This is the first case of Legionella longbeachae pneumonia from whom the organism was isolated in Japan. JAMA, 1998 Nov 25, 280(20), 1774 - 6 Cardiac actions of erythromycin: influence of female sex; Drici MD et al.; CONTEXT: Erythromycin is a widely used antibiotic that infrequently causes QT-prolongation and torsades de pointes cardiac arrhythmias . For antiarrhythmic drugs, women are at a higher risk for these cardiac arrhythmias, but few other classes of drugs have been studied . OBJECTIVES: To determine whether female sex is a risk factor for cardiac arrhythmias associated with erythromycin, and if this can be correlated with in vitro measurements of the QT-response to erythromycin in male and female rabbit hearts . DESIGN: Food and Drug Administration (FDA) MEDWATCH database analysis and in vitro experiment . MAIN OUTCOME MEASURES: Cardiac arrhythmia reports associated with erythromycin from 1970 until 1996 classified by patient sex and age, and effect of female sex on erythromycin-induced QT-prolongation in isolated perfused rabbit hearts . RESULTS: We observed a sex difference in cardiac arrhythmias associated with administration of erythromycin . A total of 346 cases were found in the FDA database: 201 females (58%), 110 males (32%), and 35 unspecified (10%) . Forty-nine were life-threatening ventricular arrhythmias and deaths directly related to intravenous erythromycin lactobionate: 33 women (67%) and 16 men (33%) (P=.03) . During the same period, no sex imbalance was present in the prescription pattern for intravenous erythromycin lacobionate (men 47%, women 49%, unspecified 4%) . Perfusion with erythromycin caused significantly greater QT-prolongation in female rabbit hearts (mean {SD}, 11.8% {2.3%}) than in male hearts (6.9% {2.1%}; P = .03) . CONCLUSIONS: As has been shown in reports of antiarrhythmic drugs, we found a female predominance in the FDA reports of erythromycin-associated cardiac arrhythmias . Based on in vitro experiments, a sex difference in cardiac repolarization response to erythromycin is a potential contributing factor. J Gastrointest Surg, 1997 Jul, 1(4), 331 - 336 Direct Inhibitory Effect of Erythromycin on the Gallbladder Muscle; Nissan A et al.; Erythromycin, a macrolide antibiotic, stimulates motor activity in various parts of the gastrointestinal tract in humans and animals . This effect of erythromycin resembles that of motilin, a gastrointestinal hormone, in evoking contractions similar to phase 3 activity of the migrating motor complex . Motilin induces contractions in the canine gallbladder but fails to evoke any response, either in vivo or in vitro, in the human gallbladder . Surprisingly, erythromycin stimulates human gallbladder emptying in healthy volunteers and in persons with diabetic autonomic neuropathy . In the present study we examined the effect of erythromycin on chemically and electrically evoked contractions of isolated gallbladders from guinea pigs and humans by use of isometric force measurements . Carbachol, a muscarinic cholinergic agonist, evoked gallbladder contractions that were diminished by erythromycin in a concentration-dependent manner: at 200 micromol/L the contractions were 86% +/- 20% of the control response, at 500 micromol/L they were 63% +/- 21% of control, and at 1000 micromol/L they were 41% +/- 20% of control (P <0.05, N = 10, mean +/- standard deviation) . Electrically evoked gallbladder contractions were reduced to 68% +/- 18% of the control response with the addition of 500 micromol/L of erythromycin and to 56% +/- 19% of control after the addition of 1000 micromol/L (P <0.05, N = 8) . Guinea pig but not human gallbladders contracted after stimulation with the alpha-adrenergic agonist phenylephrine . Erythromycin reduced these contractions in a concentration-dependent manner but had no effect on gallbladder contractions induced by bradykinin . In human gallbladder strips, erythromycin at 500 micromol/L reduced the contractile response to electrical stimulation to 71% +/- 16% of the control value (N = 10 {5 patients}, P <0.01) and the carbachol-evoked contractions to 53% +/- 24% (P <0.01, N = 32) . The inhibitory effect of erythromycin persisted in the presence of the nerve blocker tetrodotoxin at 1 micromol/L . It is concluded that erythromycin has a direct inhibitory effect on guinea pig and human gallbladder contractions. J Pept Res, 1998 Oct, 52(4), 321 - 8 Identification of the motilide pharmacophores using quantitative structure activity relationships; Khiat A et al.; Erythromycin A and some derivatives have been shown to act as agonists at the motilin receptor site (motilides) and a structural similarity between these molecules and the N-terminal fragment of motilin has been proposed . Conformational analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods have been used to determine the homology between a series of erythromycin A derivatives and motilin 1-10 . A total of 18 compounds has been studied to correlate the gastrointestinal motor stimulating (GMS) activity with the structure-related parameters determined by 3D-QSAR . Two models with good predictive power of the GMS activity are presented, leading to the prediction of motilin 1-10 activity . The models are consistent with the majority of the data available . The most significant parameters for GMS activity are a favorable dispersion interaction from the quaternary ammonium group of the desosamine ring . In motilin 1-10, the aromatic side chains of Phe1 and Tyr7 seem to play the same role as the quaternary ammonium group in models 1 and 2, respectively . Some hydroxyl groups of erythromycin A derivatives and hydrophobic groups of the Val2 and lle4 side chains of motilin also contribute to the GMS activity . The experimental GMS activities measured are in good agreement with the predicted values, with correlation coefficient values of 0.98 and 0.94 in models 1 and 2, respectively. Eur J Clin Pharmacol, 1998 Sep, 54(7), 561 - 5 Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine; Isohanni MH et al.; OBJECTIVE: We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design . METHODS: The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days . Intravenous lignocaine 1.5 mg x kg(-1) was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole . Timed plasma samples were collected until 11 h . The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography . RESULTS: The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo . Following itraconazole administration, t1/2 was 2.6 h . The values for plasma clearance and volume of distribution at steady state were similar during all the phases . Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC(0-11 h) by 45-60% . CONCLUSION: The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole . However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX . Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine. J Clin Pharm Ther, 1998 Jun, 23(3), 161 - 70 Clinical importance of non-genetic and genetic cytochrome P450 function tests in liver disease; Tanaka E; Liver disease is associated with reduced metabolic capacity for drugs that are metabolized by oxidative biotransformation . Three cytochrome P450 (P450 or CYP) gene families in liver microsomes (CYP 1, CYP2 and CYP3) appear to be responsible for much of the drug metabolism that takes place . The genetic polymorphism of the CYPs responsible for debrisoquine/ sparteine (CYP2D6) metabolism and S-mephenytoin (CYP2C19) metabolism has been well documented, but information on the impairment of each isoform in liver disease is still limited . There are two types of hepatic P450 function tests . One type consists of non-genetic P450 function tests (CYP1A2, 2A6, 2C9/10, 2E1 and 3A3/4), and probe drugs include caffeine, catalysed by CYP1A2, coumarin by CYP2A6, phenytoin by CYP2C6, chlorzoxazone by CYP2E1, and nifedipine, erythromycin and lidocaine by CYP3A3/4 . The second type of genetic P450 function tests (CYP2C19 and CYP2D6) involves probe drugs such as S-mephenytoin, catalysed by CYP2C19, and debrisoquine and sparteine, catalysed by CYP2D6 . The metabolism of the probe drugs used in non-genetic P450 function tests in patients with liver disease falls into two categories: reduced (CYP1A2, CYP2C, 2E1 and 3A) and unchanged (CYP2C) . In genetic P450 function tests there seems to be a lesser degree of inhibition in poor metabolizers (PMs) than extensive metabolizers (EMs) among patients with liver disease . There have been very few reports on changes in metabolism of the probe drugs used in genetic P450 function tests in liver disease . In this paper the subject is reviewed. Clin Ther, 1998 Sep-Oct, 20(5), 971 - 7 Serum erythromycin levels in pregnancy; Larsen B et al.; Erythromycin is the recommended therapy for pregnant women with chlamydial infection . Despite the fact that this drug has been available since 1952, relatively little is known about its pharmacokinetic behavior in pregnant women, and no investigations have been conducted in women who were in the third trimester of pregnancy . In this study, 10 women were treated with erythromycin for chlamydial infection during pregnancy; 7 of these women were in the third trimester of pregnancy, and 3 were in the second trimester . Serum samples were obtained at 0.5, 1, 2, 3, and 4 hours after a 500-mg oral dose of erythromycin base and were analyzed to determine absorption and peak serum levels of erythromycin . Results indicated that absorption was delayed and serum levels were diminished in comparison with values reported in the literature for patients in the second trimester of pregnancy . In 2 women, erythromycin serum levels were not detectable at any time during the 4 hours of the study; these 2 women also experienced the most severe gastrointestinal symptoms . Although the size of our study population was small and certainly not definitive, the data suggest that in patients in the third trimester of pregnancy, severe adverse gastrointestinal events may forewarn of subtherapeutic plasma concentrations of erythromycin, which could have consequences for the treatment outcome. Clin Infect Dis, 1998 Nov, 27(5), 1168 - 70 Isolation of Mycoplasma species from a patient with seal finger; Baker AS et al.; The etiologic agent of seal finger (speck finger) is unknown . Seal finger occurs after a seal bite, and the symptoms include acute pain, swelling, discharge, and, in some cases, there is joint involvement . The discovery of Mycoplasma species in epidemics of seal disease prompted attempts to link seal finger to mycoplasma . Mycoplasma species were isolated in cultures of a specimen from the finger of an aquarium trainer who was bitten by a seal and of a specimen from the front teeth of the biting seal . The two Mycoplasma isolates were identical biochemically; they were serum-dependent and hydrolyzed arginine . The isolates were susceptible to tetracycline but resistant to erythromycin . By growth inhibition and immunofluorescent antibody tests, both strains were identified as Mycoplasma phocacerebrale, a mycoplasma isolated in an epidemic of seal disease occurring in the Baltic Sea . The patient's infection was treated successfully with tetracycline . To our knowledge, this is the first case in which a mycoplasma has been associated with seal finger. Acta Paediatr, 1998 Oct, 87(10), 1079 - 84 Ureaplasma urealyticum, erythromycin and respiratory morbidity in high-risk preterm neonates; Jonsson B et al.; We investigated colonization with Ureaplasma urealyticum (Uu) in infants <30 weeks gestation and assessed the relationship to other risk factors influencing respiratory morbidity, plus the effect of treatment with erythromycin . Ventilated preterm infants {n = 155; median GA 26 (23-29) weeks} were cultured for Uu in endotracheal aspirate and nasopharynx . Colonized infants were randomly assigned to treatment with erythromycin 40 mg/kg/d, intravenously or orally . The rate of colonization was 29/155 (19%) and the Uu-colonized infants had lower mean gestational ages than the culture-negative infants (25 vs 26 weeks) . For the colonized infants PROM (48% vs 12%), chorioamnionitis in the mother (46% vs 17%) and vaginal delivery (71% vs 29%) were more common . More colonized infants needed supplemental oxygen at 36 weeks' postconceptual age (p < 0.05) . Erythromycin treatment was effective in reducing colonization with negative control cultures in 12/14 (86%) of treated infants . No significant differences were found between the colonized treated infants (n = 14) and those not treated (n = 14) in time with supplemental oxygen . Oxygen requirement at 36 weeks was related to lower gestational age, late appearance of PDA, late onset sepsis and signs of chorioamnionitis in the mother . We conclude that the Uu colonization is related to increasing immaturity, the presence of prolonged rupture of membranes, signs of chorioamnionitis and vaginal delivery . Treatment with erythromycin reduced colonization but did not significantly alter length of time with supplemental oxygen. Biochem Pharmacol, 1998 Nov 15, 56(10), 1279 - 85 Comparative effects of cytokines on constitutive and inducible expression of the gene encoding for the cytochrome P450 3A6 isoenzyme in cultured rabbit hepatocytes: consequences on progesterone 6beta-hydroxylation; Calleja C et al.; Cultured rabbit hepatocytes were used to compare the relative activities of cytokines to inhibit the constitutive or rifampicin (RIF)-induced expression of the cytochrome P450 3A6 gene (CYP3A6) . Human recombinant cytokines tested were interleukin-1beta (IL-1beta) (2 U/mL), interleukin-2 (IL-2) (5,000 U/mL) and interferon-gamma (IFN-gamma) (50 U/mL) . Hepatocytes were cultured in the presence or absence of 25 microM RIF for 24 hr, with or without cytokines alone or in combination . All these cytokines inhibited RIF-induced P4503A6 expression without apparent cellular toxicity . By contrast, only IFN-gamma treatment provided a significant decrease (41%) in the constitutive P4503A6 protein level . Moreover, cytokines differed in their ability to repress RIF-dependent transcriptional induction of CYP3A6: IL-1beta and IL-2 were approximately equipotent, causing an almost 40-50% suppression of CYP3A6 mRNA and protein levels, whereas IFN-gamma exerted repressive effects only on P4503A6-related erythromycin N-demethylase activity and inducible protein expression . In fact, although strongly reducing P4503A6 protein content (an approximate 70% decrease), IFN-gamma did not exhibit any influence on CYP3A6 mRNAs with the exception of its association with interleukins . All these results suggest that IL-1beta and IL-2 mainly promote a transcriptional repression mechanism, given the absence of effect of these cytokines on the basal P4503A6 level, whereas IFN-gamma exerts a post-transcriptional suppressive action on both induced and constitutive P4503A6 expression . Consequently, P4503A6-dependent progesterone 6beta-hydroxylase activity also presented a cytokine-specific pattern of inhibition, with a much greater sensitivity than P4503A6 immunoreactive protein to IL-1beta and IL-2 + IFN-gamma treatments . Thus, this study underlines the significant impact of inflammation on steroid metabolism. J Clin Pharmacol, 1998 Nov, 38(11), 1051 - 6 Lack of pharmacokinetic interaction between tiagabine and erythromycin; Thomsen MS et al.; This study was conducted to investigate the effects on the pharmacokinetics of tiagabine at steady state when coadministered with therapeutic doses of erythromycin . Tiagabine doses of 4 mg twice daily and erythromycin doses of 500 mg twice daily were administered for 4 days in an open-label, crossover, two-period interaction trial in 13 healthy volunteers . No statistically significant differences in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC tau), or half-life (t1/2) of tiagabine were observed when tiagabine was administered alone or in combination with erythromycin . A statistically significant treatment effect was observed for time to maximum concentration (tmax; 0.72 after tiagabine alone versus 0.56 hours after administration with erythromycin) . No statistically significant differences were seen between men and women except in tmax and t1/2; these differences were thought to be of no clinical significance . The decrease in tmax seen in women in this study is interpreted as a differential effect of erythromycin on gastric emptying of females and not as an interaction between tiagabine and erythromycin . No changes in laboratory parameters or vital signs were attributable to trial medication . The most common treatment-emergent adverse events that were possibly related to trial medication were central nervous system effects (e.g., headache, dizziness); all adverse events were transient, the majority were rated mild in severity, and did not require additional action . Coadministration of erythromycin in healthy subjects does not significantly affect the pharmacokinetics of tiagabine at the doses tested. Gut, 1998 Dec, 43(6), 817 - 22 Altered migrating myoelectrical complex in an animal model of cholesterol gallstone disease: the effect of erythromycin; Xu QW et al.; BACKGROUND: The ground squirrel on a high cholesterol diet exhibits prolonged intestinal transit, a pathogenetic factor in cholesterol gallstone formation . AIMS: To examine the effect of a high cholesterol diet on the characteristics of the migrating myoelectrical complex (MMC) and the potential benefit of erythromycin . METHODS: Twenty four animals received either a trace (controls) or a 1% (high) cholesterol diet . After four weeks, five bipolar jejunal and terminal ileal electrodes were implanted . Seven days later, myoelectric activity was measured in conscious, fasted animals before and after treatment with erythromycin . Biliary lipid composition was assessed . RESULTS: Compared with controls, animals fed the high cholesterol diet exhibited a prolonged MMC cycle period (70 (6) versus 83 (3) minutes; p<0.05), whereas MMC migration velocity and the proportions of the MMC represented by phases I, II, and III were unchanged . Oral erythromycin significantly shortened the MMC cycle period in animals on the control and high cholesterol diet by 59% and 54% respectively, and increased the proportion of the cycle period occupied by phase III of the MMC in both dietary groups . Gall bladder bile became saturated with cholesterol and crystals developed in nine of 12 animals on the high cholesterol diet; controls had none . CONCLUSION: Animals fed a high cholesterol diet had a prolonged MMC cycle period . This, along with diminished gall bladder motility, impairs the enterohepatic cycling of bile salts and reduces their hepatic secretion, contributing to the formation of abnormal bile . Erythromycin initiated more frequent cycling of the MMC . Its therapeutic value in cholesterol gallstone formation warrants further evaluation. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi, 1998 Sep-Oct, 39(5), 324 - 6 Effect of erythromycin on feeding intolerance in very low birth weight infants: a preliminary observation; Su BH et al.; To investigate the effect of erythromycin on feeding intolerance in very low birth weight infants, from February 1997 to December 1997 twenty infants weighing less than 1500 g, with prolonged intolerance of enteral feeding, were enrolled in this study . The protocol for erythromycin treatment was: a loading dose of 30 mg/kg/day, divided into three portions given every eight hours intravenously for 1 hour over a three day period; then a maintenance dose of 3-5 mg/kg intravenously for one hour once a day was given until full feeding was well established . The assessment of erythromycin effect was the daily net orogastric balance (volume of orogastric tube feeding minus volume of orogastric aspirates) . The mean gestational age was 27.1 +/- 2.0 weeks (mean +/- SD) and the mean birth weight was 1025 +/- 196 g . The mean age when erythromycin started was 19.5 +/- 14 days; the mean days after the initiation of erythromycin when orogastric tube feeding could be started and full feeding established were 2.4 +/- 1.1 days and 15.1 +/- 2.2 days, respectively . At the beginning of erythromycin treatment, the net balance of tube aspirates was -4.8 +/- 4.1 ml . The net balance rose significantly to 30.6 +/- 15.3 ml, 92.6 +/- 25.4 ml and 125.3 +/- 18.1 ml at 7, 14 and 21 days after erythromycin treatment, respectively . In conclusion, erythromycin treatment is a safe method to improve intolerance of enteral feeding in very low birth weight infants . It is suggested that the effect of erythromycin on gastrointestinal motility in these infants should be further investigated in the context of a randomized, controlled trial before widespread clinical implementation of this treatment. Vet Hum Toxicol, 1998, 40 Suppl 2, 48 - 52 Field trials of investigational new animal drugs; Moffitt CM; Field trials provide an opportunity to determine the efficacy and safety of drug treatments in a variety of environments and fish stocks that would not be possible or practical in laboratory settings . The steps for executing good field trials are discussed . The University of Idaho coordinates numerous field trials at over 100 hatcheries throughout the Pacific northwest as part of an intensive and extensive program to register erythromycin injectable and feed additive to control bacterial kidney disease in salmonids . A standardized toxicity test conducted at 52 hatcheries following the completion of administration of erythromycin feed additive provided a way to compare responses by fish at different times of the year, locations, and among different sizes of fish . Some of these fish were used in an assay to quantify the content of erythromycin in kidney tissue post treatment. Eur J Pharmacol, 1998 Oct 9, 358(3), 289 - 94 Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells; Takano M et al.; The effect of cytochrome P-450 3A (CYP3A) substrates (erythromycin, midazolam) and an inhibitor (ketoconazole) on P-glycoprotein-mediated transport was studied in Caco-2, the human colon adenocarcinoma cell line expressing various functions of differentiated intestinal epithelial cells . The involvement of P-glycoprotein in the transport of these drugs was also examined . The basal-to-apical transport of rhodamine 123, a P-glycoprotein substrate, was inhibited by erythromycin, midazolam and ketoconazole, as well as by P-glycoprotein inhibitors such as verapamil . The apical-to-basal transport of rhodamine 123 was increased by these drugs . The transepithelial transport of erythromycin and midazolam, but not of ketoconazole, was much greater from the basal to apical side than from the apical to basal side . The inhibitory effect of verapamil was observed on the basal to apical transport of erythromycin, but not on midazolam and ketoconazole transport . In conclusion, erythromycin, midazolam and ketoconazole could interact with P-glycoprotein-mediated transport, and P-glycoprotein could be, at least in part, involved in the transport of erythromycin, but not of midazolam and ketoconazole, in the intestinal epithelia. J Bacteriol, 1998 Nov, 180(22), 6068 - 71 mmr, a Mycobacterium tuberculosis gene conferring resistance to small cationic dyes and inhibitors; De Rossi E et al.; The mmr gene, cloned from Mycobacterium tuberculosis, was shown to confer to Mycobacterium smegmatis resistance to tetraphenylphosphonium (TPP), erythromycin, ethidium bromide, acriflavine, safranin O, and pyronin Y . The gene appears to code for a protein containing four transmembrane domains . Studies of {3H}TPP intracellular accumulation strongly suggest that the resistance mediated by the Mmr protein involves active extrusion of TPP. Vet Res Commun, 1998 Sep, 22(6), 405 - 14 Novobiocin inhibits both UDP-glucuronosyltransferase and cytochrome P450-mediated enzyme activities in pig liver microsomes; Villar D et al.; The effects of novobiocin (range 0.0125-2 mmol/L) on the hydroxylation of testosterone, the N-demethylation of erythromycin, and the glucuronidation of alpha-naphthol and paracetamol were studied using pig hepatic microsomes, pooled from five animals . The final concentrations of these substrates in the incubation mixtures were selected to meet Vmax conditions . Novobiocin caused a concentration-dependent inhibition of the glucuronidation of paracetamol; the formation of alpha-naphthol-glucuronide was reduced to a lesser degree . These results confirm and extend earlier findings in laboratory animal species that novobiocin inhibits UDP-glucuronosyltransferases (UDPGTs) . Moreover, novobiocin strongly inhibited 6 beta-hydroxylation of testosterone . The microsomal N-demethylation of erythromycin and hydroxylation of testosterone at the 15 alpha position were less affected by novobiocin . These results suggest that novobiocin inhibits not only UDPGTs, but also cytochrome P450 (CYP) enzyme activities, probably those belonging to the CYP3A subfamily . More research is needed to reveal which CYPs and UDPGTs are affected by novobiocin in vivo, in order to improve the understanding the probably the predictability of potential drug interactions with this antibiotic. J Pharmacol Exp Ther, 1998 Nov, 287(2), 712 - 9 Effects of EM574 and cisapride on gastric contractile and emptying activity in normal and drug-induced gastroparesis in dogs; Tanaka T et al.; EM574, an erythromycin derivative and potent motilin receptor agonist, is now undergoing clinical trials as a gastroprokinetic drug . The aim of this study was to compare the effect of EM574 with that of cisapride on gastric motility and emptying in normal and gastroparesis dogs . Six dogs were each implanted with two duodenal cannulas for infusion of phenolsulfonphthalein into the proximal duodenum and for aspiration of luminal samples from the distal duodenum . Both solid and liquid gastric emptying were determined by a novel freeze-drying method developed in our laboratory . A freeze-dried standard meal (100 g, 400 kcal) was given with 100 ml normal saline containing 15 g of polyethylene glycol as a liquid marker . Gastric muscle contractility was measured by means of a force transducer implanted on the gastric antrum . EM574 (3-30 microgram/kg) and cisapride (0.3-3.0 mg/kg) were administered intraduodenally at the start of feeding . Clonidine (3-30 microgram/kg) was injected subcutaneously 15 min before feeding to induce gastroparesis . EM574 and cisapride both enhanced gastric muscle contractility in a dose-dependent manner . EM574 (30 microgram/kg and 10 microgram/kg) significantly accelerated gastric emptying of solids and liquids, respectively . Cisapride (1 mg/kg) significantly accelerated solid gastric emptying, but 3.0 mg/kg significantly delayed liquid gastric emptying . Clonidine (10 and 30 microgram/kg) significantly delayed solid and liquid gastric emptying and reduced gastric muscle contractility . EM574, at a dose of 30 microgram/kg, completely restored solid and liquid gastric emptying and muscle contractility to the normal range in dogs with clonidine-induced gastroparesis . Cisapride (1 mg/kg) restored liquid gastric emptying in dogs with gastroparesis to the normal range and partially restored solid emptying . EM574 accelerated gastric muscle contractility and emptying of solids and liquids in normal dogs . The stimulating activity of EM574 on gastric muscle contractility and emptying was comparable to that of cisapride, but EM574 was as effective as cisapride in normalizing gastric muscle contractility and emptying in dogs with clonidine-induced gastroparesis. Transplantation, 1998 Oct 27, 66(8), 1089 - 93 Relationship between in vivo FK506 clearance and in vitro 13-demethylation activity in living-related liver transplantation; Nakazawa Y et al.; BACKGROUND: Although it is important to maintain an appropriate blood concentration of FK506 after liver transplantation, significant interindividual variability in the actual FK506 dosage has been observed, presumably due to the wide variability of cytochrome P450 3A4 activity in liver microsomes . METHODS: A study was conducted in patients undergoing living-related liver transplantation and their donors to investigate the relationship between the in vitro FK506 demethylation activity in graft liver microsomes and the in vivo blood clearance of FK506 . Liver biopsy tissue was obtained from 17 living donors to measure the in vitro formation rate of 13-demethyl derivative (M-I: the major metabolite of FK506) . Erythromycin N-demethylation activity in vitro was also assessed in 11 cases . The FK506 blood clearance (CLss) was calculated from its constant infusion rate and steady-state blood concentration on day 4 after transplantation in 17 recipients . RESULTS: The FK506 infusion rate varied 4.6-fold from 8.3 to 38.4 ng/min/kg . The mean CLss of FK506 was 22.1+/-10.8 ml/min (10.1-45.2 ml/min) . The M-I formation rate showed a wide variability, ranging from 0.098 to 0.571 nmol/min/mg protein . A significant correlation was observed between the in vitro estimated total metabolic ability of the graft for FK506 (M-I formation rate x graft weight) and the in vivo CLss of FK506 (r=0.770, P<0.001) . Erythromycin N-demethylation (0.066-0.443 nmol/min/mg protein) showed a strong correlation with the M-I formation rate (r=0.891, P<0.01) . CONCLUSIONS: The in vivo FK506 clearance can mainly reflect in vitro FK506 demethylation activity. Am J Respir Cell Mol Biol, 1998 Nov, 19(5), 799 - 804 Erythromycin inhibits ATP-induced intracellular calcium responses in bovine tracheal epithelial cells; Kondo M et al.; Erythromycin (EM) therapy is known to decrease airway secretion in chronic inflammatory airway diseases such as diffuse panbronchiolitis . Airway secretion is regulated by intracellular Ca2+ concentration ({Ca2+}i) . To elucidate the intracellular site of action of EM in airway epithelium, we examined the effect of EM on Ca2+ dynamics in cultured bovine tracheal epithelial cells using fura-2 . EM per se did not cause any change in {Ca2+}i . Adenosine triphosphate (ATP; 10(-4) M) induced a biphasic {Ca2+}i increase, consisting of a transient response followed by a sustained response . Pretreatment of cells with EM had little effect on the ATP-induced transient Ca2+ response but substantially reduced the sustained response in a dose-dependent manner . Clarithromycin, another 14-membered ring macrolide, likewise showed the inhibitory effect, but ampicillin and cephasolin did not . Uridine triphosphate (UTP; 10(-4) M) induced a biphasic {Ca2+}i increase similar to ATP, and the UTP-induced sustained Ca2+ response was also inhibited by EM . In Ca2+-deficient medium (1 mM ethyleneglycol-bis-(beta-aminoethyl ether)-N, N'-tetraacetic acid {EGTA}) or in the presence of La3+, the sustained Ca2+ response disappeared, suggesting that EM may inhibit Ca2+ influx induced by P2u purinoceptor stimulation . In single-cell Ca2+ image analysis, low concentration of ATP (10(-6) M) induced Ca2+ oscillations, which were also inhibited by EM . The disappearance of {Ca2+}i oscillations after addition of EM was similar to that after addition of EGTA . These results suggest that EM may decrease Ca2+-dependent airway secretion by inhibiting agonist-stimulated Ca2+ influx. Life Sci, 1998, 63(19), 1685 - 92 Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats; Watanabe M et al.; We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats . Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo . The elimination half-life (t(1/2)) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone . Similar changes observed by prednisolone pretreatment did not reach significance . The t(1/2) of the dexamethasone pretreatment group (14.4+/-0.7 min) was significantly shorter than that of the prednisolone group (20.9+/-1.5 min) . The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone . Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively . The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same. Int J Clin Pharmacol Ther, 1998 Oct, 36(10), 530 - 3 Adverse drug reactions (ADRs) in hospitalized pediatric patients . A prospective study; Gonzalez-Martin G et al.; The aim of this study was to determine the frequency and the characteristics of ADRs in 219 hospitalized pediatric patients, using an intensive and prospective drug surveillance method . The frequency of ADRs in these patients was 13.7% . The systems most commonly affected were the gastrointestinal (32.5%), the central nervous (20.0%), and the metabolic systems (17.5%) . Asparaginase, methotrexate, phenytoin, phenobarbital, erythromycin, and salbutamol were probably the drugs associated with the ADRs . According to causality, 54.2% of the ADRs were regarded as probable, and 32.2% as possible . The majority of the ADRs were moderate (51.2%), 27.9% were severe . The main treatment of the ADRs was the withdrawal of the suspected drugs . The length of the stay in the hospital and the total number of drugs given to the patients influenced significantly the frequency of ADRs . 93% of the ADRs were dose-dependent. Acta Clin Belg, 1998 Aug, 53(4), 275 - 81 Surveillance of pneumococcal resistance in Belgium during winter 1996-1997; Vanhoof R et al.; This study tested 212 pneumococcal isolates from 9 institutions for their susceptibilities to penicillin, ampicillin, amoxycillin, amoxycillin/clavulanate, cefaclor, cefuroxime, cefotaxime, imipenem, tetracycline, erythromycin, and clarithromycin using NCCLS-standardized microdilution . Penicillin-insusceptibility was 12.3% {5.7% intermediate (0.12-1 microgram/ml) and 6.6% high-level (> or = 2 micrograms/ml)}, tetracycline-insusceptibility (> or = 4 micrograms/ml) 31.1%, and erythromycin-insusceptibility (> or = 0.5 microgram/ml) 31.1% as well . Erythromycin-insusceptible isolates showed cross-insusceptibility to clarithromycin . Penicillin-susceptible isolates were susceptible to all beta-lactams . MICs of all beta-lactams rose with those of penicillin for penicillin-insusceptible isolates . Ampicillin and penicillin were equally potent against penicillin-insusceptible isolates, imipenem, cefotaxime, and amoxycillin +/- clavulanate were more potent (generally 5, 1, and 1 doubling dilution, respectively), and cefuroxime and cefaclor less potent (generally 1 and 6 doubling dilutions, respectively) . Most penicillin-insusceptible isolates were high-level resistant to cefaclor (> or = 32 micrograms/ml) . Although MICs of all beta-lactams rose with those of penicillin, resistance to penicillin was not absolute in terms of cross-resistance . Most penicillin-intermediate and high-level penicillin-resistant isolates remained fully susceptible and intermediate, respectively, to amoxycillin +/- clavulanate, cefotaxime, and imipenem, but not to cefuroxime . Penicillin-susceptible isolates were 76.9%, 42.3%, and 34.6% co-insusceptible to tetracycline, erythromycin, and tetracycline plus erythromycin, respectively . Most penicillin-, tetracycline-, and erythromycin-insusceptible isolates were of capsular types 23 >> 6 > 19 > 32, 19 > 6 > 28 > 23, and 19 > 6 > 14 > 23, respectively . Compared to winter 1994-1995, insusceptibility to penicillin, tetracycline, and erythromycin rose by some 4%, 4%, and 13%, respectively. Eur J Pharm Biopharm, 1998 Sep, 46(2), 169 - 75 Dependence between dissolution rate and porosity of compressed erythromycin acistrate tablets; Riippi M et al.; The correlation between dissolution rate and porosity of compressed erythromycin acistrate tablets was studied . The total porosity of the tablets, the pore size distribution and the specific surface area of the pores were determined using high-pressure mercury porosimetry . The particle size and specific surface area of the raw material and of the dry granulated mass of the tablets were also determined . The results show that the pore size distribution, showing the differences in pore structure, is more informative than total intruded volume of mercury . However, it is very difficult to explain the dissolution behaviour of erythromycin acistrate tablets only by porosity results of the tablets, and more work is still needed in this field. Ann Pharmacother, 1998 Oct, 32(10), 1030 - 43 Atorvastatin in the treatment of primary hypercholesterolemia and mixed dyslipidemias; Yee HS et al.; OBJECTIVE: To review the efficacy and safety of atorvastatin in the treatment of dyslipidemias . DATA SOURCES: A MEDLINE search (January 1960-April 1998), Current Contents search, additional references listed in articles, and unpublished data obtained from the manufacturer were used to identify data from scientific literature . Studies evaluating atorvastatin (i.e., abstracts, clinical trials, proceedings, data on file with the manufacturer) were considered for inclusion . STUDY SELECTION: English-language literature was reviewed to evaluate the pharmacology, pharmacokinetics, therapeutic use, and adverse effects of atorvastatin . Additional relevant citations were used in the introductory material and discussion . DATA EXTRACTION: Open and controlled animal and human clinical studies published in the English-language literature were reviewed and evaluated . Clinical trials selected for inclusion were limited to those in human subjects and included data from animals if human data were not available . DATA SYNTHESIS: Atorvastatin is a recent hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for the treatment of primary hypercholesterolemia, mixed dyslipidemias, and homozygous familial hypercholesterolemia . In patients who have not met the low-density lipoprotein cholesterol (LDL-C) goal as recommended by the National Cholesterol Education Program Adult Treatment Panel II guidelines, atorvastatin 10-80 mg/d may be used as monotherapy or as an adjunct to other lipid-lowering agents and dietary modifications . In placebo-controlled clinical trials, atorvastatin 10-80 mg/d lowered LDL-C by 35-61% and triglyceride (TG) concentrations by 14-45% . In comparative trials, atorvastatin 10-80 mg/d showed a greater reduction of serum total cholesterol (TC), LDL-C, TG concentrations, and apolipoprotein B-100 (apo B) compared with pravastatin, simvastatin, or lovastatin . In comparison, currently available HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin) lower LDL-C concentrations by approximately 20-40% and TG concentrations by approximately 10-30% . In pooled placebo-controlled clinical trials of up to a duration of 52 weeks, atorvastatin in dosages up to 80 mg/d appeared to be well tolerated . The most common adverse effect of atorvastatin was gastrointestinal upset . The incidence of elevated serum hepatic transaminases may be greater at higher dosages of atorvastatin . The risk of myopathy and/or rhabdomyolysis is increased when an HMG-CoA reductase inhibitor is taken concomitantly with cyclosporine, gemfibrozil, niacin, erythromycin, or azole antifungals . CONCLUSIONS: Atorvastatin appears to reduce TC, LDL-C, TG concentrations, and apo B to a greater extent than do currently available HMG-CoA reductase inhibitors . Atorvastatin may be preferred in patients requiring greater than a 30% reduction in LDL-C or in patients with both elevated LDL-C and TG concentrations, which may obviate the need for combination lipid-lowering therapy . Adverse effects of atorvastatin appear to be similar to those of other HMG-CoA reductase inhibitors and should be routinely monitored . Long-term safety data (> 1 y) on atorvastatin compared with other HMG-CoA reductase inhibitors are still needed . Cost-effectiveness studies comparing atorvastatin with other HMG-CoA reductase inhibitors remain a subject for further investigation . Published clinical studies evaluating the impact of atorvastatin on cardiovascular morbidity and mortality are still needed . Additionally, clinical studies evaluating the impact of lipid-lowering therapy in a larger number of women, the elderly (> 70 y), and patients with diabetes for treatment of primary and secondary prevention of coronary heart disease are needed. Scand J Infect Dis, 1998, 30(3), 309 - 11 Streptobacillus moniliformis infection: 2 cases and a literature review; Hagelskjaer L et al.; Two cases of Streptobacillus moniliformis infection are reported in farmers bitten by rats during their work . One patient had a subcutaneous abscess requiring surgical treatment and the other streptobacillary rat bite fever . Streptobacillus moniliformis was isolated from pus and blood, respectively . An erythromycin course failed to eradicate the infection in the first patient . Both patients were successfully treated with penicillin. Bioorg Med Chem, 1998 Aug, 6(8), 1171 - 7 Precursor-directed biosynthesis of 12-ethyl erythromycin; Jacobsen JR et al.; A precursor-directed method for the biosynthesis of novel 6-deoxyerythronolide B derivatives has been extended to allow alteration of the functionality at C-12 . We recently described a simple and practical method for harnessing the biosynthetic potential of the erythromycin pathway to generate novel molecules of natural product-like complexity by feeding designed synthetic molecules to an engineered mutant strain having an altered 6-deoxyerythronolide B synthase (DEBS) . Our initial applications of this technique focused on alteration of the ethyl side chain of 6-dEB (C14-C15) . We now report the extension of this approach to modification of the C-12 substituent . An appropriately designed substrate is shown to incorporate into 6-dEB biosynthesis, yielding a 6-dEB analogue bearing a 12-ethyl group . This 6-dEB analogue is a substrate for post-polyketide tailoring enzymes, and is converted into the corresponding analogue of erythromycin C . These results show that many of the downstream active sites are tolerant of this unnatural functionality and suggest that a wide variety of erythromycin derivatives should be accessible by this approach or by total biosynthesis via genetic engineering. Microbiology, 1998 Sep, 144 ( Pt 9), 2441 - 8 Genetic engineering of an industrial strain of Saccharopolyspora erythraea for stable expression of the Vitreoscilla haemoglobin gene (vhb); Brunker P et al.; Several Actinomycetes/Streptomycetes expression vectors are described for expression of the Vitreoscilla haemoglobin gene (vhb) in an industrial erythromycin-producing strain of Saccharopolyspora erythraea . Cloning of vhb under the control of either the thiostrepton-inducible PtipA promoter or the constitutive PermE* promoter led to the production of chemically active haemoglobin (VHb) in Streptomyces lividans TK24 transformed with these constructs . However, theplasmids could not be transformed into Sac . erythraea . Transformants of Sac . erythraea and/or exconjugants were obtained using a novel Escherichia coli/Streptomyces shuttle vector comprised of vhb under the control of the PermE* promoter, the Streptomyces plasmid pIJ350 origin of replication, the thiostrepton-resistance gene (tsr) for selection, and the oriT region which is necessary for conjugal transfer . Increased plasmid stability in Sac . erythraea was obtained by construction of a vector for chromosomal integration . This vector contained the Streptomyces phage phi C31 attachment site for chromosomal integration and vhb expressed under the PmerR promoter and was stably maintained in the chromosome of Sac . erythraea . Shake-flask cultivations of the transformed Sac . erythraea strain with the chromosomally integrated vhb gene show that vhb is expressed in an active form . The corresponding amount of erythromycin produced in the vhb-expressing strain was approximately 60% higher relative to the original VHb-negative strain. Biochemistry, 1998 Oct 20, 37(42), 14937 - 42 Characterization of the macrolide P-450 hydroxylase from Streptomyces venezuelae which converts narbomycin to picromycin; Betlach MC et al.; The post-polyketide synthase (PKS) biosynthetic tailoring of macrolide antibiotics usually involves one or more oxidation reactions catalyzed by cytochrome P450 monooxygenases . As the specificities of members from this class of enzymes vary significantly among PKS gene clusters, the identification and study of new macrolide P450s are important to the growing field of combinatorial biosynthesis . We have isolated the cytochrome P450 gene picK from Streptomyces venezuelae which is responsible for the C-12 hydroxylation of narbomycin to picromycin . The gene was located by searching regions proximal to modular PKS genes with a probe for macrolide P450 monooxygenases . The overproduction of PicK with a C-terminal six-His affinity tag (PicK/6-His) in Escherichia coli aided the purification of the enzyme for kinetic analysis . PicK/6-His was shown to catalyze the in vitro C-12 hydroxylation of narbomycin with a kcat of 1.4 s-1, which is similar to the value reported for the related C-12 hydroxylation of erythromycin D by the EryK hydroxylase . The unique specificity of this enzyme should be useful for the modification of novel macrolide substrates similar to narbomycin, in particular, ketolides, a promising class of semisynthetic macrolides with activity against erythromycin-resistant pathogens. Pathol Biol (Paris), 1998 Feb, 46(2), 144 - 6 {Evaluation of in vitro activity of ofloxacin against 73 strains of Chlamydia trachomatis isolated from gynecologic infections}; Catalan F et al.; The in vitro activity of ofloxacin, levofloxacin, ciprofloxacin, doxycyclin, erythromycin and roxithromycin was determined against 73 recent clinical strains of Chlamydia trachomatis isolated from genital infections . The MICs 90% were: 0.4; 0.1; 1.6; 0.2; 1.6 and 0.1 mg/l respectively . 100% of strains were susceptible to ofloxacin, roxithromycin and doxycyclin . Erythromycin and ciprofloxacin had a lower in vitro activity against C . trachomatis. Arch Toxicol, 1998 Jul-Aug, 72(8), 492 - 8 Differential alterations in levels of hepatic microsomal cytochrome P450 isozymes following intracerebroventricular injection of bacterial lipopolysaccharide in rats; Shimamoto Y et al.; To investigate the effect of central inflammation due to bacterial infection, such as meningitis, on the activities of hepatic cytochromes P450 (CYPs), rats were injected intracerebroventricularly (i.c.v.) with 0.1 microg of bacterial lipopolysaccharide (LPS) . The LPS i.c.v . injection significantly decreased the total P450 contents (by 30% of the levels of control rats treated with saline i.c.v.), the contents of CYP1A (48%), 2B (54%), 2C11 (37%) and 3A (40%) and related drug metabolizing activities, 7-ethoxycoumarin O-deethylation (36%), imipramine N-demethylation (41%) and erythromycin N-demethylation (33%) in liver microsomes 24 h after the treatment . In contrast, intraperitoneal (i.p.) injection of LPS at the same dose as i.c.v . (0.1 microg) did not significantly affect the hepatic microsomal contents of total P450 or the content of each individual CYP isozyme and its activity . CYP2D1 protein and the activity of imipramine 2-hydroxylase were not significantly decreased by LPS injection regardless of the route of administration . The inhibitory effects of 0.1 microg i.c.v . LPS on the activities of these CYPs were almost equal to those of 10 microg i.p . LPS, and 0.01 microg of i.c.v . LPS significantly decreased the activity of imipramine N-demethylase only . Therefore, the LPS i.c.v . injection resulted in CYP isozyme-selective inhibition at an ineffective dose when injected i.p. . It is suggested that a central inflammation, such as meningitis, differentially decreases the levels of hepatic CYP isozymes . A possible involvement is discussed of the central nervous system in this down-regulation. Eur J Clin Microbiol Infect Dis, 1998 Jul, 17(7), 470 - 8 Multicenter, randomized, double-blind comparison of erythromycin estolate versus amoxicillin for the treatment of acute otitis media in children . AOM Study Group; Scholz H et al.; Erythromycin is frequently prescribed in Germany for acute otitis media, but well-designed clinical trials under present epidemiological conditions are lacking . Therefore, a double-blind, randomized, multicenter trial was performed to compare the clinical efficacy and safety of erythromycin estolate versus amoxicillin in children with acute otitis media and to identify the risk factors associated with clinical failure . Investigators from 19 centers throughout Germany recruited 302 children with clinical, otoscopic, and tympanometric evidence of acute otitis media . In a double-blind fashion, patients were allocated randomly to a 10-day course of erythromycin estolate at 40 mg/kg/day in two divided doses or amoxicillin at 50 mg/kg/day in two divided doses . Clinical examinations, otoscopy, and tympanometry were performed at baseline, day 3-5, day 9-11, and at 5 weeks . Clinical outcome was assessed on day 9-11 . Two-hundred eighty children were evaluable for efficacy (erythromycin group, 141; amoxicillin group, 139) . Both groups were comparable with respect to demographic data and severity of disease at entry . Treatment was successful in 94% of the erythromycin-treated patients and in 96% of the amoxicillin-treated patients . Clinical outcome was statistically equivalent between groups within a range of 7 percentage points . Clinical recurrence was seen in eight erythromycin-treated children (5.7%) and in seven amoxicillin-treated children (5.0%) (P=0.81) . Patients with bilateral disease at entry were at higher risk of unfavourable outcome, whereas age and presence/absence of otorrhea at entry were not associated with outcome . Treatment-related adverse events were recorded in eight (5.3%) of 151 erythromycin-treated patients and in 11 (7.3%) of 151 amoxicillin-treated patients . In this study in an outpatient setting in Germany, erythromycin estolate was as safe and effective as amoxicillin in the treatment of acute otitis media . Both drugs can be administered in a convenient twice-daily dosage schedule. Drug Metab Dispos, 1998 Oct, 26(10), 970 - 6 Identification of the human liver cytochrome P450 enzymes involved in the in vitro metabolism of a novel 5-lipoxygenase inhibitor; Machinist JM et al.; In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) forms involved in the oxidative metabolism of {14C}ABT-761 and its N-dehydroxylated metabolite, {14C}ABT-438, by human liver microsomes . The two compounds were metabolized by parallel pathways, to form the corresponding methylene bridge hydroxy metabolites . There was no evidence of sulfoxidation and/or ring hydroxylation . Over the ABT-761 and ABT-438 concentration ranges studied (1-300 microM), the rate of NADPH-dependent hydroxylation was linear with respect to substrate concentration ({S}) and did not conform to saturable Michaelis-Menten kinetics . Under these conditions ({S} < KM), the intrinsic clearance (Vmax/KM) of ABT-438 was 10-fold higher than that of ABT-761 (1.7 +/- 0.8 vs . 0.17 +/- 0.06 microl/min/mg, mean +/- SD, N = 3 livers) . The hydroxylation of both compounds was shown to be highly correlated (r = 0.83, p < 0.01, N = 11 different human livers) with CYP3A-selective erythromycin N-demethylase activity, and the correlation between ABT-761 hydroxylation and tolbutamide hydroxylase (CYP2C9-selective) activity (r = 0.63, p < 0.05, N = 10) was also statistically significant . Ketoconazole (2.0 microM), a CYP3A-selective inhibitor, inhibited the hydroxylation of both compounds by 53-67%, and sulfaphenazole (CYP2C9-selective) decreased activity by 10-20% . By comparison, alpha-naphthoflavone, a known activator of CYP3A, stimulated the hydroxylation of ABT-761 (8-fold) and ABT-438 (4-fold) . In addition, the abundance-normalized rates of cDNA-expressed CYP-dependent metabolism indicated that hydroxylation was largely mediated (66-86%) by CYP3A(4) . Therefore, it is concluded that the hydroxylation of ABT-761 and ABT-438 (</=10 microM) is primarily mediated by CYP3A, although CYP2C9 may play an ancillary role. Biochem Pharmacol, 1998 Aug 15, 56(4), 473 - 81 Differential inducibility of specific mRNA corresponding to five CYP3A isoforms in female rat liver by RU486 and food deprivation: comparison with protein abundance and enzymic activities; Cheesman MJ et al.; The induction of cytochrome P450 3A (CYP3A) protein and mRNA by RU486 {17beta-hydroxy-11beta-(4-dimethylaminophenyl)-17alpha-1-pro pyl-estra-4,9-dien-3-one} treatment and food deprivation in female rat liver was studied using Western blotting and competitive reverse transcription-polymerase chain reaction (RT-PCR) . CYP3A apoprotein levels increased in response to food deprivation and to RU486 treatment, and the combination of RU486 treatment plus food deprivation had an apparent additive effect . Food deprivation and RU486 treatment also caused increases in CYP3A1, CYP3A18, and CYP3A23 mRNA, and the combined effects of these treatments on each of these mRNA forms were synergistic . CYP3A2 mRNA was not detected in any of the treatment groups, and there was a lack of concordance between CYP3A9 mRNA levels and the specific messages corresponding to the other CYP3A isoforms . CYP3A9 mRNA levels were highest in food-deprived animals, whereas RU486 inhibited CYP3A9 mRNA expression and suppressed the induction effect of food deprivation . Food deprivation and RU486 treatment each separately caused increased microsomal diazepam C3-hydroxylase activity, and the combined effects of these treatments on this monooxygenase were additive . In contrast, the {N-methyl-14C}erythromycin demethylase activity of the fasted, RU486-treated group of rats did not differ from that of the untreated group, and kinetic analyses revealed that both groups of animals exhibited similar Km and Vmax values . These results suggest that CYP3A9 may be primarily responsible for erythromycin N-demethylation and that the isoforms induced by the combination of fasting and RU486 administration are CYP3A1, CYP3A23, and, to a lesser extent, CYP3A18. Eur J Clin Microbiol Infect Dis, 1998 Jun, 17(6), 420 - 3 A comparative study on the efficacy of the new quinolone alatrofloxacin in the treatment of experimental legionellosis in guinea pigs; Garcia-de-Lomas J et al.; The in vivo efficacy of trovafloxacin, intraperitoneally administered as alatrofloxacin (CP-116,517), was assessed and compared with that of erythromycin, alone or in combination with rifampicin, in a model of Legionella pneumophila pneumonia in guinea pigs . Trovafloxacin (5 mg/kg administered as alatrofloxacin once daily for 7 days) gave a survival rate of 100% in infected animals . Clearance of bacteria and of bacteria-induced lesions from lungs was achieved by day 6 post-inoculation . The lungs of trovafloxacin-treated animals remained free of bacteria at day 28 post-challenge . Trovafloxacin proved as effective as erythromycin administered intraperitoneally, but was superior to erythromycin alone . or in combination with rifampicin, when given orally. Antimicrob Agents Chemother, 1998 Oct, 42(10), 2762 - 4 In vitro susceptibilities of Chlamydia pneumoniae strains recovered from atherosclerotic coronary arteries; Gieffers J et al.; Chlamydia pneumoniae strains have been recovered from arteriosclerotic coronary arteries, but their antibiotic susceptibility profiles have not yet been examined . We report in vitro susceptibility data for five cardiovascular C . pneumoniae isolates . These strains did not differ significantly from respiratory strains in their patterns of susceptibility to azithromycin, erythromycin, roxithromycin, ofloxacin, doxycycline, rifampin, and penicillin G . Roxithromycin was the most active macrolide, and rifampin was the most effective drug overall. Eur J Clin Pharmacol, 1998 Jul, 54(5), 421 - 5 Zolpidem 10 mg given at daytime is not antagonized by 300 mg caffeine in man; Mattila MJ et al.; OBJECTIVE: Caffeine counteracts various effects of traditional benzodiazepines (BZDs) . As zolpidem, a short-acting hypnotic, is an atypical GABAA-BZD agonist, we investigated when caffeine would counteract the effects of zolpidem as well . METHODS: In daytime study I, zolpidem 10 mg (capsule) and caffeine 150 or 300 mg (in decaffeinated coffee) were given, alone and in combinations, to parallel groups (n = 15-17) of healthy students in double-blind and placebo-controlled manner . Objective and subjective tests were done before and 45 min and 90 min after intake . Ranked delta values (changes from baseline) were analysed by one-way contrast ANOVA and Scheffe's tests . In daytime study II, four healthy subjects took zolpidem 10 mg alone, and together with blinded caffeine 250 mg or (at -45 min) erythromycin 750 mg . Objective and subjective effects were measured and plasma zolpidem concentrations assayed at baseline and 45 min and 90 min after zolpidem intake . RESULTS: In study I, practice effects after placebo (ad + 30%) were seen for letter cancellation and digit symbol substitution but not for flicker fusion tests . Zolpidem alone significantly impaired (P < 0.05 vs delta placebo) letter cancellation and digit symbol substitution at 45 min and 90 min, lowered the flicker fusion threshold at 45 min, and caused subjective drowsiness, mental slowness, clumsiness and feeling of poor performance . Caffeine alone showed a non-significant trend to improve objective performance . The combined effects of zolpidem and either dose of caffeine matched those measured after zolpidem alone . Zolpidem + caffeine 300 mg was not stronger than zolpidem + caffeine 150 mg in impairing immediate memory and causing subjective sedation . In study II, zolpidem caused objective and subjective sedation; neither caffeine nor erythromycin modulated the effects of zolpidem or plasma zolpidem concentrations . CONCLUSION: The sedative effects of 10 mg of zolpidem are not antagonized by 150-300 mg of caffeine in pharmacodynamic or pharmacokinetic terms. Ann Dermatol Venereol, 1998 May, 125(5), 328 - 30 {Hypersensitivity syndrome during Mycoplasma pneumoniae infection}; Kosseian-Bal I et al.; BACKGROUND: Skin manifestations have been described in 25% of patients with Mycoplasma pneumoniae infection . CASE REPORT: We report a case of Mycoplasma pneumoniae infection in a 29-year-old man who developed a polymorphous erythema-like reaction . Skin manifestations were associated with voluminous lymph node enlargement and high eosinophil levels both in serum and alveolar lavage . Seroconversion against Mycoplasma pneumoniae IgG was documented with ELISA . The clinical course was favorable with erythromycin . DISCUSSION: ELISA IgG seroconversion is sufficient to confirm the diagnosis of Mycoplasma pneumoniae infection as this test has an 80-90% specificity . This case was unusual by its clinical presentation and high eosinophil counts in serum and tissue samples, similar to what is found in drug-induced hypersensitivity. Nihon Kokyuki Gakkai Zasshi, 1998 May, 36(5), 482 - 7 {Severe bronchorrhea accompanying alveolar cell carcinoma: treatment with clarithromycin and inhaled beclomethasone}; Hiratsuka T et al.; We report the efficacy of oral clarithromycin and inhaled beclomethasone against severe bronchorrhea in a patient with alveolar cell carcinoma . A 54-year-old man produced about 500 to 900 ml of clear and egg-white-like sputum each day . Anti-cancer chemotherapy and erythromycin therapy did not reduce the volume of sputum . After administration of clarithromycin and inhaled beclomethasone, sputum volume decreased to about 300 nl each day and the patient's ability to perform daily activities improved . Two months later, clarithromycin was stopped and the patient was treated with inhaled beclomethasone alone . Sputum volume did not increase for 6 months, although the chestroentgenographic findings gradually worsened . Then the sputum volume gradually increased . Five months after the sputum volume began to increase, he was producing about 2 liters of sputum each day and died of respiratory failure . Although the levels of CA 19-9, SLX, and CEA in serum were all within the normal range, the sputum contained high levels of CA 19-9 (1,133,620 U/ml), SLX (3,000 U/ml), and CEA (283 ng/ml) . In patients with bronchorrhea, measurement of tumor markers in sputum may be useful for the diagnosis of alveolar cell carcinoma. Xenobiotica, 1998 Aug, 28(8), 795 - 802 Changes in the enzymatic activities of beagle liver during maturation as assessed both in vitro and in vivo; Tanaka E et al.; 1 . We have examined changes in caffeine and trimethadione (TMO) metabolism in vivo, agents which are used as probe drugs . In this study the total body clearance (Cl) of caffeine and TMO was low 1 week after birth (week 1), increased rapidly from week 3, peaked and then decreased gradually until reaching the level for the mature, adult dog . The elimination half-life (t1/2) of caffeine and TMO was prolonged during week 1; however, it then gradually became shorter . Gradually it became longer and reached the level for the adult dog . The apparent volume of distribution (Vd) of caffeine did not change throughout the study . However, the Vd of TMO was only high during week 1 . 2 . The in vitro changes in a variety of typical substrates for seven different cytochrome P450 (CYP) isozymes were examined . In this study three different patterns of metabolism can be identified: (1) activity is low immediately after birth, increases, peaks and then decreases to the adult dog level (p-nitroanisole; CYP1A1, caffeine; CYP1A2, benzphetamine; CYP3A/2B(?), aniline; 2E1 and TMO; CYP2C9/2E1/3A4); (2) activity generally increases rapidly soon after birth, continues to increase, peaks and then gradually decreases to the adult level (phenytoin; CYP2C9); and (3) activity is high (about the same level as the adult) immediately after birth, decreases and then gradually increases to the adult level (erythromycin; CYP3A4/5) . 3 . The results of these in vivo and in vitro studies suggest that changes in enzyme activity are due to differences in P450 isoenzymes during development. Xenobiotica, 1998 Aug, 28(8), 759 - 66 Effect of a new rifamycin derivative, rifalazil, on liver microsomal enzyme induction in rat and dog; Mae T et al.; 1 . The effect of a new rifamycin derivative, rifalazil (KRM-1648), on liver microsomal enzyme induction was studied in rat and dog with repeated oral administration of the compound . Relative liver weight, cytochrome b5 and P450 contents, enzyme activities of NADPH-cytochrome c reductase, aniline hydroxylase, p-nitroanisole O-demethylase, aminopyrine N-demethylase, and erythromycin N-demethylase were measured . 2 . In rat, rifalazil treatment at 300 mg/kg/day for 10 days increased cytochrome b5 content but it did not affect liver weight, P450 content or enzyme activities . In contrast, rifampicin and rifabutin increased relative liver weights, cytochrome contents and enzyme activities under similar conditions . 3 . In dog, rifalazil did not affect any parameters at 30 or 300 mg/kg/day for 13 weeks . 4 . These findings indicate that rifalazil is not an enzyme inducer in rat and dog . This property differs from other rifamycin derivatives such as rifampicin and rifabutin. Drugs, 1998, 56 Suppl 1, 15 - 23; discussion 33 Rational assessment of the interaction profile of cerivastatin supports its low propensity for drug interactions; Muck W; Pharmacokinetic drug-drug interactions influence drug efficacy, tolerability, and compliance . Such interactions are both more common and of more clinical relevance than often appreciated . The US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products have recently issued guidelines setting out in vitro and in vivo investigations to be conducted during drug development . These guidelines reflect the increasing interest of public health authorities in this topic . Cerivastatin is a novel, potent HMG-CoA reductase inhibitor that effectively reduces serum cholesterol levels at low daily doses . It is completely absorbed after oral administration, undergoes moderate first-pass metabolism and high plasma protein binding, and is cleared exclusively via hepatic cytochrome P450 (CYP) . Unlike other drugs of its class, cerivastatin has a dual metabolic pathway, with the involvement of more than one CYP isozyme . Metabolites are cleared via both biliary and renal excretion . On the basis of this pharmacokinetic profile and a knowledge of the target population, the formal in vivo interaction programme for cerivastatin investigated many important potential cerivastatin drug-drug interactions . Cerivastatin appears to lack clinically relevant interactions with digoxin, warfarin, antacid, cimetidine, nifedipine, omeprazole, erythromycin and itraconazole. Hum Reprod, 1998 Jul, 13(7), 1878 - 86 Effects of co-trimoxazole, erythromycin, amoxycillin, tetracycline and chloroquine on sperm function in vitro; Hargreaves CA et al.; This in-vitro study was designed to investigate the effects of commonly prescribed antibiotics on sperm movement characteristics, viability and the ability of spermatozoa to undergo the acrosome reaction . Spermatozoa were obtained by swim-up from normozoospermic semen and cultured for 24 h with increasing concentrations of co-trimoxazole, erythromycin, amoxycillin, tetracycline and chloroquine . Tetracycline at concentrations as low as 2.5 microg/ml led to a significant dose-dependent inhibition in percent rapid-moving spermatozoa, mean path velocity (VAP), straight-line velocity (VSL) and curvilinear velocity (VCL), but at 50 microg/ml tetracycline all spermatozoa were static . Erythromycin had significant effects on rapid movement, VAP, VSL and VCL only at concentrations >100 microg/ml . In contrast, percent rapid-moving spermatozoa was significantly enhanced at low concentrations of chloroquine (5 microg/ml), but significantly inhibited by higher concentrations . Co-trimoxazole did not adversely affect percent rapid-moving spermatozoa below 500 microg/ml, at which concentration movement was decreased by 34% . The mean lateral head displacement (ALH) was significantly enhanced by 5 microg/ml co-trimoxazole and reduced at 1 mg/ml erythromycin . The effects of these drugs were mostly irreversible . Amoxycillin had no effect on sperm movement characteristics over the dose range used, though it inhibited viability at high doses . Viability was significantly reduced at concentrations of all drugs which affect rapid sperm movement; these concentrations of drugs did not appear to affect the ability of spermatozoa to undergo the acrosome reaction . The results from this study, when combined with known effects on spermatogenesis, should facilitate the choice of drugs for the treatment of both genitourinary and unrelated infections in men who are attempting to conceive. J Cardiovasc Pharmacol, 1998 Sep, 32(3), 425 - 34 Drug-related torsades de pointes in the isolated rabbit heart: comparison of clofilium, d,l-sotalol, and erythromycin; Eckardt L et al.; Torsades de pointes is a potentially life-threatening form of polymorphic ventricular tachyarrhythmia typically seen in the presence of repolarization-prolonging agents . We investigated this particular form of tachyarrhythmia in the isolated, perfused rabbit heart . The experimental model was designed to reproduce conditions that are clinically known to be associated with an increased propensity to the development of torsades de pointes . The class III agent clofilium (1 microM) and d,l-sotalol (10 microM), as well as the antibiotic erythromycin (30-150 microM) were infused in the presence of either normal (5.88 mM) or low (1.5 mM) potassium concentration in sinus-driven or atrioventricular (AV)-blocked hearts . Ventricular tachyarrhythmias spontaneously emerged in the clofilium-, d,l-sotalol-, and erythromycin-treated AV-blocked hearts . The episodes showed typical features of torsades de pointes found in humans . They developed within 4-12 min after the onset of infusion, were normally nonsustained, and only rarely degenerated into ventricular fibrillation . Electrical stimulation at cycle lengths <600 ms and perfusion with MgSO4 suppressed arrhythmic activity . In the d,l-sotalol- and erythromycin-treated hearts, torsades de pointes occurred only in the presence of hypokalemia and bradycardia, whereas, in the presence of clofilium, bradycardia alone caused torsades de pointes . Monophasic action-potential recordings demonstrated early afterdepolarizations in endocardial and epicardial recordings . Thus the isolated AV-blocked rabbit heart represents a model for studying drug-related torsades de pointes and its mechanism. Hepatology, 1998 Sep, 28(3), 613 - 9 Effect of the prokinetic agent, erythromycin, in the Richardson ground squirrel model of cholesterol gallstone disease; Xu QW et al.; Impaired gallbladder motility and delayed intestinal transit contribute to cholesterol gallstone formation by impeding the enterohepatic circulation of bile salts and causing gallbladder stasis . The therapeutic value of erythromycin, a prokinetic motilin analog, was evaluated in an animal model of gallstone formation . Eighty ground squirrels were fed either a trace- (control) or a high- (1%) cholesterol diet . Half of each diet group received either erythromycin stearate or placebo orally twice daily for 4 weeks . Biliary lipid secretion and bile salt pool size were determined via common duct cannulation . Gallbladder contractile response to cholecystokinin (CCK) was studied in vitro . Intestinal transit was evaluated in vivo by 51Cr marker . In the placebo-treated group, fed the high- versus the trace-cholesterol diet, bile salt secretion decreased (trace-cholesterol + placebo, 21.0 +/- 1.8 nmol/min/g liver vs . high-cholesterol + placebo, 9.3 +/- 1.4 nmol/min/g liver), cholesterol saturation index (CSI) doubled (trace-cholesterol + placebo, 0.61 +/- 0.06 vs . high-cholesterol + placebo, 1.30 +/- 0.04), nucleation time shortened (trace-cholesterol + placebo, > 21 days vs . high-cholesterol + placebo, 6.4 +/- 1.0 days), cholesterol crystals formed, gallbladder contractility diminished, and intestinal transit was delayed (each P < .05) . Erythromycin treatment of animals on the high-cholesterol diet restored gallbladder contractility and intestinal transit to control levels, increased bile salt secretion, reduced the total bile salt pool, lowered the cholesterol saturation of bile, lengthened the nucleation time, and so reduced crystal formation (each P < .05) . Erythromycin enhances gallbladder motility and hastens intestinal transit, promoting more rapid enterohepatic cycling of bile salts . This increases bile salt secretion, improves cholesterol solubility, and reduces crystal development. J Perinatol, 1998 Jul-Aug, 18(4), 287 - 90 Legionella pneumonia in neonates: a literature review; Levy I et al.; It has recently been recognized that neonates may develop pneumonia as a result of Legionella pneumophila . The objective of this study is to characterize the epidemiology, risk factors, diagnosis, clinical features, and outcome of neonatal legionellosis . Review of the literature revealed nine cases of neonatal Legionella infection . Five neonates were term infants and four were preterm . Eight had potential risk factors such as prematurity, congenital heart disease, bronchopulmonary dysplasia, or corticosteroid therapy . Diagnosis was proven by culture in all cases . The main presentation was acute respiratory distress requiring mechanical ventilation . In six infants, the infection had a fatal outcome, including five who were not treated with erythromycin . All the cases were nosocomial, and environmental Legionella was documented in five cases . As has been noted in adults and children with Legionella, early recognition and institution of appropriate therapy are the most important determinants of the prognosis. Clin Pharmacol Ther, 1998 Aug, 64(2), 177 - 82 Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations; Kantola T et al.; OBJECTIVE: To study the effects of erythromycin and verapamil on the pharmacokinetics of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase . METHODS: A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks . Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days . On day 2, 40 mg simvastatin was administered orally . Serum concentrations of simvastatin, simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours . RESULTS: Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum simvastatin concentration-time curve from time zero to 24 hours {AUC(0-24)} 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01) . Erythromycin increased the mean Cmax of active simvastatin acid fivefold (p < 0.001) and the AUC(0-24) 3.9-fold (p < 0.001) . Verapamil increased the Cmax of simvastatin acid 3.4-fold (p < 0.001) and the AUC(0-24) 2.8-fold (p < 0.001) . There was more than tenfold interindividual variability in the extent of simvastatin interaction with both erythromycin and verapamil . CONCLUSIONS: Both erythromycin and verapamil interact considerably with simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism . Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with simvastatin should be avoided . As an alternative, the dosage of simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a simvastatin dosage higher than 20 mg/day is used . Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used. J Toxicol Environ Health A, 1998 Aug 7, 54(7), 509 - 27 Effects of motorcycle exhaust on cytochrome P-450-dependent monooxygenases and glutathione S-transferase in rat tissues; Ueng TH et al.; The effects of motorcycle exhaust (ME) on cytochrome P-450 (P-450)-dependent monooxygenases were determined using rats exposed to the exhaust by either inhalation, intratracheal, or intraperitoneal administration . A 4-wk ME inhalation significantly increased benzo{a}pyrene hydroxylation, 7-ethoxyresorufin O-deethylation, and NADPH-cytochrome c reductase activities in liver, kidney, and lung microsomes . Intratracheal instillation of organic extracts of ME particulate (MEP) caused a dose- and time-dependent significant increase of monooxygenase activity . Intratracheal treatment with 0.1 g MEP extract/kg markedly elevated benzo{a}pyrene hydroxylation and 7-ethoxyresorufin O-deethylation activities in the rat tissues 24 h following treatment . Intraperitoneal treatment with 0.5 g MEP extract/kg/d for 4 d resulted in significant increases of P-450 and cytochrome b5 contents and NADPH-cytochrome c reductase activity in liver microsomes . The intraperitoneal treatment also markedly increased monooxygenases activities toward methoxyresorufin, aniline, benzphetamine, and erythromycin in liver and benzo{a}pyrene and 7-ethoxyresorufin in liver, kidney, and lung . Immunoblotting analyses of microsomal proteins using a mouse monoclonal antibody (Mab) 1-12-3 against rat P-450 1A1 revealed that ME inhalation, MEP intratracheal, or MEP intraperitoneal treatment increased a P-450 1A protein in the hepatic and extrahepatic tissues . Protein blots analyzed using antibodies to P-450 enzymes showed that MEP intraperitoneal treatment caused increases of P-450 2B, 2E, and 3A subfamily proteins in the liver . The ME inhalation, MEP intratracheal, or MEP intraperitoneal treatment resulted in significant increases in glutathione S-transferase activity in liver cytosols . The present study shows that ME and MEP extract contain substances that can induce multiple forms of P-450 and glutathione S-transferase activity in the rat. Microbiology, 1998 Aug, 144 ( Pt 8), 2151 - 9 Physical-genetic map of the erythromycin-producing organism Saccharopolyspora erythraea; Reeves AR et al.; A physical map of the chromosome of the erythromycin-producing actinomycete Saccharopolyspora erythraea NRRL 2338 has been constructed using the restriction enzymes AseI and DraI . The map was constructed by a variety of methods including linking clone analysis, cross-hybridizations using labelled macrorestriction fragments, gene probing, two-dimensional PFGE and restriction enzyme site generation . Analysis of the individual macrorestriction patterns of the 17 AseI-, 6 DraI- and 22 AseI/DraI-digested fragments indicated a chromosome size of about 8 Mb . Linking clones for five contiguous AseI fragments were obtained, covering 32% of the chromosome . The linkage of an additional eight AseI fragments was aided by the finding that the rRNA operons of S . erythraea contain an AseI site within the 16S (rrs) gene . Generation of S . erythraea strains that contain additional DraI sites within selected AseI fragments, followed by PFGE analysis and Southern hybridization to determine specific linkages, facilitated the completion of the AseI map . The entire DraI map was constructed by gene probing and cross-hybridizations . PFGE analysis of agarose-embedded DNA prepared in either the presence or absence of proteinase K suggested that the S . erythraea NRRL 2338 chromosome is linear . A total of 15 genes or gene clusters were mapped to specific AseI and DraI fragments, including the erythromycin-biosynthetic gene cluster and the rRNA operons. South Med J, 1998 Aug, 91(8), 755 - 8 T wave alternans associated with HIV cardiomyopathy, erythromycin therapy, and electrolyte disturbances; Kent S et al.; We report a case of T wave alternans in a patient with HIV cardiomyopathy . T wave alternans is an unusual electrocardiographic finding in acquired long QT syndromes that can precede the development of torsades de pointes . Our patient had multiple risk factors for the development of the acquired long QT syndrome, including HIV cardiomyopathy, electrolyte disturbances, and erythromycin therapy . T wave alternans has not been described previously with HIV cardiomyopathy and only rarely with erythromycin therapy . Patients who have HIV cardiomyopathy and who receive intravenous erythromycin may benefit from monitoring for QT prolongation and electrolyte disturbances to avoid the development of torsades de pointes. Gene, 1998 Aug 17, 216(1), 215 - 23 Construction of new vectors for high-level expression in actinomycetes; Rowe CJ et al.; A new integrative vector (pCJR24) was constructed for use in the erythromycin producer Saccharopolyspora erythraea and in other actinomycetes . It includes the pathway-specific activator gene actII-ORF4 from the actinorhodin biosynthetic gene cluster of Streptomyces coelicolor . The actI promoter and the associated ribosome binding site are located upstream of an NdeI site (5'-CATATG-3') which encompasses the actI start codon allowing protein(s) to be produced at high levels in response to nutritional signals if these signals are faithfully mediated by the ActII-ORF4 activator . Several polyketide synthase genes were cloned in pCJR24 and overexpressed in S . erythraea after integration of the vector into the chromosome by homologous recombination, indicating the possibility that the S . coelicolor promoter/activator functions appropriately in S . erythraea . pCJR24-mediated recombination was also used to place the entire gene set for the erythromycin-producing polyketide synthase under the control of the actI promoter . The resulting strain produced copious quantities of erythromycins and precursor macrolides when compared with wild-type S . erythraea . The use of this system provides the means for rational strain improvement of antibiotic-producing actinomycetes. Biochem Pharmacol, 1998 Jun 1, 55(11), 1881 - 92 Influence of some novel N-substituted azoles and pyridines on rat hepatic CYP3A activity; Slama JT et al.; A series of N-substituted heteroaromatic compounds structurally related to clotrimazole was synthesized, and the effects of these compounds on ethosuximide clearance in rats were determined as a measure of their abilities to induce cytochrome P4503A (CYP3A) activity . Ethosuximide clearance and in vitro erythromycin N-demethylase activity were shown to correlate . In this series, imidazole or other related heteroaromatic "head groups" were linked to triphenylmethane or other phenylmethane derivatives . Within the series, it was found that 1-triphenylmethane-substituted imidazoles elicited the greatest increase in CYP3A activity, and that among the triphenylmethyl-substituted imidazoles, the highest activities were achieved by the substitution of F- or Cl- in either the meta or para position of one of the phenyl rings . Diphenylmethyl-substituted pyridine was effectively devoid of activity . Compounds eliciting the largest increase in CYP3A activity (viz . 1-{(3-fluorophenyl)diphenylmethyl}imidazole, 1-{(4-fluorophenyl)diphenylmethyl}imidazole, and 1-{tri-(4-fluorophenyl)methyl}imidazole) produced little or no increase in ethoxyresorufin O-dealkylase (EROD) activity (i.e . CYP1A), whereas benzylimidazole, which elicited only a small increase in CYP3A activity, produced an almost 9-fold increase in CYP1A activity . For a series of eleven compounds exhibiting a wide range of influence on CYP3A activity, a positive correlation was found between ethosuximide clearance and hepatic CYP3A mRNA levels. Chem Biol, 1998 Aug, 5(8), 407 - 12 Engineering of a minimal modular polyketide synthase, and targeted alteration of the stereospecificity of polyketide chain extension; Bohm I et al.; BACKGROUND: Polyketides are a large and structurally diverse group of natural products that include antibiotics, antifungal agents and immunosuppressant compounds . Polyketides are biosynthesised in filamentous bacteria on modular polyketide synthases (PKSs) in which each cycle of chain extension requires a different 'module' of enzymatic activities . The recently proposed dimeric model for modular PKSs predicts that even a single-module PKS should be catalytically active in the absence of other PKS components . Researchers are also interested in manipulating the stereochemical outcome of polyketide chain extension using genetic engineering of domains within each module . RESULTS: We have constructed a minimal modular PKS from the erythromycin-producing PKS (DEBS) of Saccharopolyspora erythraea . The diketide synthase (DKS1-2) consists of a single chimaeric extension module, derived from the DEBS module 1 ketoacyl-ACP synthase (KS), sandwiched between a loading module and a chain-terminating thioesterase . When DKS1-2 was expressed in S . erythraea, the strain preferentially6 accumulated the diketide (2R, 3S)-2-methyl-3-hydroxy pentanoic acid . CONCLUSIONS: These results demonstrate that, as predicted, even a single-module PKS is catalytically active in the absence of other DEBS proteins . In its normal context, the ketosynthase domain KS1 is thought to generate a (2S)-2methyl-3-hydroxy intermediate by epimerising the initial product of carbon-carbon chain formation, the (2R)-2-methyl-3-ketoester . The observed formation of the alternative (2R)-methyl-3-hydroxy product catalysed by DKS1-2 provides strong support for this proposal, and indicates how targeted alteration of stereospecificity can be achieved on a modular PKS. Arch Toxicol, 1998 Jun, 72(7), 387 - 94 Suppression of male-specific cytochrome P450 isoforms by bisphenol A in rat liver; Hanioka N et al.; We examined the effect of bisphenol A (BPA) on microsomal cytochrome P450 (P450) enzymes in rats . Rats were treated intraperitoneally with BPA daily for 4 days, at doses of 10, 20, and 40 mg/kg . Among the P450-dependent monooxygenase activities, testosterone 2alpha-hydroxylase (T2AH) and testosterone 6beta-hydroxylase (T6BH) activities, which are associated with CYP2C11 and CYP3A2 respectively, were remarkably decreased by 40 mg/kg BPA . The levels of the control activities were 13 and 50%, respectively . Furthermore, immunoblotting showed that BPA (20 or 40 mg/kg) significantly reduced CYP2C 11/6 and CYP3A2/1 protein levels in rat liver microsomes . In addition, estradiol 2-hydroxylase (ED2H) and benzphetamine N-demethylase (BZND) activities were significantly decreased by BPA at 20 and 40 mg/kg (by 19-73%) . The Km values for T2AH and T6BH in 20 and 40 mg/kg BPA-treated rats were significantly high compared with that in control rats . The Vmax for T2AH was dose-dependently decreased by BPA treatment, whereas that of T6BH was only decreased by BPA at 40 mg/kg . On the other hand, lauric acid omega-hydroxylase (LAOH) activity was significantly increased by BPA at 20 and 40 mg/kg (1.5- and 1.7-fold, respectively) . Immunoblot analysis showed that 20 and 40 mg/kg BPA induced CYP4A1/2 protein expression . However, the activities 7-ethoxyresorufin O-deethylase (EROD), 7-methoxyresorufin O-demethylase (MROD), 7-ethoxycoumarin O-deethylase (ECOD), 7-benzyloxyresorufin O-debenzylase (BROD), aminopyrine N-demethylase (APND), chlorzoxazone 6-hydroxylase (CZ6H), erythromycin N-demethylase (EMND), and testosterone 7alpha-hydroxylase (T7AH) were not affected by BPA at any dose . These results suggest that BPA affects male-specific P450 isoforms in rat liver, and that these changes closely relate to the toxicity of BPA. Equine Vet J, 1998 Jul, 30(4), 349 - 51 Acetaminophen as a marker of gastric emptying in ponies; Doherty TJ et al.; Gastric emptying was evaluated in ponies using the acetaminophen (AP) method . Fifteen minutes after i.v . administration of metoclopramide, erythromycin, yohimbine, atropine or saline, the ponies were given AP by stomach tube . Blood samples for AP analysis were collected at baseline and 15, 30, 45, 60, 75, 90, 105 and 120 min after AP administration . Time to reach peak serum concentration (Tmax), maximum serum concentration (Cmax) and area under the AP serum concentration vs . time curve (AUC) were determined for each treatment group . In the control group, Tmax was 31 min and this decreased significantly (P < 0.05) following the administration of metoclopramide . Atropine significantly increased Tmax and decreased Cmax and AUC . Yohimbine significantly increased AUC . Erythromycin did not significantly change any parameter . This study indicates that acetaminophen can be used to evaluate gastric emptying in ponies . The method is easy to perform and is minimally invasive . Metoclopramide stimulated gastric emptying of liquid in healthy, fasting ponies . Atropine significantly delayed, while erythromycin had little effect on, gastric emptying . Yohimbine increased the cumulative absorption of AP. J Pharmacol Exp Ther, 1998 Aug, 286(2), 727 - 35 Blockade of HERG and Kv1.5 by ketoconazole; Dumaine R et al.; Ketoconazole, a widely used fungicide in patients, has been associated with Q-T prolongation and torsade de pointes when co-administered with terfenadine (Seldane) . Both compounds use the same cytochrome-P450 metabolic pathway, resulting in an increase in plasma concentration of terfenadine . We previously showed that terfenadine blocked HERG (Human Ether-a-Gogo Related Gene), an important component of the repolarizing cardiac delayed rectifier IK with concentration needed to obtain 50% of the block (IC50) in the therapeutic range (300 nM) . Another target is Kv1.5 (delayed outward rectifier potassium current), an important component of human atrial ultrarapid delayed rectifier current . Whether Kv1.5 and HERG proteins are direct targets for ketoconazole has yet to be addressed . We heterologously expressed HERG and Kv1.5 in Xenopus oocytes and compared their sensitivities to ketoconazole . HERG and Kv1.5 currents were reduced comparably with apparent IC50 values of 49 microM and 107 microM, respectively, when measured using the two-microelectrode recording technique . The differences in the IC50 may help explain the preferential ventricular origin of the ketoconazole-associated arrhythmias during overdose . The mechanism of block was different between Kv1.5 and HERG . Cumulative application of terfenadine and ketoconazole at their respective IC50 concentrations resulted in current reductions that suggest an additive rather than a competitive type of block by the two drugs . We conclude that ketoconazole may potentiate the effects of terfenadine first by an indirect pharmacokinetic action to elevate plasma levels and second by a direct pharmacodynamic action on HERG currents . These potential dual actions on HERG currents suggest that precautions should be taken in long-term ketoconazole treatment, particularly for patients who have decreased liver function or are on a drug regimen requiring simultaneous medications that use cytochrome-P450 for breakdown, such as terfenadine or erythromycin, or Class III antiarrhythmic drugs. Biochemistry, 1998 Aug 4, 37(31), 11012 - 7 Origin of starter units for erythromycin biosynthesis; Weissman KJ et al.; Modular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), are multifunctional proteins that govern the synthesis of a number of clinically important natural products . The modular arrangement of active sites within these enzymes suggests the possibility of a combinatorial approach to the synthesis of novel bioactive polyketides . The efficacy of combinatorial strategies toward altering the starter unit specificity of polyketide synthases critically depends on controlling the supply of competing endogenous starter acids . Using DEBS 1-TE, a bimodular derivative of DEBS, we aimed to determine whether the beta-ketosynthase (KS) domain responsible for condensation in the first module also has the ability to prime its own biosynthesis by catalyzing the decarboxylation of methylmalonyl-CoA to produce propionyl-CoA . In contrast to earlier reports with a closely similar mini-PKS DEBS 1+TE, we have found that rigorously purified DEBS 1-TE does not catalyze the decarboxylation of methylmalonyl-CoA. Gut, 1998 Jun, 42(6), 830 - 5 Motilin induces gall bladder emptying and antral contractions in the fasted state in humans; Luiking YC et al.; BACKGROUND: Animal studies have shown that motilin affects gall bladder motility . In humans, no effect has been shown, but erythromycin, a motilin receptor agonist, induces gall bladder emptying . AIMS: To explore the effect of increasing doses of exogenous motilin on gall bladder volume and antral contractility in the fasted state in humans . METHODS: After an overnight fast, eight healthy men received increasing intravenous doses of Leu13-motilin (KW-5139) or 0.9% NaCl in a double blind, randomised fashion . Gall bladder volume and antral contraction frequency were determined by ultrasonography . RESULTS: Infusion of motilin increased plasma motilin levels . Motilin induced a reduction in gall bladder volume of 8.0 (5.0)%, 17.1 (5.0)%, 18.5 (4.7)%, and 16.1 (4.9)% of baseline volume at the end of infusion of 2, 4, 8, and 16 pmol/kg/min respectively, compared with mean stable gall bladder volumes during placebo infusion (p < 0.05) . Antral contraction frequency increased during motilin infusion, but not during placebo infusion (p < 0.05) . CONCLUSIONS: Exogenous motilin reducted fasting gall bladder volume and increased antral contractions . After reaching maximal reduction, the gall bladder volume did not decrease further during continuous motilin infusion at higher doses and stayed at the same reduced volume . The degree of gall bladder volume reduction during motilin infusion mimicked gall bladder emptying preceding antral phase III activity of the migrating motor complex in humans . This study indicates that motilin may play a physiological role in the regulation of gall bladder emptying in the fasted state. J Chromatogr A, 1998 Jul 3, 812(1-2), 287 - 93 Determination of macrolides in biological matrices by high-performance liquid chromatography with electrochemical detection; Kees F et al.; A liquid chromatographic method for the determination of macrolide antibiotics is described using a cyanopropyl column which proved to be as efficient or superior to the normally used apolar reversed-phase columns . The recovery of the macrolides from water and plasma was 80-90% . Using 0.5 ml of plasma, 30 ng/ml of clarithromycin, 50 ng/ml of roxithromycin and 10 ng/ml of azithromycin could be determined with acceptable precision and accuracy . The method has been employed in pharmacokinetic studies in humans for the determination of roxithromycin, clarithromycin and azithromycin in plasma, serum and other biological matrices . The particular selectivity of the cyanopropyl phase may also allow the simultaneous determination of erythromycin and its prodrug esters. Curr Opin Chem Biol, 1998 Jun, 2(3), 339 - 45 Combinatorial biosynthesis of erythromycin and complex polyketides; Staunton J; Modular polyketide synthases that produce many clinically important natural products such as erythromycins and lovastatins have been engineered in many ways to produce novel natural products . The structural variations have included alterations to the substituents on the macrolide ring, including the starter acid residue, using either semi-synthetic methodology or genetic engineering . It is now also possible to produce shorter polyketide chains that are released either as lactone rings (6-, 8-, 12- and 14-membered rings) or linear products . The strategies for engineering polyketide synthases to produce specific natural products are now well established . Several of the macrolides produced recently have been elaborated to produce novel antibiotics. Aliment Pharmacol Ther, 1998 Apr, 12(4), 373 - 6 Which form of erythromycin should be used to treat gastroparesis? A pharmacokinetic analysis; Ehrenpreis ED et al.; BACKGROUND: Erythromycin is a macrolide antibiotic that exhibits prokinetic effects . It has been shown to enhance antral contractility and accelerates gastric emptying rates, primarily by stimulating motilin receptors . AIM: To determine the optimal dosage form of erythromycin for use as a prokinetic agent . METHODS: Eight normal volunteers and three patients with documented gastroparesis ingested 250 mg erythromycin in tablet . suspension and intravenous forms . Serum erythromycin levels were determined at frequent intervals . These data were plotted vs . time and analysed for lag time, time to maximum concentration (tmax), maximum concentration (Cmax) and bioavailability (F) . RESULTS: The absorption kinetics of the erythromycin suspension was notable for short lag times and early tmax, while lag times and tmax were delayed with the tablet form . Median lag time was 15 min for the suspension vs . 90 min for the tablet (P < 0.005) . Median tmax for the suspension was 45 min vs . 180 min for the tablet (P < 0.005) . A non-significant decrease in F was seen with the suspension compared to the tablet (P = 0.12) . CONCLUSION: Based on the kinetic data from this study, erythromycin suspension is the ideal dosage form for administration of this drug as a prokinetic agent. Arch Surg, 1998 Jul, 133(7), 709 - 14 Enhancement of gastric emptying of solids by erythromycin in patients with Roux-en-Y gastrojejunostomy; Petrakis J et al.; BACKGROUND: Roux-en-Y reconstruction is sometimes associated with symptoms that suggest food stasis, as a result of dysmotility of either the gastric remnant and/or the efferent jejunal limb . OBJECTIVE: To study the possible effect of intravenous erythromycin lactobionate on gastric emptying of solids in patients who have undergone a Roux-en-Y procedure . PATIENTS: Twenty-four patients with a Roux-en-Y procedure participated in the study . Ten of them had undergone truncal vagotomy with pyloroplasty; the remaining 14 had undergone a Billroth II subtotal gastrectomy as the initial antiulcer procedure . Sixteen healthy subjects served as controls . METHODS: All healthy subjects and patients underwent assessment of gastric emptying of a standard radiolabeled solid meal after administration of placebo or 200 mg of erythromycin lactobionate intravenously . Scanning was done with a gamma camera, and emptying curves were constructed . From these curves the half-time of gastric emptying was calculated . RESULTS: Patients with severe symptoms of gastric stasis had a significantly longer half-time than did patients with mild or no symptoms (P=.002) . Patients with a Billroth II subtotal gastrectomy as the initial antiulcer procedure had a significantly worse grade of symptoms (P=.01) and a significantly prolonged half-time (P=.02) compared with patients with a truncal vagotomy with pyloroplasty as the initial antiulcer procedure . Erythromycin significantly reduced the half-time in the controls (P<.001) and all patients after Roux-en-Y procedure (P<.001) . CONCLUSION: Erythromycin could be a useful prokinetic drug in patients with Roux stasis syndrome. Antimicrob Agents Chemother, 1998 Aug, 42(8), 1944 - 51 Interactions between HMR 3647, a new ketolide, and human polymorphonuclear neutrophils; Vazifeh D et al.; HMR 3647, a new ketolide, is active upon intracellular pathogens . We previously demonstrated that HMR 3004 (RU 64004), another ketolide, is highly concentrated by human polymorphonuclear neutrophils (PMNs) . This prompted us to evaluate whether the presence of a 3-keto group instead of an L-cladinose, a neutral sugar characteristic of erythromycin A derivatives, confers peculiar pharmacokinetic properties with regard to cellular accumulation and efflux . After incubation with the radiolabelled drug, HMR 3647 uptake was determined by a velocity gradient centrifugation technique . HMR 3647 was avidly concentrated by PMNs, without saturation, over a 3-h incubation period, with cellular-to-extracellular concentration ratios of 31 +/- 4.2 at 5 min and up to 348 +/- 27.1 at 180 min . About 60% of HMR 3647 was located in the granular compartment; less than 6% was associated with the membranes . HMR 3647 gradually egressed from loaded cells placed in drug-free medium . Uptake was dependent on environmental temperature (activation energy, 128 +/- 9 . 4 kJ/mol) but not on extracellular pH . HMR 3647 displayed Michaelis-Menten saturation kinetics with a mean Vmax of 2315 ng/2.5 x 10(6) PMNs/5 min and a mean Km of 117 mg/liter (144 microM) . As already observed with erythromycin A-derived macrolides, extracellular Ca2+ was necessary for optimal uptake of HMR 3647 . Interestingly, verapamil increased the uptake of HMR 3647 at 5 min, but this was followed by gradual inhibition at later incubation times, a phenomenon probably related to stimulation of drug efflux . The impact of intracellular accumulation of HMR 3647 on PMN functions was also investigated . In contrast to other erythromycin A derivatives, HMR 3647 only weakly triggered granule exocytosis, but it inhibited superoxide anion production in a time- and concentration-dependent manner, with concentrations which inhibited 50% of control response of 55 (67 microM) (5 min) and 30 (36 microM) (30 min) mg/liter for formyl-methionyl-leucyl-phenylalanine stimulation and 117 (143 microM) (5 min) and 44 (54 microM) (30 min) mg/liter for phorbol myristate acetate stimulation. Pediatr Infect Dis J, 1998 Jul, 17(7), 615 - 20 Impact of erythromycin on respiratory colonization of Ureaplasma urealyticum and the development of chronic lung disease in extremely low birth weight infants; Bowman ED et al.; BACKGROUND: Chronic lung disease (CLD) is a significant cause of neonatal morbidity and mortality despite advances in neonatal care . Ureaplasma urealyticum colonization of the lower respiratory tract has been associated with CLD, particularly in extremely low birth weight infants . Despite numerous studies demonstrating the pathogenicity of this organism, treatment remains controversial . This study examines neonates colonized with U . urealyticum in the lower respiratory tract and treated with erythromycin, as compared with noncolonized neonates . METHODS: A prospective cohort study of 124 neonates weighing <1000 g at birth, requiring endotracheal intubation and ventilation . Endotracheal aspirates were cultured for U . urealyticum and conventional bacteria twice weekly for the duration of endotracheal intubation . Infants colonized with U . urealyticum were treated with intravenous erythromycin . Maximal ventilatory requirements, CLD at Day 28 and 36 weeks postconception, duration of ventilation, oxygen dependency and hospital stay were documented . RESULTS: Twenty-two infants (18%) were identified as being U . urealyticum colonized in endotracheal aspirates . Colonization was significantly associated with younger maternal age, prolonged rupture of membranes, premature labor and vaginal delivery . Of colonized neonates 14% were delivered by cesarean section, with intact membranes . As compared with noncolonized infants, there were no statistically significant differences in chronic lung disease, duration of oxygen therapy or time to discharge . CONCLUSIONS: Seven published cohort studies of similar high risk populations where U . urealyticum-colonized infants did not receive erythromycin therapy, show a consistent association with CLD (pooled relative risk + 5.21; 95% confidence interval, 2.93 to 9.64) . This association was not demonstrated in the current study and adds further weight to the need for a randomized controlled trial to be per