Arch Biochem Biophys, 1997 May 1, 341(1), 47 - 61 Inhibition of coumarin 7-hydroxylase activity in human liver microsomes; Draper AJ et al.; Nine organic solvents and 47 commonly used P450 substrates and inhibitors were examined for their effects on coumarin 7-hydroxylase (CYP2A6) activity in human liver microsomes . Of the nine organic solvents examined (final concentration 1%, v/v), only methanol did not inhibit the 7-hydroxylation of coumarin (0.5 to 50 microM) by human liver microsomes . Dioxane and tetra-hydrofuran, which are structurally related to coumarin, were the most inhibitory solvents examined . Although the rates of coumarin 7-hydroxylation varied enormously among nine samples of human liver microsomes and cDNA-expressed CYP2A6 (Vmax = 179 to 2470 pmol/ mg protein/min), the Km for coumarin 7-hydroxylation was fairly constant (ranging from 0.50 to 0.70 microM) . The following chemicals caused little or no inhibition of CYP2A6 as defined by a Ki > 200 microM: caffeine, chlorzoxazone, cimetidine, dextromethorphan, diazepam, diclofenac, erythromycin, ethinylestradiol, ethynyltestosterone, fluconazole, furafylline, furfural, hexobarbital, itraconazole, mephenytoin, methimazole, metronidazole, naringenin, naringin, nifedipine, norfloxacin, norgestrel, orphenadrine, quinidine, papaverine, phenacetin, pyrimethamine, ranitidine, spironolactone, sulfaphenazole, sulfinpyrazone, testosterone, tolbutamide, troleandomycin, and warfarin . In other words, these chemicals, at a final concentration of 100 microM, failed to inhibit CYP2A6 when the concentration of coumarin was equal to Km (0.50 microM) . The following chemicals were classified as strong inhibitors of CYP2A6 (defined by Ki < 200 microM): clotrimazole, diethyldithiocarbamate, ellipticine, ketoconazole, 8-methoxypsoralen, 4-methylpyrazole, metyrapone, miconazole, alpha-naphthoflavone, nicotine, p-nitrophenol, and tranylcypromine . The potency with which each chemical inhibited the 7-hydroxylation of coumarin was independent of which sample of human liver microsomes was studied . One of the most potent inhibitors of coumarin 7-hydroxylase was 8-methoxypsoralen (methoxsalen), which was determined to be a mechanism-based inhibitor (suicide substrate) of CYP2A6 (k(inactivation) 0.5 min-1) . With the exception of 8-methoxypsoralen, preincubation of human liver microsomes and NADPH with the aforementioned inhibitors did not increase their ability to inhibit CYP2A6 . The most potent competitive inhibitor of CYP2A6 was tranylcypromine (Ki = 0.04 microM) . Several of the chemicals that strongly inhibited CYP2A6, such as ketoconazole and tranylcypromine, are often used with the intention of selectively inhibiting human P450 enzymes other than CYP2A6 . The results of this study underscore the need for a systematic evaluation of the specificity of commonly used P450 inhibitors. Orv Hetil, 1997 Apr 20, 138(16), 1003 - 6 {Erythrocyte-induced "torsade de pointes" ventricular tachycardia}; Lengyel C et al.; A case of erythromycin-induced acquired long QT syndrome and "torsades de pointes" ventricular tachycardia is reported . The peculiar ventricular tachyarrhythmia was evoked by orally administered erythromycin (1.5 g/die) in the presence of diuretic (clopamide)-induced hypokalaemia . The pause-dependent "torsades de pointes" was preceded by prolonged QTU interval (560 ms), "particular bigeminy" and "short-long-short" RR interval sequence . The recurrent ventricular tachycardia causing syncopal attacks was abolished by the discontinuation of erythromycin treatment, K+/Mg(2+)-supplementation and oral mexiletine therapy . It is emphasized that the macrolide antibiotic/prokinetic erythromycin, applied in therapeutic dosages, blocks the rapidly activating delayed rectifier potassium current (IKr), and as such, prolongs ventricular repolarization and may be "torsadogenic". Am J Perinatol, 1997 Apr, 14(4), 233 - 7 The efficacy of prophylactic erythromycin in preventing vertical transmission of Ureaplasma urealyticum; Ogasawara KK et al.; To determine if prophylactic erythromycin alters the vertical transmission rate of Ureaplasma urealyticum . Randomized prospective study of 51 singleton pregnancies between 22 and 35 weeks' gestation with preterm premature rupture of membranes or preterm labor . Patients received oral erythromycin for 7 days in addition to routine prophylactic intravenous ampicillin or ampicillin alone . Lower genital colonization with U . urealyticum was 33 of 51 (65%) . Vertical transmission of U . urealyticum was 25% (3 of 12) in the erythromycin group and 4 of 17 (24%) for the controls . The average interval from randomization to delivery was 303.5 hr in the erythromycin group and 70.9 hr for controls (p = 0.04) . Although not statistically significant, histologic chorioamnionitis in patients colonized with Ureaplasma was lower in the erythromycin group (3 of 12, 25%) compared to the controls (10 of 17, 59%) . Prophylactic erythromycin does not decrease vertical transmission of Ureaplasma . It may decrease the incidence of histologic chorioamnionitis and increase the latency period. Aliment Pharmacol Ther, 1997 Apr, 11(2), 381 - 5 The effect of intravenous erythromycin on solid meal gastric emptying in patients with chronic symptomatic post-vagotomy-antrectomy gastroparesis; Kendall BJ et al.; BACKGROUND: Chronic symptomatic gastroparesis occurs in 3-5% of patients following vagotomy and antrectomy . Erythromycin, a macrolide antibiotic, improves gastric emptying in patients with idiopathic and diabetic gastroparesis . Erythromycin's effect on gastric emptying in patients with post-vagotomy-antrectomy gastroparesis is unknown . The aim of this study was to determine if a single dose of intravenous erythromycin (1 mg/kg or 6 mg/kg) accelerates solid meal gastric emptying in patients with chronic symptomatic post-vagotomy-antrectomy gastroparesis . METHODS: Six patients were entered into the study, three males and three females, with a mean age of 50 years . Four patients were randomized to receive erythromycin 6 mg/kg and two patients 1 mg/kg . The mean time since initial surgery was 9.2 years (range 1-16 years) with five patients having undergone a Roux-en-Y revision . RESULTS: Intravenous erythromycin significantly lowered percentage gastric retention at 120 min, from a baseline of 90.5 +/- 6% (S.E.M.) to 40.1 +/- 4.8% after erythromycin (P = 0.0002) . Erythromycin improved gastric emptying in each patient by at least 40% . Intravenous erythromycin significantly accelerated the rate of gastric emptying in the first 30 min after meal ingestion from a baseline rate of 0.072 +/- 0.06%/min to 0.96 +/- 0.31%/min after erythromycin (P = 0.028) . For each of the subsequent 30 minute time periods, erythromycin had no significant effect on the rate of gastric emptying . CONCLUSION: Intravenous erythromycin significantly improves the initial phase of solid meal gastric emptying in patients with chronic symptomatic post-antrectomy-vagotomy gastroparesis. Clin Infect Dis, 1997 Apr, 24(4), 562 - 4 Bacillary angiomatosis associated with myositis in a patient infected with human immunodeficiency virus; Whitfeld MJ et al.; A man with AIDS presented with a deep soft-tissue mass involving the right thigh . Biopsy of a skin lesion on the back and culture of a specimen from this lesion showed bacillary angiomatosis due to Bartonella (formerly Rochalimaea) quintana . Magnetic resonance imaging revealed a large heterogeneous mass involving the vastus medialis and intermedius muscles . Therapy with erythromycin caused rapid resolution of both the cutaneous lesion and the muscle lesion . Bartonella infection is proposed as an additional cause of bacterial myositis and expands the spectrum of presentation of bacillary angiomatosis. J Paediatr Child Health, 1997 Apr, 33(2), 148 - 50 Erythromycin treatment for gastrointestinal dysmotility in preterm infants; Ng PC et al.; OBJECTIVE: To report our clinical experience on the use of oral erythromycin for the treatment of severe gastrointestinal dysmotility in preterm infants . METHODOLOGY: A case series study of seven preterm infants (six were very low birthweight) with severe intestinal dysmotility in a tertiary neonatal centre . RESULTS: All responded favourably without adverse effects and tolerated full enteral feeding within 1-2 weeks of the commencement of the drug . CONCLUSIONS: As prolonged total parenteral nutrition carries significant risk of complications, this therapy could be considered in selected preterm infants who fail to establish enteral feeding after an extended period, and in whom an anatomically obstructive lesion of the gastrointestinal tract has been excluded . Meanwhile, we would caution against the widespread implementation of this therapeutic approach until formal evaluation by randomized controlled trials have established the exact role of erythromycin, or its analogues, in the treatment of intestinal dysmotility in preterm infants. Biol Pharm Bull, 1997 Apr, 20(4), 411 - 6 Effects of erythromycin, clarithromycin and rokitamycin on nifedipine metabolism in rats; Tsuruta S et al.; The effects of erythromycin, clarithromycin and rokitamycin on the metabolism of nifedipine were studied in vitro and in situ . Erythromycin, clarithromycin or rokitamycin added to nifedipine did not inhibit the formation of metabolite, M-1, of nifedipine, whereas pretreatment with erythromycin or clarithromycin significantly (p < 0.05) inhibited its formation . Only erythromycin significantly (p < 0.05) inhibited the formation of M-2 from M-1 . These observations agreed with the results obtained using an in situ rat intestinal loop technique . As assessed by the concentrations of nifedipine and M-2 in jugular and portal vein blood, the inhibition of nifedipine metabolism by erythromycin was greater after multiple doses than after a single dose . Moreover, our results suggest that rokitamycin is a less potent inhibitor of nifedipine metabolism. J Pediatr Gastroenterol Nutr, 1997 Apr, 24(4), 411 - 8 Antroduodenal motor effects of intravenous erythromycin in children with abnormalities of gastrointestinal motility; Cucchiara S et al.; BACKGROUND: The macrolide antibiotic erythromycin (EM) affects gastrointestinal motor activity by acting as agonist of motilin receptors located on the smooth muscle cells of the gastroduodenal tract . We studied the effect of intravenous EM on fasting antroduodenal motility in controls and children with gastrointestinal dysmotility . METHODS: EM lactobionate (rate, 3.0 mg/kg/h) was infused intravenously while antroduodenal manometry was recorded in 10 controls, in 7 patients with functional dyspepsia and in 6 patients with gut pseudo-obstruction . The mean (SD) age (years) was 5.7 (1.4), 6.5 (2.4), and 6.7 (3.2), respectively . Manometry was performed by means of a four- or six-lumen catheter introduced through the nose and perfused with a low compliance pneumohydraulic system . Five controls received EM and five received saline . RESULTS: EM, infused 5 minutes after passage of an activity front (AF), induced in controls a premature antroduodenal AF occurring 15.4 +/- 3.2 minutes after starting infusion; no motor changes were seen after saline; duration and propagation velocity of EM-induced AFs did not differ from spontaneous AFs . In patients with functional dyspepsia EM induced various patterns such as premature antroduodenal AFs, antral phase III-like pattern with short duodenal bursts or prolonged phasic antral waves and no duodenal activity . In patients with neurogenic pseudo-obstruction rare or absent antral activity with incoordinated or absent duodenal activity was induced; no contractions were elicited in two patients with myogenic pseudo-obstruction . CONCLUSIONS: It is confirmed that EM, given at subtherapeutic doses, is a powerful prokinetic agent that can have clinical applications in patients with gastrointestinal dysmotility; however, the effect of the drug seems to be influenced by the nature of the underlying disorder. Am J Physiol, 1997 Apr, 272(4 Pt 1), G909 - 15 A new method to measure gastric emptying in conscious dogs: a validity study and effects of EM523 and L-NNA; Tanaka T et al.; A new method for measurement of gastric emptying without the use of radioisotope markers has been developed in dogs . A test meal was given after measurement of its freeze-dried weight, and 1-ml duodenal samples were collected through an indwelling tube at 15-min intervals, and their absolute weight was measured . The duodenum was continuously perfused with phenolsulfonphthalein to determine the recovery of each sample . Three different calorie or fat-enriched meals were administered with 100 ml saline containing polyethylene glycol as a liquid marker . The results showed that increasing the calorie load of, and adding fat to, the test meal proportionally delayed gastric emptying of the solid phase . Utilizing this method, it was found that EM523, an erythromycin derivative, accelerated the gastric emptying of solids, whereas N(omega)-nitro-L-arginine (L-NNA) markedly delayed the gastric emptying of both solids and liquids . In conclusion, this freeze-drying method is a reliable technique for measuring the gastric emptying of the solid phase in dogs. J Pediatr Surg, 1997 Apr, 32(4), 605 - 8 Effect of prokinetic agents on ileal contractility in a rabbit model of gastroschisis; Langer JC et al.; Intestinal hypomotility is a major problem after repair of gastroschisis . The authors assessed the effect of four clinically available prokinetic agents on intestinal contractility using a rabbit model of gastroschisis . Gastroschisis was surgically created at 24 days' gestation in fetal rabbits . At term, 10-mm ileal muscle strips were harvested, suspended in an organ bath, and stimulated with 10(-6) mol/L carbechol with and without each prokinetic agent: metoclopromide (1 x 10(-5) mol/L), cisapride (2 x 10(-5) mol/L), erythromycin (1 x 10(-5) mol/L), and octreotide (5 x 10(-5) mol/L) . The effect of each agent on contractility was calculated as percent change from maximal response to carbechol alone . There were two control groups: sham operated fetuses, and maternal ileum . Metoclopromide was effective only in the adult rabbits . Cisapride improved contractility in newborns with gastroschisis, as well as in both newborn and adult control groups . Neither erythromycin or octreotide improved bethanechol-induced contractility in any of the animals . These data suggest that cisapride may be useful for treating hypoperistalsis in infants with gastroschisis . Clinical studies must be done to further pursue this finding. Drug Saf, 1997 Apr, 16(4), 267 - 78 Clinically significant drug interactions with new immunosuppressive agents; Mignat C; Tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), gusperimus, and monoclonal antibody preparations are new immunosuppressive agents, some of which are already approved for clinical use, while others are currently undergoing clinical trials . The present article provides an overview of adverse drug interactions between these immunosuppressants and other drugs which may be used concomitantly . Preliminary data suggest that a pharmacodynamic interaction can occur between tacrolimus and nonsteroidal anti-inflammatory drugs, associated with an increased risk of nephrotoxicity . Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations, while rifampicin (rifampicin) was found to decrease tacrolimus blood concentrations . Evidence from experimental studies suggest that several other drugs also known to affect cytochrome P450 activity may have significant effects on the pharmacokinetics of tacrolimus . On the other hand, tacrolimus itself may inhibit the metabolism of coadministered drugs . This interaction may be attributed to the enhanced renal impairment which has been observed in patients treated with tacrolimus and cyclosporin . The bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, has been reported to be reduced by aluminium/magnesium hydroxide-containing antacids and cholestyramine . Mycophenolic acid, sirolimus and gusperimus may impair bone marrow function and this adverse effect may be enhanced by concomitant administration of other myelosuppressive drugs . There is some evidence that coadministered sirolimus and cyclosporin cause an increase in each other's blood concentrations . An increased risk of central nervous system adverse effects has been described following the combined use of indomethacin and the monoclonal antibody muromonab CD3 (OKT3). Drug Metab Dispos, 1997 Apr, 25(4), 502 - 7 Human cytochrome P450 3A4-catalyzed testosterone 6 beta-hydroxylation and erythromycin N-demethylation . Competition during catalysis; Wang RW et al.; Cytochrome P450 3A4 is known to catalyze the metabolism of both endogenous substrates (such as the 6 beta-hydroxylation of testosterone) and many important therapeutic agents, including the N-demethylation of erythromycin . However, erythromycin and testosterone have been reported to have little or no effect on the metabolism of each other by recombinant CYP3A4 . In an effort to understand the basis of these observations, we studied the N-demethylation of erythromycin and the 6 beta-hydroxylation of testosterone in human liver microsomes and in microsomes from cells containing recombinant human CYP3A4 and P450 reductase under a variety of experimental conditions . In both human liver microsomal and recombinant CYP3A4 systems, erythromycin inhibited testosterone 6 beta-hydroxylation in a concentration dependent manner, and vice versa . However, the inhibition mechanism was complex . At low substrate concentrations, testosterone and erythromycin acted as competitive inhibitors to each other . Under these experimental conditions, an apparent competitive inhibition of testosterone 6 beta-hydroxylation by erythromycin was observed, with Ki values similar to that of the K(m) values for erythromycin . When the rates of testosterone 6 beta-hydroxylation and erythromycin N-demethylation were determined in microsomal incubations containing both substrates at lower concentrations, the observed rates for each reaction were in good agreement with the calculated rates based on the rate equation describing simultaneous metabolism of two substrates by a single enzyme . However, at high substrate concentrations, the kinetic results could be best explained by a mechanism involving partial competitive inhibition . We conclude from these studies that testosterone and erythromycin mutually inhibit the metabolism of each other, consistent with the fact that CYP 3A4 catalyzes the metabolism of both substrates. Biochemistry, 1997 Mar 18, 36(11), 3237 - 41 Differential interaction of erythromycin with cytochromes P450 3A1/2 in the endoplasmic reticulum: a CO flash photolysis study; Koley AP et al.; The kinetics of CO binding to cytochromes P450, measured by the flash photolysis technique, were used to probe the interaction of erythromycin with cytochromes P450 in rat liver microsomes . Addition of erythromycin generates substrate difference spectra using microsomes from rats treated with phenobarbital or dexamethasone but not from untreated rats, showing that it binds to P450s induced by these agents . In contrast, erythromycin and/or a monoclonal antibody to P450 3A1/2 accelerated CO binding to microsomes from rats treated with phenobarbital but had no effect on microsomes from untreated or dexamethasone-treated rats . Based on the differential amounts and inducibilities of the P450 3A1 and 3A2 forms in these microsomal samples, these results indicate that erythromycin increased the rate for P450 3A2 but not P450 3A1 . The divergent effects of erythromycin on these P450s, which exhibit 89% sequence similarity, were consistent with a model of the P450 substrate binding site in which erythromycin forms a more rigid complex with P450 3A1 than P450 3A2 . These results demonstrate the sensitivity of P450 conformation/dynamics to substrate binding, and show that CO binding kinetics can distinguish among closely related P450s in a microsomal environment. Eur J Pharmacol, 1997 Mar 12, 322(1), 63 - 71 EM574, an erythromycin derivative, is a motilin receptor agonist in the rabbit; Sato F et al.; This study was performed to examine whether an erythromycin derivative, de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (EM574) is a motilin receptor agonist in the rabbit gastrointestinal tract . EM574 and porcine motilin induced contractions in segments of isolated rabbit intestine with pEC50 values of 8.26 +/- 0.04 and 8.69 +/- 0.07, respectively, but not in rat or guinea pig preparations . The sensitivity and efficacy of the response to both compounds in rabbits decreased aborally and was insensitive to pretreatment with atropine or tetrodotoxin, but was markedly suppressed under Ca(2+)-free conditions . EM574 and porcine motilin specifically displaced {125I-Tyr23}canine motilin bound to gastric antral smooth muscle homogenates with plC50 values of 8.21 +/- 0.13 and 9.20 +/- 0.11, respectively . The pEC50 value for the contractile response and plC50 value for the receptor binding for motilin, EM574, erythromycin A and three other derivatives correlated well (r = 0.94, P < 0.01) . Tissue section autoradiography in the antrum revealed that specific labeled motilin binding sites were localized in the circular muscle layer and myenteric plexus, and could be reduced in the presence of an excess of EM574 . These results indicate that EM574 is a potent motilin receptor agonist in the rabbit gastrointestinal tract. Fetal Diagn Ther, 1997 Mar-Apr, 12(2), 89 - 92 Erythromycin treatment for subclinical Ureaplasma urealyticum infection in preterm labor; Antsaklis A et al.; This study was undertaken to test the effects of erythromycin as an adjunct to tocolysis for preterm labor in women with vaginal cultures positive for Ureaplasma urealyticum . The study group consisted of 18 women in active preterm labor with pregnancies between 26 and 34 weeks of gestation and intact membranes who received 500 mg erythromycin orally every 8 h for 10 days . Seventeen women with similar characteristics served as controls and received no antibiotics . In all women contractions were suppressed with ritodrine . Erythromycin treatment resulted in a statistically significant greater mean delay of delivery (36.4 days) than among the control group (23.1 days) . Higher proportion of term pregnancies (7 versus 3 pregnancies), higher mean birth weight (2,745 versus 2,474 g), lower neonatal morbidity (22.2 versus 42.2%) and shorter mean neonatal hospitalization time (9.6 versus 12.1 days) were observed, although these differences were not statistically significant . Adjunctive erythromycin treatment given to women treated for preterm labor with intact membranes and positive vaginal cultures for U . urealyticum appears to prolong gestation and to improve perinatal outcome. Curr Opin Pulm Med, 1997 Mar, 3(2), 111 - 5 Atypical pathogen pneumonia; Lieberman D et al.; The term atypical pathogens has been applied in recent years to Chlamydia pneumoniae, Mycoplasma pneumoniae, and the various species of Legionella . The incidence of pneumonia caused by these pathogens has increased with the development of specific diagnostic techniques . Atypical pathogen community-acquired pneumonia demonstrates a broad spectrum of severity from a mild disease not requiring hospitalization to adult respiratory distress syndrome necessitating mechanical ventilation . The clinical, radiological, and laboratory manifestations of the disease are similar to those of community-acquired pneumonia caused by other pathogens, and reliable etiological differentiation cannot be based on these factors alone . The possibility of shortening treatment time, at least in some patients, by antibiotic therapy with the new macrolides has been added to standard therapeutic regimens with erythromycin, tetracyclines, or quinolones. Presse Med, 1997 Mar, 26 Suppl 2, 22 - 6 {Macrolides: indications in 1997}; Bouhour D et al.; A GROWING CLASS OF ANTIBIOTICS: Since the discovery of erythromycin, teh prototype macrolide, this class of antibiotics has grown considerably . Roxithromycin, a semi-synthetic erythromycin derivative, has an improved absorbability, tolerability and stability profile . WIDE INDICATIONS: Current indications for these new compounds for respiratory tract infections are presented and discussed in terms of the most recent consensus conferences . NEW TRENDS: All current indications (expecting the respiratory tract) are discussed in light of current perspectives for this family of antibiotics . Growing interest in new bacterial species such as Mycobacterium avium intracellulare, Helicobacter pylori as well as Chlamydia pneumoniae and Mycoplasma pneumoniae contribute to new trends in antibiotics prescription. Presse Med, 1997 Mar, 26 Suppl 2, 4 - 10 {New pharmacological approaches of macrolides . Example of roxithromycin}; Bergogne-Berezin E; MACROLIDES, one of the oldest antibiotic classes, are widely used in out-patient clinics and hospitals . The major improvement in developing newer derivatives concerns pharmacokinetic properties . Increased half-lives, persisting concentrations in tissues, interstitial fluids and macrophages confer upon newer macrolides significant advantages as compared with the parent compound erythromycin . ROXITHROMYCIN, a newer macrolide has a high peak serum concentration, providing very high levels both in the interstitial fluid and intracellularly . PHARMACODYNAMIC APPROACHES are still limited with macrolides, however the very high inhibitory quotient established for tissue concentrations and interstitial fluid suggests the potential clinical efficacy of these drugs. Nippon Jibiinkoka Gakkai Kaiho, 1997 Mar, 100(3), 351 - 6 {Effect of erythromycin and clarithromycin on ion transport across dissected canine tracheal epithelium}; Kato A; Since erythromycin was shown to be effective in the treatment of patients with diffuse panbronchiolitits, newly discovered effects of macrolide antibiotics have attracted much attention . It was reported that erythromycin inhibits Cl secretion across cultured canine tracheal epithelial cells . Erythromycin may decrease the movement of water toward the lumen, thus reducing sputum volume . We tested the hypothesis that erythromycin and clarithromycin have a similar effect on the dissected canine tracheal epithelium, by measuring the short circuit current using Ussing chambers . Addition of erythromycin or clarithromycin did not change the short circuit current within 20 minutes when applied on either the mucosal side or the submucosal side . No changes in the short circuit current were observed after pretreatment of the epithelium with amiloride, an Na channel blocker, or bumetanide, a Cl transport inhibitor, and subsequent addition of the macrolide antibiotics . These data indicate that neither erythromycin nor clarithromycin has any short term effect on ion transport in the dissected canine tracheal epithelium. Br J Clin Pharmacol, 1997 Mar, 43(3), 245 - 52 Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine; Zhang H et al.; AIMS: Our previous studies using in vitro hepatic microsomal preparations suggested that the hepatic metabolism of quinine to form the major metabolite 3-hydroxyquinine is most likely catalysed by human P450 3A (CYP3A) . The present study was carried out to investigate the kinetics and to identify and further characterise the human liver CYP isoforms involved in the metabolism of quinine . METHODS: In vitro human microsomal techniques were employed . RESULTS: The mean apparent Km value for 3-hydroxyquinine formation was 83 +/- 19 (s.d.) microM, ranging from 57 microM to 123 microM in microsomes from ten human livers . There was a 6.7-fold variation in Vmax values (mean 547 +/- 416 pmol min-1 mg-1) . Quinine 3-hydroxylation was inhibited by the specific CYP3A inhibitors, troleandomycin, midazolam and erythromycin . Inhibitors selective for CYP1A1/2, CYP2D6, CYP2E1, CYP2C9/10 or CYP2C19 had little or no effect on quinine 3-hydroxylation . Using microsomes from a panel of livers, significant correlations were found only between 3-hydroxyquinine activity and other CYP3A activities (caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) and immunoreactive CYP3A content . There were no statistically significant correlation with activities selective for CYP1A2, CYP2C9 and CYP2E1 . Competitive inhibition of quinine 3-hydroxylation was observed with a substrate known to be specifically metabolized by human CYP3A, i.e . midazolam, with an apparent Ki value of 11.0 microM . CONCLUSIONS: The present results strongly indicate that the conversion of quinine to 3-hydroxyquinine is the major metabolic pathway in human liver in vitro and that the reaction is catalysed by CYP3A isoforms. Chemotherapy, 1997 Mar-Apr, 43(2), 77 - 85 Pharmacokinetic interactions between erythromycin, clarithromycin, roxithromycin and phenytoin in the rat; al-Humayyd MS; The effects of the macrolide antibiotics, erythromycin, clarithromycin and roxithromycin, on the pharmacokinetic profile of phenytoin were studied in rats . Animals were injected with phenytoin (100 mg/kg, i.p.) daily for 4 days and then they were given phenytoin (20 mg/kg, i.p.) alone or the same dose of phenytoin together with erythromycin (50 mg/kg, i.p.), clarithromycin (50 mg/kg, i.p.) or roxithromycin (50 mg/kg, i.p.) . In another set of experiments, the same protocol was followed except that erythromycin (100 mg/kg), clarithromycin (100 mg/kg) and roxithromycin (100 mg/kg) were given by the oral route . The concentrations of phenytoin in plasma were determined using a high-performance liquid chromatographic method . The area under the curve the maximum plasma concentration and the elimination half-life (t1/2) of phenytoin were significantly (p < 0.05) increased by the macrolides . In addition, the macrolides significantly (p < 0.05) reduced the level of hepatic cytochrome P-450 in the rats . These results suggest that a potentially harmful drug-drug interaction may occur if phenytoin is administered concurrently with erythromycin, clarithromycin or roxithromycin. Clin Pharmacol Ther, 1997 Mar, 61(3), 292 - 300 Dietary salt increases first-pass elimination of oral quinidine; Darbar D et al.; BACKGROUND: Some cytochrome P450 (CYP) enzymes, including CYP3A, are expressed not only in the liver but also in the intestine; the latter may therefore be an important site of drug disposition . Animal data suggests that dietary salt modulates expression of renal CYPs . We therefore hypothesized that intestinal CYP3A may be similarly modulated by dietary salt . METHODS: The effect of changes in dietary salt on the disposition of two CYP3A substrates, quinidine (administered orally and intravenously) and 14C-erythromycin (administered intravenously) were determined after normal volunteers were given high-salt (400 mEq/day) and low-salt (10 mEq/day) diets for 7 to 10 days each . RESULTS: Plasma concentrations after oral quinidine were significantly lower during the high-salt phase, with the difference between the two treatments attributable to changes within the first 1 to 4 hours after administration . For example, the area under the plasma concentration-time curve for the first hour after drug administration was 0.56 +/- 0.38 microgram.hr/ml for the high-salt diet compared with 1.57 +/- 0.60 micrograms.hr/ml for the low-salt diet (p < 0.05) . Similarly, the peak plasma concentration (Cmax) achieved was lower and the time to reach Cmax was later for the high-salt diet (p < 0.05) . In contrast, the terminal phase elimination half-lives were similar for the two diets, and no differences in disposition were found with the intravenous drug . The erythromycin breath test was unaffected by the dietary treatments . CONCLUSIONS: These results indicate an effect of dietary salt on the presystemic disposition of orally administered quinidine . Although the mechanism(s) of CYP3A activity modulation is unknown, this finding may be important in determining drug availability in conditions associated with abnormal salt homeostasis. J Bacteriol, 1997 Mar, 179(6), 2065 - 7 Role of mRNA termination in regulation of ermK; Choi SS et al.; To study the role of mRNA termination in the regulation of ermK, we introduced mismatches into terminators by in vitro mutagenesis . In wild-type ermK, only truncated transcription products were detected in the absence of induction . In contrast, only the full-length transcript was synthesized in the terminator 1 and terminator 2 double mutants, even in the absence of erythromycin . These results indicate that the expression of ermK is primarily regulated by transcriptional attenuation rather than translational attenuation . We also tested the possible contribution of translational attenuation control to the regulation of ermK by constructing a triple mutant (terminator 1 plus terminator 2 plus the methylase Shine-Dalgarno region) . A higher level of beta-galactosidase synthesis was seen in the triple mutant . Therefore, unlike with previously described attenuators, it can be concluded that both transcriptional and translational attenuation contribute to the regulation of ermK, although transcriptional attenuation plays a larger role. Ann Pharmacother, 1997 Mar, 31(3), 349 - 56 Drug interactions of macrolides: emphasis on dirithromycin; Watkins VS et al.; OBJECTIVE: To describe the drug interactions of dirithromycin, a new macrolide, and to compare them with those of other macrolides . DATA SOURCES: A literature search was performed using MEDLINE to identify articles published between January 1980 and July 1995 concerning the drug interactions of macrolides . Published abstracts were also examined . All studies using dirithromycin were performed under the sponsorship of Eli Lilly and Company . DATA SYNTHESIS: Erythromycin, the first macrolide discovered, is metabolized by the cytochrome P450 enzyme system . By decreasing their metabolism, erythromycin can interact with other drugs metabolized by the cytochrome P450 enzymes . The lack of such interactions would be a desirable feature in a newer macrolide . We describe studies performed to detect any interactions of dirithromycin with cyclosporine, theophylline, terfenadine, warfarin, and ethinyl estradiol . The studies showed that dirithromycin, like azithromycin, is much less likely to cause the interactions detected with clarithromycin and erythromycin . A review of the literature showed differences among macrolides in their abilities to inhibit cytochrome P450 enzymes and, thus, to cause drug-drug interactions . Erythromycin and clarithromycin inhibit cytochrome P450 enzymes, and have been implicated in clinically significant interactions . Azithromycin and dirithromycin neither inhibit cytochrome P450 enzymes nor are implicated in clinically significant drug-drug interactions . CONCLUSIONS: Dirithromycin, a new macrolide, does not inhibit the cytochrome P450 enzyme system . The concomitant use of dirithromycin with cyclosporine, theophylline, terfenadine, warfarin, or ethinyl estradiol was studied in pharmacokinetic and pharmacodynamic studies . In vitro, dirithromycin did not bind cytochrome P450 . In healthy subjects, erythromycin increases the clearance of cyclosporine by 51%, whereas dirithromycin causes no significant changes in the pharmacokinetics of cyclosporine . In kidney transplant recipients, administration of dirithromycin was associated with a significant (p < 0.003) decrease of 17.4% in the clearance of cyclosporine . In patients taking low-dose estradiol, the administration of dirithromycin caused a significant (p < 0.03) increase of 9.9% in the clearance of ethinyl estradiol; escape ovulation did not occur . Unlike erythromycin and clarithromycin, dirithromycin had no significant effects on the pharmacokinetics of theophylline, terfenadine, or warfarin . The alterations typical of drug interactions that are based on inhibition of the cytochrome P450 system occurring with erythromycin and clarithromycin were not observed with dirithromycin. Int Arch Allergy Immunol, 1997 Mar, 112(3), 262 - 9 The role of neutrophil elastase in human pulmonary artery endothelial cell injury; Furuno T et al.; Neutrophils are thought to play a key role in tissue injury . We investigated the role of human neutrophil-derived elastase in the induction of injury to human pulmonary artery endothelial cells . Incubation of endothelial cells with neutrophils increased the release of lactate dehydrogenase activity, thrombomodulin, and preloaded fura-2 from endothelial cells, indicating that neutrophils induce endothelial cell injury . Attachment alone of neutrophils to endothelial cells appeared to induce activation because elastase release and N-formyl-mentionyl-leucyl-phenylalanine (fMLP)-induced superoxide (O2) production from neutrophils incubated with endothelial cells were greater than from neutrophils only . When endothelial cell were incubated with neutrophils stimulated by fMLP or phorbol myristate acetate, the amount of elastase in the medium and endothelial cell damage was further enhanced . However, when neutrophils were blocked from direct attachment to endothelial cells using a membrane filter, endothelial cell damage was ameliorated, while exogenous neutrophil elastase and medium containing neutrophil-released elastase did not induce endothelial cell injury . An inhibitor of neutrophil elastase, ONO-5046 Na, as well as erythromycin, which reduces neutrophil-derived elastase, dramatically inhibited neutrophil-induced endothelial cell injury . Superoxide dismutase (SOD) partially inhibited injury . Injury was completely inhibited by treatment with a combination of ONO-5046 Na and SOD . These results suggest that attachment of neutrophils to endothelial cells is important for endothelial cell damage and that neutrophil-derived elastase plays an important role in endothelial cell injury in combination with O2 . In addition, ONO-5046 Na and erythromycin may be useful in treating diseases worsened by excessive neutrophil activity. Arch Biochem Biophys, 1997 Mar 1, 339(1), 136 - 50 Localization of multiple forms of inducible cytochromes P450 in rat liver mitochondria: immunological characteristics and patterns of xenobiotic substrate metabolism; Anandatheerthavarada HK et al.; Hepatic mitochondria contain inducible cytochromes P450 that cross-react with antibodies to P4501A1/2 and 2B1/2 . In the present study, we present evidence for the occurrence of additional P450 forms in rat liver mitochondria that cross-react with antibodies to microsomal P4503A1/2 and 2E1 . Protease protection and also immunoelectron microscopy studies were carried out to support the mitochondrial location of the immunoreactive P450s . The solubility of immunoreactive proteins in 0.1 M Na2CO3 suggests that the mitochondrial P450 forms tested are not membrane-integral proteins . The mitochondrial-associated P450 forms are capable of metabolizing resorufin derivatives, erythromycin, and p-nitrophenol in an adrenodoxin- and adrenodoxin reductase-supported system . Treatment of rats with phenobarbital (PB) resulted in the induction of mitochondrial pentoxyresorufin O-deethylase (PROD), benzoxyresorufin O-deethylase (BROD), and erythromycin N-demethylase (ERND) activities by 17-, 23-, and 2-fold, respectively . These activities were inhibited by 33 to 64% by antibodies to P4502B1/2 and P4503A1/2 . The induction of the above monooxygenase activities correlated with the levels of mitochondrial proteins cross-reacting with antibodies to P4502B1/2 and P4503A1/2 in PB-treated livers . Similarly, administration of beta-naphthoflavone (BNF) resulted in a marked elevation of O-deethylation of ethoxy-, benzoxy-, and methoxyresorufins and a 2-fold increase in ERND activity . Immunoblot and immunoinhibition experiments using P4501A1/2, P4502B1/2, P4503A1/2, and P4502E1 antibodies revealed the presence of P450 forms closely related to the microsomal inducible forms . Results of immunoinhibition studies, using antibodies to adrenodoxin and reconstitution of enzyme activity with purified P450 forms, suggested a role for the mitochondrial P450 in the metabolism of xenobiotic substrates . The purified mitochondrial P450s also exhibited overlapping substrate specificities for resorufin derivatives and erythromycin. Biochemistry, 1997 Feb 18, 36(7), 1846 - 51 Purification and characterization of bimodular and trimodular derivatives of the erythromycin polyketide synthase; Pieper R et al.; Modular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), catalyze the biosynthesis of structurally complex and medicinally important natural products . DEBS is a dimeric protein complex that consists of three large multidomain polypeptide chains, DEBS 1, DEBS 2, and DEBS 3 . In turn, each polypeptide includes two modules, where one module is responsible for a single round of condensation and associated reduction reactions . A hybrid protein comprised of the first two modules of DEBS fused to a thioesterase domain (DEBS 1 + TE) was purified to homogeneity in a fully active form (Kcat = 4.8 min-1) . Synthesis of the anticipated triketide lactone required the presence of (2RS)-methylmalonyl-CoA and NADPH . When available, propionyl-CoA is the preferred source of primer units . However, in its absence the enzyme can derive primer units via decarboxylation of a methylmalonyl extender . The two subunits of an engineered trimodular derivative of DEBS, DEBS 1 and module 3 of DEBS 2 linked to the TE domain (module 3 + TE), were also individually purified and reconstituted to produce the expected tetraketide lactone in vitro (Kcat = 0.23 min-1) . The considerably lower specific activity of this trimodular PKS relative to its bimodular counterpart presumably reflects inefficient association between DEBS 1 and module 3 + TE . As expected, module 3 + TE could be efficiently cross-linked as a homodimer . In contrast, no cross-links were detectable between modules 2 and 3, even though biosynthesis of the tetraketide requires transient interactions to occur between these two modules . Since module 3 only contains the minimal set of active sites required in a module (a ketosynthase, an acyltransferase, and an acyl carrier protein domain) and is the first active unimodular protein to be purified to homogeneity, it represents an attractive target for future biophysical and structural studies. Ned Tijdschr Geneeskd, 1997 Feb 8, 141(6), 273 - 7 {Iatrogenic collapse; can this be prevented?}; Panhuyzen-Goedkoop NM et al.; In four patients, two men aged 65 and 35 years, and two women aged 87 and 83 years, who presented with collapse, administration of Q-T time prolonging drugs (sotalol, erythromycin, disopyramide) appeared to be the cause . These patients had so-called 'concealed long Q-T syndrome' . The proarrhythmogenic properties of antiarrhythmic and other drugs and of several clinical conditions such as cardiac diseases should be kept in mind when treating patients with antiarrhythmic substances. Drug Chem Toxicol, 1997 Feb-May, 20(1-2), 11 - 9 Purification and characterization of dexamethasone inducible hepatic cytochrome P450 isozymes from rhesus monkey; Puri V et al.; Two isozymes of hepatic cytochrome P450 named DEX M-1 and M-2 have been purified and characterized from dexamethasone (DEX) pretreated (150 mg Kg-1 body wt x 4 days) rhesus monkeys by various chromatographic procedures . These isozymes demonstrated similar peptide maps . Their absolute and CO-dithionite reduced difference spectra demonstrated maximum absorbance at 417 and 449.4 nm, respectively . DEX M-1 and M-2 demonstrated polypeptide molecular wt of 50 and 52.5 KDa, specific content of 16.35 and 11.39 nmol mg-1 protein and 11 and 8 fold purification, respectively . The antibodies against these isozymes cross reacted with each other and also demonstrated slight differences in the immunoinhibition of erythromycin N-demethylase . These results demonstrated that DEX induced two different isozymes of hepatic cytochrome P450 in rhesus monkeys. Br J Clin Pharmacol, 1997 Feb, 43(2), 194 - 6 The mechanism of cyclosporine toxicity induced by clarithromycin; Spicer ST et al.; AIMS: Recently a number of case reports have described the interaction of clarithromycin with cyclosporine A, resulting in cyclosporine toxicity . This interaction is presumed to take place via the hepatic cytochrome P450 enzyme system . METHODS: Following a case of cyclosporine toxicity and acute renal failure in a transplant patient started on clarithromycin, we investigated the effect of oral clarithromycin on the hepatic P450 system in five healthy normal male volunteers, by means of the erythromycin breath test . RESULTS: Cytochrome P4503A (CYP3A) activity was reduced in all subjects by a mean level of 26% following clarithromycin treatment . This would result in a significant reduction in cyclosporine clearance in patients receiving clarithromycin . CONCLUSIONS: As clarithromycin was shown to inhibit CYP3A activity in all subjects tested, we recommend that a high degree of caution be exercised when clarithromycin is administered to patients receiving cyclosporine therapy or other drugs known to be eliminated by CYP3A-mediated metabolism. Diabetes Care, 1997 Feb, 20(2), 129 - 34 Effects of oral erythromycin on fasting and postprandial antroduodenal motility in patients with type I diabetes, measured with an ambulatory manometric technique; Samsom M et al.; OBJECTIVE: The aim of this double-blind crossover study was to evaluate the effects of oral erythromycin (250 mg t.i.d.) on fasting and postprandial gastrointestinal motility and gastrointestinal symptoms in patients with type I diabetes . RESEARCH DESIGN AND METHODS: Antroduodenal motility was recorded with an ambulatory manometric technique for a 20-h period, including a high-caloric high-fat dinner and a low-caloric low-fat breakfast and a long fasting period, after 2 weeks erythromycin and placebo treatment in 12 patients with type I diabetes . During the manometric study, plasma glucose concentrations were assessed by frequent self-testing . Gastrointestinal symptoms were scored daily to assess the severity of the symptoms (range 0-3) . RESULTS: Oral erythromycin decreased the migrating motor complex cycle length from 118.9 +/- 46.0 to 86.2 +/- 25.3 min (P = 0.03) by shortening phase II from 68.7 +/- 23.5 to 48.5 +/- 19.4 min (P < 0.05) . The total number of duodenal phase III increased from 48 to 62 (P = 0.075) . However, the degree of antral participation to duodenal phase III did not increase . Erythromycin significantly decreased the duration of the postprandial period after dinner (from 417.0 +/- 137.9 to 348.8 +/- 93.8 min, P = 0.04) . During this shorter postprandial period, the number of antral contractions (P < 0.01) and the antral motility index increased (P < 0.03), and early phase III activity at the level of the duodenum was abolished . In diabetic patients with antral hypomotility, after dinner, the mean symptom score improved significantly, from 2.07 +/- 0.86 to 1.52 +/- 0.63 (P = 0.018) . CONCLUSIONS: This ambulatory antroduodenal manometric study showed that oral erythromycin (250 mg t.i.d.) improves both fasting and postprandial antroduodenal motor activity after a high-caloric meal in patients with type I diabetes . Furthermore, in diabetic subjects with postprandial antral hypomotility, erythromycin reduces dyspeptic symptoms. J Chemother, 1997 Feb, 9(1), 23 - 31 Requirements for intracellular accumulation and release of clarithromycin and azithromycin by human phagocytes; Fietta A et al.; Determination of clarithromycin (CL) and azithromycin (AZ) uptake by human polymorphonuclear leukocytes (PMNs), monocytes and alveolar macrophages showed that AZ achieved higher levels than CL . The uptake kinetics of AZ were time-dependent over an 18 h period, while those of CL were similar to erythromycin (ER) kinetics, with a maximum level of incorporation being obtained after a 60 min incubation . The accumulation of both drugs was influenced by extracellular antibiotic-concentrations, PMN viability, extracellular calcium, physiological environmental temperature and pH . The uptake was not modified by inhibitors of cell metabolism or activators of cell membranes . After removal of extracellular antibiotic, the release of AZ from PMNs was very slow: nearly 50% of the drug remained cell-associated after 24 h incubation . The efflux of this derivative was significantly enhanced when drug-loaded PMNs were stimulated by phorbol-myristate acetate (PMA) . The kinetics of CL release indicated that this macrolide behaved like ER . Nevertheless, about 10% of the initial cell-associated antibiotic showed a prolonged retention . On the whole, these data suggest that diffusion through cell membranes and trapping into acidic compartments of PMNs are important events in CL and AZ uptake. Br J Dermatol, 1997 Feb, 136(2), 235 - 8 The comparative efficacy of benzoyl peroxide 5%/erythromycin 3% gel and erythromycin 4%/zinc 1.2% solution in the treatment of acne vulgaris; Chu A et al.; This randomized 10-week study compared the efficacy of benzoyl peroxide 5%/erythromycin 3% gel with erythromycin 4%/zinc 1.2% solution in 72 acne vulgaris patients . Physician global evaluations were significantly more improved (P < or = 0.05) in the benzoyl peroxide 5%/erythromycin 3% gel treatment group compared to erythromycin 4%/zinc 1.2% solution at week 2 and at each subsequent biweekly clinical visit . Inflammatory lesions (papules/pustules) were significantly more reduced (P < or = 0.005) in the benzoyl peroxide 5%/erythromycin 3% gel treatment group than the erythromycin 4%/zinc 1.2% solution at weeks 4 and 10 . Comedones were significantly more reduced (P < or = 0.001) in the benzoyl peroxide 5%/erythromycin 3% gel treatment group than in the erythromycin 4%/zinc 1.2% solution group at weeks 8 and 10 . Patient efficacy evaluations significantly (P < or = 0.001) favoured benzoyl peroxide 5%/erythromycin 3% gel to erythromycin 4%/zinc 1.2% solution. Dev Biol Stand, 1997, 89, 175 - 9 Factors influencing the analysis of secondary prevention of pertussis; Wirsing von Konig CH et al.; The aim of this study was to evaluate factors that influenced the spread of pertussis in secondary contacts after household exposure . The data were acquired during a prospective household-contact study into the efficacy of an acellular vaccine . The spread of the disease was monitored with respect to various case definitions of pertussis, socio-economic factors, household composition, and antibiotic therapy . A total of 453 index cases had contact with 173 unvaccinated children aged from 6 to 47 months . Depending on the clinical case definition, the attack rates (AR) in children with a laboratory-confirmed Bordetella infection increased from 55% for the WHO definition to 69%, when a less stringent definition was used . AR in children were independent of age and gender . The social status of the family had no significant influence on the AR in children . Erythromycin treatment of the index case reduced the AR from 64% to 51% (p = 0.08) . These factors should be taken into consideration when studies into the secondary prevention of pertussis by acellular vaccines are initiated. Scand J Infect Dis, 1997, 29(3), 319 - 20 Legionella jordanis pneumonia unresponsive to fluoroquinolones in a non-immunocompromised host; Baty V et al.; Legionella jordanis has seldom been reported as a cause of infection in humans . We describe a case of pneumonia due to L . jordanis that occurred in a non-immunocompromised 74-year-old patient and failed to respond to a combination of ceftriaxone and ofloxacin . Cure was achieved only after an erythromycin-rifampin combination was started. Kurume Med J, 1997, 44(2), 115 - 23 Macrolides reduce the expression of surface Mac-1 molecule on neutrophil; Okubo Y; Several reports described a favorable effect of "low-dose and long-term" erythromycin (EM) on chronic obstructive pulmonary diseases including diffuse panbronchiolitis (DPB), although its mechanism still remains obscure . We investigated the effect of some macrolides, erythromycin (EM), rokitamycin (RKM), midecamycin (MDM) on the expression of neutrophil adhesion molecule Mac-1 using LPS-stimulated human whole blood as an experimental vivo model . Samples from six healthy volunteer were treated with various concentrations (0.02 ug/ml-20 ug/ml) of EM, RKM and MDM for 1 to 3 hs . Surface expression of Mac-1 antigen was determined by use of flow-cytometry . When pretreated with EM and MDM for 1 and 3 hs, significant reduction in Mac-1 expression was observed, but with RKM no substantial reduction . These findings indicate that some macrolides such as EM suppress the surface expression of Mac-1 on neutrophil and may alleviate local alveolar injury in chronic pulmonary diseases. Dermatology, 1997, 194(4), 421 - 2 Baboon syndrome; Goossens C et al.; An 18-month-old patient developed Baboon syndrome after oral treatment with erythromycin syrup for a sore throat . The lymphoblastic transformation test was positive for erythromycin . Prick tests were negative although the intradermal test was positive at a concentration of erythromycin of 1:10,000 . The biopsy showed a perivascular lymphocytic dermatitis . Local treatment with a potent corticoid improved the lesions after 3 days . The Baboon syndrome is uncommon among children . It has a pattern similar to systemic contact dermatitis with particular features (erythema in flexural areas) . In our case, the role of erythromycin was documented . However, this antibiotic remains a relatively rare allergen. Antibiot Khimioter, 1997, 42(1), 7 - 11 {The isolation and characteristics of mutants of the Saccharopolyspora erythraea strain resistant to thiostrepton}; Nastasiak IN et al.; The formation of thiostreptone resistant spontaneous and nitrosoguanidine-induced mutants in the erythromycin-producing organism Saccharopolyspora erythraea was investigated . The investigated collection of the mutants was heterogeneous by the level of the thiostreptone resistance (2.5 to 20 micrograms/ml) . The thiostreptone resistance mutations had a pleiotropic effect: 17 per cent of the mutants was characterized by the growth thermosensitivity and 26 and 5.8 per cent of the mutants were characterized by loss of the ability to form melanine and aerial mycelium respectively . Such phenotypes were most frequent in the mutants resistant to low concentrations of thiostreptone (2 to 5 micrograms/ml) . The absolute majority of the isolated thiostreptone resistant mutants was unstable and formed both the antibiotic resistant and the antibiotic sensitive clones . The greatest portion of the strains with high antibiotic activity (20 per cent) was detected among the S . erythraea spontaneous mutants on the medium with 2.5 micrograms/ ml of thiostreptone . It was shown that the instability of the high antibiotic activity in the mutants was associated with loss of the thiostreptone resistance property. Peptides, 1997, 18(4), 593 - 608 Motilin and clinical application; Itoh Z; Motilin is a regulatory polypeptide of 22 amino acid residues and orginates in motilin cells scattered in the duodenal epithelium of most mammals and chickens . Motilin is released into the general circulation at about 100-min intervals during the interdigestive state and is the most important factor in controlling the interdigestive migrating contractions . Recent studies have revealed that motilin stimulates endogenous release of the endocrine pancreas . Clinical application of motilin as a prokinetic has become possible since erythromycin and its derivatives were proved to be nonpeptide motilin agonists. Gastroenterol Clin Biol, 1997, 21(4), 331 - 4 {Acute reversible pan-dysautonomia: effect of erythromycin on gastrointestinal involvement}; Lagasse JP et al.; We describe a case of acute autonomic neuropathy in an 18-year-old woman . Gut dysfunction was sufficiently severe for the patient to undergo laparotomy for suspected mechanical-intestinal obstruction before the diagnosis was made . Apart from the gut, other organs affected included the pupils, sweat and lachrymal glands . Cardiovascular autonomic function tests showed the involvement of sympathetic adrenergic nerves . Small bowel barium X-ray showed resolution of gastric stasis and emergence of jejunum dilatation during intravenous administration of erythromycin but this treatment did not eliminate intestinal obstructive symptoms . The patient had an incomplete recovery in 3 months . Erythromycin might have therapeutic value in patients with intestinal motility dysfunction in acute dysautonomia. Acta Clin Belg, 1997, 52(2), 112 - 5 Severe community-acquired pneumonia caused by atypical organisms; Monsieur I et al.; Three cases of community-acquired pneumonia (CAP), requiring intensive care admission, are presented . The clinical picture of a "typical" bacterial pneumonia in the three patients led to an initial empirical treatment with amoxicillin clavulanic acid or 2(nd) generation cephalosporins . The treatment had to be changed in all three because of clinical failure . Erythromycin was added to the therapy with good clinical evolution . Serology confirmed atypical organisms to be responsible . Only the chest X-ray might have suggested an "atypical" or a "viral-like" agent . A proposition is made for an empirical combination of antibiotics in severely ill patients with CAP with more than unilobar consolidation. Arch Toxicol, 1997, 71(6), 401 - 8 Cytochrome P450-dependent drug oxidation activities in liver microsomes of various animal species including rats, guinea pigs, dogs, monkeys, and humans; Shimada T et al.; Levels of cytochrome P450 (P450 or CYP) proteins immunoreactive to antibodies raised against human CYP1A2, 2A6, 2C9, 2E1, and 3A4, monkey CYP2B17, and rat CYP2D1 were determined in liver microsomes of rats, guinea pigs, dogs, monkeys, and humans . We also examined several drug oxidation activities catalyzed by liver microsomes of these animal species using eleven P450 substrates such as phenacetin, coumarin, pentoxyresorufin, phenytoin, S-mephenytoin, bufuralol, aniline, benzphetamine, ethylmorphine, erythromycin, and nifedipine; the activities were compared with the levels of individual P450 enzymes . Monkey liver P450 proteins were found to have relatively similar immunochemical properties by immunoblotting analysis to the human enzymes, which belong to the same P450 gene families . Mean catalytic activities (on basis of mg microsomal protein) of P450-dependent drug oxidations with eleven substrates were higher in liver microsomes of monkeys than of humans, except that humans showed much higher activities for aniline p-hydroxylation than those catalyzed by monkeys . However, when the catalytic activities of liver microsomes of monkeys and humans were compared on the basis of nmol of P450, both species gave relatively similar rates towards the oxidation of phenacetin, coumarin, pentoxyresorufin, phenytoin, mephenytoin, benzphetamine, ethylmorphine, erythromycin, and nifedipine, while the aniline p-hydroxylation was higher and bufuralol 1'-hydroxylation was lower in humans than monkeys . On the other hand, the immunochemical properties of P450 proteins and the activities of P450-dependent drug oxidation reactions in dogs, guinea pigs, and rats were somewhat different from those of monkeys and humans; the differences in these animal species varied with the P450 enzymes examined and the substrates used . The results presented in this study provide useful information towards species-related differences in susceptibilities of various animal species regarding actions and toxicities of drugs and xenobiotic chemicals. Respiration, 1997, 64(3), 206 - 10 Inhibition by erythromycin of human pulmonary artery endothelial cell injury induced by human neutrophils; Mitsuyama T et al.; Neutrophils are thought to play a key role in tissue injury . We investigated the role of human neutrophils in the induction of injury to the human pulmonary artery endothelial cells and the effect of erythromycin on neutrophil-induced endothelial cell damage . Incubation of unstimulated neutrophils with endothelial cells increased the release of lactate dehydrogenase (LDH) activity and preloaded fura-2 from endothelial cells . When neutrophils were activated by phorbol myristate acetate, the release of LDH and fura-2 was enhanced further . Superoxide dismutase partially inhibited the release of LDH and fura-2 induced by neutrophils, whereas erythromycin markedly inhibited the release of endothelial cell LDH and fura-2 induced by neutrophils . These results suggest that endothelial cell injury is, at least in part, mediated by the action of superoxide and that erythromycin protects against neutrophil-induced endothelial cell injury. Eur J Clin Pharmacol, 1997, 52(1), 41 - 7 Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes; Yue QY et al.; OBJECTIVE: The O- and N-demethylation of codeine is catalysed by CYP2D6 and CYP3A4 respectively . The formation rates of morphine by O-demethylation and norcodeine by N-demethylation were studied in two sets of human liver microsomes . RESULTS: Relatively high K(m) values were found for both O- and N-demethylations, suggesting a low affinity to the corresponding enzymes . The inhibitory effects of various drugs were found to be different for O- and N-demethylations . The substrates of CYP2D6 such as thioridazine, amitriptyline and metoprolol inhibited the O-demethylation of codeine preferentially, while the substrates of CYP3A4 such as cyclosporine A, midazolam and erythromycin were all strong inhibitors of the N-demethylation of codeine . Quinidine and lignocaine, although they are substrates of CYP3A, showed preferential inhibition over the O-demethylation of codeine, suggesting a low affinity to the CYP3A . Methadone and dextropropoxyphene showed a preferential inhibition of CYP2D6 over CYP3A, while theophylline did not inhibit the O- or N-demethylation to a greater extent . CONCLUSION: It seems that there was a good correspondence between the capacity of drugs to inhibit the O- and N-demethylation of codeine in human liver microsomes and their apparent metabolism by CYP2D6 or CYP3A4, respectively in vivo in man, suggesting that this in vitro inhibition test may be a useful screen for drugs which interact with these two important drug-metabolising enzymes. Scand J Infect Dis, 1997, 29(1), 83 - 6 Economic analysis of treatment with roxithromycin in comparison with erythromycin in patients with lower respiratory tract infections; Norinder A et al.; A number of new antibiotics have lately become available for treatment of lower respiratory tract infections in out-patients . The new drugs are generally more expensive than the older ones, which might be justified by better effects, improved safety, or by other advantages . In this study, a retrospective economic analysis has been made using data from a previous trial comparing a new macrolide, roxithromycin, with an older 1, erythromycin stearate in the treatment of lower respiratory tract infections . The trial was multicentre, double blind, randomized and comparative . There were no significant differences in efficacy between treatments, although the cure rate was higher for roxithromycin, 85% vs 79% for erythromycin . 20/39 of the erythromycin-treated patients reported adverse events, vs 7/40 roxithromycin-treated subjects, a highly significant difference . More detailed information was obtained by reviewing the medical records of the participants, and from questionnaires distributed to the 3 centres that had included patients in the trial . Additional visits were found necessary for 4 patients treated with erythromycin and for 1 using roxithromycin . Using the healing rates in the present investigation, and including costs for initial drug treatments, second consultations, and failed therapy, average cost-effectiveness (SEK/patient cured) was 409 for roxithromycin-treated patients, and 488 for erythromycin-treated . Roxithromycin should then be cheaper than erythromycin stearate . With the same healing rate, roxithromycin would be less cost-effective, but indirect costs and effects on quality of life are not then taken into account. Dis Esophagus, 1997 Jan, 10(1), 34 - 7 Effect of erythromycin on postprandial gastroesophageal reflux in reflux esophagitis; Pehl C et al.; The macrolide antibiotic erythromycin has recently been reported to exert profound prokinetic properties . The aim of the study was to investigate the effect of erythromycin on postprandial gastroesophageal reflux in patients with reflux esophagitis . METHODS: In 16 patients with reflux esophagitis (according to Savary and Miller: grade I, n = 8; grade II, n = 4; grade III/IV, n = 4) two pH measurements, with and without erythromycin, were performed for three postprandial hours after lunch . Erythromycin was administered in a dose of 3.5 mg/kg intravenously just prior to lunch . RESULTS: With erythromycin, the median fraction time esophageal pH < 4 was significantly decreased (7.6% versus 18.1%; P < 0.05) . This decrease was the result of a diminished frequency of reflux episodes (19 vs 25; P < 0.05) and a shortening of the median reflux duration (0.7 min vs 1.1 min; P < 0.05) . CONCLUSIONS: Intravenous administration of erythromycin decreases postprandial gastroesophageal reflux in patients with reflux esophagitis. Nihon Kyobu Shikkan Gakkai Zasshi, 1997 Jan, 35(1), 3 - 8 {Effects of erythromycin on H2O2 generation by neutrophils}; Matsumoto K et al.; Low-dose long-term erythromycin therapy has been reported to be effective in diffuse panbronchiolitis, but the mode of action remains obscure . We therefore evaluated the effect of erythromycin the generation of H2O2 by neutrophils . In vitro, erythromycin (0.1, 1.0, and 20 micrograms/ml) suppressed both spontaneous and PMA-stimulated H2O2 generation . H2O2 generation by neutrophils obtained from peripheral blood and from bronchoalveolar lavage fluid from patients with diffuse panbronchiolitis was higher than that from healthy controls . After erythromycin therapy, H2O2 generation by neutrophils was lower . Compared with the control, H2O2 generation by peripheral neutrophils was low in the patients who responded clinically to erythromycin therapy, but was high in those who did not respond . These results suggest that at least some of the therapeutic effect of erythromycin in patients with diffuse panbronchiolitis is due to reduction in H2O2 generation by neutrophils. Pediatr Dermatol, 1997 Jan-Feb, 14(1), 31 - 5 Ectrodactyly, soft-tissue syndactyly, and nodulocystic acne: coincidence or association? Krunic AL, Vesic SA, Goldner B, Novak A, Clark RE. We report severe nodulocystic acne in a 21-year-old man associated with ectrodactyly of the right foot and soft-tissue syndactyly of the third and fourth left fingers, and the first to fourth left toes . His acne was resistant to conventional topical (clindamycin phosphate, erythromycin, tretinoin, peeling agents) and systemic (tetracycline, erythromycin) antiacne medications . Moderate improvement was achieved with systemic isotretinoin . Apart from presenting this case, we imply the disparity of the clinical characteristics of our case and those of Apert syndrome, a rare congenital condition with craniofacial anomalies, symmetric syndactyly of the digits, and acneiform eruption . We discuss the possible explanation for the association of acne lesions and bone deformities based on recent reports of mutations of fibroblast growth factor receptor 2 in the great majority of patients with this syndrome, as well as current experimental data on the involvement of the keratinocyte growth factor in the process of hair follicle growth, development, and differentiation. J Dermatol, 1997 Jan, 24(1), 28 - 33 Pseudo-Kaposi's sarcoma associated with acquired arteriovenous fistula; Kim TH et al.; Pseudo-Kaposi's sarcoma or acroangiodermatitis usually has underlying conditions of increased venous pressure or circulatory abnormality . We experienced two cases of pseudo-Kaposi's sarcoma in patients with acquired iatrogenic arteriovenous fistula from hemodialysis on their forearms . The patients complained of painful swollen crusted vesicles and purple or erythematous patches or plaques on their hands and fingers . Histologic findings included features of pseudo-Kaposi's sarcoma such as proliferations of small vascular spaces with narrow vascular channels lined by spindle cells, extravasated erythrocytes, and hemosiderin deposits . Percutaneous arteriography performed in Case one excluded the possible coexistence of arteriovenous malformation . In both cases, venous pressure and skin surface temperature were increased around the lesions; these may have played important roles in the development of the lesions . Both cases improved after oral erythromycin treatment, which seemed to be safe and effective for pseudo-Kaposi's sarcoma. Am J Physiol, 1997 Jan, 272(1 Pt 1), L15 - 9 Lipopolysaccharide-induced goblet cell hypersecretion in the guinea pig trachea: inhibition by macrolides; Tamaoki J et al.; We studied the effects of macrolides on lipopolysaccharide (LPS)-induced airway goblet cell secretion in the guinea pig trachea . The goblet cell secretion was assessed in histological sections of the tracheal mucosa stained with alcian blue and periodic acid Schiff by arbitrarily determining mucus score, which is inversely related to the magnitude of mucus discharge . Inhalation of Escherichia coli LPS (5 mg/kg) caused a time-dependent decrease in mucus score, with the maximal response being from 542 +/- 49 to 92 +/- 20 arbitrary units (P < 0.001) after 3 h, which was accompanied by an increase in the number of neutrophils in the tracheal mucosa . The LPS-induced mucus discharge was inhibited by oral clarithromycin and erythromycin in a dose-dependent manner (5 and 10 mg/kg), whereas amoxicillin and cefaclor had no effect . Each dose of clarithromycin and erythromycin, but not amoxicillin or cefaclor, likewise attenuated the LPS-induced recruitment of neutrophils . These results suggest that LPS stimulates goblet cell secretion and neutrophil accumulation in the airways and that macrolides may be of value in protecting against neutrophil-associated airway hypersecretion. J La State Med Soc, 1997 Jan, 149(1), 36 - 8 An acute dystonic reaction with long-term use of ranitidine in an intensive care unit patient; Wilson LB et al.; Dystonic reactions produce twisting and repetitive movements or abnormal posturing; this sign is considered an extrapyramidal sequela that is most typically thought to arise from decreased dopamine activity in the basal ganglia . Severe dystonic reactions have been shown to occur in concert with numerous medications . Although most commonly described with anti-psychotic agents such as haloperidol and phenothiazine, dystonic reactions have been observed in those who have used fluoxetine, erythromycin, crack cocaine, phenobarbital, cisapride, and buspirone . This report details the case of a patient who developed an acute dystonic reaction while taking ranitidine for peptic ulcer prophylaxis, a complication that, to our knowledge, has yet to be described with the use of this agent. Eur Respir J, 1997 Jan, 10(1), 98 - 103 Pulmonary concentrations of dirithromycin and erythromycin during acute exacerbation of mild chronic obstructive pulmonary disease; Matera MG et al.; We compared the concentrations of dirithromycin and erythromycin at steady state in serum and the intrapulmonary region in patients suffering from acute exacerbation of mild chronic obstructive pulmonary disease . Twenty patients received dirithromycin, 500 mg given orally once daily for five consecutive days . The other 20 patients were treated with erythromycin base, which was administered orally four times daily at a total daily dose of 1000 mg for seven days . All patients were divided into eight groups, with five subjects in each group, according to sampling times (2, 4, 8, and hrs after the last dose) and treatment . After the erythromycin treatment mean serum concentrations were higher than those of dirithromycin treatment mean serum concentrations were higher than those of dirithromycin for upto 4 hours, but they were undetectable 24 hours after the last dose . At all time periods, the concentrations of dirithromycin in bronchial secretion, bronchial mucosa and epithelial lining fluid were greater than the concentration in serum . Concentrations of erythromycin were always lower than those of dirithromycin in the explored pulmonary sites . Our data demonstrated that a five day course of 500 mg of dirithromycin once daily induced higher concentrations and longer persistence in the various potential sites of pulmonary infection than a seven day course of 250 mg of erythromycin every 6 hrs . The shorter duration of therapy and the once daily dosing with good efficacy against common respiratory pathogens would be advantageous for patients and would be likely to promote better patient compliance and acceptability. Steroids, 1997 Jan, 62(1), 112 - 6 Structure of cytochrome P450eryF: substrate, inhibitors, and model compounds bound in the active site; Cupp-Vickery JR et al.; Much of our understanding of P450 reaction mechanisms derives from studies on P450cam, a bacterial camphor hydroxylase . P450cam has served as the model for understanding detailed structure/function relationships in mammalian P450 enzymes, which have not proved amenable to x-ray crystallographic techniques . To expand and improve the P450 model, we solved the structure of P450eryF, a cytochrome P450 involved in erythromycin biosynthesis . The overall structure of P450eryF is similar to that of P450cam, but differs in the exact positioning of several alpha-helices, which results in the enlargement of the substrate-binding pocket . P450eryF also differs from P450cam in having alanine in place of the highly conserved threonine residue in the active site . To assess the role of this alanine residue, two mutant forms of P450eryF and a substrate analog were examined . Our findings suggest that P450eryF has evolved an active site that utilizes the substrate to assist in catalysis . In addition, the enlarged substrate binding pocket of P450eryF enables P450eryF to bind certain steroid compounds and azole-based steroid hydroxylase inhibitors . Crystals have been obtained for P450eryF complexed with the antifungal drug ketoconazole, and the high-resolution structure has been determined. Clin Pharmacol Ther, 1997 Jan, 61(1), 93 - 6 Temporal decline in filling prescriptions for terfenadine closely in time with those for either ketoconazole or erythromycin; Burkhart GA et al.; Temporal changes in the rates of filling terfenadine prescriptions within 2 days of those for either oral erythromycin or oral ketoconazole were described with use of paid pharmacy claims data from 1988 through 1994 in state Medicaid programs from Michigan and Ohio and in a large health maintenance organization . There were rapid and significant declines in the rates of filling prescriptions for either erythromycin or ketoconazole within 2 days of prescriptions for terfenadine in all three databases that coincided with 1992 publicity about the cardiovascular risk of terfenadine . These findings suggest that the use of terfenadine with contraindicated medications has declined in response to relabeling and publicity concerning the safe use of terfenadine . Further study is necessary to estimate the absolute level of concurrent use of terfenadine with contraindicated medications. Am J Vet Res, 1997 Jan, 58(1), 56 - 61 Effect of treatment with erythromycin on bronchoalveolar lavage fluid cell populations in foals; Lakritz J et al.; OBJECTIVE: To determine whether oral administration of erythromycin alters the inflammatory response to bronchoalveolar lavage (BAL) in young horses . ANIMALS: 12 healthy, unweaned, mixed-breed foals of either sex, between 2 and 4 months old . PROCEDURE: BAL was performed; 250 ml of phosphate-buffered saline solution (300 mOsm, pH 7.4) was administered in 50-ml aliquots . Foals were carefully monitored for 4 days, then erythromycin base (25 mg/kg of body weight, PO, q 12 h) was given to foals of the treated group . After 4 days, foals were reanesthetized, and the same lung was relavaged . Cytologic examination was performed on BAL fluid (BALF) samples from both groups of foals . At 12 hours after administration of the final dose, erythromycin A and anhydroerythromycin A concentrations were determined in plasma of treated foals . RESULTS: In the second BALF sample from the same lung of control foals, percentage of neutrophils was significantly increased (53 +/- 38.0%) {corrected}, compared with that from erythromycin-treated foals (4.88 +/- 3.66%, P < 0.05), and was associated with apparent decrease in the ability of BALF cells from erythromycin-treated foals to migrate toward a chemoattractant source . Significantly fewer BALF cells adhered to a cell culture substratum after erythromycin treatment of foals . Erythromycin A was not detected in plasma of any treated foal at the time of the second BAL; anhydroerythromycin A, a degradation product of erythromycin, was detected in plasma of 5 of 6 foals (mean concentration, 0.2 +/- 0.06 micrograms/ml) . CONCLUSION AND CLINICAL RELEVANCE: Bal induces neutrophilic inflammation, which persists for at least 4 days in the lungs of young horses . Erythromycin {corrected} (25 mg/kg, PO q 12 h) diminishes this inflammatory response through a mechanism that may involve alteration of BALF cell function . Degradation of erythromycin to biologically active products or presence of parent drug in pulmonary secretions may be responsible for alterations in pulmonary lavage cell chemotaxis and adherence . Erythromycin administered orally to foals at clinically relevant doses appears to have nonantimicrobial effects that may interfere with host cell metabolism and decrease inflammatory responses in airways. Presse Med, 1996 Dec 14, 25(39), 1982 - 8 {New pharmacologic approaches to macrolides: example of roxithromycin}; Bergogne-Berezin E; Macrolides, one of the oldest antibiotic classes, are widely used in out-patient, clinics and hospitals . The major improvement in developing newer derivatives concerns pharmacokinetic properties . Increased half-lives, persisting concentrations in tissues, interstitial fluids and macrophages confer upon newer macrolides significant advantages as compared to the parent compound erythromycin . Roxithromycin, a newer macrolide has a high peak serum concentration, providing very high levels both in the interstitial fluid and intracellularly . Pharmacodynamic approaches are still limited with macrolides, however the very high inhibitory quotient established for tissue concentrations and interstitial fluid suggests the potential clinical efficacy of these drugs. Biochemistry, 1996 Dec 3, 35(48), 15244 - 8 6-deoxyerythronolide B synthase 1 is specifically acylated by a diketide intermediate at the beta-ketoacyl-acyl carrier protein synthase domain of module 2; Tsukamoto N et al.; We have used 6-deoxyerythronolide B synthase (DEBS) as a model system to investigate molecular recognition by a modular polyketide synthase (PKS) . DEBS consists of three proteins (DEBS1, -2, and -3) that biosynthesize the polyketide skeleton of the antibiotic erythromycin from propionyl-CoA and methylmalonyl-CoA . Active sites within these multifunctional proteins are organized into biosynthetic "modules", each of which catalyzes a discrete round of polyketide chain elongation and adjusts the appropriate level of beta-ketoacylthioester reduction . Using DEBS1, we demonstrate that there is a substantial degree of molecular recognition in the processing of the natural diketide chain elongation intermediate . Exogenously added (2S,3R)-2-methyl-3-hydroxypentanoic acid N-acetylcysteamine thioester is exclusively recognized by its cognate beta-ketoacyl-acyl carrier protein synthase domain in module 2 (KS2) . Labeled diketide specifically acylated DEBS1 in crude protein extracts and limited proteolysis localized the binding to module 2 . The precise site of acylation in DEBS1 was established by the finding that a Cys2200 Ala mutant of DEBS1, lacking the KS2 active-site cysteine, did not undergo acylation by the diketide . Pretreatment of the wild-type protein with the beta-ketoacyl-ACP synthase inhibitor cerulenin also blocked acylation . These results indicate that in addition to the purely organizational consequences resulting from the order of active-site domains, the programming of polyketide biosynthesis by modular PKSs involves a substantial level of molecular recognition . This conclusion has important implications for the use of PKSs to rationally design novel polyketides. Antimicrob Agents Chemother, 1996 Dec, 40(12), 2765 - 8 Prospective open randomized study comparing efficacies and safeties of a 3-day course of azithromycin and a 10-day course of erythromycin in children with community-acquired acute lower respiratory tract infections; Roord JJ et al.; The efficacies and safeties of a 3-day, 3-dose course of azithromycin (10 mg/kg of body weight per day) and a 10-day, 30-dose course of erythromycin (40 mg/kg/day) for the treatment of acute lower respiratory tract infections in children were compared in an open randomized multicenter study . Sixty-eight of 85 evaluable patients (80%) had radiologically proven pneumonia, and 20% had bronchitis . Treatment success defined as cure or major improvement was achieved in 42 of 45 (93%) azithromycin recipients versus 36 of 40 (90%) erythromycin recipients . Adverse events were reported in 12 of 45 and 6 of 40 of the patients treated with azithromycin and erythromycin, respectively, a difference which was not statistically significant . In conclusion, a 3-day course of azithromycin is as effective as a 10-day course of erythromycin in the treatment of community-acquired lower respiratory tract infections in children, with comparable safety and acceptability profiles . This shorter treatment course might have a beneficial effect on compliance, especially in the pediatric age group. J Gastroenterol, 1996 Dec, 31(6), 855 - 9 Effects of erythromycin in chronic idiopathic intestinal pseudo-obstruction; Minami T et al.; The prokinetic effects of erythromycin, a macrolide antibiotic, on the gastrointestinal tract as a motilin receptor agonist and its potential value for the treatment of gastrointestinal motility disorders have recently attracted interest . The effects of erythromycin on the clinical symptoms and gastrointestinal motility of patients with chronic idiopathic pseudo-obstruction have not been investigated extensively . We presented a case of chronic idiopathic intestinal pseudo-obstruction, in a 67-year-old man in whom oral erythromycin (900 mg/day) dramatically improved postprandial abdominal distention, nausea, and vomiting . Other agents with prokinetic effects on intestinal motility, i.e., cisapride, domperidone, metoclopramide, and trimebutine maleate did not have a favorable effect . Gastric emptying, measured by the sulfamethizole method; and intestinal transit, evaluated using radio-opaque markers, were markedly improved by treatment with erythromycin . Our experience suggests that the prokinetic effects of erythromycin may be of therapeutic value in chronic idiopathic intestinal pseudo-obstruction. Psychiatry Clin Neurosci, 1996 Dec, 50(6), 337 - 9 Hallucinations after a therapeutic dose of benzodiazepine hypnotics with co-administration of erythromycin; Tokinaga N et al.; A case of repetitive hallucinations during treatment with a therapeutic dosage of triazolam (0.25 mg/day) and nitrazepam (5 mg/day) is presented . The patient suffered from acute pneumonia and chronic renal failure . Such non-psychotic symptoms as anxiety, tremor and depressed feeling were observed initially . However, after co-administration of erythromycin (600 mg/day), visual hallucinations and abnormal bodily sensations developed repeatedly after each administration of triazolam or nitrazepam . This report suggests that benzodiazepine hypnotics even at a therapeutic dosage with co-administration of erythromycin causes serious psychotic symptoms in vulnerable patients with physical complications. Am J Physiol, 1996 Dec, 271(6 Pt 1), G1003 - 16 Electrophysiological characterization of a motilin agonist, GM611, on rabbit duodenal smooth muscle; Yamada K et al.; Effects of motilin and a newly synthesized erythromycin derivative, GM611, on membrane potential and currents of rabbit duodenal smooth muscle have been investigated by intracellular potential recording and whole cell patch-clamp technique and compared with results from contractile experiments . Motilin and GM611 (0.01-100 nM) dose dependently produced slowly sustained depolarizations (half-maximal effective dose = 0.15 and 3.9 nM for motilin and GM611, respectively) but exhibited biphasic effects on spike activities superimposed on slow waves . With small depolarizations, the number of spike discharges increased, whereas larger depolarizations markedly reduced spike amplitude . Motilin-induced (or GM611-induced) depolarization appeared to be associated with the activation of monovalent cation-selective channels, and the reduction in the spike amplitude appeared mainly to be associated with inhibition of voltage-dependent Ca2+ channels . Furthermore, data from patch-clamp experiments suggested that Ca2+ release occurred from heparin-sensitive internal stores upon stimulation of motilin receptors by these agonists . Possible implications of these electrophysiological effects in motilin- or GM611-induced tonic and phasic contractions have been discussed. J Allergy Clin Immunol, 1996 Dec, 98(6 Pt 2), S207 - 15 Eosinophil apoptosis caused by theophylline, glucocorticoids, and macrolides after stimulation with IL-5; Adachi T et al.; BACKGROUND: Glucocorticoids have long been used as the most potent drugs in the treatment of bronchial asthma . Data reported recently have led to the proposal that theophylline and macrolides have antiinflammatory effects . OBJECTIVE: We examined the abilities of theophylline, glucocorticoids, and macrolides to counteract the prolongation of eosinophil survival caused by IL-5 . METHODS: Purified guinea pig eosinophils were cultured in the presence or absence of human IL-5 and with or without the aforementioned drugs at various concentrations . The percentage of cells alive after 3 days in culture was determined . RESULTS: Aminophylline (AM), methylprednisolone (MP), erythromycin (EM), and clarithromycin (CAM) suppressed the IL-5 induced prolongation of eosinophil survival in a dose-dependent manner . The effects of these drugs on eosinophil survival were significantly greater at low concentrations of IL-5 than at high concentrations of IL-5 . When eosinophils were cultured in the presence of IL-5 (1 ng/ml) with physiologic concentrations of MP (10(-6) mol/L), AM (10(-4) mol/L), and either EM or CAM (both 10 micrograms/ml), the effect of IL-5 was almost completely abolished, and the morphologic changes in eosinophils observed by electron microscopy were consistent with apoptosis . DNA extracted from eosinophils cultured with IL-5 and each of the drugs was definitely fragmented . CONCLUSIONS: One mechanism of the effectiveness of these drugs is induction of eosinophil apoptosis . Some combination of these drugs may be useful in the treatment of bronchial asthma. Aliment Pharmacol Ther, 1996 Dec, 10(6), 967 - 73 Could oral erythromycin optimize high energy continuous enteral nutrition? Landry C, Vidon N, Sogni P, Nepveux P, Chaumeil JC, Couturier D, Chaussade S. BACKGROUND: Intravenous erythromycin has previously been reported to stimulate gastric emptying, to inhibit gastric acid secretion and to stimulate pancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers . AIM: The aim of this study was to evaluate the effects of oral erythromycin (160 mg/h) on gastrointestinal function under these conditions in seven healthy subjects . METHOD: This randomized double-blind cross-over study measured the gastric emptying rate of nutrients, gastric acid secretion, gastric pH, jejunal flow rate as well as biliopancreatic secretion and duodeno-caecal transit time during a 19.9 kJ/min continuous infusion of a nutrient solution (4.18 kJ/mL) in the antrum over a 6-h period by a perfusion method . RESULTS: The nutrition was well tolerated except by one subject with placebo perfusion . During the 6-period, total gastric volume and gastric volume of nutrient decreased during erythromycin administration by 22 +/- 8 and 22 +/- 6%, respectively . Gastric acid secretion was not modified by erythromycin . Lipase and bile salt outputs were significantly higher with erythromycin . The duodeno-caecal transit time was not statistically different with drug and placebo (169 +/- 15 and 146 +/- 19 min, respectively) . CONCLUSION: During continuous gastric infusion of a liquid diet, the effect of oral erythromycin on gastric emptying could be useful to optimize cyclic enteral nutrition or to enhance the tolerance of enteral nutrition. Ann Allergy Asthma Immunol, 1996 Dec, 77(6), 456 - 8 Anaphylaxis to erythromycin; Jorro G et al.; BACKGROUND: Erythromycin and its salts belong to the larger class of macrolides . Erythromycin is well tolerated . The most common side effects are gastrointestinal distress, nausea, and vomiting, which are dose related . Allergic and pseudoallergic reactions due to macrolide antibiotics are uncommon . Anaphylaxis and acute respiratory distress appear in the literature as case reports . METHODS: We report a 24-year-old man who presented 12 years ago a systemic allergic reaction to penicillin, confirmed by skin tests and detection of specific IgE (RAST) . Since then he had tolerated erythromycin on several occasions . Nine months ago, his general practitioner prescribed erythromycin orally as treatment for a respiratory infection . Thirty minutes after taking the first dose, 500 mg, he developed an anaphylactic reaction . The episode subsided with treatment with high dose corticosteroids, antihistamines, and epinephrine . Skin prick tests and intradermal tests were performed with erythromycin at different concentrations . We also measured total IgE and specific IgE to erythromycin by CAP and Phadezym RAST (Pharmacia, Uppsala, Sweden), respectively . We also performed a Prausnitz-Kustner test (PK test), and oral challenge test . RESULTS: Skin testing to erythromycin was not helpful because of cutaneous hyperreactiviness . No significant levels of specific IgE to erythromycin were detected . The oral challenge and the Prausnitz-Kustner test were positive . CONCLUSIONS: The positive history and oral challenge test suggested an anaphylactic reaction to erythromycin . The positive Prausnitz-Kustner test demonstrated the presence of specific IgE to erythromycin. J Am Coll Cardiol, 1996 Dec, 28(7), 1836 - 48 Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes; Antzelevitch C et al.; OBJECTIVES: This study sought to elucidate the cellular and ionic basts for erythromycin-induced long QT syndrome . BACKGROUND: Erythromycin is known to produce long QTU intervals on the electrocardiogram (ECG) and to be associated with the development of torsade de pointes (TdP) . The mechanisms responsible for the adverse effects of this widely used antibiotic are not well defined . METHODS: The present study used microelectrode and whole-cell patch-clamp techniques to assess the effects of erythromycin on epicardial, endocardial and M cells in transmural strips, arterially perfused wedges and single myocytes isolated from the canine left ventricle . RESULTS: In isolated strips, erythromycin (10 to 100 micrograms/ml) produced a much more pronounced prolongation of the action potential duration (APD) in M cells than in endocardial and epicardial cells, resulting in the development of a large dispersion of repolarization across the ventricular wall at slow stimulation rates . Erythromycin (50 to 100 micrograms/ml) induced early after depolarizations (EADs) in cells in the M (20%) but not epicardial or endocardial regions in transmural strips of ventricular free wall . Erythromycin (100 micrograms/ml) also caused APD prolongation and a transmural dispersion of repolarization, but not EADs, in intact arterially perfused wedges of canine left ventricle . These changes were attended by the development of a long QT interval on the transmural ECG . A polymorphic ventricular tachycardia closely resembling TdP was readily and reproducibly induced after erythromycin but not before . Whole-cell patch-clamp techniques, used to examine the effects of erythromycin on myocytes isolated from the M region, showed a potent effect of the drug to inhibit the rapidly activating component (IK(r)) but not the slowly activating component (IKs) of the delayed rectifier potassium current (IK) . The inward rectifier current (IK1) was unaffected . CONCLUSIONS: Our data demonstrate a preferential response of M cells to the class III actions of erythromycin, due principally to the effect of the drug to inhibit IK(r) in a population of cells largely devoid of IKs . Our findings indicate that erythromycin thus produces long QT intervals as well as a prominent dispersion of repolarization across the ventricular wall, setting the stage for induction of TdP-like tachyarrhythmias displaying characteristics typical of reentry. Am J Vet Res, 1996 Dec, 57(12), 1771 - 5 Effect of bethanechol or erythromycin on gastric emptying in horses; Ringger NC et al.; OBJECTIVE: To investigate the prokinetic effect of bethanechol and erythromycin in the upper gastrointestinal tract of healthy horses by measuring the gastric emptying (GE) rate of a radioactive meal . ANIMALS: 4 healthy adult horses . PROCEDURE: After food was withheld for 12 hours, horses were given 370 MBq of 99mTc-labeled sulfur colloid incorporated into egg albumen and 37 MBq of 111In-labeled diethyltriaminepentaacetic acid in 120 ml of water via nasogastric intubation . Intravenously administered treatments were 0.9% NaCl solution, erythromycin (0.1 or 1.0 mg/kg of body weight), or bethanechol (0.25 mg/kg) . All drugs were given in 10 ml of 0.9% NaCl solution . Dual-phase scintigraphic images were obtained by use of a gamma camera . The best-fit function was determined for each study, and the resultant curves were then analyzed by use of least squares nonlinear regression . Two variables, time to 50% emptying of the stomach (T-50) and slope of the emptying curve, were derived from the calculated power exponential equation . CONCLUSIONS: Treatment had a significant (P < 0.05) overall effect on T-50 of solid-phase GE . The T-50 of bethanechol (30.09 +/- 10.01 minutes), erythromycin at 0.1 mg/kg (59.08 +/- 10.01 minutes), and erythromycin at 1 mg/kg (60.50 +/- 10.01 minutes) were significantly shorter than T-50 after saline administration (89.97 +/- 10.01 minutes) . There was a trend (P = 0.09) for the slope of solid-phase GE of bethanechol and erythromycin (0.1 mg/ kg; P = 0.37) to be steeper than that of saline solution . For liquid-phase GE, the T-50 and the slope of bethanechol differed significantly (P < or = 0.05) from those for saline solution . CLINICAL RELEVANCE: Bethanechol and erythromycin significantly increased solid-phase GE in healthy horses and may have value for use as prokinetic agents in certain gastrointestinal tract diseases. Z Geburtshilfe Neonatol, 1996 Nov-Dec, 200(6), 241 - 4 {Whooping cough in pregnant patients and newborn infants}; Hoppe JE; Pertussis affects not only children but also adults . The disease often takes an atypical course in adults and it is frequently misdiagnosed . Pregnant women with pertussis do not suffer from serious obstetrical complications . If, however, they are contagious at the time of delivery, they may infect the neonate immediately post partum . Neonates are susceptible to pertussis and may become seriously ill with potentially fatal consequences . Neonatal pertussis is frequently misdiagnosed, too . The disease can be prevented by prophylactical administration of erythromycin to the neonate. Int J Parasitol, 1996 Nov, 26(11), 1321 - 3 Depression of the N-demethylation of erythromycin, azithromycin, clarithromycin and clindamycin in murine Toxoplasma infection; Berg-Candolfi M et al.; The N-demethylation of macrolides was studied in a murine model of infection . Mice were infected with a cystogenic strain of Toxoplasma gondii (20 or 40 cysts/mouse) and microsomes were prepared from liver homogenates and jejunum villus tip enterocytes on day 10 post-infection . The rate of N-demethylation of the anti-Toxoplasma macrolides azithromycin, clarithromycin and clindamycin was investigated and compared to that of the macrolide erythromycin, a marker of activity of the cytochrome P-450 3A (CYP3A) mono-oxygenases . In infected mice (20 cysts/mouse), the rate of N-demethylation fell in the liver and jejunum for erythromycin (-25% and -35%, respectively), azithromycin (-12% and -10%, respectively), clarithromycin (-23% and -21%, respectively) and clindamycin (-20% and -28%, respectively) . The degree of hepatic depression was more marked in mice receiving a 40-cysts burden: for erythromycin (-54%), azithromycin (-29%), clarithromycin (-49%) and clindamycin (-47%). Curr Opin Rheumatol, 1996 Nov, 8(6), 569 - 75 Gastrointestinal features of scleroderma; Sjogren RW; Gastrointestinal involvement occurs in most patients with systemic sclerosis and is subclinical in about one third . Early pathology is characterized by vasculopathy, resulting in tissue ischemia and progressive dysfunction . Noninvasive esophageal studies using semisolid bolus scintigraphy are sensitive but lack specificity . Long-term treatment of reflux with high-dose proton pump inhibitors appears safe and effective for symptom relief and may prevent recurrence of esophagitis and stricture . Dyspepsia may result from gastroparesis and antral distension . Gastric antral vascular ectasia is a vascular manifestation, and bleeding may be controlled endoscopically . Prokinetic agents effective in pseudoobstruction include metoclopramide, domperidone, cisapride, octreotide, and erythromycin . Patients with intestinal neuropathy or response to bolus octreotide are more probable long-term responders . The combination of octreotide and erythromycin may be particularly effective in systemic sclerosis . The combination of cisapride and erythromycin may cause serious cardiac arrhythmia and is contraindicated . Omeprazole may predispose to small intestinal bacterial overgrowth . Malabsorption not responding to antibiotic therapy should be investigated with small-bowel biopsy to rule out more unusual causes . Pneumatosis cystoides intestinalis may be due to excessive hydrogen production by intestinal bacteria altering the partial pressure of nitrogen in the intestinal wall . In selected cases, surgery for intestinal failure is an option with resection or bypass of affected segments or placement of enterostomy tubes for feeding or decompression . Careful preoperative characterization of intestinal segments is required. Gastroenterol Hepatol, 1996 Nov, 19(9), 459 - 61 {Cholestatic hepatitis caused by midecamycin}; Perez Moreno JM et al.; Hepatotoxicity by macrolide antibiotics, particularly erythromycin and derivatives, is a side effect extensively described in the literature . Midecamycin is a semi-synthetic derivative of this family with a wide safety margin of which isolated references of possible secondary hepatobiliary effects have been referred . The present clinical observation describes a case of cholestatic hepatitis which, in our opinion, was related to the administration of diacetyl midecamycin which evolved favorably following discontinuation of the drug . Despite its exceptional frequency and based on the wide therapeutic diffusion of this group of antibiotics, we believe this case to be of interest. In Vivo, 1996 Nov-Dec, 10(6), 585 - 96 The value of the dehydroepiandrosterone-annexed vitamin C infusion treatment in the clinical control of chronic fatigue syndrome (CFS) . II . Characterization of CFS patients with special reference to their response to a new vitamin C infusion treatment; Kodama M et al.; This study is a counterpart of the pilot study on the clinical management of chronic fatigue syndrome (CFS) by the combined use of the old (annex-free) and the new (dehydro-epiandrosterone- annexed) vitamin C infusion treatments with and without oral intake of erythromycin and chloramphenicol . We were motivated to start this clinical study by 2 reasons: i) we have made a success in the clinical management of autoimmune disease and allergy by use of the old megadose vitamin C infusion treatment, and we therefore took up CFS as a good candidate for vitamin C infusion treatment; ii) In 1995, we received a total of 313 chronic pneumonia patients whose clinical course showed a good fitness to the criteria of CFS . We assessed the nature of the disease by investigating the clinicoepidemiological aspect of our patients on the one hand and the response of the disease to both the old and new vitamin C infusion treatments with and without the use of 2 antibiotics on the other hand . Results are summarized as follows: a) the analysis of the medical records of our outpatients revealed that chronic type pneumonia epidemic in Nagoya Japan, with its onset of January 1995, showed no sign of its extinction by the end of May 1996 . The patient population contained no patients under 15 years of age, and showed a distinct female predominance in the patient number (207 females versus 106 males) . In 1995, we also experienced a simple cold epidemic with its onset of January 1995 (162 males and 224 females) . The majority of simple cold patients were under 25 years of age in both sexes . b) A chronic type pneumonia patient was distinguished from a simple cold patient in 2 respects: firstly the former required prolonged medical care (over 1 month) resulting in an incomplete cure and return to medical care upon the recurrence of disease, whereas the latter required short-term medical care (mostly within 1 week) ending up with complete cure . Secondly, the former required the long term use of 2 antibiotics (erythromycin and chloramphenicol) together with regular practice of the old and new vitamin C infusion treatments for disease control, whereas the latter recovered from the disease after the short time use of a set of conventional cold remedies . c) The clinical manifestations of our chronic pneumonia patients showed good fitness to the criteria of CFS . d) CFS was distinguished from autoimmune disease-allergy complex by the method of clinical control: the former required the long-term use of 2 antibiotics together with regular practice of the old and new vitamin C infusion treatments, whereas the latter was controllable by the single use of the old vitamin C infusion treatment . e) The combined use of the old and new vitamin C infusion treatments rather than the single use of the old vitamin C infusion treatment was more effective for the control of CFS-a finding which suggests that deficient activities of both endogenous glucocorticoid and endogenous androgen in a CFS patient are somehow related to the genesis and further development of CFS . f) Evidence was available to indicate that the sole use of the new vitamin C infusion treatment may induce a state of gonadal steroid excess together with various other problems in the recipient . The maintenance of a good balance between the old vitamin C infusion set (glucocorticoid-inducer) and the new vitamin C infusion set (inducer of both glucocorticoid and gonadal steroids) in their use was of prime importance for the successful control of CFS . g) The historical significance of CFS epidemic in 1995, and in Nagoya-Japan, is discussed in the light of the new infection concept. Hepatogastroenterology, 1996 Nov-Dec, 43(12), 1540 - 3 Gallbladder contraction induced by intravenous erythromycin administration . Relation to body mass index; Kakkos SK et al.; BACKGROUND/AIMS: To study the action of intravenously administered erythromycin lactobionate on human gallbladder volume, as a possible preventive method against gallbladder stone formation, in high risk patients such as those in sepsis, long standing fasting periods or those receiving prolonged total parenteral nutrition or octreotide . MATERIALS AND METHODS: Twenty-two volunteers randomized to receive intravenously either erythromycin lactobionate 7 mg per kg (study group) or normal saline (controls) . We measured ultrasonographically the gallbladder volume before and at 5, 15, 35, 55, 90, 120 and 180 min after the infusion . RESULTS: Erythromycin induced a biphasic gallbladder contraction, with maximum contractility at 15 min (10.2%) and between 120 and 180 min (22.6%), compared to normal saline controls . Late contractility was correlated to body mass index (BMI) . CONCLUSIONS: Erythromycin activity on gallbladder contraction is proved . Its biphasic action needs further investigation to find the involved mechanism(s) . Long term administration is also necessary to test its efficacy in preventing gallbladder dilatation. Neth J Med, 1996 Nov, 49(5), 202 - 4 Relapse of Legionella longbeachae infection in an immunocompromised patient; van't Hullenaar NG et al.; We describe the first known case of Legionella longbeachae infection in the Netherlands in a patient with myasthenia gravis . Infection with L . longbeachae relapsed after prolonged therapy with erythromycin . No environmental source of L . longbeachae could be traced. J Toxicol Sci, 1996 Nov, 21(4), 215 - 26 Effects of erythromycin and roxithromycin on oxidation of testosterone and nifedipine catalyzed by CYP3A4 in human liver microsomes; Yamazaki H et al.; Roxithromycin and erythromycin were incubated with rat and human liver microsomal or reconstituted cytochrome P450 (P450 or CYP) monooxygenase systems in the presence of an NADPH-generating system, and the effects of these chemicals on testosterone 6 beta-hydroxylation and nifedipine oxidation activities were compared with those of typical CYP3A4 inhibitors including ketoconazole, troleandomycin, and gestodene . Roxithromycin and erythromycin were found to be relatively weak inhibitors of testosterone 6 beta-hydroxylation and nifedipine oxidation activities by rat and human liver microsomes or by reconstituted systems containing CYP3A4/5 . Formation of an inhibitory P450-metabolite complex was determined spectrally by incubating troleandomycin with human liver microsomes; the extents of the complex formation were lesser in liver microsomes of humans than those of rats treated with dexamethasone . Erythromycin and roxithromycin were also activated slightly by rat liver microsomes to form P450.Fe(I