Erythromycin

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(II)-metabolite complex, although these chemicals caused very little or undetectable levels, respectively, of spectral changes by human liver microsomes even when a human sample which contained relatively high levels of CYP3A4 was used . These results suggested that roxithromycin and erythromycin were relatively less potent to inhibit CYP3A4-catalytic activities in human liver microsomes, because of their low capabilities to form P450.Fe(II)-metabolite complex.

JPEN J Parenter Enteral Nutr, 1996 Nov-Dec, 20(6), 385 - 8
Erythromycin facilitates postpyloric placement of nasoduodenal feeding tubes in intensive care unit patients: randomized, double-blinded, placebo-controlled trial; Kalliafas S et al.; BACKGROUND: To determine whether administration of erythromycin (E) could facilitate passage of a nasoenteric feeding tube into the duodenum for postpyloric feedings, this randomized, double-blind, placebo-controlled trial was performed . METHODS: Fifty-seven patients were accrued from the surgical intensive care units (ICUs) of a tertiary-care university hospital . Patients enrolled were categorized as to the presence or absence of diabetes mellitus (DM) . Those patients without DM were then subdivided into those with normal or depressed mental status . The three groups, normal (NMS), depressed mental status (DMS), or diabetes mellitus (DM), were then randomized independently to receive either E or placebo (P), followed by blind placement of a feeding tube . Tube placement was verified by an abdominal radiograph . RESULTS: Overall, the rate of postpyloric placement was 61% (19/31) in the E group, significantly better than 35% (9/26) in the P group (p < .05) . In patients with NMS, the success rate with E was improved (64%, 9/14) compared with that with P (9%, 1/11) (p < .0005) . In the DMS group, there was a 50% success rate (6/12) with E versus 63% (5/8) with P (not significant {NS}) . In the DM group, 80% (4/5) of the patients had placement of the tube in the duodenum with E and 43% (3/7) with P (NS) . CONCLUSIONS: These data suggest that, overall, E is effective in facilitating placement of a nasoenteric feeding tube into the duodenum in ICU patients . It is clearly beneficial in those patients with normal mental status and may be useful in patients with diabetes mellitus.

Xenobiotica, 1996 Nov, 26(11), 1143 - 53
Effects of roxithromycin, erythromycin and troleandomycin on their N-demethylation by rat and human cytochrome P450 enzymes; Yamazaki H et al.; 1 . The effects of treatment of rat with roxithromycin, erythromycin and troleandomycin as well as other chemicals including typical cytochrome P450 inducers were examined in rat and human liver microsomes . 2 . Erythromycin and troleandomycin but not roxithromycin caused slight increases in CYP3A1 levels and the N-demethylation of roxithromycin, erythromycin and troleandomycin and oxidation of nifedipine in rat, but none of these chemicals induced significantly CYP2B1 levels or benzphetamine N-demethylation activities . 3 . Dexamethasone and pregnenolone 16 alpha-carbonitrile induced CYP3A1 levels and N-demethylation of roxithromycin, erythromycin and troleandomycin but not of benzphetamine, in rat liver microsomes . Treatment of rat with phenobarbital caused increases in both CYP2B1 and 3A1 levels and all of the N-demethylation activities examined . Phenytoin and metyrapone produced increases in contents of 2B1 and activities of benzphetamine N-demethylation as well as of roxithromycin, erythromycin and troleandomycin, although these two inducers did not induce 3A1 protein significantly . 4 . In man, a liver sample that was high in CYP3A4 and nifedipine oxidation activity was found to be the most active in N-demethylation activities towards these substrates examined . In addition, recombinant 3A4 catalysed very efficiently the N-demethylation of roxithromycin, erythromycin and troleandomycin in reconstituted monooxygenase systems . 5 . These data suggest that erythromycin and troleandomycin, but not roxithromycin, were able to induce CYP3A1 in rat liver microsomes, and that N-demethylation of roxithromycin, erythromycin and troleandomycin were catalysed mainly by 3A1 (and partly by 2B1) in rat and by 3A4 in man.

Toxicol Appl Pharmacol, 1996 Nov, 141(1), 185 - 94
Induction of cytochrome P4501A1 and P4504A1 activities and peroxisomal proliferation by fumonisin B1; Martinez-Larranaga MR et al.; The effects of repeated exposure to fumonisin B1 (FB1) on hepatic and renal mixed function oxidase activities and peroxisomal proliferation has been examined in rats following intraperitoneal administration at three dose levels (0.125, 0.25, and 2.5 mg/kg) once a day for 6 days . At the two highest doses, FB1 increased the renal and hepatic N-demethylation of erythromycin (CYP3A1) and the hepatic O-deethylation of ethoxyresorufin (CYP1A1) . FB1, at the highest dose of 2.5 mg/kg, also increased the renal O-deethylation of ethoxyresorufin . The liver, but not the kidney, was also susceptible to FB1-dependent induction of the 12- and 11-hydroxylation of lauric acid, suggesting induction of the CYP4A subfamily . Immunoblot studies employing solubilized microsomes from FB1-treated rats revealed that FB1, at the two highest doses, increased the apoprotein levels of CYP1A1 and CYP4A1 . The same treatment with FB1 increased the beta-oxidation of palmitoyl-coenzyme A (CoA) in liver homogenates, and immunoblot analysis showed an increase in the apoprotein levels of the trans-2-enoyl-CoA hydratase trifunctional protein . The possible implications of these findings to the hepatocarcinogenicity of this mycotoxin are discussed.

J Pediatr, 1996 Nov, 129(5), 761 - 4
Efficacy of short-term treatment of pertussis with clarithromycin and azithromycin; Aoyama T et al.; The recommended treatment for pertussis is erythromycin, 40 to 50 mg/kg per day for 2 weeks . The newly developed macrolides, clarithromycin and azithromycin, have been demonstrated to be superior to erythromycin because of improved absorption and a longer half-life . As a result, we conducted two separate comparison studies to evaluate the efficacies of clarithromycin, 10 mg/kg per day, twice a day for 7 days, and azithromycin, 10 mg/kg per day, once a day for 5 days, compared with the standard erythromycin regimen . A total of 17 patients, including 10 infants 1 year of age or less, for whom pertussis had been confirmed by culture, were allocated to receive either clarithromycin or azithromycin treatment, and each patient was matched (age, sex, and immunization status) with historical control subjects who had been treated with erythromycin . Eradication rates examined at 1 week after treatment were as follows: 9 of 9 with clarithromycin versus 16 of 18 with erythromycin (psi M-H = 1.13), and 8 of 8 with azithromycin versus 13 of 16 with erythromycin (psi M-H = 1.23) . No bacterial relapse after treatment was detected in either group . All isolated strains of Bordetella pertussis were susceptible to clarithromycin, azithromycin, and erythromycin, and no change in drug susceptibility has been confirmed for the past 20 years in Japan . Because of the very low incidence of pertussis resulting from widespread use of acellular pertussis vaccination, this study did not enroll a large number of patients; however we conclude that short-term treatment with clarithromycin or azithromycin is expected to be equal or superior to the standard long-term erythromycin regimen for pertussis.

Antimicrob Agents Chemother, 1996 Nov, 40(11), 2562 - 6
Detection of erythromycin-resistant determinants by PCR; Sutcliffe J et al.; Erythromycin resistance determinants include Erm methylases, efflux pumps, and inactivating enzymes . To distinguish the different mechanisms of resistance in clinical isolates, PCR primers were designed so that amplification of the partial gene products could be detected in multiplex PCRs . This methodology enables the direct sequencing of amplified PCR products that can be used to compare resistance determinants in clinical strains . Further, this methodology could be useful in surveillance studies of erythromycin-resistant determinants.

Am J Respir Crit Care Med, 1996 Nov, 154(5), 1531 - 6
Bronchiolar disease in rheumatoid arthritis; Hayakawa H et al.; The pulmonary manifestations of rheumatoid arthritis (RA) include bronchiolar diseases such as follicular bronchiolitis (FB) and bronchiolitis obliterans (BO) . In this study, we investigated the clinical and pathologic features of FB and BO, as well as the effect of erythromycin (EM) on these diseases . The subjects included 15 RA patients with biopsy-proven bronchiolar disease (eight with FB, seven with BO) . None of the patients had Sjogren's syndrome . Eleven patients (73%) had chronic sinusitis, and 14 (93%) had a chronic cough with sputum . Bacterial culture of sputum was positive in 50% and 71% of the FB and BO patients, respectively . High-resolution computed tomography (HRCT) revealed small nodular shadows in the centrilobular regions (FB and BO), patchy areas of low attenuation (BO), and peribronchial thickening (FB and BO) . Eleven patients who received EM therapy showed a significant improvement of symptoms . In addition, none of the 15 patients died of the bronchiolar disease during follow-up . In conclusion, RA patients with FB or BO basically have a chronic clinical course with main complaint of productive cough, and EM may be useful for the management of these diseases.

Eur J Obstet Gynecol Reprod Biol, 1996 Nov, 69(2), 83 - 9
Pregnancy outcome after prenatal quinolone exposure . Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS); Schaefer C et al.; OBJECTIVE: To study potential teratogenic effects of quinolone exposure during pregnancy . STUDY DESIGN: Prospective follow-up study . Subjects are pregnant women who contacted a teratology information center for risk information on quinolone treatment . A total of 549 pregnancies was collected by the European Network of Teratology Information Services between 1986 and 1994 . In addition 116 prospectively documented pregnancies and 25 retrospective case reports on malformed children from other databases were analyzed . RESULTS: The malformation rate among the live-born babies in the prospective ENTIS cohort was approximately 4.8% . No specific patterns of congenital abnormalities were found . The results do not suggest an elevated risk for spontaneous abortion, prematurity, intrauterine growth retardation and postnatal disorders . CONCLUSION: The present study does not reveal any clear adverse reactions (fetal and neonatal toxicity, including birth defects) due to the in utero exposure to quinolones . Hence, termination of pregnancy because of such exposure is not indicated . However, considering the limitations of this study and the fact that diseases urgently requiring quinolone treatment are rare, it appears advisable to prefer penicillin, cephalosporins and erythromycin as antibiotics of choice.

J Clin Microbiol, 1996 Nov, 34(11), 2645 - 9
Multiplex PCR-based assay for detection of Bordetella pertussis in nasopharyngeal swab specimens; Wadowsky RM et al.; A multiplex PCR-based assay was developed for the detection of Bordetella pertussis in nasopharyngeal swab specimens . The assay simultaneously amplified two separate DNA targets (153 and 203 bp) within a B . pertussis repetitive element and a 438-bp target within the beta-actin gene of human DNA (PCR amplification control) . PCR products were detected by a sensitive and specific liquid hybridization gel retardation assay . A total of 496 paired nasopharyngeal swab specimens were tested by both the PCR-based assay and culture . Although 30 (6%) of the specimens inhibited the amplification of the beta-actin target, in all 29 specimens studied, the inhibition disappeared on repeat testing or was easily overcome with a 1:8 dilution or less of specimen digest . Of the 495 specimen pairs yielding a final evaluable result by the PCR-based assay, 19.0% were positive by the PCR-based assay, whereas 13.9% were positive by culture (P < 0.0001) . After resolving the PCR-positive, culture-negative results by testing an additional aliquot from these specimens by the multiplex PCR-based assay, the PCR-based assay had a sensitivity and specificity of 98.9 and 99.7%, respectively, compared with values of 73.4 and 100%, respectively, for culture . In comparison with patients with culture-confirmed pertussis, those with PCR-positive, culture-negative results were older and more likely to have had prolonged cough, immunization with pertussis vaccine, or treatment with erythromycin . This multiplex PCR-based assay is substantially more sensitive than culture and identifies specimens that contain inhibitors of PCR.

Thorax, 1996 Oct, 51(10), 1065 - 7
Diffuse panbronchiolitis in an Asian immigrant; Brugiere O et al.; Diffuse panbronchiolitis (DPB) is a disease with chronic inflammation exclusively located in the region of the respiratory bronchiole . It is largely restricted geographically to the Far East, and cases in Western countries are exceptional, even among Asian immigrants . A patient of Asian origin with DPB who had been living in France for 10 years is described . Only re-examination of the initial open lung biopsy specimen after an eight year period allowed this rare disease to be diagnosed correctly . The known efficacy of low dose erythromycin in DPB was again confirmed after failure of long term high dose corticosteroid therapy administered before an accurate diagnosis had been made.

Nihon Kyobu Shikkan Gakkai Zasshi, 1996 Oct, 34(10), 1104 - 8
{Effects of erythromycin on surfactant synthesis, secretion, and recycling by rat alveolar type II cells}; Suwabe A et al.; Effects of erythromycin on surfactant synthesis, secretion, and recycling by rat alveolar type II cells were examined . Type II cells were isolated from rat lungs and incubated with 3H-choline, a precursor of surfactant . Synthesis was quantified from the amount of 3H-phosphatidylcholine and from the distribution to lamellar body fractions as measured with sucrose density gradients . Secretion was quantified from the percent of synthesized 3H-phosphatidylcholine released into the medium over 3 hr . Recycling was quantified from the percent uptake over 1 h of 3H-labeled synthetic liposomes . Type II cells incubated with erythromycin (5-50 micrograms/ml) for 22 hrs secreted less surfactant in response to PMA and ATP than did control cells . Erythromycin did not affect synthesis or recycling of surfactant by type II cells . These results show that erythromycin inhibits surfactant secretion from type II cells, and suggest that erythromycin may be effective in surfactant-excess states such as alveolar proteinosis.

Nucl Med Commun, 1996 Oct, 17(10), 895 - 901
Lung clearance of inhaled 99Tcm-erythromycin lactobionate in non-smokers and smokers; Durak H et al.; 99Tcm-labelled erythromycin lactobionate (99Tcm-EL) was used as a radioaerosol for lung ventilation imaging in humans after animal studies had shown slow clearance of 99Tcm-EL from the alveolar spaces . We performed inhalation studies in 26 volunteers: 11 non-smokers, 13 smokers (3 of whom smoked one cigarette just before inhalation of 99Tcm-EL) and 2 patients with pulmonary emboli (PE) . The PE patients were imaged by both 99Tcm-EL and xenon-133 (133Xe) for comparison . The image quality with 99Tcm-EL was comparable to that with 133Xe, showing good peripheral penetration . The biological clearance half-lifes for 99Tcm-EL were 3.9 +/- 1.1 h in the non-smokers, 5.9 +/- 2.2 h in the smokers and 9.8 +/- 6.6 h in the three subjects who smoked a cigarette just before inhalation of the aerosol . 99Tcm-EL was cleared more slowly in the smokers and after smoke exposure, which could have indicated alveolar macrophage uptake . 99Tcm-EL can be used as an alternative to 99Tcm-diethylenetriamine pentaacetate (99Tcm-DTPA) in ventilation imaging, thus overcoming the problem of the fast clearance of 99Tcm-DTPA in smokers.

Chem Biol, 1996 Oct, 3(10), 833 - 9
A hybrid modular polyketide synthase obtained by domain swapping; Oliynyk M et al.; BACKGROUND: Modular polyketide synthases govern the synthesis of a number of medically important antibiotics, and there is therefore great interest in understanding how genetic manipulation may be used to produce hybrid synthases that might synthesize novel polyketides . In particular, we aimed to show whether an individual domain can be replaced by a comparable domain from a different polyketide synthase to form a functional hybrid enzyme . To simplify the analysis, we have used our previously-developed model system DEBS1-TE, consisting of the first two chain-extension modules of the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea . RESULTS: We show here that replacing the entire acyltransferase (AT) domain from module 1 of DEBS1-TE by the AT domain from module 2 of the rapamycin-producing polyketide synthase leads, as predicted, to the synthesis of two novel triketide lactones in good yield, in place of the two lactones produced by DEBS1-TE . Both of the novel products specifically lack a methyl group at C-4 of the lactone ring . CONCLUSIONS: Although the AT domain is a core structural domain of a modular polyketide synthase, it has been swapped to generate a truly hybrid multienzyme with a rationally altered specificity of chain extension . Identical manipulations carried out on known polyketide antibiotics might therefore generate families of potentially useful analogues that are inaccessible by chemical synthesis . These results also encourage the belief that other domains may be similarly swapped.

Pharm World Sci, 1996 Oct, 18(5), 182 - 6
Investigation on the chemical stability of erythromycin in solutions using an optimization system; Brisaert M et al.; Erythromycin, an antibiotic commonly used topically in the treatment of acne, is unstable in solution . The stability is influenced by the pH and by the presence of water . The influence of the pH on the stability of erythromycin was investigated even with the use of dimethyl isosorbide as co-solvent instead of water . The addition of zinc was attempted to ameliorate erythromycin stability as suggested in the literature . To investigate these three factors and their interactions, an optimization technique was carried out consisting of a 2(3) factorial analysis and a rotative central composite design . The erythromycin solutions were analysed with an HPLC method . The pH and the concentration of dimethyl isosorbide had a significant influence on the stability of erythromycin but the addition of zinc was not a significant factor . Moreover, there was a significant interaction between the pH and dimethyl isosorbide.

J Neurovirol, 1996 Oct, 2(5), 345 - 55
Therapeutic trials in 200 patients with HTLV-I-associated myelopathy/ tropical spastic paraparesis; Nakagawa M et al.; We report here the results of therapeutic trials in 200 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) conducted in our department between 1986 and 1993 . Motor disability grades were improved by more than one grade in 69.5% (91/131) of patients by oral administration of prednisolone, 50% (3/6) by eperisone hydrochloride only, 43.8% (7/16) by blood purification (lymphocytapheresis and plasmapheresis), 40.0% (2/5) by intrathecal injection of hydrocortisone, 30.0% (3/10) by intravenous injection of high-dose methylprednisolone, 23.3% (10/43) by interferon-alpha (intramuscular injection and inhalation), 22.2% (2/9) by azathioprine, 20.0% (4/20) by high-dose vitamin C, 16.0% (4/25) by erythromycin, 12.5% (3/24) by salazosulfapyridine, 11.8% (2/17) by mizoribine, 7.1% (1/14) by fosfomycin, and 6.3% (1/16) by thyrotropin releasing hormone . No critical side effects of these therapies were seen with the exceptions of one patient with adult respiratory distress syndrome due to cytomegalovirus infection and one patient with drug-induced hepatitis/hepatic failure . Selection of these treatments for patients with HAM/ TSP must be considered on the basis of age, sex, disease severity and complications to reduce adverse events and to improve quality of life . Although the results were a synopsis of different treatments given to 200 patients with HAM/ TSP as an open trial, we consider this the first report of a large-scale therapeutic trial in patients with HAM/TSP . The results of this study indicate that immunomodulatory therapies have some beneficial effects in HAM/TSP, and the functions of these agents are related to the pathophysiology of this disease.

Semin Gastrointest Dis, 1996 Oct, 7(4), 185 - 95
Functional disorders of the stomach; Koch KL et al.; Disorders of stomach function refer to neuromuscular abnormalities of gastric motility that involve the fundus, corpus, antrum, pylorus, and antroduodenal coordination . Symptoms related to disorders of stomach function are commonly meal-related; "dyspepsia" symptoms of epigastric fullness; or bloating, discomfort, and nausea in the postprandial period . Early satiety and prolonged stomach fullness are often present, and in severe cases the patient may vomit undigested food . Neuromuscular disorders of stomach function should not be considered until structural and metabolic diseases that may also cause these nonspecific symptoms are excluded . A thorough history, routine laboratory studies, ultrasound of the gallbladder and pancreas, and upper endoscopy will exclude the majority of diseases that may cause dyspepsia symptoms . Disorders of gastric neuromuscular function may be detected by solid-phase gastric emptying studies which detect gastroparesis and by electrogastrography which detects abnormalities of gastric myoelectrical activity termed gastric dysrhythmias . Invasive tests to determine abnormalities in gastric motility include intraluminal pressure and gastric tone/compliance recordings . Treatment approaches are limited at the present time and include dietary counseling and gastroprokinetic agents such as metoclopromide, cisapride, and erythromycin . Increased understanding of the pathophysiology of disorders of gastric neuromuscular function will lead to an improved and more rational armamentarium for the treatment of symptoms related to functional disorders of the stomach.

J Pharm Sci, 1996 Oct, 85(10), 1082 - 4
Topical delivery of erythromycin from various formulations: an in vivo hairless mouse study; Jayaraman SC et al.; Topical products containing erythromycin, a macrolide antibiotic with poor aqueous solubility, are usually formulated as high alcohol content solutions or gels . In this study, we evaluated the deposition of erythromycin base into various strata of hairless mouse skin following topical in vivo application from various low- and nonalcoholic formulations . The formulations tested included nonionic liposomal formulation composed of glyceryl dilaurate, cholesterol, and polyoxyethylene-10-stearyl either at a weight ratio of 57:15:28, two nonionic oil-in-water (o/w) liposomal emulsions containing isopropyl myristate or light mineral oil as the oil phase, a conventional o/w emulsion, a 40% hydroalcoholic solution, and two commercially available topical products . Eight hours after topical administration of these formulations, the efficiency of uptake of erythromycin into the living skin strata was in the order: liposomal isopropyl myristate emulsion > > liposomal mineral oil emulsion > > nonionic liposomes approximately Emgel approximately Theramycin-Z > > conventional emulsion > > hydroalcoholic solution . Alcohol-free liposomal systems are shown to be as efficient as high alcohol content products in facilitating permeation of erythromycin through the stratum corneum into living skin tissue.

Microbiology, 1996 Oct, 142 ( Pt 10), 2815 - 24
An amplifiable and deletable locus of Streptomyces ambofaciens RP181110 contains a very large gene homologous to polyketide synthase genes; Aigle B et al.; Streptomyces ambofaciens RP181110 produces the macrolide polyketide spiramycin . Like many other Streptomyces species, the RP181110 strain is prone to genetic instability involving genomic rearrangements (deletions and/or amplifications) in the large unstable region of the genome . It has previously been demonstrated that the amplification of a particular locus (AUD205) affects spiramycin biosynthesis and, conversely, the loss of this amplification is correlated with the restoration of antibiotic production . This report focuses on a 0.93 kb reiterated fragment specific for the AUD205 locus . Sequencing of 3596 bp including this reiteration revealed the presence of an ORF (orfPS) whose potential product was highly homologous to the EryA and Raps proteins, responsible for the biosynthesis of erythromycin in Saccharopolyspora erythraea and rapamycin in Streptomyces hygroscopicus, respectively . orfPS encodes a protein with at least four successive domains: ketoacyl synthase, acyltransferase, ketoreductase and acyl carrier protein . This organization is very similar to most eryA and rap modules . The reiterated sequence corresponds to the acyltransferase domain . orfPS was transcribed during rapid growth and stationary phase in RP181110 and overtranscribed in the amplified mutant . Both these results suggest that the gene encodes a type I polyketide synthase and its reorganization is responsible for the loss of spiramycin production in the amplified strains.

J Clin Microbiol, 1996 Oct, 34(10), 2379 - 81
Effect of hydrocortisone succinate on growth of Chlamydia pneumoniae in vitro; Tsumura N et al.; We examined the effect of hydrocortisone succinate on the growth of three isolates of Chlamydia pneumoniae in vitro . There was a significant increase in the number of inclusions seen in two of the C . pneumoniae strains in the presence of hydrocortisone . There was no significant increase in the number of inclusions with various concentrations of hydrocortisone over time . The addition of hydrocortisone did not affect the in vitro activities of azithromycin, erythromycin, and doxycycline against C . pneumoniae.

Am J Gastroenterol, 1996 Oct, 91(10), 2220 - 3
Bacillary angiomatosis associated with extensive esophageal polyposis: a new mucocutaneous manifestation of acquired immunodeficiency disease (AIDS); Chang AD et al.; Bacillary angiomatosis is a rare infection that has been associated with human immunodeficiency virus infection . The causative organism is Rochalimaea henselae and contact with cats is a risk factor . We present a case of a 37-yr-old man who had recent prolonged exposure to a cat and presented with fever, iron deficiency anemia, and guaiac-positive stools who had biopsy-proven bacillary angiomatosis skin lesions and on esophagogastroduodenoscopy had multiple, diffuse, friable, polypoid lesions in the esophagus . The histology of the esophageal polyps was identical to the skin lesions, and the polyps disappeared after treatment with erythromycin . Bacillary angiomatosis should be included in the differential diagnosis of infectious upper gastrointestinal manifestations associated with AIDS.

Am J Health Syst Pharm, 1996 Sep 15, 53(18), 2185 - 8
Compatibility of cefmetazole sodium with commonly used drugs during Y-site delivery; Hutchings SR et al.; The compatibility of cefmetazole sodium and selected other drugs during Y-site delivery was evaluated . Cefmetazole 100 mg/mL (as the sodium salt) in sterile water for injection and each of 34 drugs or solutions commonly used with it were mixed together by Y-site injection . Secondary drugs were administered at selected concentrations and rates and delivered by the method (i.v . push, i.v . infusion, or syringe pump) commonly used for the drug at the institution where the study was done . Each injection set included a filter system with a 0.8-micron filter disk . Tests were done in triplicate . After each test, the Y injection site and the tubing after it were visually inspected for precipitate and color change . If no particles or color change was detected, the filter disk was observed under a microscope . Drugs were deemed compatible with cefmetazole if unaided observation detected no color change or particles and the number of particles detected by microscopic examination was below that specified in USP guidelines . A precipitate formed when cefmetazole sodium mixed with diphenhydramine hydrochloride, droperidol, erythromycin (50 mg/mL, as the lactobionate), haloperidol lactate, prochlorperazine edisylate, promethazine hydrochloride, or vancomycin (50 mg/mL, as the hydrochloride salt) . No particles or color change was detected by unaided observation of mixtures containing dobutamine or erythromycin 10 mg/mL, but the number of particles detected by microscopic examination exceeded USP limits . All other drugs tested were compatible with cefmetazole . Cefmetazole 100 mg/mL (as the sodium salt) in sterile water for injection was shown to be compatible with 25 of 34 tested drug solutions during Y-site delivery.

Biochem Pharmacol, 1996 Sep 13, 52(5), 753 - 61
Identification of CYP3A4 as the principal enzyme catalyzing mifepristone (RU 486) oxidation in human liver microsomes; Jang GR et al.; Various complementary approaches were used to elucidate the major cytochrome P450 (CYP) enzyme responsible for mifepristone (RU 486) demethylation and hydroxylation in human liver microsomes: chemical and immunoinhibition of specific CYPs; correlation analyses between initial rates of mifepristone metabolism and relative immunodetectable CYP levels and rates of CYP marker substrate metabolism; and evaluation of metabolism by cDNA-expressed CYP3A4 . Human liver microsomes catalyzed the demethylation of mifepristone with mean (+/-SD) apparent K(m) and Vmax values of 10.6 +/- 3.8 microM and 4920 +/- 1340 pmol/min/mg protein, respectively; the corresponding values for hydroxylation of the compound were 9.9 +/- 3.5 microM and 610 +/- 260 pmol/min/mg protein . Progesterone and midazolam (CYP3A4 substrates) inhibited metabolite formation by up to 77% . The CYP3A inhibitors gestodene, triacetyloleandomycin, and 17 alpha-ethynylestradiol inhibited mifepristone demethylation and hydroxylation by 70-80%; antibodies to CYP3A4 inhibited these reactions by approximately 82 and 65%, respectively . In a bank of human liver microsomes from 14 donors, rates of mifepristone metabolism correlated significantly with relative immunodetectable CYP3A levels, rates of midazolam 1'-and 4-hydroxylation and rates of erythromycin N-demethylation, marker CYP3A catalytic activities (all r2 > or = 0.85 and P < 0.001) . No significant correlations were observed for analyses with relative immunoreactive levels or marker catalytic activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 . Recombinant CYP3A4 catalyzed mifepristone demethylation and hydroxylation with apparent K(m) values 7.4 and 4.1 microM, respectively . Collectively, these data clearly support CYP3A4 as the enzyme primarily responsible for mifepristone demethylation and hydroxylation in human liver microsomes.

Comp Biochem Physiol C Pharmacol Toxicol Endocrinol, 1996 Sep, 115(1), 55 - 60
Effects of experimental dicrocoeliosis on oxidative drug metabolism in hamster liver; Sanchez-Campos S et al.; The purpose of this investigation was to determine the effects of experimental dicrocoeliosis on the hepatic oxidative drug-metabolizing system in hamsters . Studies were carried out 80 and 120 days after infestation with an oral dose of 40 metacercariae of Dicrocoelium dendriticum . The parasitic pathology was ascertained by detection of the fluke eggs in faeces, increased serum alanine aminotransferase and aspartate aminotransferase activities, and postmortem and histological findings . Cytochrome P-450 concentration, aniline hydroxylase activity and ethoxycoumarin O-deethylase activity were significantly decreased in both groups of infected animals . Aminopyrine N-demethylase activity and erythromycin N-demethylase activity were only reduced 120 days after infection . Effects on drug metabolizing enzymes were unrelated to changes in the physical state of the microsomal membrane, as assessed by measurement of fluorescence polarization . The results of this study indicate that the capacity of the liver for handling drugs and xenobiotics may be impaired as a consequence of dicrocoeliosis.

Xenobiotica, 1996 Sep, 26(9), 909 - 19
beta-Apo-8'-carotenal, but not beta-carotene, is a strong inducer of liver cytochromes P4501A1 and 1A2 in rat; Gradelet S et al.; 1 . The catalytic activities of several phase I and II xenobiotic-metabolizing enzymes and their immunochemical detection have been investigated in liver microsomes and cytosol of the male rat, which had been fed for 15 days with diets containing 300 mg/kg beta-carotene isomers (all-trans beta-carotene or beta-carotene from Dunaliella salina rich in 9-cis isomer or isomerized beta-carotene), or apocarotenoids as beta-apo-8'-carotenal, ethyl beta-apo-8'-carotenoate and citranaxanthin . 2 . Beta-carotene, either all-trans or containing cis isomers, did not induce any significant change in the measured activities . By contrast, beta-apo-8'-carotenal increased the liver content of cytochrome P450, the activity of NADH- and NADPH-cytochrome c reductase, and strongly increased some cytochrome P450-dependent activities, particularly ethoxyresorufin O-deethylase (x158), methoxyresorufin O-demethylase (x22), pentoxy- and benzoxyresorufin O-dealkylases, but did not affect erythromycin N-demethylase nor nitrosodimethylamine N-demethylase activities . Phase II p-nitrophenol- and 4-hydroxy- biphenyl-uridine diphosphoglucuronosyl transferase activities were also increased by beta-apo-8'carotenal . Western blots of microsomal proteins clearly showed the induction of CYP1A1 and 1A2 by beta-apo-8'-carotenal . This induction profile resembles that produced by two other carotenoids: canthaxanthin and astaxanthin . Ethyl beta-apo-8'-carotenoate and citranaxanthin showed similar effects to beta-apo-8'-carotenal but of less intensity . 3 . Three carotenoids: beta-apo-8'-carotenal, canthaxanthin and astaxanthin, are inducers of CYP1A1 and 1A2 in the rat . These carotenoids form a new class of inducers of CYP1A, structurally very different from the classical inducers as 3-methylcholanthrene, beta-naphtoflavone or dioxin.

Drug Metab Dispos, 1996 Sep, 24(9), 932 - 9
Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes . Role of CYP3A4; Feierman DE et al.; The microsomal metabolism of fentanyl, a synthetic opioid commonly used in anesthesia, was investigated in human liver . Incubation of fentanyl with human hepatic microsomes fortified with NADPH resulted in the formation of a single major metabolite, namely norfentanyl, as determined by GC/MS . No evidence was obtained for the formation of either desproprionylfentanyl or N-phenylpropionamide, the latter arising via N-dealkylation of the fentanyl amide nitrogen . Kinetic analysis of microsomal fentanyl oxidation revealed a single K(m) of 117 microM and a Vmax of 3.86 nmol of norfentanyl formed/min/nmol of cytochrome P450 (P450) . Studies using chemical inhibitors of human P450 enzymes revealed that only agents known to inhibit CYP3A4 (e.g . ketoconazole and erythromycin) were capable of strongly inhibiting (> or = 90%) microsomal fentanyl oxidation . Marked inhibition (> 90%) of norfentanyl formation by liver microsomes was also observed with polyclonal antibodies to CYP3A4, whereas antibodies to other human P450s were without effect . Furthermore, rates of norfentanyl production by 10 individual human liver samples were highly correlated (r2 = 0.876, F = 56.46 p < 0.001) with immunochemically determined levels of CYP3A4 present in the samples but not with levels of CYP2C8, CYP2C9, CYP2C19, or CYP2E1 . Our results indicate that CYP3A4 is the major catalyst involved in fentanyl oxidation to norfentanyl in human liver . Alterations in CYP3A4 levels or activity, as well as the concomitant administration of other therapeutic agents metabolized by this P450 enzyme, could lead to marked perturbations in fentanyl disposition and, hence, analgesic response.

J Ky Med Assoc, 1996 Sep, 94(9), 393 - 4
Hot tub legionellosis; Tolentino A et al.; Legionella pneumophila is the cause of Legionnaires' disease, and Pontiac fever, an influenza-like condition without pneumonia . We present a case of Pontiac fever after exposure to a hot tub contaminated with L pneumophila . A 37 y/o wf presented to the office with acute onset of sore throat, fever, headache, and myalgia . Patient was hospitalized 3 days later because of worsening shortness of air . Chest x-ray was normal . Patient was treated with 2 days of IV erythromycin and was discharged home on oral erythromycin . Her Legionella IFA was 1:16,384 . Two days later, she developed chest tightness, pleuritic chest pain, and increasing shortness of air but did not have any cough or sputum production . She was re-hospitalized with a diagnosis of Pontiac fever and treated with IV erythromycin plus oral rifampin . A repeat chest x-ray remained normal . After a detailed epidemiologic history was obtained, it was noted that she became ill after using a hot tub, which her two children also used and they themselves developed a self limited illness . Water from the hot tub was positive for L pneumophila by DFA, culture, and PCR . Patient improved gradually with therapy and was discharged home . This report emphasizes the importance of a complete epidemiologic history in the diagnosis of respiratory infections . It also demonstrates that aquatic environment can be contaminated with Legionella and serve as a source of infection.

Gastroenterology, 1996 Sep, 111(3), 682 - 90
Erythromycin inhibits rabbit pyloric smooth muscle through neuronal motilin receptors; Parkman HP et al.; BACKGROUND & AIMS: Erythromycin's effect in accelerating gastric emptying is attributed primarily to increased antral contractility . The aim of this study was to characterize erythromycin's effect on pyloric muscle . METHODS: Rabbit pyloric muscle strips were studied in vitro . RESULTS: Pyloric muscle strips developed spontaneous phasic contractions with a frequency of 1.9 +/- 0.1 contractions per minute . Erythromycin and motilin had dose-dependent inhibitory effects on pyloric muscle . At the maximal effective dose (50 mumol/L), erythromycin caused cessation of spontaneous contractions for 1.8 +/- 0.2 minutes, decreasing the initial 2-minute motility index to 35% +/- 9% (P < 0.01) of basal . In the presence of tetrodotoxin, both erythromycin and motilin increased pyloric contractility . Motilin tachyphylaxis both in the presence or absence of tetrodotoxin abolished the effects of erythromycin . The inhibitory effect of erythromycin was decreased by NG-nitro-L-arginine methyl ester and the vasoactive intestinal peptide antagonist {4-Chloro-D-Phe6, Leu17}vasoactive intestinal peptide . CONCLUSIONS: These studies suggest that motilin receptors are present on both pyloric muscle and inhibitory neurons to pyloric muscle, that the primary effect of erythromycin on the pylorus is mediated by activating motilin receptors on inhibitory motor neurons, and that both nitric oxide and vasoactive intestinal peptide may mediate the inhibitory effect of erythromycin.

N Z Med J, 1996 Aug 23, 109(1028), 315 - 9
Drug associated hepatic reactions in New Zealand: 21 years experience; Pillans PI; AIMS: To review spontaneous reports of drug-associated adverse hepatic reactions . METHODS: Reports of drug-associated adverse hepatic reactions received by the New Zealand Centre for Adverse Reactions Monitoring over the 21 year period January 1974 to December 1994 were reviewed . Subdivision into three 7 year periods was undertaken to compare patterns . RESULTS: Of a total of 22,455 adverse medicine reaction (AMR) reports there were 943 reports of liver injury (4.2%) . Two hundred and five drugs were associated with hepatic reactions . The top 20 drugs accounted for 57% of all liver reactions . Fifty-seven percent were reported in females . Hepatotoxicity was most commonly reported among patients 50-80 years old . Liver reactions were associated with a 3.3% mortality, but were responsible for 7.4% of all fatal occurrences . There was a steady increase in the number of reports over the 21 years . Although the largest number of reports of liver injury were received between 1988 and 1994, mortality was lowest during this period . There were substantial differences in the medicines associated with hepatic reactions during each of the three periods, although erythromycin was the commonest cause throughout . Erythromycin was associated with two deaths . Halothane and perhexilene were the most frequent cause of death and were two of the most important causes of liver injury during the first and second periods . Diclofenac, Augmentin and flucloxacillin were important causes of hepatotoxicity during period 3 but were not associated with a fatal outcome . CONCLUSION: Hepatic reactions accounted for 4.2% of all adverse medicine reactions and 7.4% of all fatal occurrences . The top 20 drugs were responsible for 57% of all liver reactions . Despite a steady increase in the number of reports during the 21 years, mortality was lowest during the last 7 years . Differences in the medicines causing liver injury during the three periods influenced the number of fatalities . Erythromycin was the most commonly reported cause of hepatic reactions but was usually associated with a favourable outcome . There were no reported deaths with diclofenac, Augmentin or flucloxacillin.

Proc Natl Acad Sci U S A, 1996 Aug 6, 93(16), 8284 - 7
Reactivation of denatured proteins by 23S ribosomal RNA: role of domain V; Chattopadhyay S et al.; Escherichia coli ribosome, its 50S subunit, or simply the 23S rRNA can reactivate denatured proteins in vitro . Here we show that protein synthesis inhibitors chloramphenicol and erythromycin, which bind to domain V of 23S rRNA of E . coli, can inhibit reactivation of denatured pig muscle lactate dehydrogenase and fungal glucose-6-phosphate dehydrogenase by 23S rRNA completely . Oligodeoxynucleotides complementary to two regions within domain V (which cover sites of chloramphenicol resistant mutations and the putative A site of the incoming aminoacyl tRNA), but not to a region outside of domain V, also can inhibit the activity . Domain V of 23S rRNA, therefore, appears to play a crucial role in reactivation of denatured proteins.

J Pharm Biomed Anal, 1996 Aug, 14(11), 1625 - 9
Selective spectrophotometric method for the determination of erythromycin and its esters in pharmaceutical formulations using gentiana violet; Amin AS et al.; A simple and selective method for the determination of erythromycin and its stearate and succinate esters in their pure forms and in pharmaceutical formulations is described . The procedure is based on the formation of a blue-coloured (lambda max = 633 nm) complex with gentiana violet in alkaline medium . Different variables affecting the colour development were studied and optimized . The method was used to determine 2.5-25 micrograms ml-1 of erythromycin in the final measured solution . The simplicity of the method permits rapid analysis and it is thus suitable for routine control . The method is highly specific for the determination of stearate and succinate esters in pharmaceutical formulations . The reliability of the method was established by parallel determinations against the official British Pharmacopoeial method.

Cutis, 1996 Aug, 58(2), 123 - 31
Mucha-Habermann disease and its febrile ulceronecrotic variant; Tsuji T et al.; In 1916 Mucha and in 1925 Habermann reported an acute form of pityriasis lichenoides characterized by the abrupt onset of papulovesicular eruptions and gave the name, pityriasis lichenoides et varioliformis acuta (PLEVA) or Mucha-Habermann disease (MH) . In 1966, Degos reported a rare febrile ulceronecrotic variant of MH . MH occurs mainly in young adults, while febrile ulceronecrotic Mucha-Habermann's disease (FUMHD) occurs more frequently in children . The etiology of MH remains obscure, but it may be the result of a hypersensitivity reaction to an infectious agent . Although clinical and histologic features of the disease in children are similar to those of adults, more diseases need to be differentiated in pediatric patients . In addition, a number of effective therapeutic options in adults with MH are unsuitable for use in pediatric patients, to whom beginning with oral antibiotics, usually erythromycin, is recommended . A summary of previously reported fifteen cases with FUMHD, including our case, is listed.

Ther Drug Monit, 1996 Aug, 18(4), 368 - 71
Erythromycin breath test and clinical transplantation; Watkins PB; The intravenous 14C-erythromycin breath test (ERMBT) appears to be a convenient and reproducible means of measuring the activity of a major drug-metabolizing enzyme present in the liver, termed CYP3A4 . Interpatient differences in liver CYP3A4 activity, as measured by the ERMBT, seem to account, for the most part, for interindividual differences in the kinetics of cyclosporin A and FK506 . The predictability of the test may be improved as an oral form of the test and improved oral formulations of transplant medications are developed . Although the ERMBT is a promising research tool, its role in clinical transplantation has yet to be defined.

Antimicrob Agents Chemother, 1996 Aug, 40(8), 1796 - 800
Effects of two oral erythromycin ethylsuccinate formulations on the motility of the small intestine in human beings; Caron F et al.; Fourteen-membered macrolides are known to produce alterations in digestive tract motor activity; these include the induction of strong gastric contractions and a decrease in the motility of the small intestine . The aim of the study was to compare the effects of two different formulations of erythromycin ethylsuccinate (EE) on duodenojejunal motility . Compared with the more commonly used crystalline formulation of EE (CEE), the amorphous formulation (AEE) has previously been described to have greater bioavailability and to induce significantly fewer gastrointestinal side effects when given at therapeutic and what have been considered to be equivalent oral doses (i.e., CEE, 1,000 mg every 12 h; AEE, 500 mg every 12 h) . In a crossover double-blind study, duodenojejunal manometric recordings were performed for 10 volunteers treated with placebo, CEE at 1,000 mg, or AEE at 500 mg . Recordings for each volunteer were obtained for a fed period after a standard dinner and then for a nocturnal fasting period . When compared with the placebo, CEE significantly decreased the motility index of the duodenum during the 30 min after the peak serum erythromycin concentrations, shortened the duration of the fed state, and had no effect during the fasting state . In contrast, AEE did not significantly modify any motility parameter . Because AEE produced significantly lower concentrations in serum than CEE, these results do not necessarily imply that the two formulations of EE act differently on the motility of the small intestine.

Nippon Jibiinkoka Gakkai Kaiho, 1996 Aug, 99(8), 1126 - 35
{Evaluation of the effect of erythromycin on otitis media with effusion in experimental rat models}; Enomoto F et al.; The clinical efficacy of erythromycin (EM) therapy has been demonstrated in otitis media with effusion (OME) . However, the mechanism of action of this drug is not clear . In this study, to elucidate the possible mechanism of action of EM, we examined the effect of the drug on the expression of neutrophil adhesion molecules such as L-selectin and Mac-1 . Furthermore, we examined production of leukotrienes B4, C4 (LTB4, C4) and prostaglandin E2 (PGE2) in rat OME induced by injection of a lipopolysaccharide . EM down-regulated L-selectin expression, and inhibited up regulation of Mac-1 expression on peripheral blood neutrophils . Also it inhibited the accumulation of inflammatory cells such as neutrophils and macrophages in middle ear effusion (MEE) . Furthermore, EM suppressed the exudation of plasma protein and the production of LTB4, C4 and PGE2, in OME . These results suggest that EM may exert the antiinflammatory effect on MEE through suppression of leukocyte accumulation the middle ear by affecting the expression of adhesion molecules on leukocytes and inhibiting the production of arachidonic acid metabolitis.

J Antibiot (Tokyo), 1996 Aug, 49(8), 794 - 801
Bioactive metabolites of EM574 and EM523, erythromycin derivatives having strong gastrointestinal motor stimulating activity; Funabashi Y et al.; Two motilides, EM574 (N-demethyl-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal) and EM523 (N-demethyl-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal) have strong gastrointestinal motor stimulating (GMS) activity . When administered orally to dogs, these agents showed strong GMS activity, but their plasma levels were very low and the metabolites which have been determined so far using the radio-labeled compounds show only weak GMS activity . The findings suggested that unknown bioactive metabolites might be responsible for the GMS activity . From the liver of dogs given EM574 intravenously, two bioactive metabolites, EM574 P1 and P2, were isolated by solvent extraction and chromatography as detected by contractile activity . They both showed the same UV spectra as EM574 and the molecular ion peaks at m/z 760 (MH+) and 602 (MH(+)-cladinose) in the FAB-MS . From 2D-NMR experiments, the structures of EM574 P1 and P2 were unveiled to be the 15- and 14-hydroxyl derivatives of EM574, respectively . EM523 P1 and P2 were also isolated in the same procedure . In order to prepare these bioactive metabolites, EM574 and EM523 were converted enzymatically with dog liver homogenates in the presence of co-enzymes to give the corresponding P1 and P2 . The structures of the metabolites are shown in Fig 1 . They exhibited stronger contractile activity in vitro and GMS activity in vivo than the parent compounds.

J Pharmacol Exp Ther, 1996 Aug, 278(2), 957 - 63
Escherichia coli expression and substrate specificities of canine cytochrome P450 3A12 and rabbit cytochrome P450 3A6; Born SL et al.; High level Escherichia coli expression of cytochromes P450 3A12 and 3A6 has facilitated the characterization of proteins which exhibit limited activity as purified hepatic enzymes in reconstituted systems . Three 3A12 and two 3A6 constructs modified at the 5'-end to encode the bovine 17 alpha-sequence (Barnes et al., Proc . Natl . Acad . Sci . U.S.A . 88: 5597-5601, 1991), or related sequences, exhibited expression levels ranging from 2 to 89 nmol of cytochrome P450 liter-1 . Recombinant canine 3A12 catalyzed steroid 6 beta-hydroxylation and erythromycin demethylation at rates comparable to those obtained in phenobarbital-induced canine liver microsomes . In contrast, 3A12 troleandomycin demethylase activity (2.5 nmol/min/nmol) was significantly lower than that of canine phenobarbital-induced liver microsomes (6.6 nmol/min/nmol) . This difference in activity suggests that at least two 3A forms, which may differ functionally, are present within the canine liver . Purification of recombinant rabbit 3A6 revealed that homogeneous and E . coli-solubilized membrane preparations of 3A6 exhibit similar metabolic rates and identical substrate specificities; 3A activity was modulated by 25 microM alpha-naphthoflavone, which stimulated an unidentified progesterone metabolite 9-fold in 3A6 reconstituted systems in contrast to the 4-fold stimulation of 3A12 . Furthermore, 25 microM alpha-naphthoflavone inhibited erythromycin demethylation 64 and 33% by purified recombinant 3A6- or 3A6-solubilized membrane fractions, respectively; 3A12-mediated erythromycin demethylation in solubilized membrane fractions was resistant to flavonoid inhibition . These results indicate that, although 3A substrate specificities are highly conserved between species, functional differences exist between canine 3A12 and rabbit 3A6, which may be utilized to better understand 3A structure-function relationships.

J Child Adolesc Psychopharmacol, 1996 Summer, 6(2), 133 - 8
Erythromycin interaction with risperidone or clomipramine in an adolescent; Fisman S et al.; An adverse event is described which appeared when the macrolide antibiotic erythromycin was added to a regimen of risperidone 0.5 mg bid and clomipramine 50 mg tid in a 15-year-old male being treated for Tourette's, obsessive-compulsive, and attention-deficit hyperactivity disorders . An acute onset of behavioral symptoms, including agitation, labile mood, incessant talking, and argumentativeness, began within 24 h of starting the erythromycin and persisted for 9 days after its discontinuation . It was followed by a return to stable functioning on the prior risperidone-clomipramine regimen . Erythromycin, risperidone, and clomipramine are all metabolized by the hepatic cytochrome P450 system . It is postulated that the addition of erythromycin, a known inhibitor of CYP3A and CYP1A2, resulted in alterations in the metabolism of clomipramine and risperidone . Clomipramine metabolism is dependent upon the isoenzymes CYP2D6 and CYP1A2, and risperidone is a substrate for CYP2D6 . Erythromycin would inhibit demethylation of clomipramine at the 1A2 isoenzyme and lead to a dual interaction between risperidone and clomipramine at the CYP2D6 isoenzyme . The subsequent increases in plasma levels of clomipramine, risperidone, their metabolites, or a combination of these agents could explain the adverse effects noted in this patient . In the absence of risperidone, clomipramine could have been metabolically cleared by CYP2D6 . In the absence of clomipramine, risperidone clearance would not be affected by erythromycin . So the proposed mechanism requires an interaction involving all three agents: erythromycin, clomipramine, and risperidone . Alterations in plasma protein binding may also have played a role, because all three agents are extensively protein bound . Caution is urged when prescribing erythromycin with psychotropic drugs that are highly protein bound and/or are metabolized by the same P450 isoenzymes.

J Steroid Biochem Mol Biol, 1996 Jul, 58(4), 447 - 54
Effects of food deprivation and adrenalectomy on CYP3A induction by RU486 in female rats; Cheesman MJ et al.; We have studied the effects of food deprivation and adrenalectomy on the induction by RU486 of female rat liver microsomal CYP3A apoprotein, erythromycin N-demethylase and diazepam C3-hydroxylase activities . RU486 was a potent inducer of CYP3A apoprotein in intact animals and food deprivation enhanced this response . Food deprivation alone caused only weak CYP3A apoprotein induction suggesting a synergistic interaction in the regulation of protein expression . These results were reflected in the measurements of diazepam C3-hydroxylase activity . This confirms diazepam C3-hydroxylase as a useful and easily measured index of CYP3A monooxygenase content in female rat liver microsomes . Erythromycin N-demethylase did not show concordance with this pattern; this monooxygenase was much more strongly induced by food deprivation alone than by RU486 administration and, in addition, adrenalectomy abolished the induction response to food deprivation . The lack of correspondence between the apoprotein and erythromycin N-demethylase results suggests that non-CYP3A or novel, hitherto uncharacterized CYP3A isoforms may contribute to erythromycin N-demethylation in female rats . The close agreement between the results for CYP3A apoprotein and diazepam C3-hydroxylase indicates that although RU486 possesses a terminal acetylenic moeity it does not, at the dosages used here, cause mechanism-based inactivation of the CYP3A monooxygenase protein it induces . Current studies are directed to characterizing the particular CYP3A isoform(s) whose production is stimulated by RU486.

J Antimicrob Chemother, 1996 Jul, 38(1), 81 - 93
Comparison of various macrolides on stimulation of human neutrophil degranulation in vitro; Abdelghaffar H et al.; Macrolide antibiotics are taken up and concentrated by host cells, particularly phagocytes, and are likely candidates to modify cell functions . In this study, we extended our previous work concerning the effect of three 14-membered-ring macrolides (dirithromycin, erythromycin and erythromycylamine) on human neutrophil exocytosis, and found that three other erythromycin A derivatives (roxithromycin, clarithromycin and the azalide, azithromycin) also triggered neutrophil degranulation in a time- and concentration-dependent manner . After 30 min of incubation, the correlation coefficients for concentration-dependence for roxithromycin were 0.885, 0.739 and 0.750 (P < 0.005) and for clarithromycin were 0.795, 0.599, 0.733 (P < 0.02), respectively, for lysozyme, beta-glucuronidase and lactoferrin release . Although the underlying mechanism was not elucidated, these and previous data suggest that intracellular accumulation is a prerequisite . Furthermore, comparison of the characteristics of macrolide-induced exocytosis with those of exocytosis triggered by the synthetic chemotactic stimulus FMLP suggested that different mechanisms are involved . In keeping with this possibility, we showed that combined treatment (macrolides plus FMLP) resulted in totally additive exocytosis of azurophilic but not specific granules . The clinical relevance of our data remains to be ascertained.

Environ Health Perspect, 1996 Jul, 104(7), 774 - 8
Alterations of cytochrome P450-dependent monooxygenase activities in Eriocheir japonicus in response to water pollution; Ishizuka M et al.; Eriocheir japonicus, fresh-water crabs inhabiting rivers and estuaries in Japan, were investigated for cytochrome P450 (CYP)-dependent drug-metabolizing enzyme activities to see if these activities reflect the river pollution gradient . From the laboratory dose-response experiments, we found that the polycyclic aromatic hydrocarbon (PAH) 3-methylcholanthrene induced total CYP contents, ethoxycoumarin O-deethylase activity, and bunitrolol 4-hydroxylase activity in crab hepatopancreas . In the field studies, crabs collected from the river with the highest concentration of PAHs exhibited the highest levels of CYP, the highest activities of benzo{a}pyrene 3-hydroxylase, imipramine 2-hydroxylase, bunitrolol 4-hydroxylase, ethoxycoumarin O-deethylase, and the ability to metabolically activate benzo{a}pyrene, but erythromycin N-demethylase activity was not induced . The correlation between PAH levels and drug-metabolizing enzyme activities in female crabs were not as marked as in male crabs . The levels and activities of CYP did not appear to reflect the concentrations of organochlorines and polychlorinated biphenyl congeners (PCBs) studied in the fat of crab hepatopancreas.

Pharmacotherapy, 1996 Jul-Aug, 16(4), 663 - 74
QTc-interval prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature; Tschida SJ et al.; Intravenous erythromycin has recently been associated with significant QTc interval prolongation, torsades de pointes, and sudden cardiac death . The prolonged the QTc interval attributed to erythromycin typically is associated with rapid infusion rates in excess of 10 mg/minute . We prospectively assessed the relationship between QTc interval prolongation and erythromycin administration by slow intravenous infusion (mean rate 8.9 +/- 3.5 mg/minute, range 3.9-16.7 mg/minute) . Electrocardiographic (ECG) rhythm strips were prospectively obtained in 44 critically ill patients receiving intravenous antibiotics (22 received erythromycin and 22 ceftazidime, cefuroxime, cefotaxime, ceftriaxone, or ampicillin-sulbactam as controls) . The ECG recordings were obtained immediately before and within 15 minutes after drug infusions . Only the first available set of ECG strips were evaluated . Two controls had evidence of hepatic dysfunction; no patients receiving erythromycin did . The QTc interval was calculated using Bazett's formula by two blinded investigators . For controls, mean +/- 1 SD (range) QTc intervals were 423 +/- 96 (300-550) msec at baseline and 419 +/- 96 (280-610) msec after infusion (p = 0.712) . In contrast, in the erythromycin group, the interval was significantly prolonged from 524 +/- 105 (360-810) msec at baseline to 555 +/- 134 (400-980) msec after infusion (p = 0.034) . No patients experienced a dysrhythmia as a consequence of erythromycin infusion . Despite slow rates of infusion, QTc interval prolongation was significant . The clinical importance of this finding remains to be determined.

Bioorg Med Chem, 1996 Jul, 4(7), 995 - 9
Erythromycin biosynthesis: exploiting the catalytic versatility of the modular polyketide synthase; Luo G et al.; DEBS 1 + TE is a recombinant modular polyketide synthase (PKS) in which the first two biosynthetic modules of the 6-deoxyerythronolide B synthase are linked to the thioesterase domain normally found at the C-terminus of DEBS 3 . Incubation of DEBS 1 + TE with propionyl-CoA, methylamalonyl-CoA, and NADPH gives the triketide lactone (2R,3S,4S,5R)-2,4-dimethyl-3, 5-dihydroxy-n-heptanoic acid delta-lactone (2), the cyclized form of the normal triketide chain elongation product of DEBS 1 . In order to probe the molecular recognition features of the PKS and to explore its synthetic versatility, {2,3-13C2}-(2S,3R)-2-methyl-3-hydroxypentanoyl-NAC thioester (3), an analogue of the normal diketide chain elongation intermediate, and (2RS)-methyl-malonyl-CoA were incubated with DEBS 1 + TE, leading to the formation of the predicted labeled triketide ketolactone {4,5-13C2}-8, as established by 13C NMR analysis and comparison with spectra of synthetic 8 . This stereoselective conversion illustrates the potential of using modular PKSs as multifunctional catalysts for the enzymatic synthesis of novel polyketides.

Acta Otolaryngol, 1996 Jul, 116(4), 572 - 5
Inhibitory effect of erythromycin on ion transport by stria vascularis and vestibular dark cells; Liu J et al.; A previous study showed that systemic administration of erythromycin caused a reversible decline in the endocochlear and cochlear microphonic potentials . Those data were thought to suggest that erythromycin caused hearing loss by interference with ion transport processes in the stria vascularis . The present study was undertaken to test this hypothesis by measuring the effects of erythromycin perfused on either the apical or basolateral side on the transepithelial short circuit current (Isc), a measure of the K+ secretion rate . Isc was measured from preparations of strial marginal cells and the homologous vestibular dark cells in vitro with a micro-Ussing chamber . Erythromycin was found to have no effect when perfused on the apical side but to cause a reversible decrease in Isc when perfused on the basolateral side for both epithelia . These data are consistent with the notion that at least one ototoxic effect of erythromycin is the inhibition of K+ secretion in the inner ear.

Chem Res Toxicol, 1996 Jul-Aug, 9(5), 882 - 90
Microsomal oxidation of N,N-diethylformamide and its effect on P450-dependent monooxygenases in rat liver; Amato G et al.; N,N-Diethylformamide (DEF) is a hepatotoxic polar solvent in which metabolism has not been investigated . In this study we examined the following: (a) the oxidative metabolism of DEF using both liver microsomes from rats pretreated with selected P450 inducers and purified P450 enzyme (2B1, 2E1, 2C11); and (b) the effect of administration of DEF and its metabolite, the monoethylformamide (MEF), on induction and/or inhibition of the P450 isoforms in rats . DEF was deethylated by microsomal P450-dependent oxidation forming acetaldehyde and MEF according to Michaelis-Menten kinetic parameters . Microsomes from rats pretreated with acetone and pyrazole (selective P4502E1 inducers) or rats pretreated with dexamethasone and 200 mg/kg DEF were able to deethylate DEF in a biphasic manner, showing a low Km component with a Vmax of about 0.2 nmol/(min.mg of protein) and a Km between 70 microM and 250 microM . The low Km component was not present in control microsomes or in microsomes from rats treated with phenobarbital, beta-naphthoflavone, or clofibrate, where linear Kinetics were observed . The use of purified P4502E1 and 2C11 in a reconstituted system showed that 2E1, which oxidized DEF with a Vmax of 4.5 nmol/(min.nmol of P450) and a Km of 0.7 mM, can partially account for the low Km DEF deethylase, whereas 2C11, which oxidized DEF with a Vmax of 4.8 nmol/(min.nmol of P450) and a Km of 17 mM, might be the high Km deethylase . The purified 2B1 was barely able to deethylate DEF . A confirmation of the role of 2E1 in DEF metabolism was obtained by using various selective inhibitors of P450 isoforms and immunoprecipitation experiments with anti P4502E1 IgG . The low Km component of DEF deethylation in acetoneor pyrazole-induced microsomes was strongly inhibited (approximately 90%) by diethyldithiocarbamate, 4-methylpyrazole, and anti-2E1 IgG, but in 200 mg/kg DEF-induced microsomes the inhibition was partial, suggesting that other P450(s) may be involved . Administration of DEF 200 mg/kg ip for 4 days induced hepatic microsomal P4502E1-dependent aniline hydroxylase, P4502B1/2-linked pentoxyresorufin O-depentylase, 16 beta-testosterone hydroxylase P4503A1/2-associated erythromycin N-demethylase, and 6 beta-testosterone hydroxylase . Alternatively, the same dose regimen of MEF induced only the aniline hydroxylase and depressed the 3A1/2-linked activities . Immunoblot experiments verified these data . These findings indicate that DEF, at low concentrations, is predominantly oxidized by P4502E1 and that this enzyme may be induced in rodents by repeated MEF or DEF treatment, thereby increasing their own metabolism and potentially their cytotoxicity through the formation of ethyl isocyanate.

Drug Metab Dispos, 1996 Jul, 24(7), 761 - 4
Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity; Caraco Y et al.; Codeine is metabolized by glucuronidation, by O-demethylation to morphine, and by N-demethylation to norcodeine . The enzyme responsible for the O-demethylation to morphine has been identified as cytochrome P4502D6 (CYP2D6) . The purpose of the present study was to identify the specific P450 enzyme responsible for codeine N-demethylation . Microsomal preparations (250 pmol of P450) obtained from 12 human liver donors were incubated with 20 microM codeine and analyzed for norcodeine formation . Codeine N-demethylation activity was linearly correlated with nifedipine oxidation activity (r = 0.90, p < 0.001), a marker of CYP3A4, but not with codeine O-demethylation, a marker of CYP2D6 . Preincubation with troleandomycin (50 microM), or gestodene (50 microM) inhibitors of CYP3A4, decreased the rate of production of norcodeine by 60 and 45% compared to control values, respectively . Similarly, ketoconazole (10 microM) and erythromycin (10 microM) inhibited codeine N-demethylation by 75 and 35%, respectively . In contrast, the presence of quinidine, sulfaphenazole, or diethyldithiocarbamate in the incubation mixture had no effect on norcodeine formation . Preincubation with antibodies raised to CYP3A4 (5 mg lgG/nmol P450) caused 96% inhibition of norcodeine production, whereas preimmune IgG or antibodies raised to CYP2A6 and CYP2C had no effect . Additionally, significant norcodeine production was observed with purified CYP3A4 derived from human liver microsomes . In conclusion, codeine N-demethylation activity cosegregates with CYP3A4 activity . Coadministration of codeine with selective inhibitors of CYP3A4 may result in increased morphine production and enhanced pharmacodynamic effects due to shunting down the CYP2D6 pathway.

Nihon Kyobu Shikkan Gakkai Zasshi, 1996 Jul, 34(7), 785 - 9
{Two cases of recurrent, massive hemoptysis with contralateral, concurrent hemoptysis}; Hamamoto Y et al.; Bilateral, concurrent massive hemoptysis with respiratory failure is rare and difficult to manage . We encountered two patients with this condition . One was a 51-year-old woman and one was a 63-year-old woman . Both had inactive pulmonary tuberculosis and episodes of hemoptysis . Home oxygen therapy was prescribed to the former patient and bronchial artery embolization was done in the latter . The sites of initial bleeding were in the left basal segment and in the lingular segment . Bleeding was well controlled by endobronchial tamponade with a Fogarty balloon catheter in the left main bronchus, contralateral intubation, and systemic artery embolization . Use of water instead of air in the balloon was more effective in over the long term . Concurrent bleeding from the contralateral upper lobe bronchus was controlled by compression with a tracheal tube cuff at the bronchial orifice . Afterward, an infiltrative shadow was seen on the chest X-ray film and hemoptysis occurred in case 2 occurred in case 2 . Treatment with erythromycin and antituberculosis drugs brought about improvement of chest X-ray findings and disappearance of the hemoptysis.

Antimicrob Agents Chemother, 1996 Jul, 40(7), 1726 - 8
Effects of roxithromycin and erythromycin on interleukin 8-induced neutrophil recruitment and goblet cell secretion in guinea pig tracheas; Tamaoki J et al.; Inhaled interleukin 8 caused an increase in goblet cell secretion in guinea pig tracheas, which was accompanied by mucosal infiltration of neutrophils . These responses were inhibited by pretreatment with roxithromycin or erythromycin in a dose-dependent fashion . Macrolides may thus be a value in protecting against neutrophil-associated airway hypersecretion.

Food Chem Toxicol, 1996 Jul, 34(7), 595 - 601
Differential induction of isozymes of drug-metabolizing enzymes by butylated hydroxytoluene in mice and Chinese hamsters; Sun B et al.; Induction of isozymes of drug-metabolizing enzymes by butylated hydroxytoluene (BHT) was studied in the male ddY mouse and Chinese hamster . In mice given 0.05 and 0.15% BHT in the diet for 14 days cytochrome P-450 contents and the activities of uridine diphosphate-glucuronyl transferase (UDP-GT) and pentoxyresorufin O-dealkylase were markedly increased, while in those fed 0.15% BHT testosterone 6 alpha-, 16 alpha- and 16 beta-hydroxylases were greatly increased, which indicated induction of cytochrome P-450 isozymes of the CYP2B family . Western blot analysis also showed an increased level of the isozyme immunorelated to rat CYP2B2 by BHT feeding . The activities of aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase (ECOD), erythromycin N-demethylase and glutathione S-transferase (GST) remained unchanged . In Chinese hamsters given 0.05 and 0.15% BHT in the diet for 14 days activities of ECOD and GST were induced, but cytochrome P-450 contents and the activities of other enzymes were unaffected . Testosterone 15 alpha-hydroxylase was induced in hamsters fed 0.15% BHT . These findings suggested that BHT administration in the hamster induced CYP2A2-type isozyme, which was confirmed by Western blot analysis . BHT treatment enhanced activation of benzo{a} pyrene (B{a}P) as determined by the mutagenicity test, especially in Chinese hamsters . The results suggest that BHT treatment induces specific isozymes of drug-metabolizing enzymes and might modify the expression of toxicities of other chemicals.

Clin Pharmacol Ther, 1996 Jul, 60(1), 54 - 61
Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid; Neuvonen PJ et al.; BACKGROUND: Lovastatin is a cholesterol-lowering drug that can cause myopathy as a rare side effect . Concomitant use of certain drugs (e.g., cyclosporine) increases the risk of skeletal muscle toxicity . Lovastatin is metabolized by CYP3A4 . Because itraconazole is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between these drugs . METHODS: In this double-blind, randomized, two-phase crossover study, 12 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days . On day 4, each subject ingested a single 40 mg dose of lovastatin . Plasma concentrations of lovastatin, lovastatin acid, itraconazole, hydroxyitraconazole, and creatine kinase were measured up to 24 hours . RESULTS: On average, itraconazole increased the peak concentration (Cmax) of lovastatin and the area under the lovastatin concentration-time curve (AUC) more than twentyfold (p < 0.001) . The mean Cmax of the active metabolite, lovastatin acid, was increased 13-fold (range, tenfold to 23-fold; p < 0.001) and the AUC(0-24) twentyfold (p < 0.001) . In one subject plasma creatine kinase was increased tenfold within 24 hours of lovastatin administration during the itraconazole phase but not during the placebo phase . No increase in creatine kinase was observed in the other subjects . CONCLUSIONS: Itraconazole greatly increases plasma concentrations of lovastatin and lovastatin acid . Inhibition of CYP3A4-mediated metabolism probably explains the increased toxicity of lovastatin caused not only by itraconazole but also by cyclosporine, erythromycin, and other inhibitors of CYP3A4 . Their concomitant use with lovastatin and simvastatin should be avoided, or the dose of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.

Clin Pharmacol Ther, 1996 Jul, 60(1), 25 - 33
Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice; Bailey DG et al.; OBJECTIVE: To investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine . METHODS: Felodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men . Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day . Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite were studied . RESULTS: Compared with water, erythromycin produced severalfold higher felodipine area under the plasma drug concentration-time profile (AUC), plasma peak drug concentration (Cmax), and apparent elimination half-life (t1/2); however, the effect was variable among individuals . Erythromycin augmented dehydrofelodipine AUC, Cmax, and t1/2 but decreased dehydrofelodipine/felodipine ratios . The AUC of the M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were reduced . These findings support inhibition of both metabolic pathways likely mediated by CYP3A4 . Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t1/2 . Individually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice . Relative felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative felodipine Cmax but not with relative felodipine t1/2, suggesting felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination . CONCLUSIONS: Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism . Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall.

Nihon Shinkei Seishin Yakurigaku Zasshi, 1996 Jun, 16(3), 109 - 12
{The relationship between single-oral dose kinetics of alprazolam and cytochrome P4503A and cytochrome P4502C19}; Yasui N; To clarify the involvement of cytochrome P4503A (CYP3A) and CYP2C19 in the metabolism of alprazolam, the effects of pretreatment with erythromycin, which is an inhibitor of CYP3A and S-mephenytoin 4-hydroxylation capacity on the single-oral dose kinetics of alprazolam were studied in 12 healthy male volunteers . Six each were extensive metabolizers (EMs) and poor metabolizers (PMs) of S-mephenytoin 4-hydroxylation . Each subject received erythromycin 1,200 mg/day or placebo for 10 days in a double-blind, crossover manner . At 9 AM of day 8 alprazolam 0.8 mg was given orally, and blood samplings were performed up to 48 hours postdosing . Erythromycin treatment compared with placebo treatment increased significantly plasma alprazolam concentrations from 6 to 48 hours postdosing . Erythromycin significantly decreased the apparent oral clearance and prolonged the elimination half-life of alprazolam . No significant difference was found in plasma concentrations and pharmacokinetic parameters of alprazolam between the EM and PM groups . The present study thus suggests that CYP3A, but not CYP2C19, is involved in the metabolism of alprazolam.

J Antimicrob Chemother, 1996 Jun, 37 Suppl C, 133 - 42
Drug interactions with azithromycin and the macrolides: an overview; Nahata M; Evidence interactions between individual macrolides and a number of pharmacologically active compounds that are frequently co-administered to patients with bacterial infections is reviewed . Theophylline is strongly associated with erythromycin interaction; clarithromycin may also interact with this drug . Azithromycin, spiramycin and rokitamycin, however, do not appear to have any effect on theophylline pharmacokinetics . The other therapeutic agents considered are cyclosporin, the antiepileptics, carbamazepine and phenytoin, terfenadine, warfarin, oral contraceptives, agents used in the management of gastritis and peptic ulcer and zidovudine . With the exception of interaction with antacids, there is no evidence that azithromycin, unlike most other macrolides, interacts with any of these agents to produce clinically significant adverse effects . The explanation for this variation appears to be azithromycin's inability to induce and bind to the cytochrome P450 IIIA enzyme system.

Aliment Pharmacol Ther, 1996 Jun, 10(3), 421 - 6
Effect of erythromycin on human biliary motility; Wehrmann T et al.; BACKGROUND: To investigate the effects of intravenous erythromycin on human gall-bladder and sphincter of Oddi motor function . METHODS: Twelve consecutive patients with suspected sphincter of Oddi dysfunction were studied . Gall-bladder function was assessed by ultrasonography, and sphincter of Oddi motility was evaluated by means of endoscopic manometry . RESULTS: All patients were found to have normal gall-bladder function . The percentage of maximal gall-bladder emptying following a standardized, liquid test meal was significantly increased by erythromycin, whereas the postprandial residual gall-bladder volume was significantly decreased after erythromycin (P < 0.01) . Endoscopic manometry revealed the presence of sphincter of Oddi dysfunction in two of the 12 patients . Erythromycin significantly decreased the basal sphincter of Oddi pressure and slowed the sphincter of Oddi phasic contraction frequency in all patients (P < 0.01) . However, the mean duration of the sphincter phasic contractions (P < 0.05) and their amplitude (P = 0.05) were increased by the compound . CONCLUSIONS: Erythromycin stimulates gall-bladder motility but induces varying effects on human sphincter of Oddi motility.

Can J Anaesth, 1996 Jun, 43(6), 617 - 20
Failure of neuromuscular blockade reversal after rocuronium in a patient who received oral neomycin; Hasfurther DL et al.; PURPOSE: Because the aminoglycoside antibiotics and nondepolarizing muscle relaxants have interactions that vary, it is necessary to update the potential for such interactions when new drugs are introduced clinically . Rocuronium is a newly released steroidal nondepolarizing muscle relaxant with an intermediate duration of action . The following report is the first description of prolonged neuromuscular blockage after rocuronium in a patient who had received oral neomycin in anticipation of open bowel resection . CLINICAL FEATURES: A 71-yr-old woman with a two week history of bleeding pr was scheduled for exploratory laparotomy and right hemicolectomy . She received two standard bowel preparations consisting of oral erythromycin and neomycin over a two day period . Rocuronium was used to facilitate tracheal intubation and maintain muscle relaxation during a two hour operation . Despite clinical appearance of reversal of neuromuscular blockade after neostigmine and glycopyrolate, the patient complained of dyspnoea and weakness upon tracheal extubation and required reintubation twice . The reason for prolonged muscle relaxation was thought to be secondary to a rocuronium and neomycin interaction . CONCLUSION: Rocuronium, a new nondepolarizing muscle relaxant, has potential interactions with other drugs including the aminoglycoside antibiotics . This clinical report describes the failure of neuromuscular blockade reversal in a patient who received oral neomycin in anticipation of open bowel resection.

J Clin Microbiol, 1996 Jun, 34(6), 1386 - 90
Rapid susceptibility testing for nontuberculosis mycobacteria using flow cytometry; Bownds SE et al.; We demonstrated previously that susceptibility testing of Mycobacterium tuberculosis could be accomplished within 24 h after the organisms were incubated with antituberculosis agents by using fluorescein diacetate (FDA) staining and flow cytometry . Continued studies have now shown that assay suspensions containing M . avium, M . fortuitum, M . gordonae, or M . marinum incubated with various concentrations of ciprofloxacin, clarithromycin, erythromycin, kanamycin, rifampin, tobramycin hydrolyzed less FDA than drug-free controls . Suspensions of treated and nontreated mycobacteria could be easily differentiated at 6 and 24 h after the initiation of the susceptibility assays by using FDA staining and flow cytometry . In addition, multiplication of the mycobacteria was not required to discern differences between drug-free suspensions of mycobacteria and those treated with antimycobacterial agents . The flow cytometric assay is simple, reproducible, and rapid.

Antimicrob Agents Chemother, 1996 Jun, 40(6), 1548 - 51
Inhibitory effect of erythromycin on interleukin 8 production by 1 alpha,25-dihydroxyvitamin D3-stimulated THP-1 cells; Fujii T et al.; We have recently reported that long-term administration of erythromycin at a low dose reduced the number of neutrophils and concentrations of interleukin 8 (IL-8) in bronchoalveolar lavage fluid in patients with chronic lower respiratory tract disease . To investigate the mechanism of action of erythromycin, we evaluated its effect on IL-8 production in the 1 alpha,25-dihydroxyvitamin D3-stimulated human monocytic cell line THP-1 . Erythromycin at a concentration of 10 micrograms/ml significantly reduced IL-8 production by THP-1 cells stimulated with lipopolysaccharide (10 ng/ml) and 1% normal human serum compared with the amount produced by untreated cells (untreated cells, 2,448 pg/ml; erythromycin-treated cells, 872 pg/ml) . Our results suggest that erythromycin may impair IL-8 production by alveolar macrophages, ultimately reducing neutrophil accumulation in the airspace.

J Fam Pract, 1996 Jun, 42(6), 601 - 5
Effectiveness of erythromycin in the treatment of acute bronchitis; King DE et al.; BACKGROUND . Clinical trials have not shown a consistent benefit of treating bronchitis with antibiotics . Many physicians, however, treat acute bronchitis with antibiotics because of the possibility of Mycoplasma pneumoniae or other pathogens . The objectives of this study were to determine the effectiveness of erythromycin treatment in patients with acute bronchitis and to determine whether a newly developed rapid M pneumoniae antibody test is useful in predicting which patients will respond to therapy . METHODS . We conducted a randomized, double-blind, placebo-controlled clinical trial at three primary care centers in North Carolina . A convenience sample of 140 patients presenting with acute bronchitis were tested for M pneumoniae, 91 of whom were treated with either erythromycin 250 mg four times daily for 10 days or an identical-appearing placebo . RESULTS . Patients treated with erythromycin missed an average of only 0.81 +/- 1.1 days of work compared with 2.16 +/- 3.2 days for placebo-treated patients (P < .02) . There were no significant differences in cough, use of cough medicine, general feeling of well-being, or chest congestion between the erythromycin and placebo groups . Twenty-five percent of the patients tested positive for M pneumoniae . There were no differences in response to erythromycin based on whether the patient had a positive test for M pneumoniae . CONCLUSIONS . Erythromycin is effective in significantly reducing lost time from work, but it is not effective in reducing cough or other symptoms in patients with acute bronchitis, regardless of the outcome of the M pneumoniae antibody test.

J Bacteriol, 1996 Jun, 178(12), 3664 - 7
Gene inactivation in the oral spirochete Treponema denticola: construction of an flgE mutant; Li H et al.; Treponema denticola is implicated in the etiology of periodontal diseases . We now report the construction of a specific flgE mutant of T . denticola ATCC 35405 following electroporation utilizing an erythromycin resistance cassette inserted into an flgE DNA fragment . The resulting mutant displays no visible motility and lacks periplasmic flagella as would be predicted from inactivation of the gene for the flagellar hook protein.

J Mol Biol, 1996 May 31, 259(1), 1 - 6
Mutations in domain II of 23 S rRNA facilitate translation of a 23 S rRNA-encoded pentapeptide conferring erythromycin resistance; Dam M et al.; Mutations in domain II of Escherichia coli 23 S rRNA that cause resistance to erythromycin do so in a manner fundamentally different from mutations at the drug binding site in domain V of the 23 S rRNA . The domain II mutations are located in a hairpin structure between nucleotides 1198 and 1247 . This is close to a short open reading frame in the 23 S rRNA that encodes a pentapeptide (E-peptide) whose expression in vivo renders cells resistant to erythromycin . Therefore, a possible mechanism of resistance caused by domain II mutations may be related to an increased expression of the E-peptide . To test this hypothesis, a range of point mutations was generated in domain II of 23 S rRNA in the vicinity of the E-peptide open reading frame . We find a correlation between erythromycin resistance of the mutant clones and increased accessibility of the ribosome binding site of the E-peptide gene . Furthermore, the erythromycin resistance determinant in the mutants was shown to be confined to a small 23 S rRNA segment containing the coding region and the ribosome binding site of the E-peptide open reading frame . It thus appears that the domain II mutations mediate erythromycin resistance by increasing expression of the 23 S rRNA-encoded E-peptide.

Proc Natl Acad Sci U S A, 1996 May 28, 93(11), 5641 - 6
A functional peptide encoded in the Escherichia coli 23S rRNA; Tenson T et al.; A pentapeptide open reading frame equipped with a canonical ribosome-binding site is present in the Escherichia coli 23S rRNA . Overexpression of 23S rRNA fragments containing the mini-gene renders cells resistant to the ribosome-inhibiting antibiotic erythromycin . Mutations that change either the initiator or stop codons of the peptide mini-gene result in the loss of erythromycin resistance . Nonsense mutations in the mini-gene also abolish erythromycin resistance, which can be restored in the presence of the suppressor tRNA, thus proving that expression of the rRNA-encoded peptide is essential for the resistance phenotype . The ribosome appears to be the likely target of action of the rRNA-encoded pentapeptide, because in vitro translation of the peptide mini-gene decreases the inhibitory action of erythromycin on cell-free protein synthesis . Thus, the new mechanism of drug resistance reveals that in addition to the structural and functional role of rRNA in the ribosome, it may also have a peptide-coding function.

Dtsch Med Wochenschr, 1996 May 10, 121(19), 617 - 21
{Anticytoplasmic antibodies (cANCA) in syphilitic nodules of the lung}; Wockel W et al.; HISTORY AND CLINICAL FINDINGS: A chest radiograph was done in a 75-year-old man with cough productive of a whitish sputum . It showed round foci in the right middle and upper lobes . Serum anticytoplasmic antibody (cANCA) was 1 : 160, suggesting Wegener's granulomatosis . But the pulmonary foci actually increased in size on administration of prednisolone, 10 mg daily . INVESTIGATIONS: As the lung biopsy was not diagnostic, a diagnostic thoracotomy with biopsy was done and the anterior segment of the right middle lobe resected . Histological examination revealed a gumma . Active syphilis was confirmed by a TPHA-Test with a titre of 1 : 40960 . TREATMENT AND COURSE: Antisyphilitic treatment was given for 35 days, at first 1 mega (Penicillin E daily for five days, then erythromycin, 1000 mg, for five days, a penicillin rash having occurred . Serial serology showed a continual fall of the lues and cANCA titres . Four months postoperatively the titre in the TPHA test had fallen to 1 : 640, and was nonreactive after five years . cANCA titre fell to 1 : 16 and was negative 42 weeks after resection . CONCLUSION: The connection between pulmonary gumma and the presence of antiplasmatic antibodies remains unclear . Inflammatory changes in the vascular wall, which occur in both Wegener's granulomatosis and tertiary syphilis, may have played a role.

Jpn J Pharmacol, 1996 May, 71(1), 29 - 38
Vagus-dependent and vagus-independent mechanisms of action of the erythromycin derivative EM574 and motilin in dogs; Inatomi N et al.; The motor-stimulating action of de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (EM574) on the upper gastrointestinal tract was studied in fasted conscious dogs using chronically implanted force transducers and compared with those of porcine motilin and cisapride . EM574 induced gastric phase III-like migrating contractions and increased the plasma motilin levels slightly . The gastric motility induced by low doses of EM574 and motilin was abolished by a 5HT3-receptor antagonist ondansetron and acute vagal blockade, whereas under these conditions, high doses of both agents induced contractions, which were abolished by atropine . Cisapride-induced gastric motility was inhibited by atropine and acute vagal blockade, but not by ondansetron . EM574 did not stimulate gastric secretion in the basal state . These results indicate that EM574- and motilin-induced gastrointestinal motility is attributable mainly to motor-stimulating vagal cholinergic neurons, and 5HT3-receptors are probably involved in the process . At high doses, EM574 and motilin also appear to stimulate cholinergic neurons in a non-vagal pathway, probably the enteric nervous system.

J Pediatr Ophthalmol Strabismus, 1996 May-Jun, 33(3), 185 - 8
The influence of perinatal infective factors on ophthalmia neonatorum; Isenberg SJ et al.; BACKGROUND: Ophthalmia neonatorum still blinds approximately 10,000 babies annually worldwide . Identification of contributory maternal perinatal factors could possibly predict which babies are at greater risk for this disease . METHODS: In a randomized prospective study of ophthalmia neonatorum in Kenya, we studied the effect of prophylaxis with povidone-iodine, silver nitrate, and erythromycin in 3117 neonates . Four perinatal factors that may promote ophthalmia neonatorum were investigated: maternal vaginitis, birth in a nonsterile environment, presence of meconium at birth, and postnatal development of endometritis . RESULTS: No significant difference in the general ophthalmia neonatorum rate was found for any of the four factors (P > .14 by Fisher exact test) . However, with regard to venereal ophthalmia neonatorum, the 26 infants born to mothers with vaginitis had a relative risk 5.1 times that of the rest of the infants (P = 0.0013) . Their relative risk to develop gonococcal ophthalmia neonatorum in particular was 24.9 times the rest of the neonates (P = 0.0000031) . Prophylaxis was with povidone-iodine in 12 infants, silver nitrate in two, and erythromycin in 12 . The frequency of ophthalmia neonatorum was 25%, 100%, and 33%, respectively (differences not significant) . CONCLUSION: Neonates born to mothers with vaginitis should be carefully observed for the first postnatal month for the development of ophthalmia neonatorum, even though a prophylactic agent has been used.

Zhonghua Yi Xue Za Zhi (Taipei), 1996 May, 57(5), 365 - 9
Recurrent infection of Legionella pneumonia: a case report; Ko YY et al.; A 75-year-old male veteran presented with bilateral pneumonia upon admission . He had an episode of Legionnaires' disease in 1991 with complete treatment of erythromycin 500 mg orally every six hours for three weeks . After admission, recurrence of Legionnaires' disease was suspected due to increased serum Legionella antibody (1:128) and strong positive sputum Legionella antigen . Erythromycin and other parental antibiotics were administered, but respiratory failure developed promptly, followed by multiple organ failure syndrome that involved the liver, lung, bone marrow and kidney . He died 42 days after admission . We reviewed seven cases that had been reported and found recurrence of Legionella pneumonia possible after a successful treatment, especially for immunocompromised hosts . Early empirical therapy with erythromycin is recommended.

Biol Pharm Bull, 1996 May, 19(5), 733 - 7
Effect of clarithromycin on the bioavailability of cyclosporin in rats; Ohba M et al.; This study was conducted to determine the effect of clarithromycin (CAM) on the bioavailability of cyclosporin (CYA) in rats, and to compare its effect with that of erythromycin (EM) . The area under the blood CYA concentration-time curve (AUCi.v.) values after intravenous administration of CYA (2 mg/kg) in combination with CAM or EM (100 mg/kg, p.o.) were significantly increased compared with those of CYA alone, suggesting that there was metabolic inhibition of CYA in the liver by CAM or EM . The time to reach the peak concentration after oral administration of CYA (10 mg/kg) tended to be longer with increasing doses of both CAM and EM (10 and 100 mg/kg, p.o.) . Each AUCp.o . value for the CAM or EM coadministration group, except the EM (100 mg/kg) coadministration group (about 77% increase), was comparable to that for the CYA alone group . Both CAM and EM (10 and 100 mg/kg, p.o.) were shown to delay gastric emptying in a dose-dependent manner . The gastric emptying in the group treated with CAM (100 mg/kg) was significantly lower than that with EM (100 mg/kg) . It is suggested that CAM as well as EM might affect the oral bioavailability of CYA by inhibiting its metabolism and simultaneously by changing the gastrointestinal motility in rats . Thus, caution is recommended when administering CYA concomitantly with CAM to humans.

J Antimicrob Chemother, 1996 May, 37(5), 987 - 91
Interaction of macrolides with alpha dornase during DNA hydrolysis; Ripoll L et al.; Since patients with cystic fibrosis are often treated with alpha dornase to reduce sputum viscosity, and because of preliminary reports of efficacy of long-term low-dose erythromycin therapy in chronic airway diseases, it is likely that alpha dornase and macrolides might be given together in such patients . A possible interaction between these drugs was therefore investigated . Using hyperchromic effect to quantify alpha dornase activity, a time- and dose-dependent inhibitory effect on human DNA hydrolysis has been observed for erythromycin, roxithromycin and azithromycin . Inhibitory doses 50% for alpha dornase were graphically determined . Azithromycin exhibited the strongest inhibitory effect.

Clin Exp Allergy, 1996 May, 26(5), 590 - 6
Evidence of antibodies to erythromycin in serum of a patient following an episode of acute drug-induced hepatitis; Gomez-Lechon MJ et al.; BACKGROUND: A patient who had taken erythromycin orally developed mild signs of hepatocellular damage and appeared to became sensitized . After a fortuitous oral intake of the antibiotic, 18 months later, the patient developed an extensive intrahepatic cholestasis . OBJECTIVE: To confirm the allergic nature of this form of hepatitis by demonstrating the presence of serum antibodies directed at the drug . METHODS: Primary cultured human hepatocytes were used to investigate whether erythromycin can covalently bind to hepatocytes; and to demonstrate the presence of drug-directed immunoglobulins in the serum of the patient . RESULTS: As a consequence of its metabolism by hepatocytes, a small percentage of erythomycin remained bound to hepatocyte proteins . The extent of covalent binding varied among hepatocytes from different donors, and was not observed in metabolically inactive hepatocytes . Antibodies able to bind erythromycin were detected in the serum of the patient . When this serum was added to a human hepatocyte culture that had been previously incubated with the drug, binding of immunoglobulins was observed around the cell membrane and close to pseudo-bile canaliculi, thus indicating the presence of antibodies able to recognize erythromycin-labelled hepatocytes . CONCLUSIONS: The existence of serum antibodies directed at erythromycin haptens in this patient strongly suggests an allergic mechanism for this drug-induced hepatitis.

Drug Metab Dispos, 1996 May, 24(5), 523 - 8
Characterization of the effects of tebufelone on hepatic cytochromes P450 in the beagle dog; Smith BJ et al.; Tebufelone (1-{3,5-bis(1,1-dimethylethyl)-4-hydroxy-phenyl}-hex-5-yne-1-one) is an investigational ditertiary butylphenol nonsteroidal anti-inflammatory drug . The purpose of the present study was to assess the effects of tebufelone on hepatocyte ultrastructure and hepatic cytochromes p450 (P450s) in the beagle dog after 2 weeks of oral administration at dose levels of 0, 5, 15, 50, and 100 mg/kg/day (N = 1/sex/dose level) . Hepatic tissue was obtained at necropsy for histologic, ultrastructural, and biochemical evaluation . Hepatocellular hypertrophy was observed in only a single tebufelone-treated dog (50 mg/kg) . Electron microscopic evaluation, however, revealed marked dose-dependent increases in smooth endoplasmic reticulum in all of the tebufelone treatment groups . Biochemical indicators suggested that tebufelone produced mixed effects on hepatic P450s . p-Nitroanisole O-demethylase and, to a greater extent, ethoxyresorufin O-deethylase activities were decreased with increasing tebufelone dose . The precise mechanism by which tebufelone decreased ethoxyresorufin O-deethylase activity in dogs in unknown, but it was not by competitive inhibition, P450 inactivation, or reduced CYP1A expression . Tebufelone treatment increased NADPH-dependent cytochrome c reductase, total P450, and indicators of CYP2B11 (chloramphenicol covalent binding and immunochemically determined 2B11) and CYP3A12 (erythromycin N-demethylase, triacetyloleandomycin spectral complex formation, testosterone 6 beta-hydroxylase, and immunochemically determined 3A12) . The largest increase in the 2B11 and 3A12 markers occurred in the 50 or 100 mg/kg treatment groups . The greatest increase in CYP2B11 markers produced by tebufelone treatment ranged from 2- to 3-fold, whereas the increase in CYP3A12 markers ranged from 5- to 10-fold . The changes in hepatic ultrastructure and increases in CYP2B11 and CYP3A12 markers produced by tebufelone in dogs are similar to that reported for phenobarbital.

Clin Pharmacol Ther, 1996 May, 59(5), 514 - 9
A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism; Yasui N et al.; OBJECTIVE: To assess the possible involvement of CYP3A4 in the metabolism of alprazolam in vivo . METHOD: Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases . Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8 . Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske undersogelser side effect rating scale . RESULTS: Erythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 +/- 43 versus 322 +/- 49 ng . hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng . hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/- 0.31 versus 0.41 +/- 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 +/- 4.5 versus 40.3 +/- 14.4 hours) of alprazolam . However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases . CONCLUSION: This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo evidence for the involvement of CYP3A4 in its metabolism . However, the kinetic change of alprazolam by erythromycin does not result in the pharmacodynamic change of this triazolobenzodiazepine, at least after single dosing.

J Pharmacol Exp Ther, 1996 May, 277(2), 595 - 603
Selective mechanism-based inactivation of rat CYP2D by 4-allyloxymethamphetamine; Lin LY et al.; The high selectivity of amphetamine and its derivatives for CYP2D-mediated oxidations suggested the use of the phenylisopropylamine skeleton as a template for a selective inhibitor of this important enzyme . Accordingly, 4-allyloxymethamphetamine-amine (ALLMA) was synthesized and its ability to selectively inactivate CYP2D was investigated both in in vitro and in vivo experiments . Incubation studies with rat liver microsomes demonstrated that this compound suppressed the CYP2D-mediated methylenedioxymethamphetamine (MDMA) demethylation in time- and dose-dependent manner and that the inhibition required the presence of NADPH . The development of irreversible inhibition was associated with oxidation at position 4 of the aromatic ring, the common site of CYP2D-mediated oxidation of this group of compounds . In in vivo studies doses of ALLMA (1-10 mg/kg) were administered to adult male Sprague-Dawley rats and liver microsomes were obtained 3 hr later . Methamphetamine p-hydroxylation and low Km MDMA demethylation activities, both mediated by CYP2D, were reduced by more than 80% after a dose of 10 mg/kg . Cytochrome P-450 reactions attributed to P-450s other than CYP2D, such as aniline p-hydroxylation, the high Km system of MDMA demethylation and the N-demethylation of methamphetamine, benzphetamine, aminopyrine and erythromycin, all appeared to be minimally affected . The importance of aromatic ring oxidation in the metabolism is such that inhibition of CYP2D would be expected to cause a significant change in the pharmacokinetics of these compounds . The kinetics of MDMA metabolic activity in microsomes from ALLMA-pretreated rats were comparable to those from female Dark-Agouti rats, an animal model for CYP2D1 deficiency.

JAMA, 1996 May 1, 275(17), 1339 - 41
Use of terfenadine and contraindicated drugs; Thompson D et al.; OBJECTIVE--To assess changes in concurrent use of products containing terfenadine and contraindicated macrolide antibiotics (erythromycin, clarithromycin, troleandomycin) and imidazole antifungals (ketoconazole, itraconazole) following reports of serious drug-drug interactions and changes in product labeling . DESIGN--Retrospective review of computerized pharmacy claims . SETTING--A large health insurer in New England . PATIENTS--Health plan members with 1 or more paid pharmacy claims for products containing terfenadine between January 1990 and June 1994 . MAIN OUTCOME MEASURES--Among persons with paid claims for terfenadine in any given month, percentage with a prescription for any contraindicated drug that alternatively was dispensed on the same day as ("same-day dispensing") or had therapy days that overlapped those of ("overlapping use") a prescription for terfenadine . RESULTS--Concurrent use of terfenadine and contraindicated drugs declined over the study period . The rate of same-day dispensing declined by 84% from an average of 2.5 per 100 persons receiving terfenadine in 1990 to 0.4 per 100 persons during the first 6 months of 1994, while the rate of overlapping use declined by 57% (from 5.4 to 2.3 per 100 persons) . Most cases involved erythromycin . CONCLUSIONS--Despite substantial declines following reports of serious drug-drug interactions and changes in product labeling, concurrent use of terfenadine and contraindicated macrolide antibiotics and imidazole antifungals continues to occur.

Int J Cardiol, 1996 Apr 19, 54(1), 85 - 8
Drug-induced torsades de pointes in one patient with congenital long QT syndrome; Hsieh MH et al.; Although uncommon, torsades de pointes (TdP) associated with astemizole and/or erythromycin use have been reported previously . We describe a 30-year-old woman who had congenital prolongation of QT interval and TdP occurred after taking astemizole and erythromycin . Temporary cardiac pacing was successful in suppressing TdP . Prolongation of QT interval had good response to oral propranolol.

Toxicology, 1996 Apr 15, 108(1-2), 39 - 48
Dose-related effect of aflatoxin B1 on liver drug metabolizing enzymes in rabbit; Guerre P et al.; The effects of chronic administration of aflatoxin B1 (AFB1) on liver drug metabolism enzymes were measured in New Zealand rabbits divided into three groups of 5 animals, each receiving over 5 days either arabic gum or AFB1 in arabic gum at a daily oral dose of 0.05 or 0.10 mg/kg . These treatments did not lead to any lethality in any of the treated groups, but the body weight gain was altered . Biochemical exploration of plasma components revealed a dose-dependent hepatotoxicity characterized by cytolysis and cholestasis . At 0.10 mg/kd/day of AFB1, significant decreases were observed in total liver microsomal cytochrome P450, several P450-dependent monooxygenase activities, all individual P450 isoenzymes levels analysed by Western-blotting and glutathione S-transferase activities . By contrast, at 0.05 mg/kg/day of AFB1, even though total cytochrome P450 was decreased by 30%, only P450 1A1 and 3A6 isoenzymes, and aniline hydroxylation, pentoxyresorufin O-depentylation, aminopyrine, erythromycin, ethylmorphine and dimethylnitrosamine N-demethylations were affected . In the same animal group, the only glutathione S-transferase accepting CDNB (1-chloro-2,4-dinitrobenzene) as substrate was decreased by 22% . UDP-glucuronyltransferase accepting p-nitrophenol as substrate was increased in both groups of animals (33-62%) . The mechanisms that could contribute to the observed changes in drug metabolizing enzymes are discussed.

Biochem Biophys Res Commun, 1996 Apr 5, 221(1), 157 - 62
cDNA cloning of a novel CYP3A from rat brain; Wang H et al.; One full length cDNA clone, designated 3aH15, was isolated from a control male rat brain cDNA library . 3aH15 encoded a protein composed of 503 amino acid residues . The deduced amino acid sequence of 3aH15 was 92% identical to Cyp3a-13 and had a 68.4% to 76.5% homology with the other reported CYP3A sequences . Clone 3aH15 was thus named CYP3A9 . No significant induction of the CYP3A9 expression in rat brain by dexamethasone was observed by Northern blot analysis . CYP3A9 cDNA was expressed in E . coli and the expressed P450 3A9 is active in the demethylation of erythromycin as well as benzphetamine.

Xenobiotica, 1996 Apr, 26(4), 381 - 94
Suppression of intestinal and hepatic cytochrome P4503A in murine Toxoplasma infection . Effects of N-acetylcysteine and N(G)-monomethyl-L-arginine on the hepatic suppression; Berg-Candolfi M et al.; 1 . Cytochrome P4503A (CYP3A) expression was studied in a murine model of infection . Mice were infected with a cystogenic strain of Toxoplasma gondii and microsomes were prepared for liver homogenates and jejunum villus tip enterocytes on day 10 postinfection . Total cytochrome P450 (CYP) and CYP3A were quantitated, and CYP3A activity was determined . 2 . In the infected mouse, total CYP and CYP3A contents fell in the liver (-39 and - 49% respectively) and intestine (-43 and - 48 % respectively), as did the rate of metabolism of erythromycin (Ery) and cyclosporine A (CyA), two markers of CYP3A activity (-36 and -26% in the liver, -35 and -58% in the intestine) . 3 . To determine the mechanism(s) involved in the depression of hepatic CYP3A, infected mice were treated on day 7.5 post-infection with a monoclonal antibody raised against interferon-gamma (anti-IFN-gamma, or from days 7.5 to 10 post-infection with either N(G)-monomethyl-L-arginine (NMMA), an inhibitor of reactive nitrogen intermediates (RNI) production, or N-acetylcysteine (NAC), a reactive oxygen intermediates (ROI) scavenger . 4 . Total CYP content was restored in the liver of infected mice treated with anti-IFN-gamma, but with marked interindividual variability . NAC treatment led to a recovery in the liver of total CYP content (+35 %), CYP3A content (total recovery), and the rates of Ery (+59%) and CyA (+87%) metabolism, whereas inconsistent results were obtained with NMMA . These results suggest that NAC, but probably not NMMA, partially protects hepatic CYP3A from Toxoplasma-mediated suppression in mouse.

J Am Pharm Assoc (Wash), 1996 Apr, NS36(4), 263 - 9
Coprescription of terfenadine and erythromycin or ketaconazole: an assessment of potential harm; Carlson AM et al.; PURPOSE: In a retrospective study, the authors used a pharmacy claims database to analyze the rate of coprescription of terfenadine and erythromycin or ketaconazole . STUDY PERIOD: The investigators reviewed claims filed for these drugs between January 1, 1990, and June 30, 1993 . The time period allowed for comparison of coprescription rates before and after the Food and Drug Administration (FDA) required the manufacturer of terfenadine to inform the medical community of potentially serious adverse interactions . RESULTS: There were 5,802 coprescription events for terfenadine and erythromycin and 150 coprescription events for terfenadine and ketaconazole . Rates per 100,000 terfenadine users demonstrated large declines about 18 months after initial regulatory action . Coprescription events of terfenadine with either erythromycin or ketaconazole continued to occur despite regulatory action . CONCLUSIONS: Results of this study suggest important roles for the pharmacist as a risk manager, disseminating information about newly published drug interactions . Both health providers and patients are audiences for the pharmacist's drug expertise . The delay in physician reaction to new information from pharmaceutical companies and the federal government suggests an early, strong role for the pharmacist in changing prescribing behavior.

Pediatr Emerg Care, 1996 Apr, 12(2), 91 - 3
Diagnosis of whooping cough: a new era with rapid molecular diagnostics; Cimolai N et al.; A rapid diagnostic procedure, which is based upon the polymerase chain reaction (PCR) genetic amplification technology, was utilized to establish the presence of Bordetella pertussis in nasopharyngeal washes from children . Overall, 14.7% of 456 specimens were positive by either culture or the rapid assay . Culture and PCR were concordant for 62.7% of positive samples; PCR provided an additional increment of 37.3% . PCR-positive, culture-negative specimens were more likely to be found among older patients with more prolonged illness and previous erythromycin therapy (P < 0.01 for all three comparisons) . As a single laboratory assay, PCR should be recognized as the current standard for diagnosis.

Nucl Med Biol, 1996 Apr, 23(3), 291 - 3
Lung clearance of aerosolized 99mTc erythromycin lactobionate in rabbits; Durak H et al.; In order to assess the lung clearance of aerosolized 99mTc Erythromycin Lactobionate (EL), 99mTc EL was administered to 9 New Zealand rabbits by inhalation . 5 rabbits inhaled cigarette smoke before 99mTc EL . Clearance half times were 3.0 +/- 0.9 hours in normals, 5.5 +/- 1.0 hours after smoke exposure . Clearance was not affected after destroying the surfactant layer . Slower clearance after smoke exposure may be due to the inhibition of mucociliary clearance . 99mTc EL can be considered as an alternative radioaerosol for ventilation imaging.

Eur J Clin Microbiol Infect Dis, 1996 Apr, 15(4), 286 - 90
Delay in appropriate therapy of Legionella pneumonia associated with increased mortality; Heath CH et al.; The prognostic significance of delayed therapy in Legionnaires' disease is poorly defined . Thirty-nine consecutive serologically confirmed cases of Legionnaires' disease were reviewed to examine whether an association exists between delayed therapy and prognosis . Clinical and laboratory factors predictive of mortality were also sought . Thirty-one cases (79%) were classified as having severe pneumonia at diagnosis . Thirty-six patients (92%) had community-acquired infection, and three patients (8%) had nosocomial disease . Ten patients died, resulting in a crude mortality rate of 26% . At the first assessment, variables noted for pneumonia associated with death were low diastolic blood pressure (p < 0.02), low serum albumin concentration (p < 0.04), and increased number of days from onset of pneumonia to hospitalisation (prodrome) (p < 0.02) . However, multiple logistic regression analysis revealed that the prodrome was the only variable noted at diagnosis that achieved significance (p = 0.024) . Mortality also correlated with both delay in the initiation of erythromycin therapy following admission (p < 0.001) and the total delay in starting erythromycin therapy (p < 0.001) . It is therefore recommended that erythromycin be included early in the empiric therapy of severe community-acquired pneumonia.

Genetika, 1996 Apr, 32(4), 510 - 6
{Molecular genetic study of the strain Streptomyces virginiae-- the producer of virginiamycin}; Kudriavtseva EA et al.; The level and the character of the Streptomyces virginiae virginiamycin-producing strain's resistance to self-produced antibiotic and a number of antibiotics from different groups were determined . S . virginiae was shown to display constitutive and inducible resistance to self-produced antibiotic . The phenomenon of cross-inducible resistance of the strain to virginiamycin and the antibiotics erythromycin, oleandomycin, and thiostrepton was demonstrated . The pTO1 and pVGTB24 plasmids were introduced into the strain by the method of intergeneric conjugation with Escherichia coli . Site-specific integration of the pTO1 vector into the S . virginiae chromosomal attB site without disturbance of growth, differentiation, and productivity of the strain was shown . The multicopy autonomously replicating plasmids pIJ699, pIJ702, pWOR109, and the integrative pZAT22 plasmid were introduced into the strain via electrotransformation of germinating spores . The efficiency of transformation was 1-5 x 10(3) transformants per 1 microgram DNA . The stable inheritance of the plasmids in S . virginiae without structural rearrangements was shown . These results allow the use of these plasmids to clone genes into S . virginiae.

Intensive Care Med, 1996 Apr, 22(4), 301 - 4
Motility agents for the placement of weighted and unweighted feeding tubes in critically ill patients; Paz HL et al.; OBJECTIVE: To determine if successful attempts at feeding tube placement into the small bowel could be increased with the use of a weighted end or by pre-treatment with a drug to increase gastric motility . DESIGN: A prospective randomized control study, double blinded for a drug study drug, in a population of critically ill patients . SETTING: A 635-bed acute care hospital in Philadelphia, Pennsylvania . PATIENTS: Eighty-three patients in the critical care setting randomized into four groups receiving either parenteral normal saline (NS) 100 cc, erythromycin (EMY) 200 mg, or metoclopramide (MET), 10 mg, 30 min prior to attempted tube placement with either a weighted (WEI) (57 patients) or unweighted tube (UNW) (26 patients) . RESULTS: When analyzed for number of attempts prior to successful tube placement into the stomach there was a significant difference between the unweighted and weighted groups: 2.08 +/- 1.03 attempts vs 1.51 +/- 0.94, P < or = 0.015 . Duodenal migration at 24 h was demonstrated in three patients in the NS/UNW group and in two patients in the NS/WEI group as compared to no patients in either the EMY/WEI or the MET/WEI groups (p < or = 0.025, Fisher's exact test) . CONCLUSIONS: These data demonstrate that the use of weighted feeding tubes decreases the number of attempts required to achieve gastric intubation, but that motility agents given prior to tube insertion do not augment advancement of the feeding tube beyond the stomach and may in fact hinder placement into the duodenum.

Nihon Kyobu Shikkan Gakkai Zasshi, 1996 Apr, 34(4), 434 - 8
{Diffuse panbronchiolitis with P-ANCA-positive arteritis and necrotizing glomerulitis}; Saku N et al.; A 53-year-old man was admitted to our hospital with a skin eruption, a high fever, and diplopia in April of 1992 . He had been given a diagnosis of diffuse panbronchiolitis in 1981 . After administration of erythromycin began in 1987, symptoms and chest roentgenographic findings gradually improved . Arteritis of peribronchial muscular arteries with medial destruction was seen in lung biopsy specimens, and periglomerular granulomatous inflammation and necrotizing glomerulitis were seen in renal biopsy specimens . P-ANCA was found, but a test for cytoplasmic ANCA (which is the most specific antigen of Wegener's granulomatosis) was negative . Chronic pulmonary infection due to diffuse panbronchiolitis might have formed ANCA, which may have caused the vasculitis in this patient.

Dig Dis Sci, 1996 Apr, 41(4), 697 - 704
Antral axial forces postprandially and after erythromycin in organic and functional dysmotilities; Surrenti E et al.; Our aims were to measure antral axial forces in patients with suspected upper gut dysmotilities and to compare the number of antral contractions detected by an axial force catheter and by manometric sensors in the distal antrum and pylorus . Fifteen patients (2 men, 13 women; mean age 42 years) underwent studies for 3 hr fasting, 2 hr postprandially, and up to 60 min after intravenous erythromycin (3mg/kg) . Seven patients had gastroparesis or chronic intestinal pseudoobstruction, five functional disease, and three subacute obstruction . Postprandially, the number of peaks detected by the two methods was not significantly different; however, after erythromycin, the axial catheter detected more contractions (P = 0.02) . Erythromycin significantly increased the number of postprandial axial forces (from 1.2 +/- 0.3/min to 2.5 +/- 0.3/min, P < or = 0.01) in the whole group and in the organic dysmotility group (P = 0.01) . Erythromycin significantly increases the number of axial forces in functional and organic upper gut dysmotilities, but the axial force catheter is not advantageous over manometry for postprandial measurements of antral motility.

Clin Pharmacol Ther, 1996 Apr, 59(4), 429 - 35
The effects of menopause and hormone replacement therapies on prednisolone and erythromycin pharmacokinetics; Harris RZ et al.; The pharmacokinetics of oral and intravenous prednisolone and intravenous erythromycin were examined in premenopausal women, postmenopausal women not undergoing hormone replacement therapy, postmenopausal women undergoing estrogen replacement therapy, and postmenopausal women undergoing estrogen and progestin replacement therapy . The unbound clearance of prednisolone was significantly lower in postmenopausal women (11.6 +/- 2.3 ml/min/kg) than in premenopausal women (16.6 +/- 3.5 ml/min/kg) . A comparable difference was also observed in total clearance and in half-life . The bioavailability and volume of distribution of prednisolone were unaffected by menopausal status . Hormone replacement therapies did not significantly affect prednisolone pharmacokinetics . In contrast to prednisolone elimination, erythromycin elimination, as measured by the erythromycin breath test, was not significantly affected by either menopausal status or hormone replacement therapy . In addition, there was no correlation between prednisolone clearance and the erythromycin breath test result . Although cytochrome P450 3A4 (CYP3A4) has been implicated in steroid hormone metabolism, these results suggest that another enzyme system, which is decreased in menopause (rather than simply an age effect), is also involved in prednisolone metabolism.

Dtsch Med Wochenschr, 1996 Mar 29, 121(13), 402 - 5
{Treatment of radiotherapy-induced gastroparesis with erythromycin}; Sturm A et al.; HISTORY: A 75-year-old woman who had undergone a hysterectomy with adnexectomy followed by radiotherapy for endometrial carcinoma complained of postprandial nausea with vomiting after eating solid foods and of cramp-like abdominal pain, but her appetite was good . She had lost 25 kg in weight over 13 months . EXAMINATION: Physical examination, laboratory tests, radiology and gastroscopy were unremarkable . Gastric scintigraphy showed abnormally prolonged emptying . TREATMENT AND COURSE: Nausea and vomiting stopped at once after erythromycin (a motilin agonist) had been administered . It was at first given intravenously after meals (50 mg three times daily for 5 days), then orally for 10 weeks (250 mg three times daily before meals) . Subsequent examination revealed normal gastric emptying . The symptoms did not recur after erythromycin had been discontinued . CONCLUSION: Erythromycin is an effective drug against gastroparesis caused by radiotherapy, because it acts even when the enteric nerves are damaged.

Arch Intern Med, 1996 Mar 25, 156(6), 675 - 7
Erythromycin-induced clozapine toxic reaction; Cohen LG et al.; Clozapine, used in the treatment of patients with schizophrenia resistant to other neuroleptic medication, is metabolized by the hepatic microsomal system to demethyl-clozapine and clozapine-N-oxide . Changes in clozapine serum concentrations have been documented after initiation of therapy with medications known to induce or inhibit liver microsomal enzymes . These interactions are of clinical importance when diminished efficacy or increased toxic effects of clozapine therapy occur . A 34-year-old schizophrenic man had increased clozapine serum concentrations, leukocytosis, and adverse effects as a result of concomitant erythromycin therapy given for suspected lower respiratory tract infection . Symptoms included somnolence, difficulty in coordination and ambulation, slurred speech, disorientation, and incontinence . The symptoms resolved after treatment with clozapine and erythromycin were discontinued, and treatment with clozapine was gradually resumed.

Cancer Res, 1996 Mar 15, 56(6), 1296 - 302
Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans; Marre F et al.; Docetaxel metabolism mediated by cytochrome P450-dependent monooxygenases was evaluated in human liver microsomes and hepatocytes . In microsomes, the drug was converted into four major metabolites resulting from successive oxidations of the tert-butyl group on the synthetic side chain . Enzyme kinetics appeared to be biphasic with a V(max) and apparent K(m) for the high-affinity site of 9.2 pmol/min/mg and 1.1 microm, respectively . the intrinsic metabolic clearance in human liver microsomes (V(max)/K(m), 8.4 ml/min/g protein) was comparable to that in rat and dog liver microsomes, but lower in mouse liver microsomes . Although the metabolic profile was identical in all subjects, a large quantitative variation in docetaxel biotransformation rates was found in a human liver microsome library, with a ratio of 8.9 in the highest:lowest biotransformation rates . Docetaxel biotransformation was correlated significantly (0.7698; P < 0.0001) with erythromycin N-demethylase activity, but not with aniline hydroxylase or debrisoquine 4-hydroxylase . It was inhibited, both in human hepatocytes and in liver microsomes, by typical CYP3A substrates and/or inhibitors such as erythromycin, ketoconazole, nifedipine, midazolam, and troleandomycin . Docetaxel metabolism was induced in vitro in human hepatocytes by dexamethasone and rifampicin, both classical CYP3A inducers . These data suggest a major role of liver cytochrome P450 isoenzymes of the CYP3A subfamily in docetaxel biotransformation in humans . Finally, some Vinca alkaloids and doxorubicin were shown to inhibit docetaxel metabolism in human hepatocytes and liver microsomes . These findings may have clinical implications and should be taken into account in the design of combination cancer chemotherapy regimens.

J Antimicrob Chemother, 1996 Mar, 37(3), 473 - 81
Clarithromycin resistance in Helicobacter pylori: prevalence in untreated dyspeptic patients and stability in vitro; Xia HX et al.; Susceptibilities to clarithromycin and metronidazole of 444 Helicobacter pylori isolates cultured from antral biopsies of 444 dyspeptic patients were determined by disc diffusion tests (15 mu g disc for clarithromycin, 5 mu g disc for metronidazole) . Susceptibility of 46 of these isolates to erythromycin (5 mu g disc) was also tested . Minimal inhibitory concentrations (MICs) of clarithromycin for 42 selected isolates were determined by a plate dilution method . A zone diameter of 30 mm was defined as a 'cut-off' size differentiating susceptibility and resistance of the organism to clarithromycin, by comparing results obtained with the two methods . Of the 444 isolates, 424 (95.5%) were highly sensitive to clarithromycin, with zone diameters ranging from 30 to 98 mm . Twenty isolates (4.5%) were defined as resistant to clarithromycin, with zone diameters ranging between 6 and 28 mm . The incidence of clarithromycin resistance was similar in men and women and in different age groups, and was not significantly different between patients with peptic ulcer and non-ulcer dyspepsia . Among the 444 isolates, 168 (37.8%) were metronidazole resistant . There was cross resistance between clarithromycin and erythromycin, but not between clarithromycin and metronidazole . Stability of clarithromycin resistance was evaluated by the disc diffusion test and confirmed by the plate dilution method . Among the 20 clarithromycin-resistant isolates, nine (45%) reverted to be sensitive after 25 subcultures on drug-free agar . The findings in this study indicate that the incidence of clarithromycin-resistant H . pylori in untreated dyspeptic patients is low . Cross-resistance occurs between macrolides and resistance to clarithromycin in some strains is reversible.

Drugs, 1996 Mar, 51(3), 433 - 59
Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia; Plosker GL et al.; Fluvastatin, a member of the group of drugs known as HMG-CoA reductase inhibitors, is used in the treatment of patients with hypercholesterolaemia . In clinical trials in patients with primary hypercholesterolaemia, fluvastatin 20 or 40 mg/day achieved marked reductions from baseline in serum levels of low density lipoprotein (LDL)-cholesterol (19 to 31%) and total cholesterol (15 to 21%), along with modest declines in serum triglyceride levels (1 to 12%) and small increases in high density lipoprotein (HDL)-cholesterol levels (2 to 10%) . These beneficial effects on the serum lipid profile were similar to those demonstrated with other HMG-CoA reductase inhibitors, although direct comparative trials are limited . Concomitant administration of fluvastatin plus another lipid-lowering agent, such as a bile acid sequestrant, a fibrate or nicotinic acid, usually reduced serum levels of total cholesterol and LDL-cholesterol by at least a further 5 to 10% from baseline compared with fluvastatin monotherapy . Fluvastatin has a similar tolerability profile to that of other HMG-CoA reductase inhibitors . Gastrointestinal disturbances, which are usually mild and transient, were the most frequently reported adverse events with fluvastatin in clinical trials . Persistent elevation of serum transaminase levels occurred in approximately 1% of fluvastatin recipients, which is similar to the rate for other HMG-CoA reductase inhibitors . Unlike other HMG-CoA reductase inhibitors, which have been infrequently associated with myopathy and rarely with rhabdomyolysis, these events have not been associated with fluvastatin to date, although fluvastatin has not been used as extensively as agents such as lovastatin . HMG-CoA reductase inhibitors other than fluvastatin, when given in combination with drugs such as fibrates, nicotinic acid, cyclosporin or erythromycin, can increase the risk of these potentially serious adverse events . Thus far, myopathy or rhabdomyolysis have not been reported among patients receiving fluvastatin concomitantly with any of these drugs . Therefore, fluvastatin can be given with caution in combination with fibrates, nicotinic acid, cyclosporin or erythromycin . In conclusion, fluvastatin has similar efficacy and tolerability profiles to other HMG-CoA reductase inhibitors, which are among the most effective agents available for treating patients with hypercholesterolaemia . Pharmacoeconomic studies performed to date suggest an advantage for fluvastatin over other HMG-CoA reductase inhibitors, predominantly because of its relatively low acquisition costs (at least in those countries in which the evaluations were conducted) . Thus, fluvastatin is effective and well tolerated in patients with hypercholesterolaemia and appears to have an economic advantage over other HMG-CoA reductase inhibitors, primarily as a result of its relatively low acquisition costs.

Br J Clin Pharmacol, 1996 Mar, 41(3), 187 - 90
Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes; Christians U et al.; 1 . Tacrolimus, an immunosuppressive macrolide, is metabolized by enzymes of the cytochrome P450 3A subfamily . In this study, 34 drugs were tested for their interactions with tacrolimus metabolism by human liver microsomes . 2 . Fifteen drugs which inhibit the in vitro metabolism of tacrolimus were identified: bromocriptine, corticosterone, dexamethasone, ergotamine, erythromycin, ethinyloestradiol, josamycin, ketoconazole, miconazole, midazolam, nifedipine, omeprazole, tamoxifen, troleandomycin and verapamil.

Chem Res Toxicol, 1996 Mar, 9(2), 365 - 73
Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes; Iribarne C et al.; Methadone has become one of the most widely used drugs for opiate dependency treatment . This drug is extensively metabolized by the cytochrome P450 hepatic enzyme family in man, yielding an N-demethylated metabolite that cyclizes spontaneously into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine . The specific forms of cytochrome P450 involved in this oxidative N-demethylation were examined in a panel of 20 human liver microsomal preparations previously characterized with respect to their P450 enzyme contents . Methadone was demethylated with an apparent Km of 545 +/- 258 microM (n = 3) . The metabolic rates were 745 +/- 574 pmol/(min.mg of protein) . This metabolic pathway was strongly correlated with estradiol 2-hydroxylation, testosterone 6 beta-hydroxylation, nifedipine oxidation, erythromycin N-demethylation, and toremifene N-demethylation, all of these monooxygenase activities being supported by P450 3A4 . Furthermore, the total P450 3A content of liver microsomal samples, determined by immuno-quantification using a monoclonal anti-human P450 3A4 antibody, was correlated with methadone demethylation (r = 0.72; p < 0.003) . Methadone metabolism was 60-72% inhibited either by three mechanism-based inhibitors of P450 3A4 (gestodene, TAO, and erythralosamine) or by four reversible inhibitors of P450 3A (ketoconazole, dihydroergotamine, quercetin, and diazepam with an apparent Ki of 50 microM) and by two nonspecific inhibitors (metyrapone and SKF-525A) . Conversely, quinidine (inhibitor of P450 2D6), 7,8-benzoflavone (inhibitor of P450 1A), or sulfaphenazole (inhibitor of P450 2C) did not significantly inhibit, and may even have activated, methadone metabolism . Four heterologously expressed P450 proteins were able to catalyze the N-demethylation of methadone, namely, P450 2C8, P450 2C18, P450 2D6, and P450 3A4 . However, referring to their relative liver content, it can be asserted that P450 3A4 is the major enzyme involved in the N-demethylation of methadone on average . Accordingly, caution should be advised in the clinical use of methadone when other drugs are also administered that induce or inhibit P450 3A4, such as rifampicin or diazepam, respectively.

Mol Microbiol, 1996 Mar, 19(5), 977 - 84
Erythromycin production in Saccharopolyspora erythraea does not require a functional propionyl-CoA carboxylase; Donadio S et al.; Using an oligonucleotide corresponding to the consensus sequence for the biotin-binding motif, two unlinked genetic loci, bpl1 and bpl2, were cloned from the erythromycin producer Saccharopolyspora erythraea and the nucleotide sequences of a c . 4 kb segment from each determined . The two loci share a virtually identical segment of 1746 nucleotides, coinciding with most of the genes designated bcpA1 and bcpA2 present in bpl1 and bpl2, respectively . The deduced sequences of these genes are highly similar to that of the alpha-chain of mammalian propionyl-CoA carboxylase . Upstream of bcpA2 lies pccB, the gene encoding the beta-chain of this enzyme . Mutant strains carrying frameshift mutations in bcpA1 and pccB were constructed, but we failed to isolate insertional mutants in bcpA2 . Propionyl-CoA carboxylase activity was undetectable in the pccB mutant, but was unaffected in the bcpA1-defective strain . These results indicate that pccB encodes the beta-chain of propionyl-CoA carboxylases, and suggest that the alpha-chain of this enzyme, which is likely to be encoded by bcpA2, is shared with some other essential biotin-dependent enzyme . The pccB mutation had no impact on erythromycin production in complex medium.

Pharmacotherapy, 1996 Mar-Apr, 16(2), 301 - 5
Possible role of the intestinal P-450 enzyme system in a cyclosporine-clarithromycin interaction; Sketris IS et al.; Clarithromycin is a macrolide antibiotic similar in structure to erythromycin, but suggested to have fewer drug interactions . Although a pharmacokinetic interaction between clarithromycin and cyclosporine was recently reported, its magnitude and mechanism have not been explored . A 43-year-old renal transplant recipient receiving cyclosporine was treated with clarithromycin because of pneumonia . A cyclosporine pharmacokinetic study was performed 8 days after the initiation of the clarithromycin and 14 days after stopping the drug . Clarithromycin coadministration caused an approximately 2-fold increase in the area under the whole blood concentration versus time curve of cyclosporine . The oral clearance of cyclosporine was halved by clarithromycin, but the terminal elimination rate constant decreased only 15% and mean residence time 20% . These observations suggest that clarithromycin inhibits not only the hepatic metabolism but also the intestinal metabolism of cyclosporine . Caution is advised when administering the two drugs concurrently, and additional studies are necessary to elucidate the mechanism of this interaction.

Therapie, 1996 Mar-Apr, 51(2), 177 - 84
{Macrolides and drug interactions: review of the literature}; Lauby V et al.; Clarithromycin, azithromycin and dirithromycin have recently been introduced in France . We list the different drug-interactions with these three new drugs and with erythromycin, josamycin, roxithromycin, midecamycin and spiramycin.

Kansenshogaku Zasshi, 1996 Mar, 70(3), 268 - 72
{A case of Legionella micdadei pneumonia}; Miyashita N et al.; A 60-year-old male with type C chronic hepatitis was admitted to Kibikogen Rehabilitation Center with high fever, cough and general fatigue . Chest X-ray film on admission showed consolidation in the left middle and lower lung lung field . Initial treatment with intravenous ceftazidime, imipenem/cilastatin and clindamycin were ineffective due to continuous high fever and cough and spread of the pneumonia shadow . Administration of minocycline was started for suspected non-bacterial pneumonia whereupon his symptoms improved and the pneumonia shadow began to decrease in size . However, his symptoms and pneumonia shadow worsened after taking him off of minocycline due to progressive pancytopenia and liver dysfunction . He was transferred to our hospital and intravenous erythromycin treatment was initiated for suspected Legionell pneumonia because of the elevation of Legionella micdadei serum antibody titer . Immediately after starting treatment, his symptoms improved and the pneumonia shadow decreased in size . Erythromycin was stopped after the 14th day of administration . In this case, diagnosis of L . micdadei pneumonia was made because of the positive results of the polymerase chain reaction test and elevation of the L . micdadei serum antibody titer (from 0 to 1,024) . This is the second report of a L . micdadei pneumonia case here in Japan.

Am J Surg, 1996 Mar, 171(3), 316 - 9
The effect of intravenous erythromycin on esophageal motility in healthy subjects; Tzovaras G et al.; BACKGROUND: It has been confirmed that erythromycin has gastrokinetic properties of enhancing gastric emptying both in health and disease . The objective of the present study was to investigate any possible effect of erythromycin on esophageal motility . METHODS: In 14 healthy subjects, standard esophageal manometry was performed before and after the intravenous administration of 200 mg of erythromycin . The calculated manometric parameters of esophageal motility were the lower esophageal sphincter (LES) pressure; the amplitude and duration of peristalsis at 5, 10, and 15 cm proximal to the LES; and the velocity and strength of peristalsis at 5 cm proximal to the LES . RESULTS: Erythromycin significantly increased the LES pressure (P<0.001), and the amplitude (P=0.002), duration (P=0.003), strength (P=0.014) and velocity (P=0.008) of peristalsis at 5 cm proximal to LES . Erythromycin also increased the amplitude of peristalsis at 10 cm proximal to the LES (P=0.035) . CONCLUSION: Erythromycin affects the motility of the distal esophagus.

Clin Exp Immunol, 1996 Mar, 103(3), 461 - 6
Significance of IL-1beta and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) in patients with diffuse panbronchiolitis (DPB); Kadota J et al.; We evaluated the effect of erythromycin therapy on pulmonary function tests and the airway inflammatory response of patients with DPB . The number of neutrophils in BALF obtained from DPB patients was significantly higher than that of healthy volunteers . Treatment with erythromycin (600 mg/day for 12.9+/-9.5 months (mean +/- s.d.)) significantly reduced the total number of cells and neutrophils in the airway, and significantly improved pulmonary function tests . The levels of IL-1beta and IL-8 were significantly higher in DPB compared with healthy volunteers (P<0.05, P<0.05, respectively) . IL-1Ra in patients is considered to have a weak inhibitory activity for IL-1beta, with approximately five-fold concentration of IL-1beta compared with that in healthy volunteers (approx . nine-fold concentration of IL-1beta) . Erythromycin therapy significantly reduced these cytokines to levels comparable to those of healthy volunteers, and produced a trend toward reduction in the level of IL-1Ra in BALF . The level of IL-1beta correlated significantly with the concentration of neutrophils in BALF (r=0.72, P<0.01), as well as with the level of IL-1Ra (r=0.688, P<0.05) and IL-8 (r=0.653, P<0.05) . A nearly significant or significant correlation was observed between the concentration of neutrophils and levels of IL-1Ra or IL-8 in BALF (r=0.526, P=0.053 or r=0.776, P<0.01, respectively) . There was also a significant relationship between FEV(1) and the concentration of neutrophils in BALF (r=0.524, P<0.05) . Our results suggest that the relative amounts of IL-1beta and IL-1Ra or IL-8 may contribute, at least in part, to the neutrophil-mediated chronic airway inflammation in patients with chronic airway disease, and long-term erythromycin therapy may down-regulate the vigorous cycle between the cytokine network and neutrophil accumulation, with resultant reduction of neutrophil-mediated inflammatory response.

J Thorac Cardiovasc Surg, 1996 Mar, 111(3), 649 - 54
Erythromycin stimulates gastric emptying after esophagectomy with gastric replacement: a randomized clinical trial; Burt M et al.; Delayed gastric emptying after esophagogastrectomy can pose a significant early postoperative problem . Because erythromycin, which stimulates the gastric antral and duodenal motilin receptor, has been shown to significantly increase gastric emptying in patients with diabetic gastroparesis, we decided to evaluate its effect on gastric emptying after esophagogastrectomy . METHODS: Twenty-four patients (18 men and six women, age range 41 to 79 years, median 66 years) were randomized to receive either erythromycin lactobionate (200 mg in 50 ml normal saline solution intravenously) (n = 13) or placebo (50 ml normal saline solution intravenously (n = 11) 11 days after esophagogastrectomy (with pyloric drainage procedure) . After erythromycin or placebo had been infused over a 15-minute period, patients ingested a solid meal (scrambled egg with bread) labeled with technetium 99m sulfur colloid (500 microCi) over approximately 15 minutes . Dynamic images of the stomach were then acquired over 90 minutes in the supine position by gamma imaging . Results were expressed as percentage of counts retained in the stomach (percent gastric retention) over time . RESULTS: There were no side effects of erythromycin . In the placebo group, the mean percent of radiolabeled meal retained in the stomach after 90 minutes was 88%, which was significantly greater than in the erythromycin group, 37% (p < 0.001) . In addition, analysis of covariance demonstrated that the rate of gastric emptying (slope of the line) was significantly greater in the erythromycin-treated group than in the placebo group (p < 0.0001) . CONCLUSION: Early satiety after esophagogastrectomy may be due to delayed gastric emptying and not due to a decrease in the gastric reservoir . Intravenous erythromycin significantly improves gastric emptying in patients after esophagogastrectomy by stimulating gastric motility.

Arch Intern Med, 1996 Feb 26, 156(4), 456 - 8
Clinical ergotism with lingual ischemia induced by clarithromycin-ergotamine interaction; Horowitz RS et al.; The macrolide class of antibiotics, including erythromycin and troleandomycin, is associated with clinically significant adverse drug interactions . This results from macrolide inhibition of cytochrome P-450 metabolism of numerous xenobiotics, resulting in elevated serum drug levels and clinical intoxication . Animal studies, however, suggest that clarithromycin, the newest approved macrolide antibiotic, has has less potential for adverse drug reactions . We describe a patient who, on her fifth day of clarithromycin therapy, developed clinical ergotism (i.e., hypertension, lingual ischemia, and peripheral cyanosis) several hours after administration of her usual 2-mg dose of ergotamine tartrate . To our knowledge, this is the first report of clinical ergotism precipitated by clarithromycin-ergotamine interaction and suggests that, like other macrolide antibiotics, ergot preparations should be avoided in patients who are taking clarithromycin.

Schweiz Med Wochenschr, 1996 Feb 24, 126(8), 308 - 10
{Exacerbation of pseudoparalytic myasthenia gravis following azithromycin (Zithromax)}; Cadisch R et al.; We report the case of a 25-year-old female patient with severe aggravation of myasthenia gravis due to azithromycin which was prescribed for an influenza syndrome . One hour after the intake of 500 mg azithromycin the patient developed weakness of the legs and respiratory distress due to respiratory muscle failure . She was hospitalized in a comatose state and required intubation and mechanical ventilation for six days . Acute worsening of myasthenia gravis was observed in this patient in 1986 after parenteral administration of erythromycin . Erythromycin causing aggravation of myasthenia gravis by interfering with neuromuscular transmission is reported in the literature . The close temporal relationship between the intake of azithromycin and severe worsening of myasthenia gravis in our patient suggests that azithromycin, a new azalid-antibiotic of the macrolid group, can exacerbate myasthenia gravis . We conclude that azithromycin should be added to the list of drugs to be used with caution in patients with myasthenia gravis.

Biochemistry, 1996 Feb 20, 35(7), 2054 - 60
Erythromycin biosynthesis: kinetic studies on a fully active modular polyketide synthase using natural and unnatural substrates; Pieper R et al.; 6-Deoxyerythronolide B synthase (DEBS) is a modular polyketide synthase (PKS) that catalyzes the biosynthesis of the parent macrolide of erythromycin . On the basis of a recently developed cell-free assay (Pieper et al., 1995a) we report the results of steady-state kinetic studies on a modular PKS . A truncated form of DEBS (DEBS 1+TE), in which DEBS 1 is fused to the thioesterase domain from the C-terminal end of DEBS 3, was used for most of these studies . The overall k(cat) for (2S,3S,4S,5R)-2,4-dimethyl-3,5-dihydroxy-n-heptanoic acid delta-lactone (C9-lactone) synthesis is 3.4 min(-1), indicating that the enzyme is at least as active in vitro as in vivo . The apparent K(m) for (2S)-methylmalonyl-CoA consumption by DEBS 1+TE is 24 microM . The catalytic activity of DEBS 1+TE is strongly dependent on the phosphate concentration in the reaction buffer in the range 0-250 mM, suggesting that hydrophobic interactions may be crucial to the assembly of DEBS monomers into a functional complex . Although DEBS 1+TE can convert acetyl-, propionyl-, or butyryl-CoA into the corresponding C8-, C9-, and C10-lactones (Pieper et al., 1995b), it has a 32-fold preference for a propionate primer over an acetate primer and a 7.5-fold preference for a propionate primer over a butyrate primer . In the absence of any added primer unit, synthesis can be primed via decarboxylation of methylmalonyl-CoA; under these conditions the overall k(cat) for polyketide synthesis remains unchanged . Decarboxylation of methylmalonyl-CoA is negligible in the presence of saturating concentrations of propionyl-CoA but competes with the priming of the enzyme by acetyl-CoA or butyryl-CoA . The k(cat) for 6-deoxyerythronolide B synthesis by the complete DEBS is 0.5 min(-1) . Under these assay conditions, the C9-lactone is also produced as an abortive chain elongation product with a k(cat) of 0.23 min(-1), presumably due to inefficient assembly of the multimeric protein complex involving DEBS 1, 2, and 3 . Together, these results provide the first comprehensive kinetic insights into a fully active modular PKS.

Ned Tijdschr Geneeskd, 1996 Feb 17, 140(7), 375 - 7
{Possible potentiation of phenprocoumon by clarithromycin and roxithromycin}; Meyboom RH et al.; Two patients, a women of 70 and a man of 75 years old, who were using phenprocoumon chronically, and were monitored by a regional thrombosis service, received a macrolide antibiotic, clarithromycin and roxithromycin respectively, for an airway infection . Both patients developed a serious increase in hypocoagulability, requiring administration of phytomenadione and temporary decreases in phenprocoumon dose . There were no bleeding complications . After the antibiotics were discontinued, the original dosage of phenprocoumon was needed again . It is suggested that in these patients the macrolide antibiotics may have potentiated the effect of phenprocoumon, perhaps as a result of inhibition of phenprocoumon transformation by liver enzymes . In patients receiving chronic treatment with phenprocoumon, coagulation parameters should be regularly checked if they are given a macrolide antibiotic such as clarithromycin, roxithromycin or erythromycin.

Ugeskr Laeger, 1996 Feb 5, 158(6), 751 - 5
{Chlamydia trachomatis}; Ottesen M; Almost 11,000 cases of Chlamydia trachomatis (CT) are diagnosed every year in Denmark . The most important epidemiologic factor is age under 25 years . The prevalence of CT among women applying for legal abortion is five to eight percent and in a recent study the prevalence of CT among second trimester pregnant women was found to be 2.9 percent . The consequences of CT-caused infections are many, including risk of infertility, ectopic pregnancies, perinatal transmission etc . The perinatal transmission rate is high in untreated cases of CT during pregnancy, but it can be prevented by treatment of the expecting woman with erythromycin . The Danish National Board of Health do recommend screening for CT before transcervical interventions, but there are no such recommendations concerning pregnancy health care . A recent Danish study as well as many other studies have shown that it is cost-effective to screen high risk women i.e . women younger than 25 years . An introduction of such screening of Danish pregnant women younger than 25 years should therefore be considered.

Zhonghua Nei Ke Za Zhi, 1996 Feb, 35(2), 86 - 8
{Effects of changes of plasma motilin level on the motility of gallbladder in patients with chronic renal failure}; Wang X et al.; In order to study the relationship between plasma motilin and motility of gallbladder in patients with chronic renal failure (CRF) . Gallbladder volumes were determined with ultrasound in 17 normal subjects and 22 patients with CRF . Fasting gallbladder volumes (FGVs) and postprandial residual gallbladder volumes in patients with CRF were much smaller than those of normal subjects (P < 0.01, P < 0.01) . There was no significant difference of maximal percentage emptying of gallbladder between normal subjects and patients with CRF (P > 0.05) . In 17 normal subjects oral erythromycin administration reduce FGVs and postprandial residual gallbladder volumes (P < 0.05, P < 0.05) . In 22 patients with CRF oral erythromycin administration changed neither FGVs nor postprandial residual gallbladder volumes . Radioimmunoassay was employed to measure plasma motilin concentration . The results showed that mean level of plasma motilin of patients with CRF was much higher than that of normal subjects (P < 0.01) . There was sighificant negative correlation between plasma motilin level and FGVs . It is suggested that hypermotilinemia may be one of the major reasons for motility disorder of gallbladder in patients with CRF.

Antibiot Khimioter, 1996 Feb, 41(2), 5 - 8
{The problem of diagnosis and treatment of urogenital chlamydiosis in Russia}; Skripkin IuK et al.; The problems associated with the distribution, diagnosis, classification and treatment of urogenital tract chlamydiosis in Russia are discussed . Some arrangements for the improvement of the activities of the laboratory diagnostic services, the use of the International Classification of urogenital tract chlamydioses and the treatment optimization are offered . The drug of choice in the treatment of urogenital tract chlamydiosis is azithromycin (Sumamed, Pliva) . Doxycycline, erythromycin and ofloxacin are recommended as the reserve drugs.

J Hepatol, 1996 Feb, 24(2), 230 - 7
Modulation of constitutive and inducible hepatic cytochrome(s) P-450 by interferon beta in mice; Carelli M et al.; AIMS/METHODS: Interferon beta is used as a therapeutic agent, but its effects on the hepatic cytochrome P-450-dependent drug metabolizing system have not yet been characterized . We investigated the effect of interferon beta on cytochrome P-450 in mice . RESULTS: Interferon beta (2 x 10(5) units/mouse) significantly reduced total hepatic cytochrome P-450 (20%) and the activity of NADPH cytochrome C reductase (12%) 24 h after administration; lower doses had no such effect . Various monooxygenase activities were slightly reduced, the one most affected being 7-ethoxycoumarin O-deethylase (29%) . In phenobarbital-treated mice, interferon beta reduced the induction of total cytochrome P-450 (22%), the activities of pentoxyresorufin O-dealkylase (38%), benzyloxyresorufin O-dealkylase (30%), erythromycin N-demethylase (30%), 7-ethoxycoumarin O-deethylase (16%) and cytochrome P-450 2B1 (33%) and 3A (45%) proteins . In beta-naphthoflavone-treated mice, interferon beta lowered the induction of total cytochrome P-450 (18%), the activities of ethoxyresorufin O-deethylase (31%) and of 7-ethoxycoumarin O-deethylase (25%) and of cytochrome P-450 1A1 protein (31%) . CONCLUSIONS: Thus it appears that induced cytochrome(s) P-450 were susceptible to interferon beta, this effect not being influenced by the type of inducer . Since various members of the same cytochrome P-450 subfamilies catalyze oxidation of drugs in humans, our findings have potential significance as regards the fate of drugs or exogenous compounds given to patients receiving interferon beta.

Pharmacol Toxicol, 1996 Feb, 78(2), 117 - 22
Interaction between erythromycin and the benzodiazepines diazepam and flunitrazepam; Luurila H et al.; The effect of erythromycin on the pharmacokinetics and pharmacodynamics of diazepam and flunitrazepam was investigated in two randomized, double-blind, cross-over studies . Healthy volunteers ingested erythromycin for one week 500 mg t.i.d . On the 4th day they ingested a single 5 mg dose of diazepam (6 subject, Study 1) or 1 mg dose of flunitrazepam (5 subjects, Study 2), respectively . Plasma drug concentrations and psychomotor effects were measured during 42 hr after the ingestion of diazepam or flunitrazepam . In Study 1 erythromycin increased the area under the diazepam plasma concentration-time curve {AUC (0-42 hr)} by 15% (P < 0.05) and the concentration of diazepam in plasma at 42 hr by 63% (P < 0.05) . The median peak concentration (Cmax) and the half-life (t1/2) of diazepam were increased but they did not change significantly (P = 0.17 and 0.12, respectively) . Plasma N-desmethyldiazepam concentrations were slightly reduced during erythromycin treatment up to 8 hr (P < 0.05) . In Study 2 the AUC (0-42 hr) of flunitrazepam was increased by 25% (P < 0.05) during the erythromycin treatment . The t1/2 of flunitrazepam increased significantly (P < 0.05), but the Cmax remained unchanged . The psychomotor effects of diazepam or flunitrazepam were not changed significantly by erythromycin . These pharmacokinetic interactions can be explained by the reduced metabolic elimination of diazepam and flunitrazepam . The interactions of erythromycin with diazepam and flunitrazepam seem to be slight and of limited clinical significance only.

Intensive Crit Care Nurs, 1996 Feb, 12(1), 60 - 1
Clarithromycin (klaricid, Abbott); MacConnachie AM; During the 1990s newer antibiotics of the erythromycin group have been introduced . One of these, clarithromycin, may offer advantages over erythromycin in the treatment of difficult respiratory tract infections.

JAMA, 1996 Jan 3, 275(1), 37 - 41
Efficacy of acellular pertussis vaccine in early childhood after household exposure; Schmitt HJ et al.; OBJECTIVE--To evaluate the efficacy of a three-dose primary vaccination with a diphtheria-tetanus tricomponent acellular pertussis vaccine against "typical" pertussis, defined as a spasmodic cough of 21 days or longer with confirmation of Bordetella pertussis infection by culture or serology . DESIGN--Passive monitoring for suspected first household (index) cases of typical pertussis in six areas in Germany comprising 22,505 children vaccinated with study vaccine at 3, 4, and 5 months of age . Blinded, prospective follow-up of household contacts of index cases for incidence and progression of pertussis . SETTING--Six areas in Germany with a high incidence of pertussis . SUBJECTS--Four hundred fifty-three households with index cases comprising 360 evaluable contacts eligible for analysis of vaccine efficacy . MAIN OUTCOME MEASURE--Vaccine efficacy from attack rates of pertussis in household contacts classified by vaccination status . RESULTS--Of the 173 nonvaccinated household contacts, 96 developed typical pertussis, compared with seven of 112 contacts vaccinated with acellular pertussis vaccine . Vaccine efficacy was consequently calculated to be 88.7% (95% confidence interval, 76.6% to 94.6%) . Protection did not wane until at least the time recommended for booster vaccination . None of the analyzed potential confounding factors--age, socioeconomic status, erythromycin treatment, household composition, center effect, and selection bias--influenced study results in favor of the vaccine . CONCLUSIONS--Under conditions of intense household exposure, primary vaccination with acellular vaccine protected against pertussis until at least the time recommended for booster vaccination . The vaccine can be expected to be equally or more effective in settings with lower infectious pressure.

Kurume Med J, 1996, 43(4), 279 - 87
Neutrophil chemotactic activity in bronchoalveolar lavage fluid recovered from patients with diffuse panbronchiolitis; Katsuki M; The present study was aimed at elucidating the role of inflammatory cells in the pathogenesis of the chronic inflammatory changes in the bronchioles of patients with diffuse panbronchiolitis (DPB) and at determining the mechanism for the clinical efficacy of erythromycin (EM) therapy for these patients . For this purpose, neutrophil percentages, neutrophil chemotactic activity (NCA), IL-8 and TNF-alpha in the bronchoalveolar lavage fluid (BALF) were measured in 9 patients with DPB . Significantly higher neutrophil percentages, NCA and IL-8 concentrations were demonstrated in the BALF from DPB patients than from chronic bronchitis (CB) patients or healthy control subjects . The levels of these indicators of chronic inflammation in the BALF from DPB patients were significantly decreased after EM therapy . TNF-alpha was elevated in the BALF from both DPB- and CB-patients and was not decreased by treatment of the DPB patients with EM . From the above results, it can be concluded that IL-8, not TNF-alpha, is the major chemoattractant for neutrophils and that the inhibition of IL-8 production by EM induces the subsequent depression of neutrophil accumulation in the peripheral airways, and consequently, prevents the peripheral airway tissue damage due to accumulated and activated neutrophils.

Arch Toxicol, 1996, 71(1-2), 57 - 63
Expression and inducibility of cytochrome P450 proteins in the liver of chick embryo; Machala M et al.; The expression and inducibility of cytochrome P450 proteins in the liver of chick embryo were investigated using substrate probes and/or immunologically using polyclonal antibodies to the mammalian isoforms . Antibodies to CYP1A1 recognised a single protein which was inducible by structurally diverse chemicals, including aminocompounds, and was parallelled by increases in the O-dealkylations of ethoxy- and methoxyresorufin and in the bioactivation of Glu-P-1 . When probed with antibodies to CYP2E1 an immunoreacting protein was revealed which was induced by phenobarbital but not acetone; a second protein became apparent following the treatment with phenobarbital . The increase in apoprotein levels was accompanied by similar increases in p-nitrophenol hydroxylase . Antibodies to CYP2C11 recognised two immunorelated proteins, of which one was inducible by phenobarbital . The same inducer, but not dexamethasone, enhanced the N-demethylation of erythromycin but antibodies to rat CYP3A1 failed to detect any proteins . Finally, lauric acid hydroxylation was not detectable in chick embryo and, moreover, no immunoreacting band was visible following probing of microsomes with anti-CYP4A1 . It is concluded that proteins immunorelated to the mammalian CYP1 and CYP2 families are expressed in chick embryo but the regulation of the latter family in the embryo by exogenous chemicals differs markedly from that established for mammals.

Ir Med J, 1996 Jan-Feb, 89(1), 26 - 7
Orthopaedic complications following cardiac transplantation; Egan B et al.; Cardiac transplantation has become the treatment of choice for end stage heart disease . In 1990 2,000 transplants were performed worldwide . Orthopaedic Surgeons will be asked with increasing frequency to evaluate and treat bone and soft tissue problems with these patients . Orthopaedic service at the Mater Hospital has been involved in the follow-up treatment of orthopaedic complications in 46 transplant patients over a six year period . Thirty eight were male and eight were female . The ages were between 12 years and 65 years (mean 44.3) . Nine (20%) of these patients developed thirteen orthopaedic complications: A vascular Necrosis of the hip (AVN) (4), Soft tissue infections (3), Osteoporosis (2), Stress Fractures (2), Osteomyelitis (1) and Ostomalacia (1) . The mode of presentation, investigation and management of orthopaedic problems particular to these patients is described . Most patients who develop bony complications have had increased doses of steroids for episodes of rejection . This study highlights the special features of this patient population that require modification of the treatment approach such as the need to avoid the drug Erythromycin and the increased risk of AVN of the hip in patients who require high dose steroids.

Peptides, 1996, 17(7), 1237 - 41
Study of the binding of motilin to the membranes of enterocytes from rabbit jejunum; Alcalde AI et al.; The results obtained in the present work have shown that {125I}motilin bound specifically to basolateral (BL) membrane but it did not bind to the brush border (BB) membrane of the rabbit jejunum enterocyte . The {125I}motilin dissociation constant (Kd) was 95.58 +/- 15.0 pM and the receptor density (Bmax) was 2.54 +/- 0.40 fmol/mg protein . The binding of {125I}motilin to BL membrane was competitively inhibited by both unlabeled motilin and erythromycin . The IC50s were (2.1 +/- 0.4) 10(-8) M and (1.3 +/- 0.1) 10(-6) M for motilin and erythromycin, respectively, and the Ki were (6.83 +/- 1.3) 10(-9) M for motilin and (4.32 +/- 0.33) 10(-7) M for erythromycin . Saturation and competition binding studies showed interaction at only one class of binding sites in BL membrane.

Ann Dermatol Venereol, 1996, 123(6-7), 387 - 92
{Cutaneous and neurologic vasculitis disclosing EBV-selective immunodeficiency}; Grosieux C et al.; INTRODUCTION: Purtilo's syndrome or X-linked lymphoproliferative syndrome (XLP) is a rare genetic disorder affecting boys who have a selective immunodeficit towards Epstein Barr Virus (EBV) and who develop extremely severe forms of EBV infection, of which there are four major types: severe or fatal infectious mononucleosis (60 p . 100), lymphoma (23 p . 100), acquired hypo- or agamaglobulinemia (25 p . 100) and anemia or pancytopenia . We report a case of vasculitis (cutaneous and neurologic) which led to the discovery of a selective immunodeficit towards EBV, similar to Purtilo's syndrome . CASE REPORT: A 17 year-old male with no significant past medical history presented with an eruption initially felt to be consistent with pityriasis lichenoid . Treatment with erythromycin was initiated, this did not prevent the subsequent eruptions of cutaneous vasculitis lesions which were severe, prolonged, debilitating, and associated with fever and general deterioration of the patient condition . All etiologic studies were negative . A course of systemic corticosteroids was begun, but the cutaneous eruptions persisted; and in addition the patient developed signs of polyneuropathy in the lower extremities secondary to neurologic vasculitic lesions . New studies revealed an abnormal EBV serology (absence of anti-EBNA antibodies) as well as hypogammaglobulinemia, suggestive of a selective immunodeficit towards EBV resembling Purtilo's syndrome . DISCUSSION: In our patient, the development of an extensive vasculitis, characterized histologically by an intense lymphocytic infiltrate, positive for EBV, associated with hypogammaglobulinemia, and with abnormal serology suggests an anomaly in the immune response to EBV . Although the age of the patient and absence of family history make the Purtilo's syndrome uncertain, the nature of the immunodeficit is very similar and the patient could well develop a lymphoma . This case is significant in that the disease initially manifested itself as a cutaneous vasculitis, which was not been described previously.

Kurume Med J, 1996, 43(3), 207 - 217
Neutrophil chemotactic activity in cryptogenic organizing pneumonia and the response to erythromycin; Hotta M; The present study was aimed at elucidating the role of inflammatory cells in the pathogenesis of cryptogenic organizing pneumonia, and the mode of action of erythromycin in inhibiting the progression of the disease . Bronchoalveolar lavage fluid was obtained from 16 patients with cryptogenic organizing pneumonia and 4 control subjects . Neutrophil chemotactic activity was determined in relation to the concentration of two cytokines, interleukin-8 and tumor necrosis factor-alpha . Eight patients with cryptogenic organizing pneumonia, 4 with bronchoalveolar lavage fluid neutrophilia and 4 without, received low dose oral erythromycin daily (600 mg) for 2 to 3 months . Bronchoalveolar lavage fluid was obtained before and after treatment . In the bronchoalveolar lavage fluid of cryptogenic organizing pneumonia patients with bronchoalveolar lavage fluid neutrophilia, the levels of neutrophil chemotactic activity, interleukin-8, and tumor necrosis factor-alpha were significantly increased compared with levels measured in control subjects and in cryptogenic organizing pneumonia patients without bronchoalveolar lavage fluid neutrophilia . The level of interleukin-8 correlated with the percent of neutrophils and neutrophil chemotactic activity of bronchoalveolar lavage fluid, while the level of tumor necrosis factor-alpha did not . Furthermore, the levels of interleukin-8 and neutrophil chemotactic activity in the bronchoalveolar lavage fluid of cryptogenic organizing pneumonia patients with bronchoalveolar lavage fluid neutrophilia were significantly decreased following treatment with erythromycin . In contrast, the level of tumor necrosis factor-alpha was not affected by treatment with erythromycin . It is possible that cryptogenic organizing pneumonia is caused by neutrophil-mediated inflammation, and that the favorable clinical effect of erythromycin is due to inhibition of neutrophil accumulation in the peripheral airways through a biological activity other than bacteriostasis, e.g., local suppression of interleukin-8 production.

Acta Otolaryngol Suppl, 1996, 525, 73 - 8
Efficacy of long-term administration of clarithromycin in the treatment of intractable chronic sinusitis; Hashiba M et al.; Long-term erythromycin therapy has been reported as effective in the treatment of various chronic respiratory diseases, including chronic sinusitis . We investigated the clinical efficacy of long-term administration of the erythromycin derivative clarithromycin (CAM) in intractable cases of chronic sinusitis . Forty-five adult patients were treated with dosages of 400 mg/day for 8 to 12 weeks . The results were as follows . i) Improvement of symptoms and rhinoscopic findings was noted in 71.1% of the patients . ii) For periods of up to 12 weeks, clinical efficacy depended upon the duration of treatment . Administration for more than 12 weeks might further improve clinical results . iii) No significant side effects were noted during the course of CAM treatment . On the whole, CAM was at least as effective as erythromycin in the treatment of chronic sinusitis.

Peptides, 1996, 17(6), 901 - 7
Effect of motilin on gastrointestinal myoelectric activity in conscious rabbits; Guerrero-Lindner E et al.; Gastrointestinal myoelectric activity was investigated in conscious rabbits with chronically implanted electrodes . As rabbit stomach is never empty, food was removed 1 h before the beginning of recordings . Propagated activity fronts spontaneously started in the jejunum without associated changes in the antroduodenal area . Intravenous administration of either motilin (600-1500 ng/kg) or erythromycin (5-50 micrograms/kg) did not modify antral activity, but simultaneously increased duodenal and jejunal activity in a dose-dependent manner . Spontaneous and induced jejunal activity fronts showed some similarities . However, those induced did not propagate and were not followed by a quiescence period . The effects of motilin (900 ng/kg) and erythromycin (25 micrograms/kg) were resistant to atropine (0.5 mg/kg), hexamethonium (2 mg/kg), or ondansetron (0.5 mg/kg) . These results suggest that motilin is not a physiological modulator of the migrating myoelectric complex (MMC) in rabbits . Moreover, neither cholinergic nor 5-HT3 receptors are involved in either motilin or erythromycin-induced actions.

Microbiol Immunol, 1996, 40(8), 547 - 52
Continuous isolation and characterization of Chlamydia pneumoniae from a patient with diffuse panbronchiolitis; Miyashita N et al.; We succeeded in isolating Chlamydia pneumoniae organisms continuously from a 70-year-old man who had received chemotherapeutic treatment with low dosages of erythromycin for five years to improve diffuse panbronchiolitis (DPB) . He had two episodes of acute exacerbation of DPB and a total of six strains of C . pneumoniae were isolated at different stages during the past 13 months . The morphological properties and protein profiles of the elementary bodies of all the C . pneumoniae isolates were similar to each other . Interestingly, his serological response against C . pneumoniae in immunoblotting tests was differed between two episodes . The sera collected during the first episode reacted weakly to the major outer membrane protein (MOMP), whereas those collected during the second episode reacted strongly to the 60-kDa protein and weakly to MOMP . These facts suggest that the two different episodes occurred as a result of different mechanisms . Additionally, in spite of the low antibody titer by micro-immunofluorescence test in the second episode as compared with that of the first episode, the immune response against 60-kDa immunodominant protein increased markedly in the second episode, and we suspect that the second episode was due to an allergic reaction caused by this 60-kDa protein . These findings suggest that repeated or prolonged exposure to C . pneumoniae may be associated with acute exacerbations of chronic obstructive pulmonary disease, and that the patient should be noted as a possible source of C . pneumoniae infection.

Eur J Clin Pharmacol, 1996, 50(6), 501 - 8
Grapefruit juice does not enhance the effects of midazolam and triazolam in man; Vanakoski J et al.; OBJECTIVES: Since grapefruit juice (Gra) inhibits hepatic P450 (CYP3A4), we studied its potential to enhance the effects of midazolam (Mid) and triazolam (Trz), which are metabolized by the CYP3A4 isoenzyme . METHODS: In Study I parallel groups of healthy students were given orally Mid 10 mg with water or grapefruit juice (GraMid), two placebo groups receiving water or Gra . The effects of Mid were measured by psychomotor tests and by self-rating on visual analogue scales before and 30 and 90 min after intake . Study II was similar, but the post-treatment tests were at 45 and 90 min, and the active drugs used were 0.250 mg Trz, GraTrz, and Mid 10 mg . In the crossover Study III, 6 subjects took Mid 10 mg alone and with Gra (GraMid) and 750 mg erythromycin (EryMid) . Performance tests were made and blood was sampled before and 30, 60 and 90 min after intake . Midazolam and its active metabolite alpha-OH-midazolam were assayed by gas chromatography (GC) and radioreceptor assay (RRA) . RESULTS: In Study I, both Mid and GraMid impaired digit symbol substitution (DSS), letter cancellation (LC) and flicker fusion (CFF) at 90 min . GraMid had more effect (P < 0.05) than Mid on the DSS performance . Mid caused drowsiness at 30 and 90 min . Both Mid and GraMid caused clumsiness and a feeling of impaired performance at 90 min . In Study II, the active drugs impaired objective test performances (DSS, LC, CFF) at 90 min, without having a clear subjective effect . In Study III, Mid, EryMid and GraMid impaired performance in the DSS, LC and CFF tests . EryMid proved stronger than Mid and GraMid on DSS and LC tests at 30 min . Mean values of plasma midazolam (and alpha-OH-midazolam) at 30, 60, 90 and 120 min after Mid 10 mg were 68(19), 61(19), 43(14) and 42(12) micrograms.l-1 . The corresponding values after EryMid were 164(14), 137(13), 104(10) and 89(10) micrograms.l-1, and after GraMid 60(12), 69(16), 61(15) and 57 (14) micrograms.l-1 . CONCLUSIONS: The grapefruit juice used did have any particular interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in healthy young subjects.

Infection, 1996 Jan-Feb, 24(1), 73 - 5
Treatment failure in erythema migrans--a review; Weber K; Patients with erythema migrans can fail to respond to antibiotic therapy . Persistent or recurrent erythema migrans, major sequelae such as meningitis and arthritis, survival of Borrelia burgdorferi and significant and persistent increase of antibody titres against B . burgdorferi after antibiotic therapy are strong indications of a treatment failure . Most, if not all, antibiotics used so far have been associated with a treatment failure in patients with erythema migrans . Roxithromycin and erythromycin are definitely or probably ineffective . However, doxycycline, amoxicillin, cefuroxime, ceftriaxone, azithromycin and high-dose penicillin V perform comparably well.

Xenobiotica, 1996 Jan, 26(1), 49 - 63
Effects of canthaxanthin, astaxanthin, lycopene and lutein on liver xenobiotic-metabolizing enzymes in the rat; Gradelet S et al.; 1 . The catalytic activities of several phase I and II xenobiotic-metabolizing enzymes and the immunochemical detection of P4501A and 2B have been investigated in liver microsomes and cytosol of male rats fed for 15 days with diets containing canthaxanthin, astaxanthin, lycopene or lutein (as lutein esters) (300 mg/kg diet) and in rats fed increasing levels (10, 30, 100 and 300 ppm) of canthaxanthin or astaxanthin in the diet . 2 . Canthaxanthin increased the liver content of P450, the activities of NADH- and NADPH-cytochrome c reductase, and produced a substantial increase of some P450-dependent activities, especially ethoxyresorufin O-deethylase (EROD) (x 139) and methoxyresorufin O-demethylase (MROD) (x 26) . Canthaxanthin also increased pentoxy-(PROD) and benzoxyresorufin O-dealkylases (BROD), but did not affect . NADPH-cytochrome c reductase and erythromycin N-demethylase (ERDM) activities and decreased nitrosodimethylamine N-demethylase (NDMAD) activity . Phase II p-nitrophenol UDP-glucuronosyl transferase (4NP-UGT) and quinone reductase (QR) activities were also increased by canthaxanthin treatment . These enhancing effects on EROD, MROD and 4NP-UGT were clearly detectable at a dose as low as 10 ppm of canthaxanthin in the diet; the induction of QR was only observed in rats fed > or = 100 ppm . Astaxanthin induced the same pattern of enzymes activities as canthaxanthin, but to a lesser extent: its effects on phase I enzymes and 4NP-UGT were observed in rats fed > or = 100 ppm, and QR was not increased . Western blots of microsomal proteins clearly showed the induction of P4501A1 and 1A2 by canthaxanthin and astaxanthin . By contrast, lutein had no effect on the phase I and II xenobiotic-metabolizing enzymes activities measured . Lycopene only decreased NDMAD activity . 3 . The two 4-oxocarotenoids canthaxanthin and astaxanthin are substantial inducers of liver P4501A1 and 1A2 in the rat, and coinduce 4NP-UGT and QR, just like polycyclic aromatic hydrocarbon, beta-naphtoflavone or dioxin (TCDD) . However, these latter classical P4501A inducers also induce aldehyde dehydrogenase class 3 (ALDH3); this enzyme is not increased, or only marginally, by canthaxanthin and astaxanthin . These two oxocarotenoids form a new class of inducers of P4501A, are structurally very different from the classical inducers quoted above, which are ligands of the AH receptor.

Respiration, 1996, 63(1), 42 - 8
Interleukin 1 beta, tumor necrosis factor alpha, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy; Sakito O et al.; We measured the levels of interleukin (IL) 1 beta, tumor necrosis factor alpha, and IL-8 in bronchoalveolar lavage fluid (BALF) and sera of patients with diffuse panbronchiolitis (DPB) before and after administration of erythromycin or roxithromycin . The pretreatment levels of IL-1 beta and IL-8 were significantly higher in the BALF of patients with DPB than in the BALF of patients with sarcoidosis and controls . The tumor necrosis factor alpha level was also higher than in controls, but not statistically significant . There was a significant correlation between percentage of neutrophils and IL-8 level in the BALF of DPB patients (r = 0.509; p < 0.05) on the one hand and between IL-1 beta and IL-8 on the other (r = 0.476; p < 0.04) . Treatment for 1-24 months significantly reduced BALF levels of IL-1 beta and IL-8 of DPB patients in parallel with a reduction in BALF neutrophils . The serum level of IL-8 of DPB patients was higher, albeit insignificant, than that of controls and significantly lower than that in the BALF of the same patients (p = 0.0088) . Serum IL-1 beta was below the detection limit . In addition, the concentration of IL-8 in alveolar macrophages obtained from 2 volunteers before and after oral erythromycin administration also decreased ex vivo . Our results indicate that IL-8 induces the migration of neutrophils to inflammatory sites . It is possible that the macrolides impair production and/or secretion of these cytokines, ultimately reducing neutrophil accumulation in the airway.

Dermatology, 1996, 192(2), 143 - 5
Rosacea-like demodicosis in an HIV-positive child; Barrio J et al.; A second case of rosacea-like demodicosis in an HIV-positive child was seen at our center . No such cases have previously been published . The present case is a 2-year-old boy, the son of an HIV-positive mother, who responded well to oral erythromycin and topical metronidazole . The frequency of rosacea-like eruptions in HIV-negative children is very low . However, the incidence of these eruptions in HIV-positive children may have been underestimated . The pathogenic role of Demodex mites is discussed as well as the possible mechanisms for an exaggerated reaction.

Drug Metab Dispos, 1996 Jan, 24(1), 23 - 7
Erythromycin as a specific substrate for cytochrome P4503A isozymes and identification of a high-affinity erythromycin N-demethylase in adult female rats; Zhang XJ et al.; Erythromycin N-demethylation is catalyzed by cytochrome P4503A isozymes . By using {14C}methyl-labeled erythromycin, we were able to develop a N-demethylation assay that is more sensitive and specific than the colorimetric detection of formaldehyde formation . The increased sensitivity allows the use of very low substrate concentration with good sensitivity, 1 microM compared with 400 microM for the colorimetric assay . This 1 microM concentration is within pharmacological blood levels of erythromycin . Using this assay, we detected a high-affinity erythromycin N-demethylase in liver microsomes from untreated adult female rats that was previously unknown . This low KM activity could be inhibited by polyclonal anti-P4503A1 or P4503A2 antibodies to 95%, and these antibodies also detected a band in these microsomes on Western blots that had the same molecular weight (51 kDa) as cytochromes P4503A1/3A2 . Monoclonal antibodies specific for P4503A1 or P4503A2, however, did not react with this band . No inhibitory effect was observed with monoclonal antibody P124, which inhibited the erythromycin N-demethylation both in liver microsomes from untreated adult males (P4503A2) and dexamethasone-pretreated adult females (P4503A1) . Alternative P4503A substrates (testosterone, troleandomycin, cortisol, corticosterone, cyclosporin A, and 17 alpha-ethinylestradiol) inhibited erythromycin N-demethylation catalyzed by liver microsomes from untreated male, untreated female, and dexamethasone-pretreated female rats, whereas digitoxin and theophylline had no inhibitory effects . Put together, these data suggest that this demethylase in liver microsomes of untreated female rats is not P4503A1 or P4503A2, but P4503A related.

Peptides, 1996, 17(4), 701 - 7
Heterogeneity of motilin receptors in the gastrointestinal tract of the rabbit; Poitras P et al.; Motilin, a 22-amino acid peptide synthesized in endocrine cells of intestinal mucosa, stimulates GI smooth muscle contractility . To elucidate the mode of action of motilin, we attempted to determine whether motilin receptors are localized on nerve cells or on smooth muscle cells of the GI tract . Mucosa-free tissues from rabbit antrum and duodenum were homogenized separately with a Polytron prior to differential centrifugation to obtain synaptosome or plasma membrane-enriched fractions, as determined by the distribution of {3H}saxitoxin (SAX) binding (neural membranes) and 5' nucleotidase (5'N) activity (smooth muscle plasma membranes) . Motilin binding was evaluated by the displacement of {125I}motilin by motilin (1-22) on the various membrane fractions . In the antrum, motilin binding was highly correlated with SAX binding (r = 0.81, p < 0.0005), and also significantly with 5'N activity (r = 0.54, p < 0.05) . In the duodenum, motilin binding correlated significantly with 5'N activity (r = 0.67, p < 0.005), but not with SAX binding (r = -0.11, NS) . Receptor affinity, for the motilin antagonist MOT(1-12){CH2NH}10-11, for motilin(1-22), and for the motilin agonist erythromycin lactobionate was significantly (p < 0.001, p < 0.001, and p < 0.05, respectively) higher in SAX-enriched fractions from the antrum than in 5'N-enriched fractions from the duodenum . Therefore, in the rabbit: 1) motilin receptors appear to be predominantly located on nerve tissues in the antrum and restricted to smooth muscle cells in the duodenum, and 2) antral receptors and duodenal receptors displayed different pharmacological characteristics, probably corresponding to two specific and heterogeneous motilin receptor subtypes.

Peptides, 1996, 17(2), 203 - 8
Isolation, sequence, and bioactivity of chicken motilin; De Clercq P et al.; Motilin was isolated from acid extracts of the small intestine of chickens by a combination of gel filtration chromatography, ion-exchange, and reverse-phase HPLC . The purification was monitored using a radioreceptor assay . The sequence of chicken motilin is FVPFFTQSDIQKMQEK-ERNKGQ . Although the six residues differing from porcine motilin (4, 7-10, and 12) are mostly in the pharmacophore of porcine motilin, the affinity of chicken motilin and of the (1-14) fragment of chicken motilin for the motilin receptor of rabbit antral smooth muscle is not much reduced (pKds of 8.90 and 8.45), compared with the affinity of {Nle13}porcine motilin (pKd 9.12) . With smooth muscle tissue of the chicken, however, receptors could not be demonstrated with binding studies . In the tissue bath chicken motilin induced a dose-dependent tonic contraction, which was most pronounced with muscle strips prepared from chicken jejunum . This response was blocked by the Ca2+ antagonist verapamil, but atropine, TTX, L-NNA, guanethidine, prazosin, and yohimbine had no effect . The pEC50 for chicken motilin in the chicken jejunum was 7.41 . Motilins from other species had lower potencies, and {Phe3, Leu13}porcine motilin, an antagonist in the rabbit, was an agonist in the chicken . The motilin agonists erythromycin A and EM-523 were almost without effect . Tested against rabbit duodenum, chicken motilin had a smaller potency than mammalian motilins . Thus, chicken motilin and the chicken motilin receptor differ from their mammalian counterparts.

Life Sci, 1996, 59(10), 821 - 33
Study of the action of intramuscularly administered erythromycin on the L-threonine transport and the digestive enzymatic activity in rabbit jejunum; Alcalde AI et al.; Erythromycin has been shown to inhibit the intestinal transport of L-threonine and D-galactose in strips of mucosal jejunum when it was directly added to the incubation medium . Nevertheless, the effect of erythromycin administered therapeutically by intramuscular injection on both the intestinal absorption of nutrients and the intestinal digestive activity, remains unknown . The results obtained show that, firstly, the intestinal absorption of L-threonine is inhibited in animals treated with erythromycin . The kinetic study shows that the effect seems to be mainly due to an alteration of the affinity apparent constant (Kt) of the Na(+)-dependent system of transport located in the mucosal border . However, the Na(+)-dependent L-threonine transport in BBMV was not altered by the treatment with erythromycin . The (Na(+)-K+) ATPase activity in BLMV from treated jejunum was 40% of the activity in control BLMV . Secondly, the treatment with erythromycin did not modify the digestive enzymatic activity of sucrase and aminopeptidase N.

Skin Pharmacol, 1996, 9(2), 104 - 10
Evaluation of the effect of zinc acetate on the stratum corneum penetration kinetics of erythromycin in healthy male volunteers; van Hoogdalem EJ et al.; Erythromycin with or without additional zinc acetate is used topically in the treatment of acne vulgaris . A potential effect of zinc on the stratum corneum penetration of erythromycin was investigated in human volunteers . Skin surface washings and tape strippings from the skin of the back were collected after drug applications in 12 subjects for quantification of erythromycin levels . Zinc acetate increased the amount remaining on the back skin at 6 h after application from 40 +/- 19 to 56 +/- 15% of the dose and, vice versa, reduced the amount in stratum corneum strips from 22 +/- 7 to 18 +/- 7%, both with statistical significance . The effect varied with body region . Zinc acetate thus provided to prolong the residence time of erythromycin on the skin.

Vet Microbiol, 1996 Jan, 48(1-2), 41 - 50
Characterization of tetracycline and erythromycin resistance in Actinobacillus pleuropneumoniae; Wasteson Y et al.; Minimum inhibitory concentrations to tetracycline and erythromycin were determined for nineteen isolates of Actinobacillus pleuropneumoniae of Norwegian origin . The isolates were screened for rRNA methylase determinants (Erm genes) and for the tetracycline resistance Tet B determinant, using oligonucleotide probes, polymerase chain reaction and hybridization . Ten isolates (53%) carried the Erm C determinant, two isolates (10%) carried the Erm A determinant, four isolates (21%) carried both the Erm A and the Erm C determinants, and three isolates (16%) carried none of the Erm determinants examined . Eight isolates (45%) carried the Tet B determinant . Selected isolates were shown to transfer the Erm C and Erm A determinants at a frequency of 10(-7)-10(-9) per recipient cell . This is the first description of A . pleuropneumoniae carrying either Erm A, Erm C or/and Tet B determinants.

J Int Med Res, 1996 Jan-Feb, 24(1), 109 - 14
Clinical evaluation of roxithromycin in patients with acne; Akamatsu H et al.; On the basis of reports that erythromycin is effective in the treatment of acne, we investigated whether roxithromycin (ROM), a new derivative of erythromycin, might also be effective in treating acne . Roxithromycin was administered to 30 patients with acne for 8 weeks . General improvement was assessed 8 weeks after the initiation of the therapy with a six-graded scale as follows; 1: good improvement, 2: moderate improvement, 3: slight improvement, 4: no change, 5: worsening, and 6: no assessment . The percentage of good or moderate improvement was 73.3%, and that of good improvement alone was 20.0% . Our results suggest that ROM is effective in the treatment of acne.

Int J STD AIDS, 1996, 7 Suppl 1, 13 - 5
Treatment of syphilis with azithromycin; Mashkilleyson AL et al.; The efficacy of oral azithromycin (500 mg daily for 10 days or 500 mg on alternate days for 11 days) in 100 patients with seropositive syphilis was studied . Clinical manifestations regressed more rapidly in azithromycin-treated patients compared with patients who received erythromycin or penicillin, and there was also a more rapid reduction in serum antibody levels . In 90.3% of patients, the complete resolution of classic serological tests was observed within 4 months of completion of the azithromycin treatment . The immobilization (TPI) test and absorbed fluorescent treponema antibody tests became negative 12 months after treatment in 40% of patients . After 4 years of follow-up, no symptoms of neurosyphilis or syphilitic changes of visceral organs were observed.

J Toxicol Clin Toxicol, 1996, 34(1), 93 - 5
Erythromycin-induced acute pancreatitis; Fang CC et al.; BACKGROUND: Pancreatitis due to ingestion of erythromycin is rare . CASE REPORT: A 20-year-old woman took erythromycin 3 g and acetaminophen 6 g before a tooth extraction . Forty minutes later, she experienced severe abdominal pain, nausea, and vomiting . The serum amylase and lipase were elevated . She recovered from the pancreatitis without sequelae after supportive treatment . CONCLUSION: This is the fourth reported case of erythromycin-induced acute pancreatitis in the English literature.

Life Sci, 1996, 58(17), 1413 - 23
Effect of motilin, somatostatin and bombesin on gastroduodenal myoelectric activity in sheep; Plaza MA et al.; The effects of motilin, erythromycin, somatostatin and bombesin on antroduodenal myoelectric activity were investigated in conscious sheep . Myoelectric recordings were obtained from electrodes chronically implanted on the antrum and duodenal bulb . Peptides or erythromycin were infused intravenously (i.v.) during 5 min . Antagonists were injected i.v . as a bolus . Neither motilin (2.5-80 ng/kg/min) nor erythromycin (2-16 micrograms/kg/min) modified the antroduodenal myoelectric activity, although a single bolus of these compounds (250 ng/kg and 50 micrograms/kg respectively) increased the antral activity . Somatostatin at 5 ng/kg/min induced a decrease in the myoelectric activity of antrum and duodenum . However, doses of 10 to 40 ng/kg/min evoked a duodenal phase III-like activity with a subsequent quiescence period and a concomitant inhibition of the antral activity . These effects were reproduced by bombesin (2.5 to 40 ng/kg/min) . Furthermore, an initial increase in the myoelectric activity and in the frequency of slow waves were recorded in the antrum when the highest doses were used . On the other hand, atropine (0.2 mg/kg) or hexamethonium (2 mg/kg) caused a long-lasting inhibition of antroduodenal myoelectric activity . These cholinergic antagonists abolished the effects induced by somatostatin (20 ng/kg/min) but not those evoked by bombesin but not motilin are putative modulators of the migrating myoelectric complex (MMC) in sheep . Moreover, a cholinergic neural pathway is involved in the somatostatin but not in the bombesin-induced effects.

Cancer Res, 1996 Jan 1, 56(1), 58 - 65
Metabolism of docetaxel by human cytochromes P450: interactions with paclitaxel and other antineoplastic drugs; Royer I et al.; The metabolism of docetaxel by human liver microsomes was investigated in vitro and compared with that of paclitaxel . A main docetaxel metabolite was generated by human liver microsomes in the presence of NADPH: retention time in high pressure liquid chromatography and its ion fragmentation in mass spectrometry were identical to those of the authentic derivative hydroxylated at the butyl group of the C13 side chain . Kinetic measurements and chemical and immunological inhibitions demonstrated that CYP3A was implicated in the hydroxylation of docetaxel: Km (2 microM) and Vm values of docetaxel for human liver microsomes were comparable to those calculated for the formation of metabolite p-hydroxy-phenyl C3' paclitaxel (M4) . Docetaxel hydroxylation correlated only with the CYP3A content of microsomes and with CYP3A-dependent 6 beta-hydroxylation of testosterone and 16-hydroxylation of dehydroepiandrosterone . The formation of hydroxydocetaxel was strongly reduced by CYP3A inhibitors such as ketoconazole, midazolam, erythromycin, testosterone, orphenadrine, and troleandomycin, whereas quinidine (CYP2D6), hexobarbital, tolbutamide, and mephenytoin (CYP2C) had no or little effect . The hydroxylation of docetaxel exhibited a highly positive correlation with the formation of metabolite M4 of paclitaxel (r = 0.929, P < 0.0001, n = 12), but not with its 6-hydroxylation (r = 0.48, P > 0.15) . Docetaxel abolished the hydroxylation of paclitaxel metabolite M4, but was totally inactive on its 6 alpha-hydroxylation . Conversely, paclitaxel reduced significantly the hydroxylation of docetaxel . We examined in vitro the possible interaction among docetaxel, paclitaxel, and drugs which could be associated during chemotherapy . Cisplatin, verapamil, doxorubicin, vinblastine, and vincristine at concentrations usually recommended did not markedly modify taxoid metabolism . Ranitidine and diphenylhydramine had no effect, but 100 microM cimetidine partially inhibited the formation of 6 alpha-hydroxypaclitaxel . Pretreatment of patients with barbiturates strikingly stimulated docetaxel hydroxylation, whereas no acceleration of docetaxel hydroxylation was noticed in a patient receiving steroids.

N Engl J Med, 1995 Dec 28, 333(26), 1732 - 6
Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis; Hauth JC et al.; BACKGROUND . Pregnant women with bacterial vaginosis may be at increased risk for preterm delivery . We investigated whether treatment with metronidazole and erythromycin during the second trimester would lower the incidence of delivery before 37 weeks' gestation . METHODS . In 624 pregnant women at risk for delivering prematurely, vaginal and cervical cultures and other laboratory tests for bacterial vaginosis were performed at a mean of 22.9 weeks' gestation . We then performed a 2:1 double-blind randomization to treatment with metronidazole and erythromycin (433 women) or placebo (191 women) . After treatment, the vaginal and cervical tests were repeated and a second course of treatment was given to women who had bacterial vaginosis at that time (a mean of 27.6 weeks' gestation) . RESULTS . A total of 178 women (29 percent) delivered infants at less than 37 weeks' gestation . Eight women were lost to follow-up . In the remaining population, 110 of the 426 women assigned to metronidazole and erythromycin (26 percent) delivered prematurely, as compared with 68 of the 190 assigned to placebo (36 percent, P = 0.01) . However, the association between the study treatment and lower rates of prematurity was observed only among the 258 women who had bacterial vaginosis (rate of preterm delivery, 31 percent with treatment vs . 49 percent with placebo; P = 0.006) . Of the 358 women who did not have bacterial vaginosis when initially examined, 22 percent of those assigned to metronidazole and erythromycin and 25 percent of those assigned to placebo delivered prematurely (P = 0.55) . The lower rate of preterm delivery among the women with bacterial vaginosis who were assigned to the study treatment was observed both in women at risk because of previous preterm delivery (preterm delivery in the treatment group, 39 percent; and in the placebo group, 57 percent; P = 0.02) and in women who weighed less than 50 kg before pregnancy (preterm delivery in the treatment group, 14 percent; and in the placebo group, 33 percent; P = 0.04) . CONCLUSIONS . Treatment with metronidazole and erythromycin reduced rates of premature delivery in women with bacterial vaginosis and an increased risk for preterm delivery.

Eur J Pharmacol, 1995 Dec 7, 293(4), 385 - 93
Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker rat; Irizar A et al.; The hepatic expression of xenobiotic-metabolising cytochrome P450 isoforms in the genetically obese Zucker rat, a model of obesity, was compared to that of its lean littermate . Cytochrome P450 (CYP) levels were determined using diagnostic substrates and/or immunologically in Western blot analyses . When compared with the lean Zucker rat, the obese animal exhibited hyperglycaemia, hypercholesterolaemia, marked hyperinsulinaemia and hypertriglyceridaemia but was normoketonaemic . CYP3A and CYP1A2 levels were higher in the obese Zucker rat when compared with the lean littermate but, in contrast, a protein recognised by human CYP2D6 and, to a lesser extent, CYP2C11 levels were lower . Pretreatment with acetone, dexamethasone and clofibrate resulted in enhanced p-nitrophenol hydroxylase (CYP2E), erythromycin N-demethylase (CYP3A) and lauric acid hydroxylase (CYP4A) activities respectively in the liver of the lean Zucker rat but, in contrast, the obese Zucker rat was refractive to such treatment; similarly, hepatic apoprotein levels of the CYP2E and CYP4A subfamilies were increased markedly only in the lean Zucker rat . It is concluded that CYP2E, CYP3A and CYP4A subfamilies are poorly expressed in the obese Zucker rat, and this rat strain may serve as a good model for elucidating the molecular mechanisms of induction of these cytochrome P450 proteins.

Zhonghua Wai Ke Za Zhi, 1995 Dec, 33(12), 757 - 9
{Contractile effect of erythromycin on the gallbladder}; Fu D et al.; The contractile effect of erythromycin on gallbladder has not been fully understood . This effect was investigated in the isolated gallbladder of golden hamster gallstone model and in human by ultrasonography . Erythromycicn induced concentration-dependent contraction of gallbladder in 28 hamsters with normal diet and in 13 with gallstone diet . In those two groups the maximal contractile effect and the half maximal effective concentration were similar (P > 0.05) . In clinical study, the fasting volume and residual volume were significantly diminished in 23 volunteers and 15 with cholecystolithiasis and the ejection fraction and the constant emptying rate increased (P < 0.05) . Erythromycin also modulated the hypomotility of gallbladder in gallstone patients, hence could be used in gallbladder hypomotility cases.

Drug Metab Dispos, 1995 Dec, 23(12), 1379 - 82
Enhanced rates of cytochrome P450 metabolic-intermediate complex formation from nonmacrolide amines in rifampicin-treated rabbit liver microsomes; Franklin MR; The formation of cytochrome P450 metabolic-intermediate (MI) complexes from amine-containing drugs unrelated to macrolide antibiotics was investigated in hepatic microsomes from rifampicin-induced rabbits . Rifampicin treatment doubled the amount of total cytochrome P450 present . As evidenced by increased rates of erythromycin N-demethylation and MI complex formation from troleandomycin without increases in other isozyme selective oxidation reactions, the increase was predominately in the cytochrome P4503A subfamily . Fluoxetine, benzylamphetamine, propoxyphene, and norpropoxyphene formed MI complexes at rates similar to that for troleandomycin . Rates for 1-alpha-acetylmethadol and SKF 525A were 2- to 3-fold higher, and rates for the secondary amine derivatives of these two compounds, nor-1-alpha-acetylmethadol and SKF 8742A, were approximately 5-fold higher than with troleandomycin . For the SKF and acetylmethadol compounds, the rates were much higher in rifampicin-induced microsomes, compared with phenobarbital-induced microsomes . MI complex formation from benzylamphetamine was the reverse . The rate of MI complex formation from benzylamphetamine in phenobarbital-induced microsomes was similar to that from SKF 8742A and nor-1-alpha-acetylmethadol in microsomes from rabbits treated with the highest dose of rifampicin . Cytochrome P450 MI complex formation from all compounds was either low or absent from microsomes of vehicle-treated animals.

Drug Metab Dispos, 1995 Dec, 23(12), 1315 - 24
Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability; Lampen A et al.; The small intestinal metabolism of tacrolimus, which is used as an immunosuppressant in transplantation medicine, was investigated in this study . Tacrolimus was metabolized in vitro by isolated human, pig, and rat small intestinal microsomes . The metabolites generated were identified by HPLC/MS . Tacrolimus and its metabolites were quantified using HPLC or HPLC/MS . The cytochrome P450 (CYP) enzymes responsible for tacrolimus metabolism in small intestine were identified using specific CYP antibodies and inhibitors . For characterization of the interindividual variability, microsomes were isolated from small intestinal samples of patients who had undergone resection for various reasons . In an in vitro model using pig small intestinal microsomes, 32 drugs were analyzed for their interactions with tacrolimus metabolism . After incubation with human, rat, and pig small intestinal microsomes, the metabolites 13-O-demethyl and 13,15-O-demethyl tacrolimus were identified . The metabolism of tacrolimus by human small intestine was inhibited by anti-CYP3A, troleandomycin, and erythromycin, indicating that, as in the liver, CYP3A enzymes are the major enzymes for tacrolimus metabolism in the human small intestine . Metabolism of tacrolimus by small intestinal microsomes isolated from 14 different patients varied between 24 and 110 pmol/13-O-demethyl tacrolimus/min/mg microsomal protein, with a mean +/- SD of 54.2 +/- 29.2 pmol/min/mg . Of 32 drugs tested, 15 were found to inhibit small intestinal tacrolimus metabolism: bromocryptine, corticosterone, cyclosporine, dexamethasone, ergotamine, erythromycin, ethinyl estradiol, josamycin, ketoconazole, nifedipine, omeprazole, progesterone, rapamycin, troleandomycin, and verapamil . All of these drugs inhibited tacrolimus metabolism by human liver microsomes as well . It is concluded that tacrolimus is metabolized by cytochrome CYP3A enzymes in the small intestine . The rate of the CYP3A enzymatic activities varies about 5 times from patient to patient, and drugs that interfere with the in vitro metabolism of tacrolimus in the liver also inhibit its small intestinal metabolism.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 1995 Dec, 80(6), 660 - 5
Dental anxiety and the absorption of orally administered erythromycin stearate; Coulter WA et al.; Erythromycin stearate is an acid labile antibiotic, therefore fear and apprehension, which are known to affect gastric motility, may produce erratic absorption resulting in lower serum levels . The mean (SD) serum erythromycin concentration 75 minutes after a 1.5 gm oral dose of erythromycin stearate to 45 patients was 8.7 (4.8) mg/L and ranged widely from 0.4 to 20.5 mg/L . The serum concentration of erythromycin was below therapeutic levels (1.0 mg/L) in two patients . No significant association was found between anxiety and serum levels of erythromycin when age, gender, and gastric distress were taken into account . It is concluded that dental anxiety may indirectly influence the uptake of oral erythromycin stearate; but this relationship is complex, and there is no evidence from this study that increased dental anxiety decreases the uptake of the drug.

Antimicrob Agents Chemother, 1995 Dec, 39(12), 2770 - 3
Transition mutations in the 23S rRNA of erythromycin-resistant isolates of Mycoplasma pneumoniae; Lucier TS et al.; Erythromycin is the drug of choice for treatment of Mycoplasma pneumoniae infections due to its susceptibility to low levels of this antibiotic . After exposure of susceptible strains to erythromycin in vitro and in vivo, mutants resistant to erythromycin and other macrolides were isolated . Their phenotypes have been characterized, but the genetic basis for resistance has never been determined . We isolated two resistant mutants (M129-ER1 and M129-ER2) by growing M . pneumoniae M129 on agar containing different amounts of erythromycin . In broth dilution tests both strains displayed resistance to high levels of several macrolide-lincosamide-streptogramin B (MLS) antibiotics . In binding studies, ribosomes isolated from the resistant strains exhibited significantly lower affinity for {14C}erythromycin than did ribosomes from the M129 parent strain . Sequencing of DNA amplified from the region of the 2S rRNA gene encoding domain V revealed an A-to-G transition in the central loop at position 2063 of M129-ER1 and a similar A-to-G transition at position 2064 in M129-ER2 . Transitions at homologous locations in the 23S rRNA from other organisms have been shown to result in resistance to MLS antibiotics . Thus, MLS-like resistance can occur in M . pneumoniae as the result of point mutations in the 23S rRNA gene which reduce the affinity of these antibiotics for the ribosome . Since they involve only single-base changes, development of resistance to erythromycin in vivo by these mechanisms could be relatively frequent event.

Microbiology, 1995 Dec, 141 ( Pt 12), 3105 - 11
The physiology of erythromycin biosynthesis in cyclic fed batch culture; Lynch HC et al.; Antibiotic production in Saccharopolyspora erythraea was significantly enhanced in cyclic fed batch culture (c.f.b.c) compared to batch culture, whereas chemostat culture resulted in reduced production . C.f.b.c . allowed the specific growth rate to be varied, with time, according to an asymptotically decreasing trajectory without the necessity for nutrient exhaustion . It was, therefore, possible to increase productivity by increasing the growth-limiting substrate concentration . It was necessary to apply the c.f.b.c . regime to early-exponential-phase cultures in order to obtain a stable, nutrient-limited, c.f.b.c . The antibiotic production rate during any c.f.b.c . cycle was dependent on the relationship between the specific growth rate at the time and the growth rate at the start of the cycle.

Ophthalmologe, 1995 Dec, 92(6), 823 - 8
{Erythema exsudativum multiforme major}; Kuper K et al.; Erythema exudativum multiforme major (EEMM), also know as Stevens-Johnson syndrome, may cause severe conjunctival and corneal alterations . The etiology remains unknown . The aim of are study was to evaluate the clinical course, therapy and prognosis of ocular involvement . PATIENTS AND METHODS: In a retrospective study, we evaluated ten patients with EEMM who were treated between 1986 and 1994 at the University Eye Clinic Tubingen . RESULTS: The age of the four female and six male patients varied between 5 and 70 years . Drugs as a possible precipitating factor were found in all cases (acetylsalicylicacid, sulfonamide, erythromycin, cotrimoxazole, Valproinicacid, paracetamol) . Eight patients experienced an infection at the same time . Clinically, we were able to differentiate two groups regarding severity of the disease . Seven patients were characterized by ocular alterations that only involved the conjunctiva, leading to conjunctival scars . In those cases local treatment with antibiotics and corticosteroids was effective . In the second group severe ocular damage occurred, with symblephara, keratinization and consecutive perforating keratoplasty . Secondary infections became evident in a total of six cases from the two groups . SUMMARY: Drugs as a possible precipitating factor could be identified in all cases . In eight of ten patients previous infection was known . This agrees with literatures reports of viral infections (e.g . herpes simplex) as cofactors causing EEMM, especially for the aggressive form, remains unresolved . The danger of possible superinfection should always be taken into consideration.

J Pharmacol Exp Ther, 1995 Dec, 275(3), 1608 - 13
Inhibition of the rat cytochrome P450 3A2 by an antisense phosphorothioate oligodeoxynucleotide in vivo; Desjardins JP et al.; CYP3A2 is one of the most abundantly expressed cytochrome P450s (CYPs) in the rat liver and metabolizes numerous clinically important drugs . Studies were designed to examine efficacy, potency and specificity of antisense inhibition of CYP3A2 in vivo . Three phosphorothioate ODNs were used: 3A2-ATG, antisense to the CYP3A2 mRNA translational start site; 3A2-REV, 5' to 3' reverse sequence of 3A2-ATG; and C-MYC, antisense to the C-MYC mRNA translational start site . Midazolam (MZ) sleep times were used as CYP3A2-specific in vivo marker in male Sprague-Dawley rats . Administration of 1 mg/day 3A2-ATG for 2 days i.p . significantly increased MZ sleep times from 22.4 +/- 0.4 (saline) to 35.3 +/- 1.5 min . Administration of equivalent doses of noncomplementary 3A2-REV or C-MYC produced no significant changes in MZ sleep times (22.4 +/- 0.6 and 22.8 +/- 1.3, respectively) . Liver microsomal erythromycin demethylase activity, a specific CYP3A2 assay, was significantly decreased from 124 +/- 13 mumol/mg per min in saline controls to 63.8 +/- 8 in 3A2-ATG-treated rats . Enzyme activities for CYPs 2E1, 1A1/2 and 2B1/2 were not significantly different between saline controls and 3A2-ATG-treated animals . The control ODNs 3A2-REV and C-MYC had no significant changes in enzymatic activities compared to saline . Western blot analysis revealed decreases in CYP3A2 protein but not CYP2B1 protein in 3A2-ATG rat microsomes compared to controls . These studies demonstrate for the first time that antisense ODNs can effectively, potently, and specifically inhibit CYP3A2 in vivo.

Obstet Gynecol, 1995 Dec, 86(6), 1021 - 5
Amoxicillin or erythromycin for the treatment of antenatal chlamydial infection: a meta-analysis; Turrentine MA et al.; OBJECTIVE: To compare the effectiveness of amoxicillin and erythromycin for the treatment of antenatal Chlamydia trachomatis infection by meta-analysis of available trials involving random assignment of subjects . DATA SOURCES: A computer search of English-language abstracts using MEDLINE and the Cochrane Pregnancy and Childbirth Database (medical subject heading terms: pregnancy, chlamydia, erythromycin, amoxicillin, antenatal antibiotics) was supplemented with a review of the bibliographies of the relevant articles generated by the computer search . METHODS OF STUDY SELECTION: Five trials were identified, four of which met our inclusion criteria for the meta-analysis . DATA EXTRACTION AND SYNTHESIS: Trials to be included in this meta-analysis underwent trial quality evaluation and data abstraction . An estimate of the relative risk (RR) was calculated for the dichotomous outcomes using a fixed-effects model . The pooled RR for the effectiveness of amoxicillin compared with erythromycin was 1.11 (95% confidence interval {CI} 1.05-1.18), and the pooled RR for gastrointestinal side effects of amoxicillin compared with erythromycin was 0.29 (95% CI 0.20-0.42) . The pooled RR for gastrointestinal side effects that resulted in discontinuation of therapy of amoxicillin compared with erythromycin was 0.14 (95% CI 0.06-0.36) . CONCLUSION: The available data suggest that amoxicillin is more effective than erythromycin for the treatment of antenatal C trachomatis infection and has fewer gastrointestinal side effects, leading to better compliance.

Eur J Pharmacol, 1995 Nov 24, 286(3), 241 - 7
Antagonistic properties of {Phe3,Leu13}porcine motilin; Depoortere I et al.; We describe the antagonistic properties due to the replacement of Pro3 by phenylalanine in porcine motilin . The analogue, {Phe3,Leu13} porcine motilin (OHM-11526), displaces iodinated {Nle13}porcine motilin bound to a homogenate of rabbit antral smooth muscle tissue . The dissociation constant (pKd) was 9.26 +/- 0.04, versus 9.11 +/- 0.01 for motilin and 8.24 +/- 0.06 for ANQ-11125, the (1-14) fragment of OHM-11526 . The Hill coefficient was close to one and Schild plot analysis confirmed the competitive nature of the interaction . In the tissue bath OHM-11526 was unable to induce contractions of segments of rabbit duodenum . At a concentration of 10(-6) M, OHM-11526 was unable to induce contractions of segments of rabbit duodenum . At a concentration of 10(-6) M, OHM-11526 inhibited the effect of maximally effective doses of porcine motilin and of the erythromycin derivative, EM-523, but was without effect on contractions induced by acetylcholine, substance P and serotonin . Increasing doses of OHM-11526 shifted the dose-response curves of motilin and EM-523 to the right, but caused a depression of the maximal response as well . From the motilin curves, and assuming a dual competitive and non-competitive interaction, the pA2 was 7.79 +/- 0.08, the pD'2 6.91 +/- 0.08 . The EM-523 curves yielded comparable data (pA2 = 8.10 +/- 0.12 and pD'2 = 7.06 +/- 0.13) . OHM-11526 also blocked the motilin responses observed with smooth muscle strips from the rabbit and human antrum . However, in a preparation of the chicken small intestine, OHM-11526 was a full agonist with a potency (pD2 = 6.84) comparable to that of porcine motilin (pD2 = 6.71) . Our data confirm the interaction of motilides with the motilin receptor . Due to its increased affinity for the motilin receptor, OHM-11526 will be a valuable took for studying the physiology of motilin and the pharmacology of motilin and motilides.

Lancet, 1995 Nov 18, 346(8986), 1326 - 9
Pertussis in adults: frequency of transmission after household exposure; Wirsing von Konig CH et al.; Although pertussis in adults is well documented, opinions differ about incidence of adult disease and about the role of adults as reservoirs of infection . We made use of a prospective household contact study of an acellular pertussis vaccine to collect data about pertussis in adults . All members of families with an index case of pertussis were monitored for respiratory symptoms, and pertussis was confirmed by laboratory tests . In 122 households, 104 children (85%) and 18 adults (15%) were the source of pertussis . These households consisted of 265 adults (aged 19-83 years), in 84 of whom (31%) pertussis was confirmed . Of these 84, 81% had respiratory symptoms for 21 days or more . The spread of pertussis was independent of whether a child (74/104) or an adult (14/18) was the index case . Most adult index cases had no pertussis recall (odds ratio 11.8) . The overall attack rate in adult contacts was 0.267 and was independent of the social status and the size of the family and of a pertussis recall, although it differed significantly between women and men (p < 0.05) . Erythromycin treatment of the index case reduced the attack rate significantly (p < 0.05) . Patients whose first pertussis episode dated back more than 20 years had similar symptoms and attack rates to patients without a recall . We conclude that adults are often involved in the spread of pertussis, and that they can be susceptible to reinfection 20 years after a first pertussis episode.

Nature, 1995 Nov 16, 378(6554), 263 - 6
Cell-free synthesis of polyketides by recombinant erythromycin polyketide synthases; Pieper R et al.; Modular polyketide synthases (PKSs) are complex multi-enzyme proteins that catalyse the bacterial biosynthesis of many pharmaceutically useful polyketides . The PKSs are organized into a series of modules, each containing the active catalytic sites required for one step in the synthesis process . Here we report a method for cell-free enzymatic synthesis of 6-deoxyerythronolide B (6-dEB), the parent molecule of the antibiotic erythromycin A, using recombinant 6-deoxyerythronolide B synthase (DEBS), a modular PKS with at least 28 distinct active sites . We have also synthesized in vitro a triketide lactone by using a truncated mutant of DEBS . The availability of such cell-free synthetic routes will allow direct investigation of the structural and mechanistic basis for the unusual combination of high substrate specificity and tolerance to genetic reprogramming found in this enzyme family.

Arerugi, 1995 Nov, 44(11), 1322 - 30
Suppression of cytokine production of human memory T cells by roxithromycin; Hirohata S et al.; Recent reports have suggested that erythromycin (EM) might have immunomodulatory activities . Roxithromycin (Rox) is a new macrolide, which has more favorable pharmacokinetic properties than EM . The current studies therefore examined the effects of Rox on the in vitro function of human T cells . Interferon-gamma (IFN-gamma) production was induced from highly purified T cells and CD45RA (-) T cell subsets from normal individuals by stimulation with immobilized anti-CD3 . Rox at its pharmacologically attainable concentrations suppressed the IFN-gamma production of CD45RA (-) T cells stimulated with immobilized anti-CD3, but not that of unfractionated T cells . EM also preferentially suppressed the IFN-gamma production of CD45RA (-) T cells, but less effectively than Rox . Rox also preferentially suppressed the IL-2 production of immobilized anti-CD3 stimulated CD45RA (-) T cells . These results suggest that Rox may preferentially suppress the IFN-gamma production of memory T cells, but not that of naive T cells . Moreover, the data call for considering Rox as a possible immunomodulator for the treatment of various autoimmune disorders in which the abnormal function of CD45RA (-) T cells is involved, especially Behcet's disease.

Biochem Cell Biol, 1995 Nov-Dec, 73(11-12), 1061 - 70
Comparison of functional peptide encoded in the Escherichia coli 23S rRNA with other peptides involved in cis-regulation of translation; Tenson T et al.; A new approach for studying functional rRNA fragments has been developed based on using a plasmid library expressing random fragments of rRNA . A 34 nucleotide long fragment of Escherichia coli 23S rRNA has been identified that renders cells resistant to erythromycin, when expressed in vivo . The rRNA fragment contains a five codon long open reading frame, initiating at GUG and terminating at UAA, with a Shine-Dalgarno sequence located at an appropriate distance from the initiator codon . Translation of this mini-gene is required for the observed erythromycin resistance . Experiments with in vitro translated, or synthetic, peptide indicate the ribosome as a likely target for the action of the identified rRNA-encoded peptide, which apparently remains associated with the ribosome after completion of its translation . The known properties of the rRNA-encoded peptide are compared with information about other functionally active short peptides that can be involved in regulation of translation.

Pharmacotherapy, 1995 Nov-Dec, 15(6), 687 - 92
QT interval prolongation and torsades de pointes due to erythromycin lactobionate; Oberg KC et al.; STUDY OBJECTIVES . To discern the frequency of torsades de pointes and QT prolongation in patients receiving intravenous erythromycin lactobionate; to examine the degree of QT prolongation and QT dispersion due to intravenous erythromycin in a typical clinical setting; and to identify any concurrent factors that might predispose patients to excessive QT prolongation or torsades de pointes while receiving intravenous erythromycin . DESIGN . Retrospective cohort trial . SETTING . A university teaching hospital . PATIENTS . All inpatients who received intravenous erythromycin lactobionate during a 1-year period . MEASUREMENTS AND MAIN RESULTS . The records of 278 consecutive patients were analyzed, of whom 49 had 12-lead electrocardiograms while receiving and not receiving erythromycin . The dosages of erythromycin ranged from 18-83 (42 +/- 18) mg/kg/day . Of the 49 patients, the baseline QTc was 432 +/- 39 msec, compared with 483 +/- 62 msec during erythromycin therapy (p < 0.01) . In 30 of 49 patients with heart disease, the increase in QTc due to erythromycin was 15 +/- 11%, compared with 8.6 +/- 10% in the 19 patients without heart disease (p < 0.05) . The degree of QTc dispersion was 34 +/- 16 msec at baseline, compared with 80 +/- 35 msec with erythromycin (p < 0.01) . Overall, 19 (39%) of 49 patients had a moderate to severe delay in ventricular repolarization (QTc > or = 500 msec) . Of the 278 patients prescribed intravenous erythromycin over the year, it caused torsades de pointes in just one (< or = 0.4%) . CONCLUSION . Erythromycin lactobionate-induced torsades de pointes is rare, although QT prolongation is common . Some patients may be at risk for suffering torsades de pointes due to this agent, particularly if heart disease or other factors that may further delay ventricular repolarization are present.

Drug Metab Dispos, 1995 Nov, 23(11), 1253 - 62
Oxidative metabolism of zolpidem by human liver cytochrome P450S; Pichard L et al.; The aim of this study was to identify the form(s) of cytochrome P450 (CYP) responsible for the biotransformation of zolpidem to its alcohol derivatives which, after rapid conversion to carboxylic acids, represents the main way of metabolism in humans . In human liver microsomes, zolpidem was converted to alcohol derivatives . Production of these correlated with the level of CYP3A4 and with cyclosporin oxidation and erythromycin N-demethylation activities, but not with the level of CYP1A2 nor with ethoxyresorufin O-deethylation or S-mephenytoin 4'-hydroxylation activities . Liver microsomes from CYP2D6-deficient patients exhibited normal activity . Production of alcohol derivatives was significantly inhibited by anti-CYP3A antibodies and by ketoconazole . Antibodies directed against other CYP forms (including CYP1A1, CYP1A2, CYP2A6, CYP2B4, and CYP2C8), and CYP-specific substrates or inhibitors (including propranolol, coumarin, mephenytoin, sulfaphenazole, quinidine, aniline, and lauric acid) produced a moderate or no inhibitory effect . cDNA-expressed CYP3A4 and CYP1A2 generated significant amounts of one of the alcohol derivatives, whereas CYP2D6 generated both of them in similar amounts . In human hepatocytes in primary culture, zolpidem was extensively and almost exclusively converted to one of the carboxylic acid derivatives, the main species identified in vivo . Treatment of cells with inducers of CYP1A (beta-naphthoflavone) and CYP3A (rifampicin and phenobarbital) greatly increased the rate of production of this metabolite . We conclude that the formation of alcohol derivatives of zolpidem is rate-limiting and principally mediated by CYP3A4 . Both CYP1A2 and CYP2D6 participate in alcohol formation; but, because of their low relative level of expression in the human liver, their contribution is minor.

Drug Metab Dispos, 1995 Nov, 23(11), 1231 - 41
Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomolgus monkey; Sharer JE et al.; The metabolism of probe substrates of phase I and phase II enzymes in vitro were compared in hepatic subcellular fractions from humans, cynomolgus monkeys, rhesus monkeys, and beagle dogs . These studies were undertaken to compare the suitability of these species as models of metabolism in drug development . Eight cytochrome P450-dependent activities were measured in microsomal incubations: ethoxyresorufin O-deethylase, coumarin 7-hydroxylase, tolbutamide 4-hydroxylase, S-mephenytoin 4'-hydroxylase, bufuralol 1'-hydroxylase, N-nitrosodimethylamine N-demethylase, midazolam 1'-hydroxylase, and erythromycin N-demethylase . Seven phase II activities were determined in the appropriate subcellular fractions:acetaminophen UDP-glucurono-syltransferase, acetaminophen sulfotransferase, 17 alpha-ethinylestradiol UDP-glucuronosyltransferase, 17 alpha-ethinylestradiol sulfotransferase, 6-mercaptopurine methylase, dichloronitrobenzene (DCNB) glutathione S-transferase, and isoniazid N-acetylase . Hepatic subcellular fractions from cynomolgus and rhesus monkeys showed significantly higher activities than those from humans for ethoxyresorufin O-deethylase, bufuralol 1'-hydroxylase, midazolam 1'-hydroxylase, erythromycin N-demethylase, acetaminophen UDP-glucuronosyltransferase, acetaminophen sulfotransferase, and tolbutamide 4-hydroxylase . Cynomolgus monkey had higher activity than humans and rhesus monkeys for S-mephenytoin 4'-hydroxylase erythromycin N-demethylase . Rhesus monkey and human cytosol displayed an apparent genetic polymorphism in the N-acetylation of isoniazid, whereas cynomolgus monkey cytosol did not . All other monkey activities were not significantly different than human . Dog subcellular fractions showed higher activity than humans for midazolam 1'-hydroxylase, erythromycin N-demethylase, acetaminophen UDP-glucuronosyltransferase, acetaminophen sulfotransferase, 17 alpha-ethinylestradiol sulfotransferase, and DCNB glutathione S-transferase . Furthermore, dog samples had significantly lower activity for coumarin 7-hydroxylase and 6-mercaptopurine methylase, and no detectable activity for tolbutamide 4-hydroxylase or isoniazid N-acetylase . All other activities were not significantly different from human . These results reveal minor differences between the cynomolgus and rhesus monkey in drug metabolism capacities in vitro, but both species are generally more metabolically active than humans in both phase I and phase II metabolism, whereas dogs had more diverse deviations from humans.

Baillieres Clin Rheumatol, 1995 Nov, 9(4), 711 - 29
Innovative treatment approaches for rheumatoid arthritis . Cyclosporin, leflunomide and nitrogen mustard; Furst DE; Cyclosporin A (CSA) Cyclosporin inhibits IL-2 release and T-cell activation and, secondarily, affects B-cell function . It also inhibits bone resorption, at least in vitro . This drug's bio-availability averages 25-35% but is highly variable . Food and grapefruit juice enhance bio-availability and newer formulations may make its absorption more reliable . It is highly concentrated in fatty tissues and red blood cells but does not cross the blood-brain barrier . CSA is metabolized to numerous metabolites by the liver and its elimination half-life is 6-12 hours in the absence of severe liver disease . Biliary excretion accounts for 94% of CSAs elimination . Because it is highly metabolized, its metabolism can be inhibited by other drugs (e.g . ketoconazole and erythromycin) or its metabolism can be induced (e.g . anticonvulsants) . Cyclosporin is more effective than placebo for the treatment of rheumatoid arthritis and as effective as other antirheumatics . There is potential for the use of CSAs in DMARD combinations . The principal toxicities of cyclosporin are gastro-intestinal and renal, with the latter being of more concern . Leflunomide (LF) . Leflunomide may be a pyrimidine synthesis inhibitor, although tyrosine kinase inhibitor may also be part of its mechanism of action . Its active metabolite is excreted renally to a large degree, with a prolonged elimination half-life of about 11 days . Since LF is activated by liver metabolism, renal failure may have less effect on kinetics than severe liver disease . Early data on efficacy indicate efficacy at 10-25 mg/day, although more well-controlled data is necessary . Toxicity relates to the skin, liver and GI tract, although some degree of weight loss was also found . Nitrogen mustard (NM) . Nitrogen mustard is an alkylating agent whose pharmacokinetics are poorly understood . Small, open studies in RA indicate that NM has a potential for relatively rapid response (1-2 weeks) but, clearly, much work remains to be done . As an alkylating agent, GI and hematological toxicities are of greatest concern.

Clin Infect Dis, 1995 Nov, 21(5), 1318 - 21
Chronic Q fever of pregnancy presenting as Coxiella burnetii placentitis: successful outcome following therapy with erythromycin and rifampin; Bental T et al.; Chronic Q fever has been associated with endocarditis, granulomatous hepatitis, and osteomyelitis but only rarely with pregnancy . The apparent predilection of Coxiella burnetii, the organism causing Q fever, for the human placenta suggests that chronic Q fever of pregnancy is due to placentitis . We describe a patient with chronic, clinically apparent Q fever in pregnancy and a successful outcome . The diagnosis was made both by serology and by isolation of C . burnetii from the patient's serum and placenta . Therapy with erythromycin and rifampin contributed to the delivery of a healthy baby . The mother's infection was clinically cured by subsequent therapy with doxycycline and rifampin.

Pediatr Infect Dis J, 1995 Nov, 14(11), 969 - 75
Field effectiveness of erythromycin prophylaxis to prevent pertussis within families; De Serres G et al.; To evaluate the field effectiveness of erythromycin prophylaxis for pertussis within families, a retrospective cohort study was conducted among 246 families . Overall 41% of the subjects (387 of 940) had been sick . The secondary attack rate was 65% for infants younger than 2 years, 54% for those 2 to 4 years old and 39% for children 5 to 9 years old, and it declined thereafter . The secondary attack rate decreased from 25% in families without prophylaxis to 17% in families with prophylaxis . The protection induced by prophylaxis did not vary with age or vaccination status . When prophylaxis was used before the onset of a secondary case, the secondary attack rate was 4% compared with 35% when given after a secondary case (P < 0.001) . Erythromycin prophylaxis seems to be efficient in preventing secondary cases but is most useful when administered before the occurrence of the first secondary case.

Xenobiotica, 1995 Nov, 25(10), 1051 - 62
Cyclophosphamide administered repeatedly to the male rat and as a single dose to the female rat . Its effects on hepatic and pulmonary P450 and associated enzymes; Angley MT et al.; 1 . Two different aspects of the effects of the cytotoxic agent cyclophosphamide (CP) on rat P450 and associated enzymes have been examined . 2 . First, the effects of CP, administered as a single 200 mg/kg dose, on hepatic and pulmonary P450 and some associated enzymes in the female rat have been investigated . Second, the effects of repeat doses of CP (40 mg/kg on days 0-4 with killing on days 5, 8 and 11) to the male rat have been examined . 3 . CP decreased the activity of the female rat hepatic enzymes 2A1, 2C6 and/or 2C12 and 2E1, NADPH-P450 oxidoreductase and 17 beta-oxidoreductase and the pulmonary enzyme 2B, 7 days after its administration . The decreases in the activity of the enzymes 2E1 and NADPH-P450 oxidoreductase were accompanied by a corresponding change in the amount of enzyme protein indicating that the alteration in expression of these enzymes occurred via changes in transcription and/or translation or protein degradation . 4 . CP also impaired its own activation 7 days after its administration to the female rat . 5 . The change in female enzyme profile was accompanied by a reduction in the hormones oestradiol, T4 and T3 7 days after CP administration . 6 . Despite an apparent trend for an increase in activity on day 5, a decrease on day 8 and a subsequent increase on day 11, repeat doses of CP to the male rat generally did not alter the P450 isoforms 2A2, 2B1, 2C11, 2E1 and 3A2 or 17 beta-oxidoreductase, NADPH-P450 oxidoreductase and steroid 5 alpha-reductase . 7 . Chronic administration of CP to the male rat significantly reduced erythromycin demethylase and NADPH-P450 oxidoreductase 8 days following commencement of dosing and significantly increased 2A2 11 days following commencement of dosing . There was also a statistically significant increase in pulmonary 2B 5 days following commencement of dosing . 8 . Plasma testosterone and TSH were unchanged following repeated dosing with CP while T3 was significantly decreased on days 5, 8 and 11 and T4 was significantly decreased on day 8.

Dig Dis Sci, 1995 Nov, 40(11), 2446 - 9
Effect of oral erythromycin on colonic transit in patients with idiopathic constipation . A pilot study; Sharma SS et al.; Erythromycin, a motilin receptor agonist has been shown to have prokinetic effects on the upper gastrointestinal tract and gallbladder . Colonic effects of the drug are controversial, and it is debated whether human colon contains motilin receptors . In this study we evaluated the effects of erythromycin on colonic transit and stool frequency in 11 patients with idiopathic constipation over a 1-month period in an open study . The dose used was 1 g/day for two weeks followed by 500 mg/day for another two weeks . The mean (SE) total and segmental colonic transit was measured before and seven days after therapy in seven of these patients . A daily record of stool frequency was maintained in all 11 patients . Erythromycin shortened the total colonic transit from 86.2 (14.6) to 44.8 (8.99) hr (P < 0.01); however, segmental transit studies revealed a significant effect (P < 0.01) only in the right colon and rectosigmoid region . No significant side effects were observed with short-term therapy . These preliminary results suggest that erythromycin is of therapeutic value in patients with idiopathic constipation.

Toxicol Appl Pharmacol, 1995 Nov, 135(1), 89 - 99
Expression and inducibility of antigens in severe combined immunodeficient mice recognized by human anti-P450 antibodies; Rajasenan RS et al.; Engrafting components of human immune systems in severe combined immunodeficient (SCID) mice has been utilized to investigate the pathogenesis of several human autoimmune diseases and may provide a model for studying idiosyncratic drug toxicity . The purpose of this investigation was to examine in SCID mice the tissue distribution and inducibility of antigens recognized by anti-cytochrome P450 (CYP) antibodies in sera from patients with hypersensitivity reactions to the aromatic anticonvulsants phenytoin, phenobarbital, and carbamazepine . Microsomal proteins were prepared from liver, skin, kidney, intestine, and lung of SCID mice pretreated with vehicle (50% propylene glycol/DMSO), phenytoin, carbamazepine, phenobarbital, or dexamethasone . Proteins immunoreactive with anti-CYP2C and anti-CYP3A antisera were detected in all organs examined . Antibodies in patient sera recognized a 53-kDa hepatic microsomal protein that was expressed to a limited extent in vehicle-pretreated microsomes, but which was induced by dexamethasone, phenytoin, and phenobarbital, but not carbamazepine . This antigen was very similar to a 52.5-kDa protein immunoreactive with anti-CYP3A polyclonal antibody . The expression and inducibility of the 53-kDa antigen correlated significantly with testosterone 6 beta-, 2 beta-, and 15 beta-hydroxylation and erythromycin N-demethylase activity, all markers of CYP3A activity, and is tentatively identified as CYP3A11 . No immunoreactivity was observed in murine extrahepatic organs including skin, kidney, intestine, and lung . Therefore, further development of the SCID mouse model may require xenotransplantation of human target organs like skin together with transfer of patient immune systems to reproduce the serological and pathological features of human anticonvulsant hypersensitivity reactions.

Biochim Biophys Acta, 1995 Oct 17, 1272(2), 89 - 94
Induction of hepatic CYP1A2 by the oral administration of caffeine to rats: lack of association with the Ah locus; Ayalogu EO et al.; Caffeine was administered to male Wistar albino rats for two weeks at three concentrations, namely 0.1, 0.2 and 0.3%, and hepatic cytochrome P450-dependent mixed-function oxidase determined . Caffeine administration gave rise to a marked, dose-dependent increase in the O-deethylation of ethoxyresorufin and, to a lesser extent, in the O-depentylation of pentoxyresorufin . Erythromycin N-demethylase, p-nitrophenol hydroxylase and lauric acid hydroxylase activities, as well as total cytochrome P450 content were unaffected by this treatment . Immunoblot analysis revealed that caffeine gave rise to a dose-dependent increase in the hepatic CYP1A2, and at the highest dose only, CYP2B apoprotein levels . Apoprotein levels of CYP3A and CYP2E1 were not modulated by the treatment with caffeine at all dose levels studied . Caffeine could not displace {3H}TCDD from the rat hepatic cytosolic Ah receptor . Computer analysis showed that caffeine is essentially a planar molecule with an area/depth ratio 4.8, characteristic of CYP1A substrates/inducers . Molecular modelling revealed that the caffeine molecule could orientate itself within the putative CYP1A2 active site so as to facilitate demethylation of the N-1, N-3 and N-7 positions . However, at physiological pH, the N-9 nitrogen atom is likely to be partially protonated, allowing it to participate in an electrostatic interaction with the negatively-charged glutamate 318-residue, favouring N-3 demethylation, the major pathway of metabolism in both humans and animals . In conclusion caffeine, being essentially planar, is an inducer of CYP1A2 in rat liver.

Comp Biochem Physiol C Pharmacol Toxicol Endocrinol, 1995 Oct, 112(2), 163 - 8
Differential induction of cytochrome P-450 isozymes by rifampicin in the Chinese hamster, Cricetus griseus; Ushio F et al.; Treatment of male and female Chinese hamsters with rifampicin at intraperitoneal doses of 25 and 50 mg/kg did not increase the cytochrome P-450 content of the liver except for a 1.3-fold increase in male hamsters at a dose of 50 mg/kg . Enhancement of the activities of erythromycin N-demethylase and testosterone hydroxylases, except for 15 alpha-hydroxylation, was observed in the livers of both male and female hamsters treated with rifampicin at both doses . Western blot analysis revealed that rifampicin caused no change in the content of CYP3A subfamily proteins in the liver, whereas changes in that of CYP2A subfamily proteins were evident.

J Pediatr Surg, 1995 Oct, 30(10), 1511 - 2
Delayed gastric emptying in a neonate, associated with a partial defect in the gastric smooth muscle; Ohki Y et al.; A girl born after 36 weeks' gestation had emesis 15 hours after birth . She required total parenteral nutrition (TPN) because of persistent gastric retention . When milk was given, the volume of gastric aspirate 3 hours after feeding often was greater than the volume given . Domperidon and erythromycin were ineffective . Upper gastrointestinal series showed slow gastric emptying but no abnormalities in the stomach . No stenosis or obstruction below pylorus was found . Endoscopy showed normal gastric mucosa . Manometry showed normal antroduodenal motility patterns . Transpyloric feeding, which started at age 73 days, was successful and enabled cessation of the TPN . Laparotomy at 119 days of age showed partial absence of the muscle and serosal layer in the anterior wall of the gastric body (1 x 4 cm) . The mucosal layer was intact and partly adhered to the peritoneum and the left lobe of the liver . The defect was surgically corrected by plicating the place . The postoperative course was excellent, and oral feeding was fully established within 2 weeks . Although the cause of the partial muscle defect in the case is unclear, this case suggests that this rare condition can cause severe chronic gastric retention.

Drug Metab Dispos, 1995 Oct, 23(10), 1163 - 74
Identification of the human liver cytochrome P450 enzymes involved in the metabolism of zileuton (ABT-077) and its N-dehydroxylated metabolite, Abbott-66193; Machinist JM et al.; In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) forms involved in the oxidative metabolism of {14C}zileuton (ABT-077) and its N-dehydroxylated metabolite, {14C}Abbott-66193, by human liver microsomes . The two compounds were metabolized by parallel pathways to form the corresponding ring-hydroxylated and diastereomer sulfoxide metabolites . Results suggested that whereas the metabolism of zileuton and Abbott-66193 were mediated by the same CYP forms, the CYP forms responsible for hydroxylation (CYP1A2 and CYP2C9/10) were distinct from those involved in sulfoxidation (CYP3A > CYP2C9/10) . Sulfoxidation (zileuton, Km = 0.82 +/- 0.40 mM, Vmax = 39.1 +/- 21.8 pmol/min/mg; Abbott-66193, Km = 0.23 +/- 0.06 mM, Vmax = 507 +/- 215 pmol/min/mg; mean +/- SD, N=3) was highly correlated with the CYP3A-specific erythromycin N-demethylase activity (r=0794-0.856; p<0.01, N=11) in human microsomes and was inhibited (32-67%) by ketoconazole and troleandomycin . In addition, purified recombinant human CYP3A4/rat NADPH-P450 reductase fusion protein catalyzed only the sulfoxidation of zileuton and Abbott-66193; no hydroxylated metabolites were detected . On the other hand, hydroxylation of the two compounds (zileuton, Km = 0.34 +/- 0.25 mM, Vmax = 17.8 +/- 5.58 pmol/min/mg; Abbott-66193,Km = 0.39 +/- 0.14 mM, Vmax = 1061 +/- 220 pmol/min/mg) was significantly correlated with 7-ethoxyresorufin O-deethylase (CYP1A2; r=0.652-0.762; p<0.01, N=11) and tolbutamide methyl hydroxylase (CYP2C9/10; r=0.863-0.935; p<0.01, N=10) activity in human liver microsome, and was inhibited (26-51%) by well-known CYP1A2 inhibitors (furafylline and alpha-naphthoflavone) . Furthermore, microsomes from human B-lymphoblastoid cells expressing CYP1A2 catalyzed only the hydroxylation of zileuton and Abbott-66193; sulfoxide were not formed . Abbott-66193 was a better substrate for CYP2C9/10, when compared with zileuton: 1) the effect of sulfaphenazole on hydroxylation in human liver microsomes was more pronounced for Abbott-66193 than zileuton (56% vs . 9% inhibition); and 2) the rate of Abbott-66193 hydroxylation by purified CYP2C9 was almost 30-fold greater than that of zilueton.

Antimicrob Agents Chemother, 1995 Oct, 39(10), 2359 - 63
Nucleotide sequence and characterization of erythromycin resistance determinant that encodes macrolide 2'-phosphotransferase I in Escherichia coli; Noguchi N et al.; The DNA fragment (3.3 kb) containing the erythromycin resistance determinant was cloned from Escherichia coli Tf481A and sequenced . Deletion and complementation analyses indicated that the expression of high-level resistance to erythromycin requires two genes, mphA and mrx, which encode macrolide 2'-phosphotransferase I and an unidentified hydrophobic protein, respectively.

Pediatr Infect Dis J, 1995 Oct, 14(10), 870 - 4
Clinical course of pertussis in immunized children; Bortolussi R et al.; To describe the clinical course of Bordetella pertussis infection in a highly immunized childhood population, we studied prospectively endemic and epidemic pertussis in a metropolitan population with an immunization rate > 90% during an 8-year period from 1987 through 1994 . Patients with a possible diagnosis of pertussis were referred by family or emergency room physicians for nasopharyngeal culture . Patients with a culture positive for B . pertussis were contacted by a nurse who completed a detailed questionnaire for the index case and all family members . Repeat home visits were made each week for 4 weeks . Of the 189 patients with pertussis who were evaluated 103 subjects were < 5 years of age . Congestion predated the onset of cough by up to 1 week in 35 (34%) cases . Seventy (68%) subjects < 5 years of age developed a paroxysmal cough within the first week of their illness . Ninety-one (88%) cases < 5 years old had a persistent paroxysmal cough for > 21 days . Coughing in this group lasted from 16 to 91 days (median 48) . Erythromycin therapy appeared to shorten the duration of cough; however, patients were not randomized to receive erythromycin at a specific time . Despite adequate immunization some children develop pertussis . The clinical course in these patients is milder than in unimmunized subjects . Nevertheless the symptomatology in these children should still be readily identified by most physicians using classical clinical criteria of pertussis.

Aliment Pharmacol Ther, 1995 Oct, 9(5), 529 - 33
Erythromycin shortens orocaecal transit time in diabetic male subjects: a double-blind placebo-controlled study; Minocha A et al.; BACKGROUND: The effects of erythromycin on small bowel motility are controversial . Orocaecal transit time (OCTT) is considered to be a valid measure of small bowel motility . METHODS: We studied the effect of erythromycin on OCTT in diabetic male subjects in a double-blind placebo-controlled crossover fashion . After an overnight fast, subjects received erythromycin 500 mg, 250 mg or placebo, on 3 different days . A standard solid meal containing 20 g lactulose was administered 30 min after the erythromycin ingestion . Exhaled breath was collected and hydrogen concentration was assessed over 5 h . Breath hydrogen concentrations for each session were analysed over time by a generalized logistic function generating a sigmoidal curve . Front transit time was recorded as the time point when a sustained rise in breath hydrogen concentration of at least 5 p.p.m . was first observed . RESULTS: The mean +/- S.E.M . time taken for the front of the meal to reach the caecum was 92.5 +/- 9.5, 86.1 +/- 16.5 and 62.3 +/- 12.1 min for placebo, erythromycin 250 mg and erythromycin 500 mg, respectively . The OCTT was significantly decreased with erythromycin 500 mg compared to placebo (P < 0.05) . CONCLUSION: Oral administration of 500 mg erythromycin has prokinetic effect on orocaecal transit in male patients with diabetes mellitus.

Infect Control Hosp Epidemiol, 1995 Oct, 16(10), 556 - 63
Containment of pertussis in the regional pediatric hospital during the Greater Cincinnati epidemic of 1993; Christie CD et al.; OBJECTIVE: To describe methods of preventing nosocomial pertussis in patients, employees, and visitors to a hospital during a communitywide epidemic in Greater Cincinnati . DESIGN: Six-month descriptive study of the methods, effectiveness, and cost of a program to prevent nosocomial pertussis . SETTING: Three hundred sixty-one bed, tertiary-care, university, pediatric hospital . RESULTS: We educated 3,764 hospital employees about pertussis . We evaluated 206 employees with respiratory illnesses, based on clinical presentation, pertussis exposure, and work setting . Eighty-seven had pertussis: 84 coughed for > or = 2 weeks (outbreak clinical case definition), 65 had paroxysms, 27 whooped, 22 had posttussive emesis, and 13 were positive by direct fluorescent antibody or culture for Bordetella pertussis . Seventy-nine employees were sent on 5-day furloughs . Six hundred twenty-two employees received 14 days of erythromycin (579) or trimethoprim-sulfamethoxazole (43) . Symptomatic patients were identified at triage in the emergency department and placed in respiratory isolation . Suspect pertussis cases were admitted in respiratory isolation . Among 49 toddlers who were given erythromycin and managed in "coughing respiratory cohorts," eight had proven pertussis . Inpatients were restricted to assigned nursing units . Respiratory masks were required for those entering the test referral center, where more than 3,500 pertussis cultures were performed . Hospitalwide visitor restriction was enforced for those aged 14 years or younger and for those with respiratory symptoms . Only parents and guardians were permitted to visit the newborn intensive care unit . A child-care service managed 488 inpatient sibling visitors . Four symptomatic children in the employees' child-care center were excluded pending physician evaluation; one had pertussis . CONCLUSIONS: Control measures appeared effective . Pertussis occurred in 87 (2%) employees . Among 102 children hospitalized with pertussis, respiratory isolation was delayed in nine cases, and one case was nosocomial . Program expenses totalled $85,400 . Adult booster immunization with acellular pertussis vaccine might represent the safest and least expensive strategy for preventing epidemic pertussis, and controlled trials of acellular pertussis vaccine in hospital employees are needed.

Obstet Gynecol, 1995 Oct, 86(4 Pt 2), 648 - 50
Chlamydial psittacosis during pregnancy: a case report; Gherman RB et al.; BACKGROUND: Chlamydia psittaci infection typically causes a mild influenza-like illness in humans . However, during pregnancy, this disease may present with severe headache, hypoxemia, thrombocytopenia, anemia, hepatic dysfunction, and disseminated intravascular coagulation . Limited reports of ovine-acquired psittacosis indicate appreciable maternal-fetal morbidity and mortality . CASE: A 19-year-old woman, gravida 1, para 0, at 32 weeks and 3 days' gestation developed C psittaci pneumonia after exposure to a parakeet . Worsening maternal respiratory status, development of a coagulopathy, and fetal compromise prompted cesarean delivery . CONCLUSION: Avian strains of C psittaci can cause atypical pneumonia during pregnancy . Massive placental infection with impaired placental perfusion may ensue subsequently . Given the serious nature of the disease and the ineffectiveness of erythromycin treatment, administration of tetracyclines may be justified, despite the possible adverse fetal effects . With persistent disease, early delivery of the fetus may provide good maternal and fetal outcomes.

Am Fam Physician, 1995 Oct, 52(5), 1447 - 53
Torsades de pointes and long QT syndromes; Janeira LF; Torsades de pointes is a polymorphic form of ventricular tachycardia that is usually associated with prolongation of the QT interval . This QT prolongation may be either congenital or acquired . Etiologies for the acquired form include hypokalemia, hypomagnesemia, hypocalcemia, starvation, sick sinus syndrome, atrioventricular block and drug effects . Medications that have been implicated include most antiarrhythmic agents, some nonsedating histamine blockers, erythromycin and ketoconazole . Accurate and timely recognition of torsades de pointes is critically important because of the risk that traditional antiarrhythmic drug treatment will likely worsen the problem rather than improve it . Effective treatment requires withdrawal of any offending drugs or correction of the underlying cause of the QT prolongation . Beta blockers have been shown to be effective in preventing problems in congenitally at-risk patients . An implantable cardioverter defibrillator should be considered in some patients with recurrent episodes.

Pharmacol Res, 1995 Sep, 32(3), 141 - 8
A rifampicin-induced hepatic microsomal enzyme system for the generation of cyclosporine metabolites; Tamolang MB et al.; A drug-induced rabbit hepatic microsomal enzyme system has been developed to produce milligram quantities of cyclosporine metabolites (CMs) . Using a rifampicin-induced microsomal preparation in the presence of a NADPH regenerating system, 60% of the cyclosporine (CsA) was converted to CMs in 2 h . The CMs were recovered by solid phase extraction, and separated by gradient high performance liquid chromatography with two Ultrasphere Ocyl (C8) columns connected in tandem . More than 20 CMs were resolved . The quantities of major CMs produced by 45 mg of microsomal proteins were established by comparing peak areas with known concentrations of authentic CM standards . These major CMs included AM1, AM9, AM19, AM4N, AM1c and the aldehydic isomers (AM1cAL plus AM1AL) . Other CMs that were not quantified included AM14N, AM4N9, AM1A, AM1c9, and AM1D1 . Several CMs remained to be identified . All CMs were detected by radioimmunoassay using a non-specific CsA antiserum . The purity of the CMs were confirmed by fast atomic bombardment mass spectrometry . Similar findings were observed when erythromycin or trolandomycin was used to induce the hepatic microsomal enzymes . The procedure used to generate CMs was simple . With the enzyme fraction derived from one rabbit liver, 90 to 100 mg of CMs can be obtained . In this study, the metabolite patterns of CsA produced by rabbit liver microsomes were shown to resemble those observed for humans . These results indicate the possibility of using rabbit models to predict CsA biotransformation in man . The CMs generated by this enzyme system can be used to acquire information relevant to the situation in man.

Rhinology, 1995 Sep, 33(3), 166 - 70
Evaluation of endoscopic sinus surgery for chronic sinusitis: post-operative erythromycin therapy; Moriyama H et al.; We discuss the results of endoscopic endonasal sinus surgery for chronic pan-sinusitis characterized by nasal polyposis, especially the effects of post-operative long-term administration of low-dose erythromycin (EM) therapy . The subjects analysed in this retrospective study are surgical cases who had initially been operated for chronic pan-sinusitis . They are classified into one group who has received a post-operative long-term, low-dose EM regimen and into another group who has not received this treatment . The groups have been compared with respect to: (1) the degree of improvement in the post-operative subjective symptoms; (2) postoperative objective findings of the ethmoidal sinus and the ostium of the frontal sinus; and (3) the degree of improvement in the maxillary sinus lesion . Better improvement is achieved in subjective symptoms and objective findings in the EM group than in the non-EM group.

Nihon Kyobu Shikkan Gakkai Zasshi, 1995 Sep, 33(9), 1019 - 23
{Diffuse panbronchioliltis associated with bullous pemphigoid}; Oshikawa K et al.; A 64-year-old woman complained of multiple blisters in 1990 . She had had a productive cough since 1975 . Immunofluorescence study of a specimen obtained from a skin biopsy showed staining in a linear pattern for both IgG and C3 in the epithelial basement membrane zone (BMZ) of the dermal-epidermal junction, and a high titer of anti-BMZ antibody . These findings led to the diagnosis of bullous pemphigoid . Corticosteroid therapy was started, and resulted in some stabilization of the skin lesion . Exertional dyspnea and a productive cough developed gradually, and the patient was referred to our department in 1992 . Chest X-ray film and CT findings revealed a diffuse granular shadow and bronchiectatic change, predominantly in the lower lung fields . Laboratory tests showed a high titer of cold hemagglutinin and a high level of serum immunoglobulin A . Pulmonary function tests showed a combined destructive-restrictive defect and hypoxemia (PaO2 = 58.5 Torr) . From these findings diffuse panbronchiolitis was diagnosed . A low dose of erythromycin alleviated the patient's pulmonary symptoms and improved the chest radiographic findings.

Int J Clin Pharmacol Ther, 1995 Sep, 33(9), 518 - 23
150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects; Vanakoski J et al.; Fluconazole, an azole antifungal agent, moderately inhibits the CYP3A-mediated metabolism of midazolam in vitro . We therefore studied whether such an interaction takes place in vivo following oral administration of these drugs, given as relevant double blinded doses in capsule form . In study I parallel groups of healthy subjects received oral midazolam 10 mg (MID 10) or 15 mg (MID 15), placebo, or MID 10 mg + 150 mg fluconazole (FLU) given 2 h earlier . Objective and subjective performance tests were made before, and 30 and 90 min after the intake of midazolam . MID 10 and MID 15 moderately impaired performance on digit symbol substitution, letter cancellation and flicker fusion tests, and visual analogue scales revealed mild sedation . FLU + MID 10 had similar or slightly stronger effects than MID 10; it differed from MID 10 in that it lowered the flicker fusion threshold and produced subjective slowness and overall impairment . In study II 5 subjects received MID 10 after placebo, after FLU, and after 750 mg erythromycin (ERY) at 1-week intervals, following a crossover and double-blinded study design . Blood was sampled before MID intake and 30, 60 and 90 min after it, and performance was measured . FLU and ERY increased the effect of MID on flicker fusion and letter cancellation performances, and increased the HPLC-assayed plasma midazolam (ERY + 100%, FLU + 50%) in comparison to that measured after MID ingested alone . When the concentrations of midazolam together with its active metabolite alpha-OH-midazolam were assayed by radioreceptor technique the increases caused by ERY and FLU were less and compatible with the pharmacodynamic data.(ABSTRACT TRUNCATED AT 250 WORDS)

Am Fam Physician, 1995 Sep 1, 52(3), 957 - 62, 965-6
Prokinetic therapy for gastroesophageal reflux disease; Robinson M; Prokinetic drugs theoretically have the ability to correct the pathophysiologic abnormalities of gastrointestinal motility that lead to gastroesophageal reflux disease . However, the prokinetic agents bethanechol and metoclopramide have been associated with central nervous system and other side effects, as well as uncertain efficacy . In addition, erythromycin seems unsuitable for use as an oral prokinetic agent . A recently introduced prokinetic agent, cisapride, has a minimum incidence of side effects and is effective in the treatment of reflux symptoms, but trials in the United States have not confirmed the symptomatic improvement or healing of erosive esophagitis that has been demonstrated in studies abroad . An expanded role may unfold for cisapride and additional new prokinetic drugs as primary therapy for reflux in some patients, as adjunctive treatment with an antisecretory agent, or as maintenance treatment for a subset of patients with gastroesophageal reflux . Therapy tailored to individual pathophysiology is appropriate and may offer cost savings and improved clinical outcome.

Am J Physiol, 1995 Sep, 269(3 Pt 1), G418 - 26
Gastrokinetic effects of erythromycin: myogenic and neurogenic mechanisms of action in rabbit stomach; Parkman HP et al.; The aims of this study were to determine regional differences and the mechanism of gastric contractile effects of erythromycin . Rabbit gastric circular muscle strips were studied in vitro . The threshold dose for erythromycin was significantly less and the maximum contraction greater in the antrum (1 microM and 0.9 +/- 0.3 kg/cm2) than in the fundus (10 microM and 0.3 +/- 0.1 kg/cm2) . Erythromycin-induced antral contractions were decreased by motilin tachyphylaxis but unaffected by tetrodotoxin, atropine, hexamethonium, or ondansetron . At a subthreshold dose (0.1 microM), erythromycin increased the frequency, but not the amplitude, of bethanechol (10 +/- 3%)-and substance P-induced (13 +/- 5%) phasic antral contractions . This chronotropic effect was inhibited with tetrodotoxin, atropine, or motilin tachyphylaxis . Erythromycin (10 microM) and motilin (1 microM) enhanced the amplitude of substance P-induced tonic fundic contractions by 38 and 32%, respectively, without effect on bethanechol-induced contractions . In summary, erythromycin contracts antral muscle more potently and forcefully than fundic muscle . Erythromycin increases antral contractility by two mechanisms: an inotropic effect acting on smooth muscle motilin receptors, and, at lower doses, a cholinergic chronotropic effect mediated through neuronal motilin receptors.

Nebr Med J, 1995 Sep, 80(9), 285 - 6
Erythromycin induced torsades de pointes; Wong CB et al.; Erythromycin is a widely used antibiotic in today's armamentarium of antibiotics . Although erythromycin induced ventricular tachyarrhythmia is rare, this potentially life-threatening reaction should be kept in mind . The relative rarity of 'torsades de pointes' arrhythmia suggests that other predisposing factors contribute to the acquired long QT syndrome . Since more and more macrolide products have been approved by the Food and Drug Administration for use in the United States, the potential problem with 'torsades de pointes' may exist with each of the macrolide antibiotic . Until the exact mechanisms of the arrhythmia are worked out, close monitoring of rhythms and QT intervals of high risk patients who require erythromycin is certainly advisable . Only a heightened awareness among the physicians and medical personnel can the adverse outcome be minimized.

Dig Dis Sci, 1995 Sep, 40(9), 1892 - 901
Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction; Verne GN et al.; Treatment of chronic intestinal pseudoobstruction with prokinetic agents has been disappointing . Our study was designed to determine if octreotide and erythromycin would provide sustained relief from nausea, abdominal pain, and bloating in pseudoobstruction . Using gastrointestinal manometry, quantitative parameters of the activity front of the migrating motor complex at baseline and after prokinetic therapy with erythromycin and octreotide were determined in 14 patients with intestinal pseudoobstruction who had nausea, abdominal pain, and bloating . Patients were treated with erythromycin and octreotide for 20-33 weeks . Octreotide increased the frequency, duration, and motility index of activity fronts (AFs) from 1.2 +/- 0.3 AFs/4 hr, 2.7 +/- 0.7 min, and 85 +/- 23 min mm Hg to 4.1 +/- 0.8 AFs/4 hr, 5.5 +/- 0.7 min, and 152 +/- 24 min mm Hg, respectively (P < 0.05) . Antral activity was decreased from 63 +/- 14 to 23 +/- 8% by octreotide (P < 0.05) . Erythromycin induced antral activity; however, small intestinal motor activity was suppressed . While on erythromycin and octreotide, five patients had long-term improvement of nausea and abdominal pain . All responders had at least 5 AFs/4 hr induced by octreotide . We conclude that octreotide and erythromycin relieve abdominal pain and nausea in pseudoobstruction . Patients who have at least 5 AFs/4 hr after octreotide administration are most likely to clinically respond.

What Is Molecular Microbiology?, What Is Fermentation?, What Is Cell Biology?, What Is Bioreactor?, What Is Rhizobia?, n, Microbe, s, Bacteriology, i, Microbes, c, Microorganisms, e, Microbiology, e, Microflora, e, Alcaligenes, i, Staphylococcus aureus, i, Escherichia coli, s, Agrobacterium, r, Yeasts, c, Yeasts, i, Antibiotics, i, Salmonella, a, Escherichia coli, c, Meningococcus, o, Cell suspensions, a, Microbial, s, Escherichia coli, r, Bacteria, o, Vibriosis, a, Antibiotics, o, Streptococci, c, Campylobacter, a, Bacteriophage, c, Escherichia coli

Scientific Publications - Work Done by Microbiology Reader Bioscreen C
Agricultural Microbiology Anaerobic Microbiology Antimicrobial Susceptibility Artificial Atmosphere Bioassay of Antibiotics Biofilm Microbiology Bioreactor Technology Biotechnology Cell Biology Clinical Microbiology Environmental Microbiology Experiments with Yeast	Fermentation Food Microbiology Functional Genomics Gene Technology Growth Media Development Growth Rate and Lag Time Industrial Microbiology Medical/Pharmaceutical Field Microbiological Assay Microbiological Research Microbiology of Cosmetics go to a specific theme...	Military Microbiology Molecular Microbiology Mutagenicity and Genotoxicity Oral Microbiology Patents Postantibiotic Studies Soil Microbiology Spore Microbiology Veterinary Microbiology Waste/Wastewater Treatment Water Microbiology Wine Microbiology

� 2005 Transgalactic Ltd (manufacturer of Bioscreen C software) | Privacy Statement | P.O. Box 1393, 00101 Helsinki, Finland, phone: +358 9 85172920, fax: +358 9 8749481, e-mail: microbiology@bionewsonline.com

Last modified: May 25, 2005