Clin Pharmacol Ther, 1995 Sep, 58(3), 269 - 78 Loratadine administered concomitantly with erythromycin: pharmacokinetic and electrocardiographic evaluations; Brannan MD et al.; OBJECTIVE: To evaluate the effects of coadministration of loratadine and erythromycin on the pharmacokinetics and electrocardiographic repolarization (QTc) pharmacodynamics of loratadine and its metabolite descarboethoxyloratadine in healthy volunteers . METHODS: Twenty-four healthy volunteers were studied in a prospective, double-blind crossover design while confined in a Clinical Research Center . The primary pharmacodynamic end point of the study was the difference between baseline and day 10 mean QTc intervals obtained from surface electrocardiograms . Plasma concentrations of loratadine, descarboethoxyloratadine, and erythromycin were measured on treatment day 10 for pharmacokinetic analysis . Subjects received in random sequence the following three treatments for 10 consecutive days during three separate study periods: 10 mg loratadine every morning plus 500 mg erythromycin stearate every 8 hours, or 10 mg loratadine every morning plus placebo every 8 hours, or placebo every morning plus 500 mg erythromycin stearate . RESULTS: Concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine (40% increase in area under the plasma concentration-time curve {AUC}) and descarboethoxyloratadine (46% increase in AUC) compared with loratadine alone . Analysis of variance showed no difference between the treatment groups in effect on QTc intervals compared with baseline, and no significant change from baseline was observed . No clinically relevant changes in the safety profile of loratadine were observed, and there were no reports of sedation nor syncope . CONCLUSION: Although concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine and descarboethoxyloratadine, no clinically relevant changes in the safety profile of loratadine were observed . In this study, 10 mg loratadine administered orally for 10 consecutive days was well tolerated when coadministered with therapeutic doses of erythromycin stearate. Gastroenterology, 1995 Sep, 109(3), 707 - 17 Calcium currents in human and canine jejunal circular smooth muscle cells; Farrugia G et al.; BACKGROUND & AIMS: Although calcium plays an essential role in intestinal smooth muscle contractile activity, calcium entry pathways in canine and human small intestine are largely unknown . The goal of this study was to characterize calcium channels, a potential entry pathway for calcium, in isolated circular smooth muscle cells of canine and human jejunum . METHODS: Single freshly dissociated human and canine jejunal circular smooth muscle cells were studied using single-channel and perforated whole-cell patch clamp recordings as well as fluorescence dual wavelength ratio imaging . RESULTS: An inward whole-cell current was identified that was carried by a 17 pS (80 mmol/L Ba2+) dihydropyridine-sensitive, barium-permeable channel . The current was potentiated by BayK 8644 (1 mumol/L; n = 3; 82% +/- 34%), acetylcholine (1 mumol/L; n = 8; 42% +/- 5%), and erythromycin (1 mumol/L; n = 9; 70% +/- 11%) and was completely blocked by nifedipine (1 mumol/L; n = 6) or diltiazem (200 mumol/L; n = 4) . Application of BayK 8644 (1 mumol/L), acetylcholine (1 mumol/L), or erythromycin (1 mumol/L) to Fura-2-loaded smooth muscle cells bathed in Krebs' solution containing 2.54 mmol/L calcium increased intracellular calcium levels . CONCLUSIONS: A calcium entry pathway was identified in canine and human jejunal circular smooth muscle cells . The pathway was mediated by a dihydropyridine-sensitive calcium channel . The channel allowed the entry of significant amounts of calcium at physiological extracellular calcium concentration. Nucl Med Commun, 1995 Sep, 16(9), 790 - 3 Effects of oral erythromycin on upper gastrointestinal motility in patients with non-insulin-dependent diabetes mellitus; Kao CH et al.; Twenty patients (18 males, 2 females) with type II (non-insulin-dependent) diabetes mellitus were enrolled in the study . They were aged 49-72 years (mean age 65 years) . Radionuclide-labelled water was used to measure oesophageal motility, expressed as the oesophageal mean transit time (MTT) . A radionuclide-labelled solid meal was used to measure gastric motility, expressed as the half-time of gastric emptying (T1/2GET) . A baseline study was performed before oral erythromycin therapy . After a 2-week course of treatment, the subjects underwent a second study . Fasting blood sugar (FBS) was also monitored in each study . In the baseline study, MTT was 8.88 +/- 2.00 s and T1/2GET was 198.0 +/- 58.9 min . After treatment with erythromycin, MTT decreased to 7.48 +/- 2.24 s (P < 0.01) and T1/2GET decreased to 137.1 +/- 71.2 min (P < 0.01) . In addition, the FBS decreased from 159.0 +/- 40.2 mg dl-1 at baseline to 139.2 +/- 39.8 mg dl-1 after 2 weeks of erythromycin treatment (P < 0.05) . We conclude that erythromycin is an effective prokinetic agent for diabetic gastroparesis, and that improved oesophageal transit and gastric emptying may improve glycaemic control. Regul Pept, 1995 Aug 22, 58(3), 157 - 61 Effect of antrectomy and truncal vagotomy on erythromycin induced pancreatic polypeptide secretion; Masclee AA et al.; Erythromycin, a motilin agonist, enhances gastrointestinal motility but also stimulates endogenous pancreatic polypeptide (PP) secretion . We investigated whether the effect of erythromycin on PP release is dependent on (1) prokinetic activity of erythromycin generated from the antrum and (2) the long vagus nerve since erythromycin acts via cholinergic neurons . Erythromycin induced PP secretion was determined in 14 patients with antrectomy (6 patients with Billroth I type anastomosis, 8 patients with Billroth II type anastomosis), in 6 patients with truncal vagotomy and pyloroplasty but without gastric resection and in 8 healthy controls . Plasma PP levels in response to erythromycin (3 mg/kg i.v.) were determined at regular intervals for 180 min . Erythromycin induced a significant increase in plasma PP in the control subjects from 22 +/- 4 pmol/l (basal) to 49 +/- 4 pmol/l at 10 min . In the patients with truncal vagotomy plasma PP secretion after erythromycin was significantly (P < 0.05) increased (peak increment vs . basal: 98 +/- 10 pmol/l vs . 27 +/- 2 pmol/l) and prolonged compared to controls . In the patients with antrectomy no significant increases in plasma PP over basal were observed after erythromycin infusion . It is concluded that erythromycin stimulates PP secretion in healthy controls . The PP response to erythromycin is exaggerated after truncal vagotomy but absent after antrectomy indicating that the antrum is essential for erythromycin induced PP secretion. Gaoxiong Yi Xue Ke Xue Za Zhi, 1995 Aug, 11(8), 430 - 5 Effects of oral erythromycin on esophageal motility in patients with noninsulin-dependent diabetes mellitus; Tsai SC et al.; Fifteen patients with non-insulin dependent diabetes mellitus (NIDDM) were included in the study . Esophageal motility, including esophageal mean transit time (MTT), residual fraction (RF), and retrograde index (RI), was evaluated and calculated by the radionuclide esophageal transit test (RETT) . The baseline study was performed before the oral erythromycin therapy . After a 2-week course treatment, the subjects underwent a second study . The results showed that (A) in the baseline study, 93% (14/15) of NIDDM patients had a longer MTT, 67% (10/15) had a higher RF and 80% (12/15) had a higher RI; and (B) after treatment with erythromycin, 73% (11/15) of the patients had a shorter MTT and a lower RF, and 60% (9/15) of the patients had a lower RI . We conclude that (1) most of the NIDDM patients had esophageal motility disorders and (2) a 2-week oral erythromycin therapy can improve diabetic esophagoparesis, as evaluated by non-invasive REET. Crit Care Med, 1995 Aug, 23(8), 1356 - 62 Effect of erythromycin on gastric motility in mechanically ventilated critically ill patients: a double-blind, randomized, placebo-controlled study; Dive A et al.; OBJECTIVE: To document the action of erythromycin on gastric emptying and motility in mechanically ventilated patients . DESIGN: Crossover, double-blind, randomized, placebo-controlled study . SETTING: General intensive care unit in a university hospital . PATIENTS: Ten patients, mechanically ventilated, in a stable hemodynamic condition . INTERVENTIONS: Erythromycin (200 mg i.v . over 30 mins) and placebo were infused at mid-morning, on two consecutive days, in a random order . Pressure changes in the gastric antrum were recorded by means of a multi-lumen manometric tube (perfused catheter technique) over a period of 300 mins, beginning with the institution of the erythromycin or placebo infusion . Gastric emptying was simultaneously assessed by the kinetics of the absorption of acetaminophen delivered into the stomach (1 g with 20 mL of water) immediately before the infusion . MEASUREMENTS AND MAIN RESULTS: Motility was quantified by determining the number of contractions, the amplitude of contractions, and the Motility Index (Motility Index = natural logarithm {sum of amplitude x number of contractions} + 1) . Comparison between placebo and erythromycin was made for the first hour after the infusion and for the whole recording session . The maximal acetaminophen concentration, the time to reach the peak acetaminophen concentration, and the area under the concentration-time curve at 60 mins were obtained from serial determinations of plasma acetaminophen concentrations . Compared with placebo, the mean number of contractions (104 +/- 34 vs . 5 +/- 8; p = .003), the mean amplitude of contractions (52 +/- 16 vs . 20 +/- 17 mm Hg; p = .005), and the Motility Index (13.06 +/- 0.95 vs . 4.45 +/- 3.54; p = .004) were significantly increased during the first hour after erythromycin infusion compared with placebo . Number of contractions (p = .017) and Motility Index (p < .001) after erythromycin infusion remained significantly higher when values throughout the whole recording session were considered . The following data were noted after erythromycin was infused: a) the time to reach the peak acetaminophen concentration was shorter (32 +/- 8 vs . 171 +/- 93 mins; p = .007); b) the maximal acetaminophen concentration was higher (22.09 +/- 6.23 vs . 5.38 +/- 3.80 micrograms/mL; p = .007); and c) the area under the concentration-time curve at 60 mins increased markedly (730 +/- 269 vs . 72 +/- 42 micrograms/min/mL; p = .002) as compared with placebo . CONCLUSION: In mechanically ventilated patients, intravenous erythromycin (200 mg over 30 mins) increases indices of antral motility and accelerates gastric emptying as assessed by the kinetics of acetaminophen absorption. J Nucl Med, 1995 Aug, 36(8), 1355 - 62 Clinical aerosol inhalation cine-scintigraphy to evaluate mucociliary transport system in diffuse panbronchiolitis; Imai T et al.; This study evaluates the mucociliary transport system in patients with diffuse panbronchiolitis using aerosol inhalation cine-scintigraphy (AICS) . METHODS: Forty-one subjects, 10 healthy controls and 31 patients with diffuse panbronchiolitis, were studied . In addition, the mucociliary transport system was evaluated in 11 patients who had received erythromycin therapy for 3-8.3 yr . Following inhalation of 99mTc-human serum albumin aerosol for 3-5 min in a sitting position, the subjects were placed on the imaging table in the supine position and posterior images were obtained dynamically for 20 sec/frame over 2 hr with a gamma camera linked to a digital computer . The 360 20-sec serial frames were edited into a cinematographic presentation at 200-msec intervals . Clinical evaluation of the mucociliary transport system was based on the bolus movement of radioactive aerosol from the main bronchi to the trachea and the movement patterns, which were divided into four types using the movement in the controls as a standard (type I): type I, rapid and smooth movement; type II, slow movement; type III, stagnation at the carina; and type IV, complete stasis . RESULTS: All patients with diffuse panbronchiolitis had types III and IV, indicating that mucociliary transport system was severely impaired . Of the 11 patients on erythromycin therapy, 8 had movement pattern type IV and 3 had movement pattern type III before erythromycin therapy . In eight patients (72.7%), movement pattern was improved to type I or II after therapy . CONCLUSION: Aerosol inhalation cine-scintigraphy helps evaluate the clinical usefulness of erythromycin therapy in diffuse panbronchiolitis. Am J Health Syst Pharm, 1995 Aug 1, 52(15), 1639 - 45 Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors; Garnett WR; Drug-drug, drug-food, and drug-disease interactions involving hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are reviewed . The four available HMG-CoA reductase inhibitors-lovastatin, simvastatin, pravastatin, and fluvastatin-have different potentials for drug interactions, probably because of their different pharmacokinetic characteristics . Interactions of some of these cholesterol-lowering agents with cyclosporine, erythromycin, high-dose niacin, or gemfibrozil may produce myopathy with or without rhabdomyolysis . Interactions with other commonly prescribed agents, such as bile acid sequestrants, coumarin anticoagulants, and cardiovascular drugs, may alter the pharmacokinetics of either drug, but the clinical significance is generally minor . Food may affect plasma lovastatin concentrations, systemic pravastatin bioavailability, and the maximum serum concentration (Cmax) and time to achieve Cmax for fluvastatin . Hepatic dysfunction may influence the pharmacokinetics of pravastatin; all HMG-CoA reductase inhibitors are contraindicated in patients with liver disease or unexplained elevations in serum aminotransferases . Severe renal insufficiency may necessitate dosage modification in lovastatin recipients . Renal dysfunction seems to affect the pharmacokinetics of pravastatin, simvastatin, and fluvastatin only minimally, but caution is still warranted . Although the HMG-CoA reductase inhibitors rarely have severe adverse effects, they may interact, in some cases dangerously, with other drugs, with food, and with disease states. Hum Exp Toxicol, 1995 Aug, 14(8), 623 - 9 Inhibitory effects of H2-receptor antagonists on cytochrome P450 in male ICR mice; Kim DH et al.; 1 . The present study was undertaken to examine the effects of H2-receptor antagonists including newly developed mifentidine derivatives, IY-80843 and IY-80845, on cytochrome P450(P450) in vitro and in vivo . 2 . Initially, 3-methylcholanthrene-, phenobarbital-, ethanol- and dexamethasone-induced liver microsomes were prepared from male ICR mice to study in vitro effects of above chemicals on ethoxyresorufin O-deethylase(EROD), pentoxyresorufin O-dealkylase(PROD), p-nitrophenol hydroxylase and erythromycin N-demethylase(ERDM) activities, respectively . It was found that histamine, cimetidine and famotidine were not inhibitory to four enzyme activities . Meanwhile, mifentidine slightly inhibited EROD and PROD activities and its derivatives IY-80843 and IY-80845 strongly inhibited PROD, EROD and ERDM activities . 3 . Prolongation of hexobarbital-induced sleeping time was determined in male ICR mice to confirm in vitro inhibitory effects of mifentidine and its derivatives in vivo . It was observed that cimetidine, mifentidine, IY-80843 and IY-80845 caused dose-dependent increases in the sleeping time, indicating the inhibition of P450 responsible for hexobarbital metabolism . 4 . It was concluded that mifentidine and its derivatives are P450 inhibitors and that our newly synthesized IY-80843 is most inhibitory . 5 . The present results indicate that mifentidine and its derivatives not only antagonise the H2-receptor but also inhibit P450 enzymes. Eur J Gastroenterol Hepatol, 1995 Aug, 7(8), 797 - 802 Effects of erythromycin on gastric emptying, duodeno-caecal transit time, gastric and biliopancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers; Landry C et al.; OBJECTIVE: Erythromycin, a macrolide antibiotic, has been reported to increase gastric emptying . The aim of this study was to evaluate the effects of intravenous erythromycin (150 mg/h) on gastric emptying, small intestinal transit time, gastric and biliopancreatic secretions during gastric infusion of a liquid diet in healthy volunteers . DESIGN: A randomized double-blind crossover study (erythromycin versus placebo) . METHODS: Gastric emptying rates of nutrients, gastric acid secretion, gastric pH, jejunal flow rates, as well as biliopancreatic secretions and duodeno-caecal transit time, were evaluated during a continuous infusion at 4.5 kcal/min of a nutrient solution (1 kcal/ml) in the antrum, over a 6 h period, by a perfusion method . RESULTS: During the 6 h period, total gastric volume and gastric acid secretion decreased during erythromycin administration of 37 and 22%, respectively (area under the curves) . Lipase outputs were significantly higher with erythromycin than placebo . Bile salt output was not significantly different between erythromycin and placebo . Duodeno-caecal transit time increased significantly during erythromycin infusion compared with placebo (191 +/- 12 versus 159 +/- 17 min; P < 0.05) . CONCLUSION: During continuous gastric infusion of a liquid diet, intravenous erythromycin has a powerful effect on gastrointestinal function . The motor and secretory effects may enhance the tolerance and the efficiency of enteral nutrition in humans. Antimicrob Agents Chemother, 1995 Aug, 39(8), 1676 - 82 Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides; Mtairag EM et al.; We compared the uptakes and intracellular locations of four 14-membered-ring macrolides (roxithromycin, dirithromycin, erythromycin, and erythromycylamine) in human polymorphonuclear neutrophils (PMNs) in vitro . Intracellular location was assessed by cell fractionation and uptake kinetics in cytoplasts (granule-poor PMNs) . Trapping of dirithromycin within PMN granules (up to 80% at 30 min) was significantly more marked than the intracellular trapping of the other drugs (erythromycylamine, 45% +/- 5.1%; erythromycin, 42% +/- 3.7%; roxithromycin, 35% +/- 3.0%) . A new finding was that, in the absence of extracellular calcium, the uptakes of all of the macrolides by PMNs and cytoplasts were significantly impaired, by about 50% (PMN) and 90% (cytoplasts) . Furthermore, inorganic Ca2+ channel blockers inhibited macrolide uptake in a concentration-dependent manner, with 50% inhibitory concentrations of 1.6 to 2.0 mM and 29 to 35 microM, respectively, for Ni2+ and La3+ . The intracellular distributions of the drugs were unchanged in the presence of Ni2+ and La3+ and in Ca(2+)-free medium supplemented with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid . The organic Ca2+ channel blocker nifedipine had no effect on macrolide uptake, whereas verapamil inhibited it in a time- and concentration-dependent manner . These data show the importance of extracellular Ca2+ in macrolide uptake by phagocytes and suggest a link with Ca2+ channels or a Ca2+ channel-operated mechanism. J Antimicrob Chemother, 1995 Jul, 36(1), 129 - 36 Acquired resistance in Mycobacterium avium complex strains isolated from AIDS patients and beige mice during treatment with clarithromycin; Doucet-Populaire F et al.; Clarithromycin has been reported to select clarithromycin resistant mutants of Mycobacterium avium complex (MAC) during treatment with clarithromycin in AIDS patients and beige mice . We selected resistant mutants in vitro at a frequency of 5 x 10(-9) . Clarithromycin resistant strains of MAC isolated in AIDS patients and beige mice as well as derivatives selected in vitro had a unique pattern of acquired cross-resistance to macrolides and related antibiotics . In contrast, the pattern of resistance to non-macrolide antibiotics remained unchanged in clarithromycin resistant strains . A dramatic decrease in ribosome affinity for clarithromycin and erythromycin was found in clarithromycin resistant strains, but no mutation was found in the peptidyl domain of the 23S rRNA, indicating that another ribosomal modification is involved. J Infect, 1995 Jul, 31(1), 77 - 8 Prevalence of genital infections in medical inpatients in Blantyre, Malawi; Maher D et al.; The limited information on the prevalence of sexually transmitted diseases (STDs) in Malawi suggests that they are common . In studies in Lilongwe in 1989 and Blantyre in 1990, the prevalence of STDs was 4.4% in unselected outpatients and 42% in antenatal clinic patients respectively . Malawi is one of the countries worst affected by the HIV pandemic, with an estimated national HIV seroprevalence of 10% in the age group over 15 years and of 32% in pregnant women who attended antenatal clinics in Blantyre in 1993 . Heterosexual intercourse is the main mode of HIV transmission in sub-Saharan Africa, accounting for up to 80% of cases of HIV infection . Concomitant genital ulcer disease facilitates sexual transmission of HIV . Non-ulcerative STDs may also play a role in facilitating sexual transmission of HIV but the evidence is less clear . The identification and treatment of people with STDs therefore presents an opportunity for decreasing HIV transmission . Queen Elizabeth Central Hospital (QECH) is the District Hospital for Blantyre, Malawi's largest city (about 500,000 population) and the tertiary referral hospital for Malawi's Southern Region . There are two general medical wards, one male and one female, to which about 11,000 patients were admitted in 1993 . Bed occupancy can run at up to 150-200% and resources are limited . The top ten causes of admission are malaria, gastroenteritis, anaemia, pneumonia, dysentery, tuberculosis, AIDS, meningitis, hypertension and ascites . The leading causes of death are AIDS and tuberculosisPIP: Malawi is one of the countries that has been most affected by the HIV epidemic with an estimated national HIV seroprevalence rate of 10% in the age group over 15 years and 32% among pregnant women who attended prenatal clinics in Blantyre in 1993 . Queen Elizabeth Central Hospital (QECH) is the district hospital in Blantyre, Malawi, and the tertiary referral hospital for Malawi's southern region . About 11,000 patients were admitted there in 1993 . The aim of this cross-sectional study was to determine the prevalence of sexually transmitted diseases (STDs) in inpatients under general medical care in view of the limited examination facilities in the wards . All patients who were in the general medical wards on June 23, 1994, were enrolled for the study . After obtaining informed consent, external genital lesions were identified visually noting the presence of ulcers, warts, and urethral discharge in men . The patients' case notes were reviewed to identify those with known current STDs . A total of 123 patients were examined: 62 males (age range 20-90 years) and 61 females (age range 16-65 years) . There were 6 (9.7%) males vs . 8 (13.1%) females with discrete ulcers; no males vs . 2 (3.3%) females had nondiscrete ulcers; 3 (4.8%) males and 6 (9.8%) females had genital warts; 6 (9.7%) males had urethral discharge; and 13 (21%) males vs . 14 (23%) females had one or more lesions . One man had Kaposi's sarcoma of the glans penis . The survey showed that STDS are common in general medical patients in Blantyre with an overall prevalence of 22% . This percentage is an underestimate given the fact that the limited facilities precluded the diagnosis of trichomoniasis, gonorrhea, and chlamydia in women . Of the 123 patients, 14 (11.4%) who had discrete genital ulcers received treatment with erythromycin and penicillin to cover the main possible causes (chancroid, syphilis, and lymphogranuloma venereum) . In view of the known link between STDs and the risk of HIV transmission, treatment of STDs may be more effective in preventing sexual transmission of HIV . Fogorv Sz, 1995 Jul, 88(7), 219 - 24 {Excretion of erythromycin, clindamycin and lincomycin into the saliva}; Kelentey BA et al.; In rabbit experiments (n = 10) the salivary and serum levels of several antibiotics were studied after per os (clindamycin, erythromycin and lincomycin) and iv . (erythromycin) administration . Erythromycin was excreted into the saliva in a considerable degree (in 60-75% of the serum level) and displayed therapeutical levels for 5-6 hrs, whereas clindamycin and lincomycin reached in the saliva only 25-30% of the serum level and therapeutic levels were maintained only for 3 hours. Gastroenterology, 1995 Jul, 109(1), 32 - 9 Erythromycin enhances fasting and postprandial proximal gastric tone in humans; Bruley des Varannes S et al.; BACKGROUND & AIMS: Low doses of erythromycin induce antral contractions and accelerate gastric emptying . However, the effect of erythromycin on the proximal stomach remains unknown . The aim of this study was to assess the effect and mechanism(s) of action of erythromycin on proximal gastric tone in humans . METHODS: Gastric tone was measured using an electronic barostat in two groups of 6 subjects both in the fasting state and after a 200-kcal meal . On different occasions, subjects received saline, atropine alone (6 micrograms.kg-1.h-1 for 30 minutes), erythromycin alone (1.5 mg/kg in the fasting state and 1.5 and 3.0 mg/kg in the postprandial state), and erythromycin plus atropine . RESULTS: Low-dose (1.5 mg/kg) erythromycin enhanced fasting gastric tone, but only the 3.0-mg/kg dose reduced the duration of meal-induced relaxation (37 +/- 14 vs . 105 +/- 20 minutes; P < 0.01) . Atropine did not change the fasting or postprandial gastric tone as well as the erythromycin-induced responses . Plasma motilin levels were unaffected by erythromycin infusion . No correlation was observed between gastric tone and plasma motilin or erythromycin levels . CONCLUSIONS: Erythromycin enhances fasting and postprandial proximal gastric tone in humans by a mechanism that does not seem to involve endogenous motilin release or a cholinergic pathway. Arch Environ Health, 1995 Jul-Aug, 50(4), 293 - 7 Liver damage in pharmaceutical industry workers; Tomei F et al.; A group of workers who were employed at a pharmaceutical manufacturing company and who participated in the entire production cycle were studied . Numerous substances, including iodo-chloro-oxyquinoline, erythromycin, disinfectants, small amounts of cortisones, and preserving agents (prevan and parabenzoates), were used in the manufacturing processes . A control group comprised individuals who were not exposed to hepatotoxic substances . This investigation was designed to determine the risk of hepatotoxicity in the pharmaceutical industry, and a protocol was used that allowed for ease of screening . In the presence of a physician, all subjects completed a clinical history questionnaire . They all underwent a general clinical examination, and specific blood chemistry tests were performed . Certain liver indices that were correlated with cytotoxicity were significantly higher in the pharmaceutical workers than among the controls . The findings confirmed that there was a problem of hepatic involvement among workers in this sector, indicating that the clinical-biohumoral screening protocol used in this study was valid for identifying subjects at risk of hepatotoxicity. Z Gastroenterol, 1995 Jul, 33(6), 340 - 4 Effect of 4 x 250 mg erythromycin on human gastrointestinal transit; Ueberschaer B et al.; The motilin agonist erythromycin affects gastrointestinal motility . We studied its influence on gastric, intestinal, and colonic transit of indigestible solids . Ten healthy volunteers measured the gastrointestinal transit of a 6-8 mm metal sphere by metal detector with oral intake of 250 mg erythromycin q.i.d . or placebo in randomized order . Postprandial gastric emptying of the sphere after a standard meal was measured after a single i.v . dose of 250 mg erythromycin, subsequently followed by determination of small and large bowel transit . Motilin serum levels were measured for one hour . Gastric transit of the sphere was shortened from 243 +/- 34 to 72 +/- 46 min (mean +/- SD) (p = 0.002) and shifted from the interdigestive to the digestive phase . Small and large bowel transit were not influenced, and gastric transit times and motilin serum levels were not correlated . In conclusion, 250 mg erythromycin shortened postprandial gastric emptying of indigestible solids, most likely due to overcoming of pyloric sieving function by strong gastric antral contractions without effecting the transit through the lower part of the gastrointestinal tract. J Antibiot (Tokyo), 1995 Jul, 48(7), 647 - 51 Erythromycin biosynthesis . Highly efficient incorporation of polyketide chain elongation intermediates into 6-deoxyerythronolide B in an engineered Streptomyces host; Cane DE et al.; Feeding of (2S,3R)-{2,3-13C2}-2-methyl-3-hydroxypentanoyl NAC thioester (1a) to the recombinant organism Streptomyces coelicolor CH999/pCK7 harboring the complete set of eryA genes from Saccharopolyspora erythraea encoding the 6-deoxyerythronolide B synthase (DEBS) resulted in the formation of 6-deoxyerythronolide B (2a) labeled with 13C at C-12 and C-13, as evidenced by the appearance of a pair of enhanced and coupled doublets in the 13C NMR spectrum . The level of 13C enrichment was 15-20 atom% 13C, as much as 100 times higher than the usually observed efficiency of incorporation of NAC thioesters into polyketide metabolites . Similar incorporation of (2S,3R)-{3-2H,3-13C}-2-methyl-3-hydroxypentanoyl NAC thioester (1b) gave 6-deoxyerythronolide B (2b) labeled with both 13C and deuterium at C-13 . The intact incorporation of both precursors confirms the normal functioning of the recombinant DEBS proteins in the heterologous host. Chest, 1995 Jul, 108(1), 116 - 22 Leukotriene B4 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis; Oda H et al.; Leukotriene B4 (LTB4) is a potent proinflammatory mediator that may be of particular relevance to the pathology of several respiratory diseases . We have previously reported that neutrophil chemotactic mediators in the lavage fluid of patients with diffuse panbronchiolitis (DPB) consist of many components . In this study, we evaluated the effect of erythromycin (EM) on the pathogenesis of DPB, by examining the level of LTB4 in the bronchoalveolar lavage (BAL) fluid, and determining the relationship between the level and neutrophil accumulation into the respiratory tract . Pre-EM treatment neutrophil chemotactic activity (NCA) in the patients with DPB was significantly increased compared with that in five healthy nonsmoking volunteers (HVs) (p < 0.001), and the level was markedly reduced after EM treatment (p < 0.001) . The amounts of LTB4, detected in the BAL fluid from the patients, was also significantly higher than those in control subjects (3.5 +/- 1.1 ng/mL vs 0.1 +/- 0.0 ng/mL, p < 0.001), and the level was significantly reduced after EM treatment (0.6 +/- 0.3 ng/mL, p < 0.01) . In addition, the percent reduction of the level of LTB4 was significantly correlated with NCA (r = 0.832, p < 0.01); the reduction was also significantly correlated with neutrophil percentage before and after EM treatment (r = 0.778, p < 0.05) . These findings provide evidence for the potent role of LTB4 in the respiratory tracts of patients with DPB and suggest that this lipoxygenase metabolite is involved in the recruitment of neutrophils into the airways of the patients . Our findings suggest that LTB4 is one of the most important chemotactic mediators that has a pathogenetic role in the airway damage of DPB . Erythromycin might inhibit the production of this mediator, restrict the neutrophil accumulation, modulate the excessive inflammation in the respiratory tract, and ultimately improve the pathogenesis of DPB. Clin Infect Dis, 1995 Jul, 21(1), 177 - 81 Incidence and pathogenicity of Arcanobacterium haemolyticum during a 2-year study in Ottawa; Mackenzie A et al.; Arcanobacterium haemolyticum has been described as a rare cause of systemic invasive disease and is occasionally isolated from throat swabs . We describe a 2-year study of the incidence and clinical features of A . haemolyticus infection in a pediatric and adolescent population . A total of 11,620 throat swabs were examined for A . haemolyticum with use of a locally developed selective medium . Controls (2,241) were healthy students who were recruited from a separate study . A . haemolyticum was isolated from 42 patients, with the maximum incidence in the 15 to 18-year-old age group; in this subset the incidence was 2.5% . There were no isolates of A . haemolyticum found in the healthy controls, and the difference in incidence between patients and controls in the 15 to 18-year-old age group was highly significant (P < .01) . Approximately half of the patients infected with A . haemolyticum had a rash . In 5 patients, A . haemolyticum was associated with a positive monospot test . The organism was highly susceptible to erythromycin and less susceptible to penicillin . The evidence from this study suggests that A . haemolyticum may be a pathogen with maximum incidence in the 15 to 18-year-old age group. Nihon Kyobu Shikkan Gakkai Zasshi, 1995 Jul, 33(7), 775 - 9 {A case of Legionella pneumonia successfully treated with roxithromycin}; Heki U et al.; A 56-year-old man was admitted to our hospital because of a high fever . An abnormal shadow was seen on his chest X-ray film . He was treated with piperacillin, isepamycin, and minocycline, but his fever remained and the abnormal shadow got worse . Because he had proteinuria, a severe headache, hyponatremia, and hypophosphatemia, Legionella pneumonia was suspected . A skin test for erythromycin was positive, so roxithromycin was given orally . By the next day the fever had remitted, the appearance of the chest X-ray film had improved, and his symptoms were promptly relieved . This case suggests that roxithromycin can be effective against Legionella pneumonia. Nihon Kyobu Shikkan Gakkai Zasshi, 1995 Jul, 33(7), 771 - 4 {A case of cystic fibrosis in a Japanese student}; Nakanishi N et al.; A 16-year-old boy was admitted to our hospital because of coughing, sputum, and exertional dyspnea . Seven months after birth cystic fibrosis had been diagnosed . The chest roentgenogram on admission showed diffuse reticulonodular shadows and overinflation . Pulmonary function tests revealed obstructive and restrictive impairment . Erythromycin and Lomefloxacin were administered by mouth, and aminoglycosides were administered by inhalation . His symptoms were alleviated, and he is now an outpatient . In Japan, cystic fibrosis is rare, and this patient is extremely rare because he has grown up to be a 16-year-old . In this case, low-dose and long-term erythromycin administration was very effective. Circulation, 1995 Jun 15, 91(12), 3010 - 6 Erythromycin blocks the rapid component of the delayed rectifier potassium current and lengthens repolarization of guinea pig ventricular myocytes; Daleau P et al.; BACKGROUND: Administration of erythromycin to humans has been associated with lengthening of cardiac repolarization and even proarrhythmia . The objectives of our study were to describe effects of erythromycin on repolarization of isolated hearts and to determine effects of the drug on major K+ currents involved in cardiac repolarization . METHODS AND RESULTS: A first set of experiments was conducted in isolated, buffer-perfused guinea pig hearts electrically stimulated at a basic cycle length of 250 ms . In this model, erythromycin 10(-4) mol/L increased monophasic action potential duration measured at 90% repolarization (MAPD90) by 40 +/- 7 ms . Increase in MAPD90 was reproducibly observed in seven hearts studied . To study the mechanism of these effects on cardiac repolarization, a second set of experiments was performed in isolated guinea pig ventricular myocytes using the whole cell configuration of the patch-clamp technique . In these cells, erythromycin 10(-4) mol/L decreased by about 40% (P < .05 versus baseline) the time-dependent outward K+ current elicited by short depolarizations (250 ms) to low depolarizing voltages (-20 to 0 mV) . In contrast, the drug was without significant effects on the time-dependent K+ current elicited by long pulses (5000 ms) to high depolarizing voltages (+10 to +50 mV), on the time-independent background current (mostly IKl), and on the slow inward calcium current . CONCLUSIONS: The outward time-dependent K+ current blocked by erythromycin in isolated guinea pig ventricular myocytes had characteristics similar to those described for IKr . Selective block of this component of IK gives an explanation for the effects of erythromycin on cardiac repolarization . These effects were observed at clinically relevant concentrations reached after intravenous administration of the drug and warn for potential interactions with other action potential-lengthening drugs. Science, 1995 Jun 9, 268(5216), 1487 - 9 Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage; Cortes J et al.; Macrocyclic polyketides exhibit an impressive range of medically useful activities, and there is great interest in manipulating the genes that govern their synthesis . The 6-deoxyerythronolide B synthase (DEBS) of Saccharopolyspora erythraea, which synthesizes the aglycone core of the antibiotic erythromycin A, has been modified by repositioning of a chain-terminating cyclase domain to the carboxyl-terminus of DEBS1, the multienzyme that catalyzes the first two rounds of polyketide chain extension . The resulting mutant markedly accelerates formation of the predicted triketide lactone, compared to a control in which the repositioned domain is inactive . Repositioning of the cyclase should be generally useful for redirecting polyketide synthesis to obtain polyketides of specified chain lengths. Antibiot Khimioter, 1995 Jun, 40(6), 40 - 2 {Chemotherapeutic effectiveness of erythromycin, rifampicin and tetracyclines in chlamydiosis and mycoplasmosis in children}; Vasilos LV et al.; The data on the incidence of Chlamydia and Mycoplasma infections in children with inflammatory diseases of the respiration organs are presented . The peculiarities of the clinical manifestations and the attempts to carry out the clinical differential diagnostication are described . The chemotherapeutic efficacies of erythromycin, rifampicin and tetracycline in the treatment of pneumonia due to Chlamydia and Mycoplasma in children were studied . There was observed similarity in the clinical signs of the infections . The differential diagnostication without the data on the disease etiology was shown impossible . Marked chemotherapeutic efficacies of erythromycin and rifampicin in the treatment of chlamydiosis and mycoplasmosis in infants were stated . The tetracyclines were found to be efficient in the treatment of older children. Pathol Biol (Paris), 1995 Jun, 43(6), 569 - 72 Review of azithromycin activity against Legionella spp; Edelstein PH; Azithromycin is about as active against Legionella spp . in vitro as is erythromycin, with modal MICs approximately 0.5 to 0.125 microgram/ml, depending on the method used . In contrast, azithromycin is much more active against intracellular L . pneumophila than is erythromycin . In a guinea pig model of Legionnaires' disease, azithromycin is much more active than is erythromycin or clarithromycin . Despite the paucity of reports of treatment of Legionnaires' disease with azithromycin, it is likely to be as or more effective than erythromycin. Pathol Biol (Paris), 1995 Jun, 43(6), 498 - 504 {Azithromycin: tissue pharmacology}; Bergogne-Berezin E; Among macrolide derivatives, azithromycin which is an azalide, is a totally original new drug as to its pharmacokinetics in serum and tissues . Compared to reference compounds such as erythromycin or roxithromycin, pharmacokinetic parameters of azithromycin are characterized by: (i) much lower serum concentrations; (ii) a much longer elimination half-life (48-96 h); (iii) high and persistent tissue concentrations . The latter characteristic has been demonstrated in animal models (experimental H . influenzae pneumonia in mice) and in human studies . In lung parenchyma, azithromycin concentrations were higher and more persistent (72 h) in infected mice (12 mg/kg) as compared to non infected mice (controls) receiving the same dose of azithromycin (50 mg/kg); this may result from high intracellular concentrations in polymorphonuclear leucocytes and release of the drug at pulmonary sites of infection . In man, concentrations of azithromycin have been measured in lung parenchyma, bronchial secretions, tonsils, during exploratory or surgical conditions . After a single dose of 500 mg of azithromycin, local levels may reach up to 10 mg/kg with persistence of high levels for > or = 72 h in lungs, tonsils, sinus and bronchial secretions (1.5 to 8.6 mg/kg or mg/l) . Five consecutive doses of azithromycin (500 mg per day) maintained for 10 days tonsil concentrations higher than the MICs for susceptible bacteria.(ABSTRACT TRUNCATED AT 250 WORDS) Ginekol Pol, 1995 Jun, 66(6), 354 - 6 {Roxithromycin (Rulid) in treatment of Chlamydia trachomatis genital infections in women}; Radowicki S et al.; New macrolide antibiotic, roxithromycin (erythromycin--like group), was tested in treatment of chlamydial genital infection in women . In comparison with doxycycline, roxithromycin showed higher clinical efficiency with fewer sides effects. Dig Dis Sci, 1995 Jun, 40(6), 1365 - 71 L-arginine/nitric oxide pathway modulates gastric motility and gallbladder emptying induced by erythromycin and liquid meal in humans; Fiorucci S et al.; There is recent evidence that nitric oxide, a soluble gas produced from L-arginine, is released by the smooth muscle cells and neurons of the gastrointestinal tract where it exerts a myorelaxive action . However, little is known about the effects nitric oxide has on gastric and gallbladder motility during the inter- and postprandial phases in man . We therefore investigated the effects 200 mg/kg/hr L-arginine exerts on the gastric and gallbladder motility induced by 2 mg/kg erythromycin or a liquid meal in 21 subjects in a double-blind, placebo-controlled study . Gastric and gallbladder emptying were evaluated by sonography . Fasting antral motility was expressed as antral motility index (MI) . In fasting subjects, L-arginine administration determined a threefold increase in plasma nitrite concentrations . Administration of erythromycin caused a significant rise in the antral MI, which was inhibited by L-arginine (P < 0.05) . Ingestion of a liquid meal also significantly increased antral MI, but it returned to basal values 90 min after the end of the meal . Although L-arginine administration caused a significant reduction in the antral MI (P < 0.05), it did not inhibit gastric emptying . L-Arginine provoked an approximately 40% increase in basal gallbladder volume, completely blocked erythromycin-induced emptying, and partially, but significantly, prevented the emptying induced by a liquid meal (P < 0.01) . Our study suggests that nitric oxide may be implicated in the physiological modulation of gastric and gallbladder motility during the inter- and postprandial phases in man. Am J Gastroenterol, 1995 Jun, 90(6), 973 - 7 Effect of erythromycin on gallbladder emptying in patients with antrectomy or truncal vagotomy; Masclee AA et al.; OBJECTIVES: Erythromycin, a motilin-like agent, stimulates gallbladder contraction in healthy control subjects . Because the action of erythromycin is cholinergic dependent and possibly related to premature phase III migrating motor complex activity in the antrum, we investigated the effect of erythromycin on gallbladder volume in six patients with truncal vagotomy without gastric resection and 14 patients with antrectomy (6 with Billroth I anastomosis, 8 with Billroth II anastomosis), and we compared the results obtained with those in eight healthy controls . In addition, the effect of meal ingestion on gallbladder volume was studied . METHODS: Gallbladder volumes, measured with ultrasonography, were determined every 15 min for 180 min after erythromycin infusion (3 mg/kg i.v.), as well as 30 and 60 min after meal ingestion . RESULTS: Basal gallbladder volumes were not significantly different among the four groups . Erythromycin induced a significant (p < 0.01-0.05) gallbladder contraction of maximal 46 +/- 6% in the controls, 49 +/- 9% in the patients with truncal vagotomy, and 38 +/- 7% in the patients with antrectomy and Billroth I anastomosis . In the patients with antrectomy and Billroth II anastomosis, no significant reduction in gallbladder volume after erythromycin was observed . Meal-induced gallbladder contraction was normal in all patients, including those with Billroth II anastomosis . CONCLUSIONS: These results indicate that neither the long vagus nerve nor the antrum is essential for erythromycin-induced effects on the gallbladder . Because no significant reduction in gallbladder volume in response to erythromycin was observed in the patients with antrectomy and Billroth II anastomosis, we suggest that duodenojejunal anatomical integrity is essential for erythromycin-induced gallbladder contraction. J Bacteriol, 1995 Jun, 177(12), 3616 - 8 A gratuitous inducer of cat-86, amicetin, inhibits bacterial peptidyl transferase; Gu Z et al.; Expression of the chloramphenicol resistance gene cat-86 is regulated by translation attenuation . Among the three ribosomally targeted antibiotics that can induce the gene, only amicetin has an unknown mode of action . Here we demonstrate that the nucleoside antibiotic amicetin is an inhibitor of bacterial peptidyl transferase . Thus, the three inducers of cat-86, chloramphenicol, erythromycin, and amicetin, interact with the peptidyl transferase region of bacterial ribosomes. Zhonghua Yi Xue Za Zhi (Taipei), 1995 Jun, 55(6), 447 - 51 Effect of oral erythromycin on patients with diabetic gastroparesis; Pan DY et al.; BACKGROUND . Abnormal gastrointestinal motility is a well recognized complication of diabetes mellitus, and disordered gastric emptying may hamper glycemic control . The objects of this study were to investigate the effect of oral erythromycin on gastric emptying and to evaluate the effect of corrected gastric emptying on glycemic control in patients with diabetic gastroparesis . METHODS . Twenty patients of Type II (non-insulin-dependent) diabetes mellitus with typical symptoms of gastroparesis and delayed solid phase gastric emptying were studied . There were 18 males and 2 females, aged 49 to 72 years . Erythromycin (erythromycin estolate) was given orally at a dose of 250 mg, 3 times daily, 30 minutes before each meal . Radionuclide-labelled solid phase gastric emptying and fasting blood sugar (FBS) were studied after one day of erythromycin therapy, and again after 2 weeks of the therapy . The half time of gastric emptying (GETt1/2) represented the time needed for 50 percent of the initial radioactivity to leave the stomach, and was used to express the gastric emptying status . RESULTS . The GETt1/2 decreased from 198.0 +/- 58.9 minutes at baseline to 139.1 +/- 67.6 minutes following one day of erythromycin therapy (p < 0.01), and to 137.1 +/- 71.2 minutes after two weeks of treatment (vs . baseline p < 0.01) . The FBS decreased from 159.0 +/- 40.2 mg/dl at baseline to 149.0 +/- 38.5 mg/dl following one day of therapy (p = 0.12, NS), and to 139.2 +/- 39.8 mg/dl after two weeks of treatment (vs . baseline p < 0.02) . CONCLUSIONS . It was concluded that erythromycin is an effective prokinetic agent for diabetic gastroparesis, and that corrected gastric emptying may improve glycemic control. Kansenshogaku Zasshi, 1995 Jun, 69(6), 646 - 53 {An outbreak of Pontiac fever due to Legionella pneumophila serogroup 7 . I . Clinical aspects}; Mori M et al.; In August 1994, an epidemic of acute febrile illness occurred at the Education Center Building of a company in Shibuya-ku, Tokyo . All 43 trainees attended in two groups and 2 staff members of the Center fell ill . The 45 patients came to one of our hospitals in two groups, and 35 patients were treated . The patients were 4 males and 31 females, and the average age was 29.0 years . The duration until falling ill was 36 to 90 hours after entering the Center . Symptoms were fever, lumbago arthralgia, headache, dyspnea, general fatigue, etc . Physical examination revealed slightly injected mucosa of the pharynx in a patient who complained of a sore throat . On laboratory examination, leukocytosis with a left shift of the nucleus and elevation of serum CRP levels were found . Erythromycin (600 mg, daily) and nonsteroidal antiinflammatory drugs (NSAIDs) were given by mouth to almost every patient . Two patients were hospitalized . The illness was self-limited, generally lasting from two to five days . Strains of legionellae isolated from the water of the cooling tower located at the top of the Center, were identified as L . pneumophila serogroup 7 . Since seroconversion in a patient against the cooling tower strain from 1:16 to 1:256 was determined and the clinical courses agreed with the definition of Pontiac fever by Glick et al, we concluded that the epidemic was an outbreak of Pontiac fever due to L . pneumophila serogroup 7 . Pontiac fever is considered to be one of the community-acquired diseases . Thus, we have to note that Pontiac fever may be misdiagnosed as we examine patients who complain of the symptoms noted above. Bratisl Lek Listy, 1995 Jun, 96(6), 317 - 21 {Modern views on pneumococcal infections in infants and toddlers}; Kotulova D et al.; Pneumococci colonize the upper respiratory tract predominantly in sucklings and toddlers . By means of their factors of virulence (capsule, ahesines, peptidoglycan, and polysaccharides of the capsule, cytoplasmic membrane enzymes) they can either avoid or impair the immunity mechanisms causing thus severe infections especially in children younger than three years of age and in patients with immunity defects . Regarding the possibility of occurrence of pneumococci with altered susceptibility to penicillin and some other drugs (erythromycin, cotrimaxazol, ceftriaxon, chloramphenicol, tetracycline) it is necessary to treat severe pneumococcal infections on the basis of in vitro detected susceptibility. Biol Pharm Bull, 1995 Jun, 18(6), 876 - 81 Effects of roxithromycin on proliferation of peripheral blood mononuclear cells and production of lipopolysaccharide-induced cytokines; Yoshimura T et al.; Roxithromycin (RXM), a new macrolide antibiotic, has a 14-member macrocycline ring structure which is similar to that of erythromycin . We investigated the effects of RXM on the proliferation of peripheral blood mononuclear cells (PBMCs) and the production of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) by PBMCs stimulated with lipopolysaccharide (LPS) . At concentrations greater than 25.0 micrograms/ml, RXM suppressed the proliferation of PBMCs stimulated with phytohemagglutinin, probably due to cytotoxicity . When the PBMCs were incubated with RXM for 7 d, the number of adherent cells (monocyte/macrophages) increased . Incubation with RXM at a concentration of 25.0 micrograms/ml induced the greatest increase (p < 0.05) . IL-1 beta and TNF-alpha were present 3 h after LPS-stimulation, and IL-1 beta production reached a peak at 12 h and TNF-alpha production at between 6 and 12 h, and then their production declined . RXM (25 micrograms/ml) suppressed the production of IL-1 beta and TNF-alpha slightly during the entire course of the incubation . This suppression was dose-dependent . Anti-human granulocyte-macrophage colony-stimulating factor and anti-human macrophage colony stimulating factor antibodies had no effect on the RXM-induced proliferation of adherent cells . Suppression of the production of IL-1 beta and TNF-alpha by RXM suggested that this drug might have anti-inflammatory and immunosuppressive effects. Intern Med, 1995 Jun, 34(6), 469 - 74 Effect of 14-membered ring macrolide therapy on chronic respiratory tract infections and polymorphonuclear leukocyte activity; Shirai T et al.; We studied the efficacy of the long-term administration of 14-membered ring macrolides in treating patients with diffuse panbronchiolitis (DPB) (34 patients) and bronchiectasis (BE) (40 patients) . Oral administration of erythromycin (400 or 600 mg), roxithromycin (150 or 300 mg) or clarithromycin (200 or 400 mg) given daily for at least 2 months, was evaluated . The efficacy of erythromycin, roxithromycin, and clarithromycin in DPB was 19/24 (79%), 6/7 (86%), and 2/3 (67%), respectively . Efficacy of these agents in BE exceeded 50% . We determined the effect of these macrolides on the activity of polymophonuclear leukocytes (PMNs) obtained from healthy volunteers . There were no significant differences between the effects of these 14-membered ring macrolides and josamycin, a 16-membered ring macrolide which was previously found to be ineffective in treating DPB . Thus, the effectiveness of the 14-membered ring macrolides in treating DPB appears to depend on mechanism(s) other than alterations in PMN activity. Xenobiotica, 1995 Jun, 25(6), 575 - 84 Effects of bioflavonoids on hepatic P450 activities; Obermeier MT et al.; 1 . The effects of tangeretin, green tea flavonoids, and other flavonoids on 7-ethoxyresorufin-O-deethylase (EROD; 450 1A), 7-pentoxyresorufin-O-dealkylase (PROD; P450 2B), p-nitrophenol hydroxylase (PNPH, P450 2E1), and erythromycin-N-demethylase (ERDM; P450 3A) were examined in induced rat liver microsomes . EROD, PNPH, ERDM, and nifedipine oxidase (NIFO; P450 3A4) were examined in human liver microsomes . 2 . All flavonoids tested inhibited EROD activity at higher concentrations in liver microsomes . Flavone and tangeretin were potent inhibitors of EROD, with IC50's of 0.7 and 0.8 microM respectively in rat liver microsomes and 0.15 and 16 microM respectively in human liver microsomes . The green tea flavonoid (-)-epicatechin-3-gallate (ECG) was the most potent inhibitor of EROD in human liver microsomes (IC50 = 75 microM) . The effect of the green tea flavonoids on EROD was complex; in addition to inhibition at high concentrations of flavonoid, moderate activation was seen at lower concentrations . 3 . 450 2B-, 2E1- and 3A-dependent activities in rat and human liver microsomes were only moderately inhibited by any of the flavonoids tested, and, in general, ECG was the most potent inhibitor for these activities with IC50's ranging from 75 to 300 microM . 4 . Tangeretin inhibited EROD activity (P450 1A2) in human liver microsomes in a competitive manner with a Ki = 68 nM . Tangeretin inhibited NIFO activity (P450 3A4) in human liver microsomes in an uncompetitive manner with Ki = 72 microM. Biochem Pharmacol, 1995 May 26, 49(11), 1665 - 73 Rapid changes in cytochrome P4502E1 (CYP2E1) activity and other P450 isozymes following ethanol withdrawal in rats; Roberts BJ et al.; This study describes the effects of chronic ethanol (ETOH) treatment and withdrawal on the rat hepatic mixed-function mono-oxygenase system . Male Sprague-Dawley rats (150-200 g, 10 per group) were administered ETOH as part of the Lieber-deCarli liquid diet for 3 weeks . Ethanol was removed, and the animals were euthanized at 0, 24, 48, 72 and 168 hr post-withdrawal . Microsomes were prepared, and ethanol-inducible cytochrome P4502E1 (CYP2E1) activity was measured using the enzyme markers N-nitrosodimethylamine demethylase (NDMAd), p-nitrophenol hydroxylase (PNPH) and aniline hydroxylase (AH) . Activities were found to be induced significantly after chronic ETOH feeding using all three assays (NDMAd, 5-fold; PNPH, 3.5-fold; AH, 9-fold) . Upon ETOH withdrawal, all three activities dropped markedly, with NDMAd and PNPH at control values at 24 hr and all subsequent time points . AH activity remained 3-fold higher than controls at 24, 48 and 72 hr . Western blot analyses showed that immunoreactive CYP2E1 returned to control at 24 hr, consonant with NDMAd and PNPH activities . The prolonged induction of AH activity following ETOH withdrawal indicates that it is not a specific marker of CYP2E1-catalyzed reactions . Collectively, these data are suggestive of a rapid mechanism of CYP2E1 degradation in the rat liver . Of the other parameters investigated in this study, total cytochrome P450 content was increased 2.5-fold after ETOH feeding, with levels dropping markedly 24 hr post-withdrawal . NADPH-dependent cytochrome c reductase activity was unchanged throughout the course of the study . CYP1A1, CYP2B1 and CYP3A activities were assessed by the substrate probes ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD) and erythromycin N-demethylase (ERNd) . EROD and PROD were induced significantly by ETOH administration (2-fold) at 0 hr, with EROD remaining elevated over controls 24 hr post-withdrawal . Quantitative western blot analysis of CYP1A1 and CYP2B1 revealed a pattern of immunostaining generally consistent with but less variable than levels predicted by the respective substrate markers . Both proteins were induced significantly by chronic ethanol administration (CYP1A1, 1.9-fold; CYP2B1, 4-fold) . Induction of these P450 isoforms persisted for several days following withdrawal . In contrast, immunoreactive CYP1A2 was found to decrease significantly (by 30-40%) during ethanol withdrawal (24, 48, 72, 168 hr) . ERNd activity was induced significantly by chronic ETOH feeding (2.5-fold) and remained so for 24 hr into the withdrawal period (2-fold) . Immunoreactive CYP3A1 was also induced significantly following ETOH administration (0 hr) and 24 hr following withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS) J Mol Biol, 1995 May 26, 249(1), 1 - 10 Mapping important nucleotides in the peptidyl transferase centre of 23 S rRNA using a random mutagenesis approach; Porse BT et al.; Random mutations were generated in the lower half of the peptidyl transferase loop in domain V of 23 S rRNA from Escherichia coli using a polymerase chain reaction (PCR) approach, a rapid procedure for identifying mutants and a plasmid-based expression system . The effects of 21 single-site mutations, at 18 different positions, on cell growth, mutant rRNA incorporation into ribosomes and peptidyl transferase activity of the mutant ribosomes were analysed . The general importance of the whole region for the peptidyl transferase centre was emphasized by the finding that 14 of the mutants were sick, or very sick, when ribosomes containing chromosomal-encoded 23 S rRNA were inhibited by erythromycin, and all except one of these exhibited low levels of peptidyl transferase activity in their mutated ribosomes . Two mutations, psi 2580-->C and U2584-->G that both yielded inactive ribosomes were assigned to the donor substrate binding site and a possible base-pairing interaction between the 3'-terminal sequence of the peptidyl-tRNA and the sequence psi/U-G-G2582, that is conserved in all the non-mitochondrial 23 S-like rRNA sequences, is proposed . Three sites that have been implicated in aminoacyl-tRNA binding were mutated: mutant m6A2503G yielded inactive ribosomes, while ribosomes from mutants Um2552A/C and U2555C yielded low and normal activities, respectively . Three mutants, U2528C, G2550A and A2565U, provide evidence for conformational rearrangements occurring in the peptidyl transferase centre which may be affected by the subunit-subunit interaction . Other mutants which yielded ribosomes that were seriously defective in peptidyl transferase activity were U2493A, U2493C, A2497G, A2530G, G2557A and A2589G. Biochem Biophys Res Commun, 1995 May 25, 210(3), 781 - 6 Erythromycin suppresses interleukin 6 expression by human bronchial epithelial cells: a potential mechanism of its anti-inflammatory action; Takizawa H et al.; We evaluated the effects of several antibiotics on IL-6 expression by human bronchial epithelial cells, potent sources of this proinflammatory cytokine important in airway inflammation . Among those tested, erythromycin (EM) and clarithromycin (CAM) uniquely suppressed mRNA levels as well as the release of IL-6 at the therapeutic and non-cytotoxic concentration (10(-6)M) . Our findings suggested that these macrolide antibiotics had suppressive effect on cytokine expression in human cells, and this new mode of action may have relevance to their clinical effectiveness in airway inflammatory diseases. Biochem Pharmacol, 1995 May 17, 49(10), 1443 - 52 Inactivation of chick embryo hepatic cytochrome P450 1A, 2H and 3A following in ovo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine and 3-{2-(2,4,6-trimethylphenyl)thioethyl}-4-methylsydnone; McNamee JP et al.; Rat hepatic cytochrome P450 (P450) isozymes 1A1, 2C6, 2C11, 3A1 and 3A2 are targets for mechanism-based inactivation by the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC) . It is of interest to determine whether similar P450 isozymes are targets of porphyrinogenic drugs in the chick embryo liver . The chick embryo expresses P450 2H1/2 isozymes, which are similar to the rat P450 2B1/2 isozymes, a polycyclic aromatic hydrocarbon-inducible P450 1A isozyme, and a pregnenolone 16 alpha-carbonitrile-inducible P450 3A isozyme . We have found previously that chick embryo hepatic P450 1A and 3A isozymes are targeted for in vitro mechanism-based inactivation by 4-ethyl DDC and by the sydnone 3-{2-(2,4,6-trimethylphenyl)thioethyl}-4-methylsydnone (TTMS) . Marked differences have been observed between the in vitro and in vivo effects of porphyrinogenic drugs on P450 isozymes . Thus, the first objective of this study was to determine whether chick embryo hepatic P450 1A and 3A isozymes are subject to in ovo inactivation by these porphyrinogenic compounds . Our second objective was to determine whether the chick embryo hepatic P450 2H isozyme(s) was subject to in ovo and in vitro inactivation by 4-ethyl DDC and TTMS . Using hepatic microsomes prepared from beta-naphthoflavone-, dexamethasone-, phenobarbital-, and glutethimide-induced 19-day-old chick embryos, we found that total P450 content was decreased significantly in microsomes prepared from all treatment groups following in ovo administration of 4-ethyl DDC and TTMS . Moreover, in ovo administration of both 4-ethyl DDC and TTMS caused a significant decrease of 7-ethoxyresorufin O-deethylase, erythromycin N-demethylase, and benzphetamine N-demethylase activities, which are selective catalytic markers for chick embryo hepatic P450 1A, 3A and 2H isozymes, respectively . In addition, in vitro administration of 4-ethyl DDC and TTMS caused mechanism-based inactivation of benzphetamine N-demethylase activity in microsomes from phenobarbital- and glutethimide-treated chick embryos, showing that the chick embryo hepatic P450 2H isozyme is a target for mechanism-based inactivation . Therefore, it was concluded that the chick embryo hepatic P450 1A, 2H and 3A isozymes serve as targets for both in ovo and in vitro mechanism-based inactivation by 4-ethyl DDC and TTMS. J Med Chem, 1995 May 12, 38(10), 1793 - 8 Synthesis of 4"-deoxy motilides: identification of a potent and orally active prokinetic drug candidate; Lartey PA et al.; As an approach to discovering highly potent motilides with oral activity, novel 4"-deoxy derivatives of 8,9-anhydroerythromycin 6,9-hemiacetal were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities . These compounds were orders of magnitude more potent than their 4"-hydroxy analogs in inducing smooth muscle contractions in an in vitro rabbit duodenal assay . Removal of the 12-hydroxy group, which was aimed at improving oral bioavailability, also afforded further potentiation in in vitro activity, leading to the identification of 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal (ABT-229) as a potential prokinetic drug . ABT-229 was > 300,000 times more potent than erythromycin in vitro and had 39% oral bioavailability in dog compared to its 4",12-dihydroxy congener (EM-523), which was only 400 times more potent than erythromycin and had relatively low (1.4%) oral bioavailability. Biochem Pharmacol, 1995 May 11, 49(9), 1269 - 75 Role of cytochrome P450 2C9 and an allelic variant in the 4'-hydroxylation of (R)- and (S)-flurbiprofen; Tracy TS et al.; Flurbiprofen is a chiral non-steroidal anti-inflammatory drug used in the treatment of pain or inflammation . The primary routes of biotransformation for (R)- and (S)-flurbiprofen are oxidation (presumably cytochrome P450) and conjugation . To date, the specific cytochrome P450 (P450) involved in the oxidative metabolism of this compound (specifically 4'-hydroxylation) has not been elucidated . Experiments were conducted to characterize the kinetic parameters (Km and Vmax) for the 4'-hydroxylation of (R)- and (S)-flurbiprofen in human liver microsomes, to determine if enantiomeric interactions occur when both enantiomers are present, and to identify the specific P450 form(s) involved in this reaction . In human liver microsomes, the Km and Vmax (mean +/- SD) for (R)-4'-hydroxy-flurbiprofen formation were 3.1 +/- 0.8 microM and 305 +/- 168 pmol.min-1.mg protein)-1, respectively . In comparison, the Km and Vmax (mean +/- SD) for (S)-4'-hydroxy-flurbiprofen formation were 1.9 +/- 0.4 microM and 343 +/- 196 pmol.min-1.mg protein-1, respectively . Enantiomeric interaction studies revealed a decrease in Km and Vmax for both enantiomers and an apparent loss of stereoselectivity . Racemic-warfarin, tolbutamide, alpha-naphthoflavone and erythromycin were studied as potential inhibitors of this process . The estimated Ki values for the inhibition of (R)- and (S)-4'-hydroxy-flurbiprofen formation by racemic-warfarin were 2.2 and 4.7 microM . This reaction was also inhibited by tolbutamide . In contrast, erythromycin and alpha-naphthoflavone had no appreciable effect on 4'-hydroxy-flurbiprofen formation . cDNA-expression of individual forms was used to determine which P450 was involved in 4'-hydroxy-flurbiprofen formation . P450 2C9 and an allelic variant (R144C) readily catalyzed the formation of 4'-hydroxy-flurbiprofen . P450 1A2 was also active albeit with a turnover rate 1/140th that of P450 2C9R144C (P450s 2C8, 2E1 and 3A4 were not active toward either enantiomer) . The results of these studies indicate that the enantiomers of flurbiprofen may exhibit stereoselectivity with respect to enzyme affinity but have roughly equal maximum formation velocities . Additionally, these two enantiomers may compete for the enzyme resulting in lower maximum velocities for both enantiomers . Finally, of those P450 forms examined, only P450 2C9 and an allelic variant catalyzed the 4'-hydroxylation of both (R)- and (S)-flurbiprofen. Arch Bronconeumol, 1995 May, 31(5), 249 - 51 {Pleuropericarditis as the only manifestation of Legionella pneumophila infection}; Torrus Tendero D et al.; Pleural effusion caused by Legionella is seen fairly frequently but is hardly ever of great clinical significance . Pericardial involvement has been described only rarely . We present a case of pleuropericarditis as the only sign of infection by Legionella pneumophila in a 66-years-old man with no prior history of disease . The patient came to the hospital with chest pain suggestive of pleurisy, low-grade fever, dry cough and dyspnea . The etiology was not suspected and the diagnosis was made retrospectively based on indirect immunofluorescence . After 3 weeks of treatment with high dose of erythromycin the patient recovered and remains asymptomatic to date . We conclude that infection by Legionella pneumophila should be suspected in patients with pleurisy or pericarditis of unknown cause. Curr Microbiol, 1995 May, 30(5), 273 - 9 Erythromycin inhibits the assembly of the large ribosomal subunit in growing Escherichia coli cells; Chittum HS et al.; Erythromycin and other macrolide antibiotics have been examined for their effects on ribosome assembly in growing Escherichia coli cells . Formation of the 50S ribosomal subunit was specifically inhibited by erythromycin and azithromycin . Other related compounds tested, including oleandomycin, clarithromycin, spiramycin, and virginiamycin M1, did not influence assembly . Erythromycin did not promote the breakdown of ribosomes formed in the absence of the drug . Two erythromycin-resistant mutants with alterations in ribosomal proteins L4 and L22 were also examined for an effect on assembly . Subunit assembly was affected in the mutant containing the L22 alteration only at erythromycin concentrations fourfold greater than those needed to stop assembly in wild-type cells . Ribosomal subunit assembly was only marginally affected at the highest drug concentration tested in the cells that contained the altered L4 protein . These novel results indicate that erythromycin has two effects on translation, preventing elongation of the polypeptide chain and also inhibiting the formation of the large ribosomal subunit. Am J Respir Crit Care Med, 1995 May, 151(5), 1582 - 8 Effect of erythromycin on endotoxin-induced microvascular leakage in the rat trachea and lungs; Tamaoki J et al.; To determine whether the macrolide antibiotic erythromycin prevents microvascular leakage produced by lipopolysaccharide (LPS), we studied tracheae and lungs of pathogen-free rats . Tracheal vascular permeability and neutrophil recruitment were assessed by the percent area occupied by Monastral blue-labeled blood vessels and by myeloperoxidase-containing granulocytes, respectively, in tracheal whole mounts . Pulmonary microvascular leakage was evaluated by lung wet-to-dry (W/D) weight ratio . Inhalation of Escherichia coli LPS (5 mg/kg) caused time-dependent increases in tracheal vascular permeability, neutrophil influx, and lung W/D ratio . These responses were inhibited by pretreatment with oral erythromycin, but not by ampicillin or cefaclor, in a dose-dependent manner: erythromycin at 10 mg/kg daily for 1 wk reduced the area density of Monastral blue-labeled vessels from 6.7 +/- 1.2 to 1.4 +/- 0.3% (p < 0.01), the number of neutrophils (from 365 +/- 51 to 149 +/- 30 cells/mm2, p < 0.01), and lung W/D weight ratio (from 6.76 +/- 0.30 to 5.39 +/- 0.21, p < 0.01) . This inhibitory effect of erythromycin was abolished by depletion of circulating neutrophils with cyclophosphamide . These results suggest that LPS causes acute lung injury, microvascular leakage, and neutrophil recruitment in the trachea, and that erythromycin protects against these changes, probably by acting on neutrophils. Ann Pharmacother, 1995 May, 29(5), 486 - 8 Delirium probably induced by clarithromycin in a patient receiving fluoxetine; Pollak PT et al.; BACKGROUND: Clarithromycin is a macrolide antibiotic very similar to erythromycin in structure and spectrum of activity . It has gained increasing use since its release in Canada in May 1992, partly because it is promoted as having less potential for drug interactions and adverse effects . However, as with all new medications, a high degree of vigilance for unreported adverse effects is advisable . CASE SUMMARY: A healthy 53-year-old lawyer was receiving long-term fluoxetine 80 mg hs and nitrazepam 10 mg hs for depression and mild sleep apnea . Subsequent to initiation of treatment with clarithromycin for a respiratory infection, he rapidly developed delirium, which cleared quickly after stopping all 3 medications . The delirium and psychosis did not recur when the infection was treated with erythromycin alone or after restarting fluoxetine and nitrazepam therapy at previous dosages in the absence of antibiotics . DISCUSSION: This man's delirium is consistent with fluoxetine intoxication, which appears to have resulted from inhibition of hepatic cytochrome P450 metabolism by clarithromycin . Undiagnosed, this serious drug reaction could have lead to serious medical and social consequences . CONCLUSIONS: As the use of clarithromycin increases, the potential for interactions with other drugs metabolized by the P450 enzyme system may be realized . Clinicians should consider which other medications a patient is receiving before prescribing clarithromycin or any macrolide antibiotic with potential to influence the P450 system. Bioorg Med Chem, 1995 May, 3(5), 587 - 604 Conformational change due to esterification of hydroxy groups in erythromycin A and its major metabolite: analysis of these derivatives with different biological properties using NMR and molecular dynamics (MD) data; Ladam P et al.; A conformational study is performed on the acylated erythromycin and erythralosamine derivatives from comparison between experimental results (NMR) and theoretical calculations by Molecular Dynamics (MD) in attempts to correlate their conformations with their abilities to generate cytochrome P450-nitroso metabolite complexes in vitro . As the 3'-dimethyl-amino function of the desosamine is metabolized and responsible for the interaction with cytochrome P450, its position, mobility and steric hindrance in the proximity of this functional group are related to its biological properties . The major conformations of the lactone ring were termed A (A1, A2, A3) and B (B1, B2), and this macrocycle flexibility induced five different orientations a, b, c, d and e for the desosamine sugar . Conformations A and B differ in many ways but the major change is the inward folding of the C(3) fragment in B . Conformer a exhibits an orientation of the desosamine nearly perpendicular to the macrocycle whereas the two units are in the same plane in conformations c and e . For conformation b, the cladinose unit lifts up above the macrocycle . Conformation d exhibits a turned-back cladinose . In the erythromycin derivatives esterification at the beta position to the N(CH3)2 group of the desosamine reduces the degree of freedom of the macrocyclic lactone ring which corresponds to conformation A only . The desosamine sugar was found to be perpendicular to the macrocycle (a conformer) and both sugar groups are parallel to reduce the steric energy . In the erythralosamine derivatives, the macrocycle is always present as conformation B with the two conformations b and c of the sugar rings . The steric parameters favour the b conformers in which the amino group is tilted up, while in 3,2'-dibenzoylated stacking aromatic attraction stabilizes the planar c conformer . Both isomers are thus shown to adopt well-defined conformations and to be well-adapted for a comparative structure-activity correlation studies . There is a significant relationship between the conformation b and the formation of cytochrome P450-nitroso metabolite complexes. Clin Infect Dis, 1995 May, 20(5), 1311 - 6 Q fever in the Greek Island of Crete: epidemiologic, clinical, and therapeutic data from 98 cases; Tselentis Y et al.; A retrospective study was undertaken in Crete, Greece, to investigate the epidemiologic, clinical, and therapeutic aspects of Q fever . Over a period of 5 years (1989-1993), 1,298 patients were examined and 98 cases were identified . Individuals who were aged 20-29 years and 30-39 years appeared to have an increased risk of infection . Contact with animals was found to be a major risk factor for acquisition of Q fever . The predominant clinical manifestations of the infection were fever (91.7% of patients) and respiratory disease (88.5%), whereas hepatitis was the dominant feature in only a minority (7.1%) of patients . Chest radiographs frequently revealed pulmonary interstitial changes (36.4% of patients) and alveolar changes (34.4%) . Abnormal echocardiographic findings were also observed . There was no difference in the duration of fever whether the patient received therapy with tetracycline or erythromycin, a finding that may be explained by the delay in initiating tetracycline therapy. Clin Infect Dis, 1995 May, 20(5), 1158 - 62 Treatment of Legionella pneumophila lung abscess with clindamycin; Buggy BP et al.; Clindamycin was used to successfully treat a lung abscess caused by Legionella pneumophila . The activity of clindamycin, erythromycin, and rifampin against cell-associated growth of L . pneumophila in human monocytes was determined by broth time-kill methodology . More killing of cell-associated growth of L . pneumophila was achieved with clindamycin than with erythromycin . Synergy with rifampin was demonstrated with both erythromycin and clindamycin. Ann Epidemiol, 1995 May, 5(3), 201 - 9 Terfenadine-associated ventricular arrhythmias and QTc interval prolongation . A retrospective cohort comparison with other antihistamines among members of a health maintenance organization; Hanrahan JP et al.; This study compared the occurrence of syncope, ventricular arrhythmias, and corrected QT interval (QTc) prolongation over a 2 1/2-year period in persons prescribed terfenadine versus other prescription antihistamines among 265,000 members of the Harvard Community Health Plan (HCHP), the largest staff-model health maintenance organization in New England . HCHP maintains an automated medical record system with coded diagnoses for each ambulatory and hospital visit, and a similar automated pharmacy system with information for each member on all prescriptions filled at its pharmacies . Among 0.86 million exposure days of terfenadine and 1.04 million exposure days of other antihistamines, we found no excess risk of either clinical/arrhythmia events (odds ratio (OR), 0.86; 95% confidence interval (CI), 0.52 to 1.44) or QTc prolongation (OR, 1.00; 95% CI, 0.64 to 1.57) during courses of terfenadine versus those of other antihistamines . Joint courses of antihistamines and oral erythromycin were associated with an increased risk of QTc prolongation (OR, 2.33; 95% CI, 1.31 to 4.15), and there was a trend for this to be observed more frequently with terfenadine (OR, 2.37; 95% CI, 0.73 to 7.51; P = 0.14). J Antimicrob Chemother, 1995 May, 35(5), 593 - 601 Viomycin does not stimulate the dissociation of peptidyl-tRNA; Menninger JR; Peptidyl-transfer RNA normally dissociates at a low rate from the ribosomes of Escherichia coli during protein synthesis but accumulates under nonpermissive conditions in cells with a temperature-sensitive allele (pthts) of the gene encoding peptidyl-transfer RNA hydrolase . The antibiotic-hypersensitive strain E . coli DB-11 with the pthts mutation was exposed to viomycin, then placed at nonpermissive temperatures . Under these conditions in the absence of drugs, peptidyl-tRNA accumulates, protein synthesis is inhibited and pthts cells die . When viomycin was present at sufficient concentration to arrest protein synthesis, cell death was not accelerated, error-inducing effects of streptomycin were not counteracted and, at high doses, cytoplasmic accumulation of peptidyl-transfer RNA was slowed down . Blocking the translocation of peptidyl-transfer RNA with viomycin did not stimulate its dissociation from ribosomes . Erythromycin-enhanced cell death was not affected by viomycin at doses sufficient to block amino acid incorporation, suggesting that short peptidyl-transfer RNAs could still be synthesized and dissociated from ribosomes. Xenobiotica, 1995 May, 25(5), 433 - 41 Small intestinal sulphoxidation of albendazole; Villaverde C et al.; 1 . The in vitro sulphoxidation of Albendazole (ABZ) by rat intestinal microsomes has been examined . The results revealed intestinal sulphoxidation of ABZ by intestinal microsomes in a NADPH-dependent enzymatic system . The kinetic constants for sulphoxidase activity were Vmax = 46 pmol/min/mg protein and Michaelis constant Km = 6.8 microM . 2 . The possible effect of inducers (Arochlor 1254 and ABZ pretreatment) and inhibitors (erythromycin, methimazole, carbon monoxide and fenbendazole), was also studied . In rat pretreated with Arochlor 1254, Vmax was 52 pmol/min/mg protein, whereas oral administration of ABZ increased the intestinal sulphoxidation of the drug, Vmax being 103 pmol/min/mg protein . 3 . Erythromycin did not change the enzymatic bioconversion of ABZ, but methimazole and carbon monoxide inhibited the enzyme activity by approximately 60 and 30% respectively . Fenbendazole (a structural analogue of ABZ) was a competitive inhibitor of the sulphoxidation process, characterized by a Ki or 69 microM . 4 . These data demonstrate that the intestinal enzymes contributing to the initial sulphoxidation of ABZ may be similar to the hepatic enzymes involved in the biotransformation process by the P450 and FMO systems, a conclusion that needs to be further established. Gene, 1995 Apr 14, 156(1), 101 - 6 Cloning and heterologous expression of the genes encoding nonspecific electron transport components for a cytochrome P450 system of Saccharopolyspora erythraea involved in erythromycin production; Zotchev SB et al.; The forA gene encoding a protein that can function as a NADH:ferredoxin oxidoreductase (For) has been cloned from Saccharopolyspora erythraea, the erythromycin A (ErA) producer . In a previous study For protein, together with the FdxA ferredoxin from the same organism, was shown to be able to reconstitute the cytochrome P450 system responsible for the hydroxylation of 6-deoxyerythronolide B, an intermediate of ErA biosynthesis . Nucleotide sequence data suggest that the cloned forA gene codes for For, the putative pyruvate dehydrogenase component, dihydrolipoamide dehydrogenase, or its close homolog . Overexpression of forA appeared to be toxic to Escherichia coli. Am Surg, 1995 Apr, 61(4), 368 - 70 Efficacy of preoperative bowel preparation at home; Philip RS; A preliminary study was designed to determine whether preoperative bowel preparation for colorectal surgery could be performed safely at home . Medical charts of 62 patients covering 4 years of elective major colorectal surgery done by a single general surgeon were retrospectively reviewed . Patients were divided into four groups, depending on the year in which they had surgery . Each patient had been given an easy-to-understand instruction sheet as well as prescriptions for mannitol solution, neomycin, and erythromycin base . The changeover from hospital-based to home-based bowel cleansing was gradual . In the first year of the study, all patients had bowel preparation in hospital; in the final year, 88% of patients had bowel cleansing at home . Home bowel preparation resulted in no identifiable increase in morbidity or mortality . No death or wound infection occurred in any patient group . Preoperative home bowel preparation can be done safely by the patient without increased morbidity or mortality . Ordering this preparation for most colorectal surgery patients could save about $150 million in hospital costs per year in the United States. Clin Infect Dis, 1995 Apr, 20(4), 812 - 7 Cutaneous Mycobacterium kansasii infection: case report and review; Breathnach A et al.; A case of cutaneous Mycobacterium kansasii infection is reported, and 28 similar cases are reviewed . Cutaneous infection may resemble sporotrichosis and is often associated with systemic illness, immunosuppression, skin pathology, or contact with contaminated water . Immunosuppressed patients with M . kansasii infection may present with atypical clinical features (such as cellulitis and seroma) and atypical histology (absence of granulomas), which may delay diagnosis and effective treatment . The incidence of disseminated M . kansasii infection, which has a worse prognosis, is higher among immunosuppressed patients . When M . kansasii infection is confined to the skin, the disease is usually indolent . Chemotherapy with a variety of agents, including traditional antituberculous agents as well as erythromycin, minocycline, and doxycycline, has been successful, although in vitro resistance to isoniazid and p-aminosalicylic acid is common . Reducing the dose of corticosteroids may be a beneficial adjunct to therapy for M . kansasii infection. Antimicrob Agents Chemother, 1995 Apr, 39(4), 872 - 7 Erythromycin shortens neutrophil survival by accelerating apoptosis; Aoshiba K et al.; Erythromycin is reported to have an anti-inflammatory action, which may account for its clinical effectiveness in the treatment of chronic inflammatory diseases such as diffuse panbronchiolitis . To evaluate the anti-inflammatory action of erythromycin, we examined the survival of isolated neutrophils with and without erythromycin . Erythromycin shortened neutrophil survival in a dose-dependent fashion, with a maximum effect at 10 micrograms/ml {corrected} and above . Survival at 24 h was 63.4% in medium with 10 micrograms of erythromycin per ml compared with 82.7% in control medium (P < 0.01) . This shortening of survival was brought about by acceleration of apoptosis, as evidenced by transmission electron microscopy . In a manner similar to that of erythromycin, other macrolide antibiotics, i.e., clarithromycin, roxithromycin, and midecamycin, also shortened neutrophil survival, but neither the beta-lactams ampicillin and cefazolin nor the aminoglycoside gentamicin affected their survival . Erythromycin increased intracellular levels of cyclic AMP (cAMP) to 150% of control levels in neutrophils . Forskolin, rolipram, and dibutyryl-cAMP, which are known to increase intracellular cAMP levels, also shortened neutrophil survival . H-89, an inhibitor of cAMP-dependent protein kinase A, partially blocked the survival-shortening effect of erythromycin . Our findings suggest that erythromycin shortens neutrophil survival at least in part through elevation of intracellular cAMP levels. Arch Environ Contam Toxicol, 1995 Apr, 28(3), 273 - 80 Induction of rat liver drug-metabolizing enzymes by tetrachloroethylene; Hanioka N et al.; The effect of tetrachloroethylene on Phase I and II drug-metabolizing enzymes in rat liver was examined . Rats were treated orally with tetrachloroethylene daily for five days, at doses of 125, 250, 500, 1,000 and 2,000 mg/kg . The higher doses (> 500 mg/kg) of tetrachloroethylene induced the hepatic microsomal 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase activities associated with the CYP2B subfamily . 7-ethoxyresorufin O-deethylase activity was also induced about 2-fold compared with that of control rats at 500, 1,000, and 2,000 mg/kg dose levels of tetrachloroethylene . However, 7-ethoxycoumarin O-deethylase and 7-methoxyresorufin O-demethylase activities were increased significantly at only the 1,000 mg/kg dose level of tetrachloroethylene (1.4- and 1.5-fold) . Although other cytochrome P450-mediated monooxygenase activities such as nitrosodimethylamine N-demethylase, aminopyrine N-demethylase and erythromycin N-demethylase were also induced by tetrachloroethylene, the relative induction to control activity was lower than those of 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase . Western immunoblotting showed that the levels of CYP2B1 and CYP2B2 proteins in liver microsomes were increased at doses of 1,000 and 2,000 mg/kg of tetrachloroethylene . In addition to cytochrome P450-mediated monooxygenases, there was significant induction of the Phase II drug-metabolizing enzymes, DT-diaphorase, glutathione S-transferase activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and UDP-glucuronyltransferase activities towards 4-nitrophenol and 7-hydroxycoumarin . The results indicate that tetrachloroethylene induces both Phase I (CYP2B-mediated monooxygenase) and Phase II drug-metabolizing enzymes (DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase) in the rat liver. J Infect Dis, 1995 Apr, 171(4), 1053 - 6 Use and safety of acellular pertussis vaccine among adult hospital staff during an outbreak of pertussis; Shefer A et al.; During May and June 1993, 10 patients and 5 members of the clinical staff at a hospital in California were diagnosed with Bordetella pertussis infection . In addition to erythromycin prophylaxis, 630 (48%) of 1330 staff members received a half dose of acellular pertussis vaccine with tetanus and diphtheria toxoids (DTaP) . To identify side effects of the vaccine, a questionnaire was completed by 344 (54%) of 630 vaccinated staff . Side effects were reported by 117 respondents (34%); 64 were classified as mild (local reaction at injection site) and 50 as moderate (systemic complaints or local reaction resulting in limitation of arm movement) . Three vaccinees (< 1%) reported missing 1 or more days of work because of their symptoms . Local reactions at the injection site occurred in 100 (29%), systemic symptoms in 38 (11%), and limitation of arm movement in 18 (5%) . This study indicates that use of half dose of DTaP in adults appears safe and should be considered as an adjunct to chemoprophylaxis during institutional outbreaks. Am J Respir Crit Care Med, 1995 Apr, 151(4), 1228 - 32 Effects of erythromycin on the rabbit pleura: its potential role as a pleural sclerosant; Carvalho P et al.; Tetracycline (TCN) has been considered the agent of choice for pleurodesis in patients with symptomatic malignant pleural effusions and recurrent pneumothoraces . However, the intravenous form of TCN used for pleurodesis is no longer available . Erythromycin, like TCN, often produces irritation when administered intravenously . In view of these irritant properties, we tested the effect of erythromycin as a pleural sclerosant in rabbits as compared with TCN . Normal saline was used as a control . Adult rabbits weighing 2.5 to 3.0 kg underwent sterile placement of a silastic pleural tube in the right pleural space . Erythromycin (n = 17) or TCN (n = 6), each in doses of 35 mg/kg in 2 ml saline, was administered via the tube . Control animals (n = 6) received 2 ml saline . The chest tubes were left in place for removal of pleural fluid and to maintain lung expansion . Animals were killed 8 d after receiving the various treatments, and their pleural surfaces were examined grossly and histologically . Numerous adhesions were present between the visceral and parietal pleurae in all animals receiving erythromycin and TCN, but not in those receiving saline . On light microscopy, pleurae treated with erythromycin or TCN were histologically identical, showing inflammation, edema, and fibroblast proliferation in the submesothelial tissues . The saline-treated animals had a normal pleura . Because erythromycin produced pleural inflammation and adhesions within 8 d of treatment, we propose that it may have a potential role as a pleural sclerosant. Pharmacol Toxicol, 1995 Apr, 76(4), 255 - 8 Interaction between erythromycin and nitrazepam in healthy volunteers; Luurila H et al.; Interaction between erythromycin, a strong inhibitor of CYP3A4, and nitrazepam, a long-acting benzodiazepine, was investigated in a double-blind and randomized cross-over study of two phases . Ten healthy volunteers received erythromycin (500 mg x 3) orally or placebo for 6 days . On the fourth day they were given a challenge dose of 5 mg nitrazepam . Plasma samples were collected and psychomotor effects were measured during 42 hr after intake of nitrazepam . There was a statistically significant pharmacokinetic interaction between erythromycin and nitrazepam . Erythromycin increased the area under the nitrazepam concentration-time curve by 25% (P < 0.05) and the peak concentration by 30% (P < 0.05) . The concentration peak time of nitrazepam was shortened by over 50% (P < 0.05) . The elimination half-lives did not change . Accordingly, as far as the metabolism of nitrazepam is concerned, erythromycin does not cause any major changes in the metabolism of nitrazepam . In psychomotor performance only minor differences were seen . It is concluded that the interaction between erythromycin and nitrazepam is of little clinical significance. Drug Metab Dispos, 1995 Apr, 23(4), 490 - 6 Catalytic role of cytochrome P4503A4 in multiple pathways of alfentanil metabolism; Labroo RB et al.; The synthetic opioid alfentanil (ALF) undergoes extensive metabolism via two major pathways: piperidine nitrogen dealkylation to noralfentanil (NA) and amide nitrogen dealkylation to N-phenylpropionamide (AMX) . It is unknown whether AMX results from amide N-dealkylation of ALF directly, or indirectly from NA, the major metabolite of ALF . The major objectives of this investigation were to determine the metabolic origin of AMX and to identify the cytochrome P450 isoforms in human liver microsomes catalyzing ALF metabolism . Metabolites were quantitated by GC/MS . Significant amide N-dealkylation of ALF but not of NA by human liver microsomes was observed, indicating that AMX is derived directly from ALF and that there are two primary routes of ALF metabolism . Three strategies were used to identify the P450 isoform(s) catalyzing each of the two metabolic pathways: effect of isoform-selective inhibitors on metabolite formation catalyzed by human liver microsomes, correlation of metabolite formation rate with microsomal P450 isoform protein content and catalytic activity in a population of human livers, and metabolism by cDNA-expressed P450 isoforms . The mechanism-based P4503A4 inhibitor, troleandomycin, significantly inhibited formation of both NA and AMX . Other P4503A4 inhibitors, including midazolam, erythromycin, and ketoconazole, also diminished ALF metabolism to both metabolites . Formation rates of both NA and AMX were significantly correlated with microsomal P4503A4 protein content and catalytic activity . Of six expressed human P450 isoforms (P450s 1A2, 2A6, 2B6, 2D6, 2E1, and 3A4), only P4503A4 exhibited significant catalytic activity toward ALF dealkylation to NA and AMX . These results indicate the predominant role of P4503A4 in both major pathways of ALF metabolism. Biochem Pharmacol, 1995 Mar 15, 49(6), 799 - 808 Hepatic microsomal induction profile of carbamic acid {{2,6-bis(1- methylethyl)phenoxy} sulfonyl}-2,6-bis(1-methylethyl) phenyl ester, monosodium salt (PD138142-15), a novel lipid regulating agent; Robertson DG et al.; Induction of hepatic microsomal cytochrome P450 produced by carbamic acid {2,6-bis(1-methylethyl)phenoxy}sulfonyl}-2,6-bis(1-methylethyl) phenyl ester, monosodium salt (PD138142-15), a novel water-soluble inhibitor of acyl-CoA: cholesterol acyltransferase, was examined in male and female rats, dogs, and monkeys, and in male guinea pigs . Relative to control, PD138142-15 increased hepatic microsomal total spectral P450 in all species examined . Hepatic microsomal ethoxyresorufin-O-deethylase, pentoxyresorufin-O-dealkylase, and peroxisomal carnitine acetyltransferase activities and cyanide-insensitive Beta-oxidation were affected only marginally . Erythromycin-N-demethylase activity was increased (2- to 6-fold) in all three species in which it was examined (rat, dog and pig) . Marked increases in immunoreactive P450 3A were noted in the rats and dogs, while slight increases were seen in monkeys . Pharmacokinetic studies of PD138142-15 in rats and dogs revealed pronounced decreases (80-90%) in plasma Cmax and AUC within 2 weeks of initiation of daily dosing . In spite of the marked decline in plasma drug levels, efficacy in dogs, as determined by serum cholesterol levels, was maintained for up to 6 weeks with continued dosing . Potential acid (gastric) breakdown products of PD 138142-15 were examined for their hepatic cytochrome P450 induction profiles in rats adn were found to differ both quantitatively and qualitatively from profiles produced by the parent compound . This suggested that induction observed in rats was due to parent PD138142-15 and not to any of the known potential acid breakdown products . The cumulative data establish that PD 138142-15 is an inducer of P450 3A in rats and dogs . The results also suggest that P450 3A is induced in monkeys and pigs as well, although the data are less definitive . Decreases in plasma drug levels imply that the compound may be an autoinducer in dogs and rats . The maintenance of efficacy in spite of decreased drugs levels in dogs suggests that the effects on serum cholesterol are due to a metabolite or that cholesterol lowering effects occur before the compound is metabolized by the liver. Arch Biochem Biophys, 1995 Mar 10, 317(2), 374 - 84 Expression of cytochrome P450 3A5 in Escherichia coli: effects of 5' modification, purification, spectral characterization, reconstitution conditions, and catalytic activities; Gillam EM et al.; Cytochrome P450 (P450) 3A5 is a human enzyme with 85% amino acid sequence identity to the more predominantly expressed P450 3A4 and has been reported to have overlapping catalytic specificity . The 5'-terminus of a P450 3A5 cDNA was modified for optimal expression in Escherichia coli using the vector pCW, by aligning the MALLLAVFL N-terminal sequence of recombinant bovine P450 17A (H . J . Barnes, M . P . Arlotto, and M . R . Waterman, (1991) Proc . Natl . Acad . Sci . USA 88, 5597-5601) to the 3A5 cDNA . Two constructs were made, differing by their identity with the modified 3A4 N-terminal sequence (E . M . J . Gillam, T . Baba, B-R . Kim, S . Ohmori, and F . P . Guengerich, (1993) Arch . Biochem . Biophys . 305, 123-131) . The first modified sequence (3A5#1) was identical to recombinant P450 3A4 up to codon 15, the 3A5 sequence being introduced thereafter . In the other (3A5#2), the successful 3A4 N-terminal nucleotide sequence was attached to codon 30 . The yield was greater than fourfold higher in the first construct {up to 260 nmol (liter culture)-1} . The recombinant P450 3A5 (construct 1) was purified to electrophoretic homogeneity using a variation of a three-step procedure developed previously for P450 3A4, with an overall yield of approximately 40% . Purified P450 3A5 was active in nifedipine oxidation, testosterone 6 beta-hydroxylation, aflatoxin 3 alpha-hydroxylation and 8,9-epoxidation, ethylmorphine N-demethylation, erythromycin N-demethylation, and d-benzphetamine N-demethylation . The reconstitution of nifedipine oxidation, testosterone 6 beta-hydroxylation, and the aflatoxin oxidation activities showed dependence upon the presence of cytochrome b5, divalent cations, phospholipid mixtures, glutathione, and cholate similar to that previously found for purified P450 3A4 . However, rates of the N-demethylations of ethylmorphine, erythromycin, and d-benzphetamine were as high or higher for P450 3A5 than P450 3A4 and were not particularly dependent upon modifications of reconstitution systems {corrected}. J Biol Chem, 1995 Mar 10, 270(10), 5014 - 8 CO binding kinetics of human cytochrome P450 3A4 . Specific interaction of substrates with kinetically distinguishable conformers; Koley AP et al.; The kinetics of CO binding to human cytochrome P450 3A4 was examined by the flash photolysis technique, employing the membrane-bound P450 expressed in baculovirus-infected SF9 insect cells . Triexponential kinetics was observed, indicating that P450 3A4 is composed of multiple, kinetically distinguishable conformers . To define the substrate specificity of individual P450 3A4 conformers we evaluated the effect of a series of substrates of varying sizes and structures on the CO binding kinetics . The rate of CO binding to the total mixture of P450 3A4 conformers was increased in the presence of nifedipine and erythromycin, decreased by quinidine, testosterone, and warfarin, and unaffected by cimetidine and 17 alpha-ethynylestradiol . A recently developed kinetic difference method (Koley, A . P., Robinson, R . C., Markowitz, A., and Friedman, F . K . (1994) Biochemistry 33, 2484-2489) was used to define the kinetic parameters of individual P450 3A4 conformers . The results showed that different conformers have distinct substrate specificities . The substrates had markedly variable effects on the CO binding kinetics of their target P450 3A4 conformers and thus differentially modulate their conformations . These results demonstrate that the interaction of a particular substrate with a specific P450 3A4 conformer can be assessed in the presence of multiple conformers. Masui, 1995 Mar 3, 44(3), 402 - 6 {Mycoplasma pneumonia found by the occurrence of atelectasis during the induction of anesthesia in a child with tetralogy of Fallot}; Matsukado T et al.; A 3-yr-old girl was scheduled to undergo surgical repair of tetralogy of Fallot . She had no sign or data indicating an infectious disease, other than a slight dry cough for a few days prior to the proposed operation . During the induction of anesthesia with nitrous oxide, oxygen and sevoflurane, transient moist rale was noticed with a precordial stethoscope . Her trachea was intubated without any difficulty after the administration of pancuronium, followed by a chest auscultation, which revealed vesicular sound bilaterally but no rale . However, a chest X-ray taken after the right subclavian vein catheterization showed a massive hypoaeration in the upper left pulmonary region . The presence of the right-to-left intracardiac shunt made it impossible to detect the occurrence of atelectasis by a decrease in SpO2 . Fiberoptic bronchoscopy showed no obstruction of the bronchus and no hypersecretion initially, but physical therapy and humidification made it possible to aspirate intratracheal sputum . Because there seemed to be an imbalance between the relatively uneventful induction of anesthesia and the relative resistance of atelectasis to authentic therapies, the operation was postponed, and the antibody to mycoplasma pneumoniae was titrated . The titer in the serum was 1:80, and increased to 1:560 6 days later . Chest X-rays revealed normal lung condition 3 days later, and she was given erythromycin, 800 mg.day-1 for 2 weeks . We conclude that we should be alert to possible asymptomatic mycoplasma infection, which potentially makes patients susceptible to atelectasis during the perioperative period. Am J Physiol, 1995 Mar, 268(3 Pt 1), G424 - 30 Relationship between surface electrogastrography and antropyloric pressures; Sun WM et al.; The cutaneous electrogastrogram (EGG) and intraluminal antropyloroduodenal pressures were recorded in 12 healthy volunteers for 30-min periods during phase II of the interdigestive motor complex, during intraduodenal infusion of 10% triglyceride, and after intravenous erythromycin (3 mg/kg) . During phase II, the frequency of the EGG was relatively constant in each individual, with a median frequency of 0.046 Hz {2.8 counts per minute (cpm)} . EGG frequency was greater (P < 0.05) than the median rate of antral pressure waves (1.8 cpm) . The suppression of antral pressure waves (P < 0.05) and stimulation of isolated pyloric pressure waves (IPPWs) (P < 0.05) produced by triglyceride infusion were not associated with changes in EGG frequency compared with phase II . The frequency of the EGG and the rate of IPPWs were comparable . After erythromycin, EGG frequency was 0.03 Hz (1.8 cpm), less than during both phase II and triglyceride infusion (P < 0.05) and almost identical to the rate of antral pressure waves . Pressure waves were nearly always associated with an EGG signal . In contrast, the temporal relationship between the EGG signal and pressure waves was variable . During triglyceride infusion (r = 0.83, P < 0.001) and after erythromycin (r = 0.83, P < 0.001) there was a close (approximately 1:1) relationship between the rate of pressure waves and EGG frequency . However, there was no significant relationship (r = 0.32, not significant) between the number of pressure waves and EGG frequency frequency during pase II.(ABSTRACT TRUNCATED AT 250 WORDS) J Allergy Clin Immunol, 1995 Mar, 95(3), 668 - 71 In vitro detection of specific IgE antibodies to erythromycin; Pascual C et al.; BACKGROUND: In vitro tests for detecting drug-specific IgE would be useful in identifying patients at risk for immediate hypersensitivity reactions to therapeutic doses of a drug . OBJECTIVE: We attempted to verify that IgE-mediated reactions to erythromycin occur and to identify IgE antibodies specific for erythromycin in serum from a patient who had urticaria immediately after administration of the drug . METHODS: Skin prick testing was performed on the patient and five control subjects . Serum from the patient, pooled sera from nonatopic subjects allergic to common aeroallergens, and cord blood controls were analyzed for erythromycin-specific IgE by radioimmunoassay . Sepharose (Pharmacia, Uppsala, Sweden) was used as solid phase covalently linked to erythromycin . RESULTS: We were able to detect erythromycin-specific IgE antibodies in serum from the patient who had an allergic reaction to this antibiotic, but specific IgE could not be detected in control sera . CONCLUSION: Immunologic IgE-mediated reactions to erythromycin do occur, and in vitro diagnosis of such reactions can be made by using Sepharose as a solid phase covalently linked to this drug. Am J Respir Crit Care Med, 1995 Mar, 151(3 Pt 1), 895 - 8 Recurrence of diffuse panbronchiolitis after lung transplantation; Baz MA et al.; Diffuse panbronchiolitis (DBP) is characterized by chronic inflammation of the upper and lower respiratory tract . DPB has been found almost exclusively in oriental populations . We describe the occurrence of a case of DPB in an African American patient who underwent bilateral sequential lung transplantation . Ten weeks after transplantation, DPB recurred in the lung allograft, with rapid and significant deterioration in graft function . Allograft function improved within a few weeks after beginning treatment with erythromycin . This early recurrence is suggestive of a systemic etiology of DPB . Although recurrence of other systemic diseases has been reported after lung transplantation, no previous patients have been reported with early functional deterioration based solely on disease recurrence. Leuk Lymphoma, 1995 Mar, 17(1-2), 189 - 90 Legionnaires' disease during induction of remission chemotherapy for acute nonlymphocytic leukemia; Landau Z et al.; Two patients with acute nonlymphocytic leukemia (ANLL) who developed neutropenia, bilateral lung infiltrates, and did not respond to conventional antibiotic therapy nor amphotericin B are described . Clinical awareness and suspicion of Legionnaires' disease (LD) and early administration of erythromycin lead to their cure before the diagnosis of LD was confirmed. Am J Vet Res, 1995 Mar, 56(3), 362 - 5 Impact of age-related alteration of plasma alpha 1-acid glycoprotein concentration on erythromycin pharmacokinetics in pigs; Kinoshita T et al.; Erythromycin (EM) pharmacokinetic variables were studied after IV administration of the drug (10 mg/kg of body weight) to 1-, 6-, and 15-day-old pigs . With advancing age, from 1 day to 15 days after birth, half-life of EM became shorter (3.0 hours to 1.4 hour), whereas apparent volume of distribution, total body clearance (CLt), and intrinsic clearance became greater: 0.68 to 3.28 (L/kg), 0.15 to 1.42 (L/h/kg), and 1.81 to 3.56 (L/h/kg), respectively . The percentage of plasma protein binding of EM decreased from 91 to 56%, correlating well with volume of distribution and CLt values . The altered binding percentage depended on plasma alpha 1-acid glycoprotein (AGP) concentration, but not on albumin concentration . With advancing age, plasma AGP concentration was markedly decreased from approximately 6,000 micrograms/ml to 700 micrograms/ml . Despite a twofold increase in intrinsic clearance with advancing age, CLt increased ninefold, implying that the decreased protein binding contributed to the increase of CLt more preferentially than did maturational development of elimination capacity . Therefore, the altered protein binding of EM attributable to the change in plasma AGP concentration could be a major causal factor of the age-related pharmacokinetic variables of EM in pigs. Jpn J Antibiot, 1995 Mar, 48(3), 437 - 40 {Determination of 1H- or 13C NMR spectra of oleandomycin (OL), the esterolitic cleavage compound of OL and OL 2'-phosphate using two-dimensional methods in D2O solution}; O'Hara K et al.; All signals of 1H- and 13C NMR spectra of oleandomycin and the esterolitic cleavage compound of oleandomycin, and all signals of 1H-NMR spectra of oleandomycin 2'-phosphate were determined using two-dimensional methods as 1H-1H and 13C-1H COSY NMR, and DEPT NMR in D2O solution . The two modified products of oleandomycin were prepared by two strains of Escherichia coli highly resistant to erythromycin<