Erythromycin

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 . These results are basically useful in determination of the structure of novel metabolites of oleandomycin inactivated by bacterial action.

Arch Pediatr, 1995 Mar, 2(3), 245 - 8
{Malassezia furfur septicemia after bone marrow graft}; Schoepfer C et al.; BACKGROUND--Systemic Malassezia furfur (Mf) infections are only seen in neonates and immunocompromised patients . CASE REPORT--A 2-year-8-month-old boy was given chemotherapy for mediastinal T cell lymphoma . Meningeal relapse supervened 10 months later, requiring polychemotherapy plus CNS irradiation followed by bone marrow transplantation . Three days after transplantation, fever associated with neutropenia required administration of ceftazidime, amikacin, vancomycin plus acyclovir followed by amphotericin B, cefotaxime plus erythromycin . Blood cultures were negative, but blood swears showed yeasts into polynuclear cells after cytocentrifugation; these yeasts were also present in the central catheter removed after a few days course of amphotericin B, flucytosine plus fluconazole . The patient was then given GM-CSF subcutaneously (5 micrograms/kg/day), followed by progressive correction of aplasia and cure of the Mf infection . CONCLUSION--This is a new case of systemic Mf infection seen in an immunocompromised child receiving parenteral nutrition with lipids.

J Infect, 1995 Mar, 30(2), 135 - 40
Q-fever pneumonia in the Negev region of Israel: a review of 20 patients hospitalised over a period of one year; Lieberman D et al.; BACKGROUND: Three-hundred and forty-six patients with community acquired pneumonia were included in a prospective study of patients hospitalised over a 12-month period in the Soroka Medical Center in Beer-Sheva, Israel . Q-fever pneumonia (QFP) was diagnosed in 20 patients (5.8%) . A detailed epidemiological and clinical description of this disease, is presented . METHODS: QFP was diagnosed by conventional criteria using a commercial immunofluorescent assay . RESULTS: The age of patients was 41 +/- 14 years (mean +/- S.D., range 20-69) . Twelve of the patients were males . No concomitant or chronic disease was present in 16 patients . Chest radiograms revealed alveolar or air space pneumonia in 10 patients, bronchopneumonia in nine and interstitial pneumonia in one patient . The mean febrile period was 10.5 +/- 5.3 days . There was serological evidence of co-infection with Mycoplasma pneumonia in six patients, and with Legionella pneumophila in one patient . Patients treated with beta-lactam antibiotics recovered as quickly as those treated with tetracyclines or erythromycin . CONCLUSIONS: The Negev region of Israel is an endemic area for Q-fever . The diagnosis of QFP can be made only on the basis of a specific serological test . Clinical, radiologic or laboratory findings are not diagnostically definitive . The importance of specific therapy is unclear.

Neurogastroenterol Motil, 1995 Mar, 7(1), 47 - 54
Gastric but not duodenal motor effects of oral erythromycin are dose related; Mathis C et al.; There has been increasing interest in the potential use of erythromycin as a prokinetic agent, despite limited data on the effect of oral administration on gastrointestinal motility . We have now evaluated, in 15 conscious pigs fitted with strain gauges, the response of (i) basal gastric motility and (ii) gastric motility during inhibition with intraduodenal triglycerides infusion to increasing doses of oral erythromycin . In the basal state, erythromycin led to dose-dependent increases in both the amplitude (10-30 mg kg-1) and the frequency (10-55 mg kg-1) of gastric contractions . The corpus was more responsive than the antrum, with an increase in amplitude at lower doses . The amplitude of the duodenal contractions was also improved but not in a dose-dependent manner . Gastroduodenal coordination was unchanged regardless of the dose of erythromycin . Following inhibition of gastric motility, a dose of erythromycin below 45 mg kg-1 increased both the amplitude of gastric contractions and the gastroduodenal coordination, although individual doses produced smaller increases in amplitude than in the basal state . These results suggest that erythromycin has a different mechanism of action in the stomach compared with the duodenum . The reduced effectiveness of large doses of erythromycin has important therapeutic implications.

Pharmacotherapy, 1995 Mar-Apr, 15(2), 164 - 9
Effect of erythromycin on ethanol's pharmacokinetics and perception of intoxication; Min DI et al.; STUDY OBJECTIVE . To determine the effect of erythromycin on ethanol's pharmacokinetics and perception of intoxication . DESIGN . Double-blind, randomized, placebo-controlled, crossover study . SETTING . A clinical research center . PARTICIPANTS . Ten healthy volunteers . INTERVENTIONS . Erythromycin base 500 mg or identical placebo was administered 3 times/day for 7 days . On day 8, ethanol 0.8 g/kg was administered by mouth concurrently with erythromycin or placebo . A 2-week washout period was allowed between each treatment arm . MEASUREMENTS AND MAIN RESULTS . Twelve blood samples were obtained over a 12-hour period to determine ethanol concentrations . Perception of intoxication was determined at each time point using a 10-cm visual analog scale . Ethanol concentrations were determined using a gas chromatographic method . Mean +/- SD ethanol pharmacokinetics for erythromycin versus placebo were time to peak ethanol plasma concentrations 1.1 +/- 0.4 hours versus 1.3 +/- 0.3 hours, peak ethanol concentrations 118 +/- 18 mg/dl versus 114 +/- 27 mg/dl, ethanol oral clearance (CL/F) 2.9 +/- 0.8 ml/min/kg versus 3.4 +/- 2.2 ml/min/kg, and area under the curve 481 +/- 104 mg.hour/dl versus 465 +/- 132 mg.hour/dl (p > 0.05) . The blood ethanol concentrations and perception of intoxication scores on a visual analog scale were well correlated (r2 = 0.78, p < 0.01) . Mean +/- SD areas under the effect versus time curve were 35.1 +/- 20.7 cm/hour and 31.5 +/- 18.2 cm/hour for erythromycin and placebo, respectively (p > 0.05) . CONCLUSION . Oral erythromycin base 1500 mg/day compared with placebo does not alter ethanol's pharmacokinetics or perception of intoxication in healthy volunteers.

J Formos Med Assoc, 1995 Mar, 94(3), 123 - 6
Legionnaires' disease with acute renal failure: report of two cases; Lin SL et al.; Acute renal failure in Legionnaires' disease is rare, but the mortality rate is high {1-3} . Although the actual pathogenesis is not clear, the renal pathology discloses either acute tubulointerstitial nephritis or acute tubular necrosis in most cases {3} . We report two cases of Legionnaires' disease complicated by acute renal failure . One patient was completely healthy before, and the other had underlying gouty arthritis and diabetes mellitus . Their renal function was normal before these episodes . The diagnosis of Legionella infection was proved by the indirect fluorescent antibody test on paired sera . After erythromycin treatment, both patients survived . One patient required long-term maintenance hemodialysis, and the other recovered to only mild azotemia after a follow-up period of 5 months . Including our cases, only 55 patients have been reported to have Legionella-induced acute renal failure . This is a rare and serious complication of Legionnaires' disease . Early recognition and treatment is mandatory.

Biochemistry, 1995 Feb 14, 34(6), 1858 - 66
Overproduction and characterization of the erythromycin C-12 hydroxylase, EryK; Lambalot RH et al.; Hydroxylation of C-12 is one of the final steps in the biosynthesis of erythromycin A (ErA) . A point of uncertainty in the erythromycin pathway has been whether the C-12 hydroxylase operates on each of two possible substrates, erythromycin B (ErB) and erythromycin D (ErD) . Stassi et al . have cloned the gene, designated eryK, which encodes the P-450 monooxygenase responsible for erythromycin C-12 hydroxylation in Saccharopolyspora erythraea {Stassi, D., Donadio, S., Staver, M . J., & Katz, L . (1993) J . Bacteriol . 175, 182-189} . We report the overproduction of EryK in Escherichia coli as insoluble inclusion bodies; the solubilization, refolding, and reconstitution of active holo-EryK; and kinetic confirmation of a 1200-1900-fold preference of the enzyme for ErD over the alternative C-12 hydroxylase substrate ErB . Our results indicate that ErB is a shunt metabolite in the erythromycin biosynthetic pathway.

Regul Pept, 1995 Feb 14, 55(3), 227 - 35
Transduction mechanism of motilin and motilides in rabbit duodenal smooth muscle; Depoortere I et al.; The present study was undertaken to explore motilin's transduction pathway in the rabbit . Guanine nucleotides inhibited 125I-motilin binding in rabbit antral tissue and increased the dissociation of motilin from its receptor . Motilin, the motilin agonist erythromycin A enol ether (EM-201) and carbachol (taken as control) increased the production of inositol phosphates in rabbit duodenal smooth muscle strips labeled with myo-{2-3H}inositol . The effect of carbachol was blocked by atropine . Dose-response curves revealed that 50% of this effect was obtained with 3.9 nM motilin, 170 nM EM-201, 0.54 microM carbachol . Chromatographic separation of the inositol phosphate metabolites showed significant increases in the levels of {3H}inositol bisphosphate and of {3H}inositol trisphosphate . The three substances were without effect upon the metabolism of cAMP, nor did they modulate the rise in cAMP induced by GTP . We propose that motilin's transduction pathway uses a G protein that causes an increase in inositol trisphosphate which is rapidly metabolized, and which may release calcium from intracellular stores.

Presse Med, 1995 Feb 4, 24(5), 278 - 82
Clinical aspects of Chlamydia pneumoniae infection; Cook PJ et al.; This recently recognised member of the genus Chlamydia is one of the most widespread pathogens of man, though up to 90% of infected people have few or no symptoms . Several studies have estimated the population prevalence of antibodies to C . pneumoniae at 40-55% in the northern hemisphere, and over 60% in under-developed countries . The incidence of infections follows a cyclical pattern, with peaks at regular intervals of 2-10 years, but no apparent seasonal periodicity . Nosocomial transmission may be mediated by environmental surfaces as well as aerosols, and immunosuppression, for example by the human immunodeficiency virus, predisposes to infection . Chlamydia pneumoniae causes predominantly atypical pneumonia, often severe in adults, especially the elderly; including 5-10% of community-acquired pneumonia in Scandinavian countries . Serological evidence indicates associations with asthma, bronchitis, exacerbations of chronic airflow obstruction, otitis media and bronchiolitis . Several studies, using both serological and morbid anatomical techniques, also indicate associations with vascular atheroma and ischaemic heart disease, and with acute myocardial infarction . Chronic, latent and recurrent infections have been documented, and it is postulated that, like chronic or recurrent C . trachomatis infections, these may produce disease as a consequence of the host's immunological hypersensitivity . Several techniques are available for serological diagnosis: the technique of choice is micro-immunofluorescence, using fixed whole elementary or reticulate bodies as antigen, but antibody responses are highly variable . Traditional alternatives, antigen detection (by direct immunofluorescence or enzyme immunoassay) and cell culture, have major disadvantages . Polymerase chain reactions have not yet been widely applied to the clinical setting . tetracycline antibiotics, erythromycin and quinolones are not very efficacious in the treatment of C . pneumoniae infection . The azalide antibiotic, azithromycin, and the macrolide, clarithromycin, are active in vitro against C . pneumoniae, and may become treatments of choice . The development of anti-chlamydial vaccines remains an important research goal.

Gene, 1995 Feb 3, 153(1), 33 - 40
Cloning of the genes encoding thymidine diphosphoglucose 4,6-dehydratase and thymidine diphospho-4-keto-6-deoxyglucose 3,5-epimerase from the erythromycin-producing Saccharopolyspora erythraea; Linton KJ et al.; Genes involved in deoxysugar metabolism, encoding thymidine diphospho (TDP)-glucose 4,6-dehydratase (gdh) and a putative TDP-4-keto-6-deoxyglucose 3,5-epimerase (kde), were cloned from the erythromycin (Er)-producing Saccharopolyspora erythraea by means of an oligodeoxynucleotide corresponding to a segment of the purified Gdh protein . Determination of the nucleotide sequence established that kde lies 3' to gdh . The function of gdh was confirmed by an enzymatic assay following expression of the gene in Escherichia coli . Southern analysis indicated that Sa . erythraea contains only one copy of gdh and kde . It was not possible to establish whether these genes are required for Er biosynthesis, but they appear to be essential for cellular metabolism, since resolution of a partial diploid containing a wt and a disrupted copy of gdh always maintained the wt gene . These loci do not lie within or near the known boundaries of the cluster of Er-production and -resistance genes, nor do they appear to be flanked by other deoxysugar biosynthesis genes.

Can J Ophthalmol, 1995 Feb, 30(1), 11 - 20
Perioperative ofloxacin vs . tobramycin: efficacy in external ocular adnexal sterilization and anterior chamber penetration; Kirsch LS et al.; OBJECTIVE: To compare the efficacy of two treatment regimens, tobramycin drops-erythromycin ointment and ofloxacin drops-placebo ointment, in sterilizing the external ocular adnexa when given perioperatively . A second objective was to determine the aqueous humour concentration of ofloxacin and tobramycin . DESIGN: Randomized double-blinded clinical trial . SETTING: University-affiliated hospital . PATIENTS: Patients aged 18 years or more scheduled to undergo planned cataract surgery who were judged likely to complete the trial . NUMBERS: Of 55 patients enrolled 6 were disqualified and 49 completed the trial . INTERVENTIONS: Preoperative instillation of 10 drops of a 0.3% solution of ofloxacin (26 eyes) or tobramycin (23 eyes) in the operative eye, starting the evening before surgery . Tobramycin-treated eyes received erythromycin ointment after surgery; ofloxacin-treated eyes received petrolatum ointment . Lid and conjunctival swabs were obtained from both eyes on the day before surgery (visit 1), at surgery (visit 2) and on the first postoperative day (visit 3) . Aqueous humour samples were obtained from the study eyes at surgery . MAIN OUTCOME MEASURES: Threshold growth of bacteria on culture, aqueous humour concentration of ofloxacin or tobramycin . RESULTS: At visit 1, 96% of all eyes had positive cultures; this result persisted at visits 2 and 3 for the control eyes . For the treated eyes the incidence of positive cultures decreased from visit to visit . By visit 3 lid cultures were positive for 7 (27%) of the ofloxacin-treated eyes and 7 (30%) of the tobramycin-treated eyes; conjunctival cultures were positive for 0 (0%) of the ofloxacin-treated eyes and 1 (4%) of the tobramycin-treated eyes . No significant differences were seen in culture positivity between the treatment groups at any visit . The mean aqueous humour concentration of ofloxacin was significantly higher than that of tobramycin (0.4084 vs . 0.0279 microgram/mL) (p < 0.001) . CONCLUSIONS: Both ofloxacin-placebo treatment and tobramycin-erythromycin treatment were more effective than no treatment in sterilizing the external ocular adnexa . The two treatments were equally efficacious in eliminating bacteria, more successfully in the conjunctiva than the lids . Topically administered ofloxacin demonstrated significantly greater anterior chamber penetration than topically administered tobramycin.

Drug Saf, 1995 Feb, 12(2), 97 - 109
Cardiac glycosides . Drug interactions of clinical significance; Magnani B et al.; Several commonly coadministered drugs interfere significantly with the pharmacokinetics or pharmacodynamics of cardiac glycosides . Only a few of these interactions (e.g . amiodarone, propafenone, quinidine) take place consistently, and although their extent may vary in individual patients, digitalis dosage adjustments should be made to avoid underdigitalization or toxicity . In other instances the appearance of clinically significant interactions depends on individual pharmacokinetic/metabolic characteristics (e.g . erythromycin, tetracycline), and the result cannot be anticipated on clinical grounds . Some interactions are controversial, having not been confirmed by all studies; others have been shown only in healthy volunteers but lack the definition of their relevance in the context of disease states . In view of the possible impact on the individual patient, close clinical monitoring (which may be supplemented with evaluation of digitalis plasma concentration) is recommended when prescribing cardiac glycosides with other therapeutic agents for which the possibility of an interaction has been reported.

Curr Microbiol, 1995 Feb, 30(2), 105 - 9
A stable and efficient transformation system for Butyrivibrio fibrisolvens OB156; Beard CE et al.; A 9.5-kb shuttle vector capable of replication and selection in both Escherichia coli and Butyrivibrio fibrisolvens was constructed . Plasmid pUC118 provided replication functions and ampicillin resistance selection in E . coli . In B . fibrisolvens, replication was controlled by the native plasmid pRJF1 from strain OB156, and selectability was provided by a 3.5-kb fragment of plasmid pAM beta 1 containing the erythromycin resistance gene . Optimum conditions for transformation were 15 kV/cm, 2 h recovery, and plating in an agar overlay on medium containing 10 micrograms erythromycin/ml . Maximum efficiency was 1.1 x 10(5) transformants per micrograms plasmid DNA (average 3 x 10(4)), and restriction mechanisms reduced efficiency by a factor of 2 x 10(2) . Nonselective growth for 200 generations gave no measurable loss of plasmid.

Nat Struct Biol, 1995 Feb, 2(2), 144 - 53
Structure of cytochrome P450eryF involved in erythromycin biosynthesis; Cupp-Vickery JR et al.; Cytochrome P450eryF catalyzes the 6S-hydroxylation of 6-deoxyerythronolide B, the initial reaction in a multistep pathway to convert 6-deoxyerythronolide B into the antibiotic, erythromycin . The overall structure of P450eryF is similar to that of P450cam but differs in the exact positioning of several alpha-helices . The largest difference occurs in the B' helix and results in the enlargement of the substrate-binding pocket of P450eryF . The substrate is positioned with the macrolide ring perpendicular to the haem plane and contacts seven hydrophobic residues and three solvent molecules . The substrate participates in a network of hydrogen bonds that may provide a proton shuttle pathway in the oxygen cleavage reaction.

Clin Infect Dis, 1995 Feb, 20(2), 387 - 90
Lues maligna, or ulceronodular syphilis, in a man infected with human immunodeficiency virus: case report and review; Sands M et al.; A 30-year-old bisexual man who was infected with human immunodeficiency virus (HIV) and had a history of anaphylaxis to penicillin developed lues maligna, or ulceronodular secondary syphilis . Therapy with parenteral erythromycin failed, and he was subsequently treated with ceftriaxone following penicillin desensitization . A review of the English-language literature identified 14 cases of lues maligna reported between the early 1900s and 1988 . From 1989 to 1994, an additional 12 cases (including the current case) were reported . Of those 12 cases, 11 occurred in patients who either were infected with HIV or were at high risk for HIV infection . Patients infected with HIV may be at increased risk of developing this severe form of secondary syphilis . Lues maligna should be considered in the differential diagnosis of HIV-infected patients who present with ulceronodular lesions.

Clin Infect Dis, 1995 Feb, 20(2), 329 - 34
Legionella bozemanii cavitary pneumonia poorly responsive to erythromycin: case report and review; Taylor TH et al.; A case of pneumonia due to Legionella bozemanii--only the 20th culture-proven case reported so far--progressed with cavitation 9 days after the initiation of intravenous therapy with erythromycin . Review of all 20 reported cases revealed a similar propensity toward radiographic progression (25%) and cavitation (25%) during therapy . A slow response to long courses of erythromycin was the rule (35% of cases) . In two instances, long courses of intravenous erythromycin failed and the patient died . Pleural effusion was reported in 60% of patients, including two with empyema . Overall mortality was high (40%) . Although mortality was only 21% among patients who lived long enough to receive adequate courses of erythromycin, all three such patients who died had received erythromycin alone . Combination therapy with erythromycin and rifampin proved more effective in terms of survival . Infections due to non-pneumophila Legionella may be overlooked because of the organisms' special serological and culture requirements.

Scand J Gastroenterol, 1995 Feb, 30(2), 139 - 45
Comparison between physiologic and erythromycin-induced interdigestive motility; Bjornsson ES et al.; BACKGROUND: The last part of duodenal phase III of the migrating motor complex behaves as a retroperistaltic pump . We have compared the phase-III-like gastroduodenojejunal activity induced by erythromycin with the naturally occurring phase III, focusing on peristaltic patterns . The effect of two doses of erythromycin, 3 mg/kg/h and 12 mg/kg/h (in four subjects), or saline, given intravenously for 15 min, was studied in nine fasting healthy subjects (five men and four women) . METHODS: Motility was recorded on three different days . On one day standard 5-h eight-channel antroduodenojejunal manometry was performed and saline infused 30 min after the first phase III . On the other two study days, erythromycin in the low or the high dose was infused and recording performed for another 2-h period . RESULTS: The low dose of erythromycin induced a phase III in the stomach in all subjects within 12.8 +/- 1.4 min . In contrast, the higher dose did not induce phase-III activity within the 1st h after infusion but induced marked antral pressure waves . The duration of the erythromycin-induced phase III and the naturally occurring antral phase III was 4.7 +/- 1.7 and 1.9 +/- 0.3 min, respectively (p < 0.01) . The duration of the erythromycin-induced phase III in the proximal jejunum was 44% shorter than the spontaneous one (p < 0.01) . The propagation velocity, from the proximal duodenum to the proximal jejunum, of the erythromycin-induced phase III was slower than that of the spontaneous phase III: 5.7 +/- 0.9 and 15.9 +/- 3.9 cm/min, respectively (p < 0.01) . In the proximal duodenum the proportion of retrograde pressure waves (of all propagating waves) was about 10% in early phase III, increasing to about 85% in late phase III in both the spontaneous and erythromycin-induced phase III . In the proximal jejunum retrograde pressure waves were not observed in phase III . CONCLUSIONS: Erythromycin given in a low dose is very effective in inducing phase-III-like motility . The last part of duodenal phase III is characterized by retroperistalsis also when this motility phase is induced by erythromycin.

Nihon Kyobu Shikkan Gakkai Zasshi, 1995 Feb, 33(2), 192 - 6
{A case in which bronchorrhea was alleviated by oral erythromycin and inhalation of beclomethasone and furosemide}; Yamaguchi M et al.; A 55-year-old woman with bronchorrhea and bronchial asthma was admitted to our hospital in June, 1992 . On admission, she was producing a large volume of sputum (200 ml) each day . The volume decreased with oral administration of erythromycin and inhalation of beclomethasone . Next, inhalation of furosemide was added to the regimen, which lead to symptomatic improvement in mucus clearance, although the sputum increased in volume . The concentrations of albumin, fucose, sialic acid, and phosphatidylcholine in the sputum changed with these treatments, as did the lecithin/sphingomyelin ratio . These observations suggest that these drugs affect not only the quantity but also the quality of sputum.

Gaoxiong Yi Xue Ke Xue Za Zhi, 1995 Feb, 11(2), 62 - 8
Effects of intravenous erythromycin on antroduodenal motility in humans: non-invasive observations with real-time ultrasound; Huang CK et al.; Erythromycin has been shown to act on motilin receptors on gastrointestinal smooth muscle in vitro and to accelerate gastric emptying in normal subjects as well as in patients with diabetic mellitus . To evaluate the motor pattern that accounts for this accelerated emptying, the effects of 12.5 mg/min erythromycin vs . placebo on postprandial motility of the antroduodenum was examined with real-time ultrasound in 15 normal subjects . During 10 minutes of observation, erythromycin significantly increased forward transpyloric flow episode (1.04 +/- 0.19 vs . 0.37 +/- 0.41; p < 0.05), forward transpyloric flow duration (5.79 < 4.49 vs . 3.19 < 1.72 seconds; p < 0.05) and improved antro-pyloro-duodenal coordination (0.43 +/- 0.23 vs . 0.21 +/- 0.17; p < 0.05) . However, no significant differences were found for gastric peristaltic cycle (22.62 +/- 3.06 vs . 23.40 +/- 2.14 seconds; p > 0.05), retrograde transpyloric flow episode (0.13 +/- 0.16 vs . 0.18 +/- 0.29; p > 0.05), and retrograde transpyloric flow duration (1.24 +/- 0.30 vs . 1.38 +/- 0.58 seconds; p > 0.05) . We conclude that erythromycin increases episode and duration of forward transpyloric flow, and improves antro-pyloro-duodenal coordination, which may play a role in accelerating gastric emptying.

Presse Med, 1995 Jan 14, 24(2), 137 - 42
{Resistant pneumococci in pediatrics: therapeutic implications}; Bingen E et al.; Pneumococci is the number one pathogen causing pneumonia and bacteraemia in children in France . After H . influenzae, it is the second most frequent cause of conjunctivitis and otitis as well as purulent meningitis in 3-month to 3-year-old children (a situation which will undoubtedly be modified by Hib H . influenzae b vaccinations) . It also predominates in bronchial superinfections and occult bacteraemia . Penicillin G . has been given for pneumococci infections for years leading the development of resistant strains (20.1% of the strains isolated in France in 1992 were resistant to beta-lactamines . Other resistances include macrolides (44% of the strains), tetracyclins (28%), cotrimoxazol (32%), chloramphenicol (25%) and erythromycin-sulphisoxazol (20%) . Thus no other family of oral antibiotics can be successfully substituted for beta-lactamines for routine treatment . Lifestyle and health care organization is a major factor of risk which could explain why the incidence of resistant strains is greater in high density urban populations or in countries were young children are cared for in groups . Therapeutic strategies for easily accessible localizations (septicaemias, pneumonia) can be easily established on the basis of minimal inhibiting concentrations, but for certain sites (otitis, meningitis) more problems are raised . For example, the probability of resistance to penicillin R in acute otitis has been estimated at 75% for children living in the Paris area . We therefore recommend amoxillin (150 to 200 mg/kg/day) or pristinamycin or possibly ceftriaxon (50 mg/kg/day during 3 days) . Similar probabilistic strategies are established for purulent meningitis and other childhood pneumococci infections.

Epilepsia, 1995, 36 Suppl 5, S8 - 13
Cytochrome P450 isozymes and antiepileptic drug interactions; Levy RH; Recent findings about individual isoforms of the cytochromes P450 involved in the metabolism of phenytoin (PHT) and carbamazepine (CBZ) make prediction of inhibition-based interactions possible . PHT is eliminated principally by hydroxylation to p-HPPH, a reaction catalyzed primarily by CYP2C9 and secondarily by CYP2C19 (S-mephenytoin hydroxylase) . The principle of isoform specificity (drugs metabolized by the same isoform should exhibit interactions with the same inhibitors) was applied to the interactions of PHT with 17 inhibitors using two probes for CYP2C9, S-warfarin and tolbutamide . Eleven of 17 interactions (sulfaphenazole, phenylbutazone, fluconazole, azapropazone, cotrimoxazole, propoxyphene, miconazole, amiodarone, disulfiram, metronidazole, and stiripentol) could be explained by inhibition of CYP2C9 . The remaining interactions (felbamate, omeprazole, cimetidine, fluoxetine, imipramine, and diazepam) were attributed to inhibition of CYP2C19 . For CBZ, studies utilizing chemical inhibitors, immunoinhibition, liver bank correlations, and expressed enzymes established that CYP3A4 is the main enzyme catalyzing formation of CBZ-10, 11-epoxide . This explains the pronounced interactions of CBZ with erythromycin, troleandomycin, and other macrolide antibiotics (clarithromycin, josamycin, flurythromycin, and ponsinomycin) . Work is in progress to explain the interactions of CBZ with other inhibitors . The literature contains no other information on isoforms involved in the metabolism of other major antiepileptic drugs.

Eur J Clin Pharmacol, 1995, 49(1-2), 57 - 60
A double-blind controlled evaluation of the sebosuppressive activity of topical erythromycin-zinc complex; Pierard-Franchimont C et al.; In a double-blind randomised study, 14 volunteers applied 4% erythromycin plus 1.2% zinc (Zineryt lotion) and 4% erythromycin lotions, each on half of the forehead twice daily for 3 months . The sebum output was evaluated at 3-week intervals using the photometric and the lipid-sensitive film methods . Evaluations of casual level (CL) and sebum excretion rate (SER) were made with a Sebumeter, and total area of lipid spots (TAS) was measured on Sebutapes . Compared to baseline values, the formulation of the erythromycin-zinc complex induced significant reductions in SER after 6 and 9 weeks, and in CL and TAS at 3, 6, 9 and 12 weeks . The mean reduction in TAS was over 20% for four successive 1-h samplings on completion of the study . Significant reductions in CL, SER and TAS were observed for the erythromycin-zinc formulation compared to the control lotion at 6 and 9 weeks, and also at 3 weeks for SER and TAS, and at 12 weeks for CL and TAS . This study indicates that sebum output is significantly reduced by the erythromycin-zinc complex . This reduction is theoretically beneficial for the acneic patient.

J Pediatr Gastroenterol Nutr, 1995, 21 Suppl 1, S60 - 2
Treatment of cyclic vomiting in childhood with erythromycin; Vanderhoof JA et al.; Cyclic vomiting syndrome (CVS) is an unusual cause of episodic emesis in children . It manifests as intermittent episodes of severe vomiting, similar in time of onset and duration, with no symptoms during the intervening period . Dehydration necessitating intravenous fluid therapy may occur . Most therapeutic maneuvers have proven unsuccessful . We report the use of erythromycin as a prokinetic agent in the treatment of cyclic vomiting in 24 children (10 boys, 14 girls) . Many patients had mild associated abdominal pain with their vomiting . Fourteen patients had previously been given metoclopramide but none responded . Two patients were mildly developmentally delayed . Twenty-four patients were given oral erythromycin ethylsuccinate, approximately 20 mg/kg/day, in two to four divided doses for 7 days . This dose was repeated as needed when symptoms reappeared . Eighteen of 24 patients reported total resolution of symptoms when re-evaluated at 2 and 6 months . All males responded, eight of 18 responders were female, and all six with partial or no response to therapy were female . This uncontrolled trial suggests that erythromycin may be a useful prokinetic agent in the treatment of CVS in childhood . Because the study was uncontrolled, placebo effect cannot be excluded . Case-controlled, double-blinded prospective trials should be considered to evaluate the effectiveness of erythromycin in CVS.

Scand J Infect Dis, 1995, 27(5), 519 - 21
Severe psittacosis during pregnancy and suppression of antibody response with early therapy; Khatib R et al.; A cluster of 3 cases of psittacosis occurred among members of one family . The initial case was a pregnant woman who presented with extensive multilobar infiltrates and severe respiratory distress necessitating mechanical ventilation . Her respiratory failure worsened during 36 h of erythromycin therapy . Improvement coincided with the termination of pregnancy and the initiation of doxycycline treatment . The remaining patients developed milder illness . Serologic assessment of the affected subjects suggests that early treatment may suppress antibody response.

Scand J Gastroenterol Suppl, 1995, 213, 7 - 16
Gastroparesis: diagnosis and management; Horowitz M et al.; Gastroparesis occurs frequently and may be associated with gastrointestinal symptoms, impaired oral drug absorption and, in diabetic patients, poor blood glucose control . Although current knowledge of the mechanisms responsible for delayed gastric emptying is limited, it is clear that gastroparesis arises from a spectrum of motor dysfunctions . There is a poor correlation between symptoms and delay in gastric emptying, and objective measurement is therefore required for the diagnosis of gastroparesis . Scintigraphic measurement of gastric emptying is at present the only clinically applicable method, although other techniques, particularly radioisotopic breath tests and ultrasound, show considerable promise . Therapy with the prokinetic drugs, cisapride, domperidone, metoclopramide, and erythromycin, forms the mainstay of treatment . Although there have been few formal comparisons, cisapride is considered to be the drug of first choice . Current knowledge of the etiology, pathophysiology, investigation, and treatment of gastroparesis is discussed in this review.

Acta Clin Belg, 1995, 50(6), 363 - 7
Legionnaires' disease and acute renal insufficiency: report of a case and review of the literature; Verhaeverbeke I et al.; We report the case of a 73-year-old man, who developed acute renal failure in association with a Legionella pneumophila serotype 1 pneumonia . Renal biopsy revealed a tubulointerstitial nephritis . Treatment with erythromycin, rifampicin and haemodialysis resulted in a clinical resolution of the pulmonary and renal syndromes.

Respiration, 1995, 62(5), 269 - 73
Inhibition by erythromycin of superoxide anion production by human polymorphonuclear leukocytes through the action of cyclic AMP-dependent protein kinase; Mitsuyama T et al.; The long-term low-dose administration of erythromycin is effective in treating chronic inflammatory diseases of the lower respiratory tract . The aim of this study was to clarify the mechanism for this therapeutic effect of erythromycin . We measured its effect on the production of superoxide anion (O2-) by polymorphonuclear leukocytes (PMN) that was induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) or by phorbol myristate acetate (PMA) . 25 microM erythromycin inhibited fMLP-induced O2- production by about 50%, but not PMA-induced O2- production . Moreover, this inhibition was overcome by adding an inhibitor of cyclic AMP-dependent protein kinase (PKA), H-89 . The fMLP-induced O2- production was also inhibited by isoproterenol, a beta-adrenergic agonist, and by dibutyryl cyclic AMP, a cell membrane permeating analogue of cyclic AMP . The inhibition was also overcome by the addition of H-89 . Therefore, the effect of erythromycin seemed to be, in part, mediated through the activation of PKA . The inhibition by erythromycin of O2- generation by PMN may contribute to the beneficial effect of this drug in treating chronic respiratory diseases.

Peptides, 1995, 16(7), 1243 - 52
Excitatory action of {Leu13}motilin on the gastrointestinal smooth muscle isolated from the chicken; Kitazawa T et al.; The effects of a porcine motilin analogue, {Leu13}motilin (LMT) on the smooth muscle preparations isolated from the chicken gastrointestinal (GI) tract were investigated in vitro . In the proventriculus, LMT (100 nM to 30 microM) caused an atropine-sensitive contraction and enhanced the electrical field stimulation (EFS)- or 1,1-dimethyl-4-phenyl-piperazinium (DMPP)-induced contraction without affecting the response to acetylcholine (ACh) . LMT also caused a concentration-dependent contraction of the intestinal tract (duodenum, jejunum, ileum, and colon) . The responsiveness to LMT was strongest in the jejunum and weakest in the colon . The responses to LMT in the intestinal segments were not affected by tetrodotoxin, atropine, hexamethonium, pyrilamine, spantide, and 5-hydroxyltryptamine-induced desensitzation, but significantly decreased by verapamil or removal of external Ca2+ . LMT did not enhance the EFS- or DMPP-induced contraction in the ileum . Canine motilin also contracted the intestinal segments in a similar concentration range to LMT with an equal potency, but erythromycin A (EMA) and N-ethyl-N-demethyl-8,9-anhydroerythromycin A, 6-9-hemiketal (EM523) showed only a weak contractile activity even at high concentration (up to 100 microM), indicating that motilin receptors in the chicken intestine were somewhat different from those of mammals . In conclusion, LMT produces an excitatory response in the chicken GI tract with a different sensitivity from region to region . The mechanisms of the action were different between the proventriculus and small intestine; that is, LMT contracts the small intestine through the direct action on the smooth muscle cells, but this peptide acts on the enteric cholinergic neurones and stimulates ACh release, and thus regulates autonomic neuroeffector transmission in the proventriculus.

Pharmazie, 1995 Jan, 50(1), 56 - 60
{Comparison of the bioavailabilities of erythromycin estolate and erythromycin ethylsuccinate dry suspension preparations in steady state}; Potthast H et al.; Relative bioavailability of erythromycin was determined after multiple-dose administration of erythromycin estolate in comparison to erythromycin ethylsuccinate both given as oral suspensions to twelve healthy volunteers . The daily erythromycin dose of erythromycin ethylsuccinate was 50% higher than the respective dose of erythromycin estolate; the dosage interval tau was 12 h for erythromycin estolate and 8 h for erythromycin ethylsuccinate . This scheme was planned in accordance to advices of the respective manufactures . Results of the study confirm the differences in extent of bioavailability of both erythromycin derivatives known from single-dose investigations . Furthermore, the experimental data show that a twice daily administration of 1000 mg erythromycin as erythromycin estolat resulted in sufficiently high plasma concentration of the active compound.

Br J Surg, 1995 Jan, 82(1), 91 - 4
Gastric motility following oesophagectomy; Walsh TN et al.; The motility of the vagally denervated transposed stomach after oesophagectomy was examined by ambulatory gastric manometry and videofluoroscopy . Two groups of subjects were studied . Group 1 comprised ten patients who had undergone oesophagectomy 6-12 months previously and group 2 consisted of six normal control subjects . Studies were performed on fasting and fed subjects, and following injection of erythromycin 8 mg/kg . No distinguishable manometric wave activity was seen in either group while fasting . Feeding generated a measurable wave pattern in the patient group only . A significant increase in the mean (s.e.m.) distal wave amplitude was identified after infusion of erythromycin in both patients (34.0(15.1) versus 12.2(3.1) mmHg, P < 0.05) and controls (15.1(3.4) versus 5.0(0.0) mmHg, P = 0.05) . The response to erythromycin was more rapid in patients than in controls (mean(s.e.m.) 113(16) versus 377(133) s, P < 0.05) and the effect persisted for longer (more than 1 h) in those who had undergone oesophagectomy . Videofluoroscopy confirmed purposeful motility in both the normal and vagally denervated stomach . It is concluded that the transposed stomach is a dynamic conduit . Enhancement of motility was greatest in the denervated stomach, indicative of denervation supersensitivity.

Chemotherapy, 1995 Jan-Feb, 41(1), 59 - 69
Antitumor effect of erythromycin in mice; Hamada K et al.; Oral administration of erythromycin in the dose range of 1-10 mg/kg increased the survival times of tumor-bearing mice in both allogeneic and syngeneic mouse systems by two- to three-fold as compared with those of vehicle control mice, with the maximum effect at a dose of 5 mg/kg/day . During the early phase of tumor transplantation, tumoricidal macrophages and natural killer cells were active in the antitumor resistance of erythromycin-treated mice . Thereafter, the tumoricidal activity of macrophages became stronger as serum levels of interleukin-4 (IL-4) rose . Furthermore, treatment of mice with anti-IL-4 monoclonal antibody abolished the antitumor resistance conferred by erythromycin . These results indicate that erythromycin exhibits an indirect antineoplastic activity by enhancing the production of IL-4 which augments the tumoricidal activity of macrophages.

Clin Pharmacol Ther, 1995 Jan, 57(1), 89 - 94
Possible inhibition of hepatic metabolism of quinidine by erythromycin; Spinler SA et al.; OBJECTIVE: To present and analyze a patient case illustrating a possible drug interaction between quinidine and erythromycin . METHODS: This is a case report of one hospitalized patient . The setting for this analysis was a university hospital . Through a MEDLINE search of all English medical literature (1966 to 1994) documenting possible interactions between quinidine and erythromycin, retrospective patient chart review, and analysis of the relationship between serum quinidine concentrations and significant clinical events, deduce the possibility of a quinidine and erythromycin pharmacokinetic and pharmacodynamic interaction in this particular patient case . RESULTS: This case demonstrated a probable erythromycin-quinidine pharmacokinetic interaction that led to a decrease in quinidine apparent clearance, an increase in quinidine serum concentrations, and a possible quinidine toxicity . CONCLUSION: Serum quinidine concentrations, electrocardiograms, and other factors that may predispose patients to torsades de pointes, such as hypokalemia and hypomagnesemia, should be monitored closely if quinidine is coadministered with erythromycin.

Clin Pharmacol Ther, 1995 Jan, 57(1), 16 - 24
The erythromycin breath test predicts the clearance of midazolam; Lown KS et al.; Midazolam, a commonly used sedative and amnestic medication, has recently been shown to be largely metabolized in the liver by a cytochrome P450, termed CYP3A4 . There is at least a tenfold intersubject variability in the liver content and catalytic activity of CYP3A4, which may in part account for the known interpatient differences in the kinetics of midazolam . To test this hypothesis, we determined the intravenous midazolam kinetics of 20 medically stable, hospitalized patients, whose hepatic CYP3A4 activities were determined with use of the {14C-N-methyl}erythromycin breath test . During the kinetic study, we also performed psychometric testing designed to quantitate the level of sedation and amnesia . We found a significant positive correlation between the erythromycin breath test results and weight adjusted clearance (in milliliters per minute per kilogram) of both total midazolam (r = 0.52; p = 0.03) and unbound midazolam (r = 0.61; p < 0.01) . The relatively low dose of midazolam used (0.0145 mg/kg) produced significant but transient sedation and memory impairment in some of the patients . We conclude that interpatient differences in liver CYP3A4 activity in part account for the variations in midazolam kinetics . Our observations account for reported drug interactions involving midazolam and suggest that patients with low CYP3A4 activity may be most susceptible to prolonged amnestic effects occasionally produced by this short-acting benzodiazepine.

Dig Dis Sci, 1995 Jan, 40(1), 141 - 6
Gastric emptying response to variable oral erythromycin dosing in diabetic gastroparesis; Desautels SG et al.; Intravenous erythromycin has been shown to improve gastric emptying in diabetic gastroparesis . Oral erythromycin also accelerates gastric emptying, but to a lesser degree . To determine if this is a dose-dependent phenomenon, gastric emptying was measured in 10 insulin-requiring diabetic patients with gastroparesis after administration of either 250 mg or 1000 mg of erythromycin or placebo . The drugs were orally administered in a randomized, double-blind fashion 30 min prior to ingestion of a meal containing {99mTc}-sulfur colloid-labeled beef stew and {111In}DTPA-labeled orange juice . Anterior and posterior gastric images were recorded for 3 hr at 15-min intervals using an externally positioned gamma camera . The results demonstrated that both doses of oral erythromycin significantly improved solid-phase gastric emptying . The mean half-emptying time of solids was decreased from 151 +/- 40 min with placebo to 58 +/- 10 min and 40 +/- 9 min with 250 mg and 1000 mg of erythromycin, respectively . However, a dose-dependent relationship was not demonstrated with the two doses of erythromycin employed . These results suggest that for most patients with diabetic gastroparesis, a single 250-mg dose of erythromycin will significantly improve gastric emptying . It is possible that a dose-dependent relationship will be demonstrated with doses of erythromycin less than 250 mg.

Chest, 1995 Jan, 107(1), 120 - 5
Reversible airway lesions in diffuse panbronchiolitis . Detection by high-resolution computed tomography; Ichikawa Y et al.; The clinical effectiveness of erythromycin for patients with diffuse panbronchiolitis (DPB) was previously recognized . However, it remains unknown what kind of airway lesions change with the clinical effectiveness induced by erythromycin . We performed the present study to clarify this unknown . We devised a method for scoring findings on high-resolution computed tomography (HRCT) to aid in the objective evaluation of the airway lesions in patients with DPB . The 18 patients with DPB were treated with oral erythromycin, 600 mg/d . All patients were evaluated by pulmonary function tests and HRCT before and after 3 months of therapy . Characteristic HRCT findings in patients with DPB pretherapy were small nodules, airway ectasia, periairway thickening, and mucus plugging . After erythromycin therapy, there was significant reduction in scores for the extent of small nodular opacities, the severity of periairway thickening, and the extent of mucus plugging with a corresponding significant improvement in results of the pulmonary function test parameters . The present study demonstrated reversible airway lesions in patients with DPB in response to erythromycin therapy.

Infection, 1995, 23 Suppl 1, S33 - 8
Prevention of Pneumocystis carinii pneumonia and of cerebral toxoplasmosis by roxithromycin in HIV-infected patients; Durant J et al.; The prevention of cerebral toxoplasmosis and of Pneumocystis carinii pneumonia is an essential objective in the management of patients infected with HIV . Given that roxithromycin is active in vitro against Toxoplasma gondii and that in 1989 Dolermann reported the effective treatment of P . carinii respiratory infections with erythromycin, a randomized pilot study was undertaken in 52 patients infected with HIV . Patients were treated with either: a monthly dose of pentamidine aerosol (300 mg); roxithromycin once a week (300 mg t.i.d.); or a combination of pentamidine aerosol and roxithromycin . Intention to treat analysis was applied to these 52 patients, all of whom received at least one treatment dose . Five out of 18 patients treated with pentamidine aerosol, 1/17 patients treated with pentamidine aerosol + roxithromycin and none of the 17 patients treated with roxithromycin developed cerebral toxoplasmosis (p = 0.038) . P . carinii pneumonia was diagnosed in one patient in the pentamidine aerosol-treated group, in one patient treated with roxithromycin and in none of the patients treated with pentamidine aerosol + roxithromycin (non-significant difference) . Four cases of Mycobacterium tuberculosis and Mycobacterium avium-intracellulare infection were seen in the pentamidine aerosol-treated group (p = 0.028) and none in the roxithromycin groups . Adverse events leading to the discontinuation of treatment occurred in 5/34 (14.7%) patients treated with roxithromycin . Nausea, abdominal pain and raised transaminases occurred in four patients and a skin allergy in the final patient . Roxithromycin appears to be effective in the prevention of pulmonary pneumocystis infection and of cerebral toxoplasmosis in HIV-infected patients . However, these results require confirmation in a larger study.

J Antimicrob Chemother, 1995 Jan, 35(1), 161 - 5
In-vitro antimycoplasmal activity of flurithromycin; Furneri PM et al.; The in vitro activity of flurithromycin, a 14-membered macrolide drug, was found to be similar to that of erythromycin against 41 strains of Mycoplasma spp . and 100 strains of Ureaplasma urealyticum . All 28 strains of Mycoplasma hominis were uniformly resistant to both macrolides with MICs > 256 mg/L, U . urealyticum showed intermediate resistance with MIC50s of 0.5 and 1 mg/L for erythromycin and flurithromycin, respectively, whereas the ten strains of Mycoplasma pneumonia were susceptible to < or = 0.03 mg/L of both macrolides.

Drug Metab Dispos, 1995 Jan, 23(1), 137 - 42
Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver; Jonsson G et al.; Budesonide is a synthetic glucocorticosteroid that is commonly used in topical treatment of asthma and rhinitis . The main metabolites formed from budesonide in human liver microsomes have been identified as 16 alpha-hydroxyprednisolone and 6 beta-hydroxy-budesonide . Although it is apparent that the cytochrome P450 (CYP) system is involved, the actual subfamily has not been identified . In attempts to do this, budesonide was incubated with microsomes from ten different human liver samples where various CYP activities had been rank ordered . We found a strong correlation between formation of the two main metabolites and testosterone 6 beta-hydroxylation (correlation 0.98 and 0.95), a marker for CYP3A . When budesonide (10 microM) was incubated with human liver microsomes in the presence of compounds known to interact with different isoforms or subfamilies of CYP, ketoconazole was found to be the strongest inhibitor of budesonide metabolism (IC50: approximately 0.1 microM) followed by troleandomycin (IC50: approximately 1 microM), erythromycin, and cyclosporin, all substances known to interact with CYP3A isoenzymes . Substances known to interact with CYP2C (sulfaphenazole, mephenytoin, and tolbutamide) and with CYP2D6 (bufuralol and quinidine) did not specifically inhibit the metabolism of budesonide . In addition, formation of the budesonide metabolites (16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide) was inhibited by antibodies against the CYP3A subfamily, but not by antibodies against the CYP1A subfamily or control immunoglobulin G . We conclude that the formation of 16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide from budesonide is catalyzed by isoenzymes within the CYP3A subfamily.

Scand J Infect Dis, 1995, 27(2), 131 - 4
Are penicillin treatment failures in Arcanobacterium haemolyticum pharyngotonsillitis caused by intracellularly residing bacteria?
Osterlund A.
Arcanobacterium haemolyticum is an infrequent agent of pharyngotonsillitis in children and young adults . Despite the fact that A . haemolyticum is fully sensitive to penicillin in vitro, penicillin treatment failures are frequent . The ability of A . haemolyticum to invade HEp-2 cells and survive intracellulary was investigated . All 12 strains tested, of which 10 were isolated from patients with pharyngotonsillitis, and 2 were reference strains, were internalized by the HEp-2 cells . Four strains tested further, one of the reference strains and 3 of the clinical isolates, proved able to survive intracellularly for 4 days, thus creating intracellular reservoirs of bacteria . It was also shown that erythromycin, an antibiotic known to penetrate well intracellularly, efficiently killed these bacteria.

Arch Toxicol, 1995, 69(5), 346 - 9
In vitro metabolism of cyclosporin A with rabbit renal or hepatic microsomes: analysis by HPLC-FPIA and HPLC-MS; Pham-Huy C et al.; Cyclosporin A (CsA) is in vivo mainly metabolized by hepatic cytochrome P450 IIIA to more than 21 metabolites, the major ones known as: M1, M17 and M21 . The aim of this work is to explore the in vitro metabolism of CsA after incubation, in the presence of NADPH, with renal or hepatic microsomes obtained from rabbits pretreated with rifampycin (enzyme inducer) or erythromycin (enzyme inhibitor) . The presumed metabolites were separated by semi-preparative high-performance liquid chromatography (HPLC) and identified in each collected fraction by fluorescence polarization immunoassay (FPIA) (HPLC-FPIA) using a non-specific polyclonal antibody . They were also analyzed by HPLC-mass spectrometry (MS) using fast atom bombardment (HPLC-MS-FAB) . Five collected fractions gave positive results with FPIA . The major metabolites found were M1, M17 and M21 after identification by HPLC-MS-FAB and comparison with three corresponding standard metabolites . The CsA biotransformation rates were calculated by the amount of unmetabolized CsA and were linear with time . These mean rates (Vm) for 12-min incubation by renal microsomes of rabbits treated with rifampicin or erythromycin or untreated (control) were 0.11, 0.02 and 0.04 nmol/min x mg microsomal protein, respectively . These rates were 15-, 37-, and 30-fold lower than those obtained with hepatic microsomes of rabbits treated identically . As CsA metabolites are less cytotoxic than the parent drug, this weak renal biotransformation of CsA after in vitro incubation should be one of the mechanisms of its in vivo nephrotoxicity.

Skin Pharmacol, 1995, 8(3), 162 - 6
Effects of human recombinant interferon-alpha 2b on P450-dependent isozymes in rat liver and skin; Goerz G et al.; Adult female Wistar rats divided into two groups (6 animals each) were subcutaneously treated with 10(5) units/day recombinant human interferon-alpha 2b (hrIFN-alpha 2b) and corresponding quantities of the vehicle, respectively, over a period of 7 days . Microsomal protein, P450 content, and the activities of aminopyrine-N-demethylase (ADM), 7-ethoxyresofurin-O-deethylase (7-ERO-D) and of erythromycin-N-demethylase (EMDM) were determined in the liver microsomes . Moreover, 7-ERO-D and EMDM activities were determined in the skin microsomes of the treated animals . In the liver microsomes hrIFN-alpha 2b caused a statistically significant increase in ADM activity and a statistically significant decrease in 7-ERO-D and EMDM activities, as compared to the controls . However, in the pooled skin microsomes 7-ERO-D activity showed a trend to increase under the administration of hrIFN-alpha 2b, whereas EMDM activity could not be detected in the treated or the control animals . The results of the present study indicate that hrIFN-alpha 2b is capable of affecting the activities of P450-dependent isozymes in the rat liver and skin in a different manner . Our findings support the hypothesis that clinically relevant interactions may occur during the concomitant administration of hrIFN-alpha 2b and other compounds that are metabolized by hepatic and cutaneous P450 monooxygenases.

Acta Gastroenterol Belg, 1995 Jan-Feb, 58(1), 21 - 30
Georges Brohee Prize 1994 . Motilin and the enteric nervous system in the control of interdigestive and postprandial gastric motility; Tack J; The upper gastrointestinal tract displays two different functional states: the interdigestive or fasting state, and the fed state . The fasting state is characterized by a cyclical motor pattern, the migrating motor complex (MMC) . The control of the MMC is incompletely understood . Plasma levels of the hormone motilin fluctuate in synchrony with MMC, but it is still controversial whether a motilin peak triggers the MMC or whether the MMC causes motilin release . We used the motilin agonistic properties of erythromycin to resolve this issue in man . Administration of a low dose of erythromycin induced a MMC which started from the gastric antrum, unaccompanied by a motilin peak . This finding argues against a release of motilin secondary to the MMC and supports our hypothesis that in man motilin peaks trigger the MMC . We observed that higher doses of erythromycin no longer induced a MMC, but stimulated antral contractility . The enteric nervous system is involved in the control of both the fasting and fed state at each level of the gastrointestinal tract . We hypothesized that the target for motilin to trigger the MMC is the enteric nervous system in the gastric antrum . Yet, no physiological data on antral enteric neurons were available . We performed the first electrophysiological study of myenteric neurons of the gastric antrum, revealing unique electrical and synaptic properties in comparison to other regions of the gastrointestinal tract . We confirmed the role of the enteric nervous system of the gastric antrum in the control of the MMC by directly demonstrating the presence of motilin receptors on a subpopulation of neurons . We demonstrated that endogenous and exogenous substances that stimulate (cholecystokinin, cisapride, erythromycin) or inhibit (norepinephrine, 5-hydroxytryptamine) gastric emptying all act on antral enteric neurons . These observations strongly support the hypothesis that the enteric nervous system in the gastric antrum plays a key role in the coordination of antral peristalsis and the regulation of gastric emptying . Finally, we hypothesized that the actions of erythromycin on motilin receptors on enteric neurons and intestinal smooth muscle offer a potential for therapeutic applications in gastrointestinal motility disorders . We confirmed this by demonstrating gastrointestinal motility stimulating activity of erythromycin in patients with diabetic gastroparesis.

Gene Expr, 1995, 4(6), 357 - 67
Translation-targeted therapeutics for viral diseases; Harford JB; Viruses utilize the protein synthetic machinery of their host . Nonetheless, certain features of the synthesis of viral proteins are distinct from those of host-cell translation . Examples include internal ribosome entry sites in some viral mRNAs and ribosomal frameshifting during production of retroviral proteins . Viruses often inhibit host translation and/or possess mechanisms leading to preferential synthesis of viral proteins . In addition, a participant in the cellular antiviral response is the enzyme PKR (protein kinase, RNA activated), which is involved in the control of cellular translation . Thus, viruses and host cells wage war on the battlefield of translation . The distinctive features of protein synthesis in virally infected cells provide potential targets for therapeutic intervention . Translation-targeted therapeutics have precedence in antibiotics like tetracycline and erythromycin . Means for discovery of translation-targeted therapeutics for viral disease are discussed.

Curr Clin Top Infect Dis, 1995, 15, 76 - 96
Prophylaxis in bowel surgery; Nichols RL et al.; The busy colon and rectal surgeon deals daily with a sea of bacteria . Using good surgical judgment as well as time-honored techniques and innovative equipment the postoperative results are generally good . The role that appropriately administered efficacious antibiotics play in this scenario should not be underestimated and can only be realized when historical controls are evaluated . The results of these studies of antibiotic bowel preparation suggest that many different approaches may be equally effective in reducing infection after elective colonic resection . Certain features, however, appear to be common to most of the studies . 1 Oral antibiotic regimens with both aerobic and anaerobic activity (e.g., neomycin/erythromycin base) were used . 2 The oral agents were given in limited doses the day before operation . 3 Addition of systemic antibiotic agents without broad-spectrum coverage to the oral regimen generally did not improve the results . 4 Use of broad-spectrum parenteral antibiotic agents alone was associated with a lower infection rate than the use of systemic agents having only limited coverage . 5 Addition of a broad-spectrum parenteral antibiotic to the oral antibiotics may further reduce the postoperative infection rate . 6 Parenteral or oral antibiotics should be administered only for short periods of time during the perioperative period . Since the general acceptance of the approach outlined above, infection rates have decreased and the number of clinical studies reported has drastically decreased . The authors do feel, however, that there is a need for further study to outline possible benefits of other appropriate regimens (34).

Hautarzt, 1995 Jan, 46(1), 39 - 43
{Bacillary angiomatosis}; Plettenberg A et al.; Bacillary angiomatosis (BA) is a rare infectious disease usually associated with HIV infection . Recent molecular biologic investigations confirm that both Rochalimaea henselae and Rochalimaea quintana can cause BA . The bacteria can be identified by Warthin-Starry staining and electron microscopy . The typical clinical signs are solitary or multiple dermal or subcutaneous nodules . Bone, liver, spleen and other organs may also be involved . We describe the clinical and histological features of a 39-year-old HIV-infected patient with cutaneous and bony lesions of BA . All manifestations of BA disappeared during therapy with erythromycin.

Acta Vet Hung, 1995, 43(2-3), 335 - 45
Toxicological studies on potentiated ionophores in chickens . II . Compatibility study; Lehel J et al.; Two trials were carried out on a total of 2 x 360 Tetra-82 broiler chickens to study how the presence of the antioxidant duokvin as potentiating agent influenced the compatibility of reduced doses of monensin (12.5 mg/kg of feed) or maduramicin (3.0 mg/kg of feed) with other chemotherapeutic agents (tiamulin, erythromycin, sulfaquinoxaline, sulfachlorpyrazine, flumequine, tylosin, kitasamycin) widely used in broiler rearing . Compatibility was assessed on the basis of the appearance of clinical signs suggestive of toxic interaction, the mortality rate, body mass gain, feed consumption and drinking water intake, and changes in AST and LDH activities of the blood plasma . The monensin-duokvin combination (12.5 mg monensin/kg of feed + 120 mg duokvin/kg of feed) was found to be compatible with erythromycin, sulfaquinoxaline, sulfachlorpyrazine, flumequine, tylosin and kitasamycin . For tiamulin, a slight incompatibility was observed; however, this was much less severe than that found for monensin administered at a dose of 100 mg/kg of feed . The maduramicin-duokvin combination (3.0 mg maduramicin/kg of feed + 120 mg duokvin/kg of feed) was compatible with all the compounds tested; thus, it can be safely applied also in combination with tiamulin.

Carcinogenesis, 1994 Dec, 15(12), 2715 - 20
Involvement of cytochrome P4503A in catalysis of tamoxifen activation and covalent binding to rat and human liver microsomes; Mani C et al.; Tamoxifen is the major therapeutic agent for the treatment of hormone-dependent breast cancer . Tamoxifen treatment appears to be associated with an increased incidence of endometrial carcinoma in humans and hepatocellular carcinoma in rats . These carcinogenic effects of tamoxifen might be induced by the formation of a tamoxifen reactive intermediate that binds covalently to macromolecules . Liver microsomal cytochrome P450s (CYPs) catalyze the metabolism of tamoxifen, forming a reactive intermediate that binds irreversibly to microsomal proteins, primarily to a 54 kDa protein (Mani, C . and Kupfer, D., Cancer Res., 51, 6052-6058, 1991) . The current study identifies the P450 enzymes that catalyze the activation of tamoxifen to a reactive intermediate in rats and humans . Among the species examined, rats, chickens and humans demonstrate low tamoxifen binding activity, ranging from 0.1 to 0.4 nmol bound/mg protein/h . In contrast, hamsters and mice exhibit high binding, 1.2 and 1.6 nmol/mg protein/h respectively . Treatment of male rats with phenobarbital or pregnenolone-16 alpha-carbonitrile (PCN) markedly elevated the binding of tamoxifen to liver microsomal proteins . Methylcholanthrene treatment had no effect on binding . These findings suggested the involvement of CYP3A in catalysis of the covalent binding . Alternate substrates of CYP3A, cortisol and erythromycin, inhibited tamoxifen binding in liver microsomes from PCN- and phenobarbital-treated rats . Treatment of rats with troleandomycin (TAO), an inducer of CYP3A, followed by the dissociation of the TAO-CYP3A complex, elevated the covalent binding to liver microsomes approximately 3-fold . Antibodies against rat CYP3A1 strongly inhibited tamoxifen binding to liver microsomes from PCN- and phenobarbital-treated rats, whereas the antibodies anti-CYP2B1/2B2 did not inhibit binding . In humans, tamoxifen binding was inhibited by the anti-rat CYP3A1 IgG and also by alternate substrates of CYP3A . These results indicate that the activation of tamoxifen to a reactive intermediate by rat and human liver microsomes is principally catalyzed by CYP3A enzymes.

Dig Dis Sci, 1994 Dec, 39(12 Suppl), 76S - 78S
Motilin receptor: a model for development of prokinetics; Peeters TL et al.; Erythromycin and related macrolides act as smooth muscle and neural receptors to contract rabbit duodenum and induce phase III migrating motor complex (MMC) activity in intact dogs . A recently developed motilin antagonist confirms that motility effects of erythromycin are mediated by motilin receptors . Despite species, organ, and tissue heterogeneity of motilin receptors, binding experiments with rodent antral smooth muscle tissue provide a good model for the development of this new class of prokinetics.

Dig Dis Sci, 1994 Dec, 39(12 Suppl), 14S - 17S
Axial forces during gastric emptying in health and models of disease; Camilleri M et al.; The propulsive forces involved in gastric emptying of solid and liquid chyme are incompletely characterized, and the contribution of the proximal region of the stomach to overall propulsion has not been quantifiable . We have used an axial force catheter to characterize longitudinally directed forces during gastric emptying in man . The topography of these forces has been described relative to circumferential contractions, and the contribution of axial forces in experimental models of dumping and gastric stasis were quantified by assessing the effects of intravenous erythromycin and intraduodenal lipid, respectively . There is an excellent correlation between axial forces and gastric emptying of solids in health and in models of gastric dysmotility, suggesting that the axial force catheter semiquantitatively measures propulsive forces during emptying of the human stomach.

Dig Dis Sci, 1994 Dec, 39(12 Suppl), 104S - 106S
{*C}octanoic acid breath test to measure gastric emptying rate of solids; Maes BD et al.; We have developed a breath test to measure solid gastric emptying using a standardized scrambled egg test meal (250 kcal) labeled with {14C}octanoic acid or {13C}octanoic acid . In vitro incubation studies showed that octanoic acid is a reliable marker of the solid phase . The breath test was validated in 36 subjects by simultaneous radioscintigraphic and breath test measurements . Nine healthy volunteers were studied after intravenous administration of 200 mg erythromycin and peroral administration of 30 mg propantheline, respectively . Erythromycin significantly enhanced gastric emptying, while propantheline significantly reduced gastric emptying rates . We conclude that the {*C}octanoic breath test is a promising and reliable test for measuring the gastric emptying rate of solids.

Pediatr Dermatol, 1994 Dec, 11(4), 338 - 41
Bacillary angiomatosis in an immunocompetent child: the first reported case; Paul MA et al.; Bacillary angiomatosis, an infectious process associated with Rochalima spp., was thought until recently to be restricted to HIV-infected or otherwise immunosuppressed patients . In 1993, bacillary angiomatosis was reported in several immunocompetent adults . An extensive literature review failed to find references to bacillary angiomatosis in immunocompetent children . We describe a 6-year-old female who presented with a single, rapidly growing, friable, erythematous papule on her neck . Histologic examination of a biopsy specimen confirmed the diagnosis of bacillary angiomatosis . The patient was otherwise healthy, and her physical examination was normal . Laboratory studies, including HIV serology, were normal . The patient was treated with six weeks of oral erythromycin without evidence of recurrence . We present and discuss the implications of the first case of bacillary angiomatosis in an immunocompetent child.

Analyst, 1994 Dec, 119(12), 2743 - 7
Determination of josamycin residues in porcine tissues using high-performance liquid chromatography with pre-column derivatization and spectrofluorimetric detection; Leroy P et al.; A simple, selective and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the measurement of josamycin residues in four porcine tissues (i.e., muscle, liver, kidney and fat) . The sample preparation consisted of a homogenization step in an acetonitrile-10 mmol l-1 phosphate buffer mixture, pH 6.0 (35 + 65), centrifugation and a liquid-liquid extractive clean-up of the resulting supernatant with isooctane . Pre-column derivatization of josamycin was performed using cyclohexa-1,3-dione in ammonium acetate buffer, pH 5.0 (90 degrees C for 2 h) . The derivative was chromatographed in an isocratic reversed-phase HPLC system . A LiChrospher RP 18 end-capped (5 microns) column was eluted with an acetonitrile-methanol-10 mmol l-1 phosphate buffer mixture, pH 6.0 (45 + 5 + 50) . The capacity factor of the josamycin derivative was 17.5 . Detection was achieved using spectrofluorimetry (lambda ex = 375 nm; lambda em = 450 nm) . The structure of the derivative was assessed by using mass spectrometry . Full selectivity was obtained in the HPLC system versus other macrolide antibiotics (tylosin, spiramycin and erythromycin), aldehydes (formaldehyde, acetaldehyde and benzaldehyde) and endogenous compounds . Linearity and repeatability were tested . Correlation coefficients, for calibration curves in the range of 0.1-3.2 micrograms g-1, were greater than 0.999 for all tissues and the relative standard deviation (S(r)) was 4.9% (1.6 micrograms g-1; n = 6); recovery was higher than 88%.

Analyst, 1994 Dec, 119(12), 2717 - 21
Identification of tylosin in bovine muscle at the maximum residue limit level by liquid chromatography-mass spectrometry, using a particle beam interface; Delepine B et al.; A particle beam liquid chromatography-mass spectrometric method is presented as a confirmatory technique for analysis of tylosin residues in bovine muscle . After chloroform extraction and a diol solid-phase extraction clean-up, on-line liquid chromatography-mass spectrometry (LC-MS) of extracts is carried out on an RP-18 bonded silica column . The analyte is introduced into the ion source by a particle beam interface and identified by negative chemical ionization with selective ion monitoring . The tylosin molecular ion is obtained with this ionization mode . The response of the ion chromatogram peak areas is linear for the three levels of spiked muscle analysed (0.5, 1 and 2 maximum residue limit) . Under these LC-MS conditions, other macrolide antibiotics such as spiramycin and erythromycin do not interfere with tylosin.

Ther Drug Monit, 1994 Dec, 16(6), 548 - 51
Lack of interaction of erythromycin with temazepam; Luurila H et al.; Erythromycin is a strong inhibitor of cytochrome P450 {CYP3A4} and has a potentially dangerous interaction with midazolam and triazolam . The possible interaction between erythromycin and a short-acting benzodiazepine, temazepam, was investigated in a double-blind, randomized crossover study . Ten healthy volunteers received 500 mg erythromycin or placebo orally three times a day for 6 days followed by a challenge dose of 20 mg temazepam . Plasma samples were collected for the determination of temazepam, oxazepam, and erythromycin, and psychomotor effects were measured during the 24 h after intake of temazepam . Erythromycin did not change the pharmacokinetics or pharmacodynamics of temazepam to a statistically significant degree . The metabolic fate of temazepam and its almost complete bioavailability explain the lack of interaction . Temazepam, unlike midazolam or triazolam, can thus be prescribed in the usual doses for patients receiving erythromycin.

J Antimicrob Chemother, 1994 Dec, 34(6), 1025 - 9
Additive effect of clarithromycin combined with 14-hydroxy clarithromycin, erythromycin, amoxycillin, metronidazole or omeprazole against Helicobacter pylori; Cederbrant G et al.; The in-vitro activities of clarithromycin, 14-OH clarithromycin, erythromycin, amoxycillin, metronidazole and omeprazole against Helicobacter pylori were determined at pH 7.2 and 5.5 . At pH 5.5 the activities of clarithromycin and erythromycin decreased approximately 16 times while 14-OH clarithromycin was less influenced . Chequerboard titration indicated that the combined activity of clarithromycin and the other compounds was additive.

Eur Respir J, 1994 Dec, 7(12), 2249 - 51
Bronchioloalveolar carcinoma with bronchorrhoea treated with erythromycin; Suga T et al.; Recent reports have shown that erythromycin inhibits bronchial hypersecretion, and, accordingly, erythromycin was administered to a patient with bronchioloalveolar carcinoma with bronchorrhoea . After administration of erythromycin, marked reduction in the volume of sputum was observed, and the patient's quality of life was improved . It is concluded that erythromycin may reduce hypersecretion in bronchioloalveolar carcinoma.

Lancet, 1994 Nov 26, 344(8935), 1461 - 5
Randomised comparison of amoxycillin and erythromycin in treatment of genital chlamydial infection in pregnancy; Alary M et al.; Erythromycin, the standard treatment for chlamydial infection in pregnant women, commonly causes side-effects, which limits its efficacy . In a randomised, double-blind study, we compared amoxycillin with erythromycin in this setting . 210 pregnant women with Chlamydia trachomatis infection were randomly assigned 7 days' treatment with amoxycillin (500 mg three times daily) or erythromycin (500 mg four times daily) . Control cultures were obtained 21 days after treatment, during late pregnancy, and from the infant within a week of birth . Treatment was judged a failure if any post-treatment culture was positive or if the patient had to stop therapy because of severe side-effects . 11 women (5.2%) were lost to follow-up . 1 (of 100) amoxycillin-treated women had to stop treatment because of severe side-effects compared with 12 (of 99) erythromycin-treated women (p = 0.002) . 1 woman in the amoxycillin group had a positive culture at the third-trimester examination . No positive post-treatment culture was found in the erythromycin group . Severe gastrointestinal side-effects were more common in women who received erythromycin (31 vs 6%, p < 0.001) . The overall failure rate was therefore 2% in the amoxycillin group and 12% in the erythromycin group (p = 0.005) . These results suggest that amoxycillin is an acceptable alternative to erythromycin for C trachomatis infection in pregnant women.

Am Fam Physician, 1994 Nov 15, 50(7), 1479 - 86
Management of infants born to women with sexually transmitted diseases; Schutze GE et al.; Since infants who acquire sexually transmitted diseases from their mothers are rarely symptomatic at birth, many recommendations are based on the maternal history and results of serologic screening tests . Management of an infant born to a mother with syphilis is based primarily on the mother's history of the disease and treatment . With gonorrhea, a single dose of ceftriaxone should be given to the infant if the mother is infected . Infants born to mothers with chlamydial infection are at risk of conjunctivitis and pneumonitis within the first two to 12 weeks of life . These infants should receive erythromycin 24 hours after birth . With herpes simplex infection, conjunctival and nasopharyngeal cultures should be obtained 24 to 48 hours after birth . Intravenous acyclovir should be given in cases of neonatal infection . Hepatitis B immune globulin should be given as soon as possible to an infant whose mother is HBsAg-seropositive . Infants born to mothers who are seropositive for human immunodeficiency virus should be started on zidovudine within 24 hours after birth.

Nippon Rinsho, 1994 Nov, 52(11), 3019 - 25
{Therapy for HAM/TSP and AIDS}; Nakagawa M et al.; (1) We evaluated efficacy of several treatments for HTLV-I-associated myelopathy (HAM) on the basis of our study on 254 HAM patients and of literature review . Improvement of motor disability more than fair response was obtained as follows: 82% in prednisolone, 69% in interferon-alpha, 92% in fosfomycin, 82% in high-dose vitamin C, 72% in blood purification therapy, 70% in heparin, 59% in salazosulfapyridine, 56% in thyrotropin-releasing hormone, 55% in erythromycin, 50% in mizoribine . (2) In the absence of clear guideline, the efficacy of zidovudine in the AIDS dementia complex has been demonstrated . There are also efficacy of amytriptylinein controlling HIV headache, corticosteroid in mononeuritis multiple and inflammatory myositis, hydrocortisone in autonomic neuropathy and plasmapheresis in distal sensory neuropathy respectively . Otherwise, it is emphasized that ddI, ddC and d4T have peripheral neuropathy as major, dose related side effect.

J Bacteriol, 1994 Nov, 176(22), 6999 - 7004
Domain V of 23S rRNA contains all the structural elements necessary for recognition by the ErmE methyltransferase; Vester B et al.; The ErmE methyltransferase from the erythromycin-producing actinomycete Saccharopolyspora erythraea dimethylates the N-6 position of adenine 2058 in domain V of 23S rRNA . This modification confers resistance to erythromycin and to other macrolide, lincosamide, and streptogramin B antibiotics . We investigated what structural elements in 23S rRNA are required for specific recognition by the ErmE methyltransferase . The ermE gene was cloned into R1 plasmid derivatives, providing a means of inducible expression in Escherichia coli . Expression of the methyltransferase in vivo confers resistance to erythromycin and clindamycin . The degree of resistance corresponds to the level of ermE expression . In turn, ermE expression also correlates with the proportion of 23S rRNA molecules that are dimethylated at adenine 2058 . The methyltransferase was isolated in an active, concentrated form from E . coli, and the enzyme efficiently modifies 23S rRNA in vitro . Removal of most of the 23S rRNA structure, so that only domain V (nucleotides 2000 to 2624) remains, does not affect the efficiency of modification by the methyltransferase . In addition, modification still occurs after the rRNA tertiary structure has been disrupted by removal of magnesium ions . We conclude that the main features that are specifically recognized by the ErmE methyltransferase are displayed within the primary and secondary structures of 23S rRNA domain V.

Dig Dis Sci, 1994 Nov, 39(11), 2295 - 300
Erythromycin enhances gastric emptying in patients with gastroparesis after vagotomy and antrectomy; Ramirez B et al.; We studied the effect of erythromycin on gastric emptying in nine patients with gastroparesis following truncal vagotomy and antrectomy, and assessed their clinical response to chronic oral erythromycin . Gastric emptying was evaluated using a solid-phase radio-labeled meal . Patients were studied after erythromycin 200 mg intravenously (N = 9) and after an oral suspension of erythromycin 200 mg (N = 7) each given 15 min after ingestion of the meal . Three parameters of gastric emptying were analyzed: half-emptying time (T1/2), area under the curve, and percent gastric residual at 2 hr . Nine patients were subsequently placed on oral suspension erythromycin 150 mg three times a day before meals (range 125-250 mg three times a day) and symptoms of nausea, vomiting, postprandial fullness, and abdominal pain were assessed before and after erythromycin . Intravenous erythromycin markedly accelerated the gastric emptying (all three parameters studied) of solids (P < 0.01) in seven of nine patients with postsurgical gastroparesis {baseline T1/2 154 +/- 15 min; after intravenous erythromycin, T1/2 56 +/- 17 min (mean +/- SEM)} . Oral erythromycin enhanced (P < 0.05) the gastric emptying rate (T1/2, area under the curve) in five of seven patients (baseline T1/2 146 +/- 16 min; after oral erythromycin, T1/2 87 +/- 20 min) . Of the nine patients who were placed on oral maintenance erythromycin, three showed clinical improvement after two weeks . In summary, erythromycin significantly enhances gastric emptying in many patients with vagotomy and antrectomy-induced gastroparesis; however, only a small subset of patients respond clinically to chronic oral erythromycin.

Carcinogenesis, 1994 Nov, 15(11), 2575 - 9
Selective induction of rat hepatic CYP1 and CYP4 proteins and of peroxisomal proliferation by green tea; Bu-Abbas A et al.; Rats were exposed to freshly prepared aqueous extracts of green tea (2.5% w/v) as the sole source of drinking water for 4 weeks . Hepatic cytochrome P450 activity was determined using chemical probes, showing selectivity for particular isoforms, and by immunoblot analysis employing polyclonal antibodies . Exposure to green tea gave rise to increases in the O-demethylation of methoxyresorufin and, to a lesser extent, in the dealkylations of ethoxyresorufin and pentoxyresorufin . An increase was also seen in lauric acid hydroxylation but, in contrast, the N-demethylation of erythromycin was inhibited . p-Nitrophenol oxidase activity was unaffected by the same treatment . Immunoblot analysis revealed increases in the apoprotein levels of CYP1A2 and CYP4A1 following treatment with green tea . A significant increase was also noted in the CN(-)-insensitive palmitoyl CoA oxidation and this was paralleled by an increase in the levels of the peroxisomal trifunctional protein determined immunologically . Hepatic S9 and microsomal preparations from tea-treated animals were more effective than controls in activating 2-amino-3-methylimidazol{4,5-f}quinoline and 2-aminoanthracene to mutagens in the Ames test . When N-nitrosopyrrolidine served as the promutagen, tea did not influence its mutagenicity when isolated microsomes comprised the activation system but a significant inhibition was observed when hepatic S9 was used . The above findings are discussed within the context of the established anticarcinogenic and anti-mutagenic properties of green tea.

Ann Intern Med, 1994 Nov 1, 121(9), 676 - 83
Interactions of warfarin with drugs and food; Wells PS et al.; PURPOSE: To evaluate the quality of studies about drugs and food interactions with warfarin and their clinical relevance . DATA SOURCES: MEDLINE and TOXLINE databases from 1966 to October 1993 using the Medical Subject Headings warfarin, drug interactions, and English only . STUDY SELECTION: All articles reporting original data on drug and food interactions with warfarin . DATA EXTRACTION: Each report, rated independently by at least two investigators (using causality assessment), received a summary score indicating the level of assurance (level 1 = highly probable, level 2 = probable, level 3 = possible, and level 4 = doubtful) that a clinically important interaction had or had not occurred . Inter-rater agreement was assessed using a weighted kappa statistic . RESULTS: Of 793 retrieved citations, 120 contained original reports on 186 interactions . The weighted kappa statistic was 0.67, representing substantial agreement . Of 86 different drugs and foods appraised, 43 had level 1 evidence . Of these, 26 drugs and foods did interact with warfarin . Warfarin's anticoagulant effect was potentiated by 6 antibiotics (cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, and miconazole); 5 cardiac drugs (amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone); phenylbutazone; piroxicam; alcohol (only with concomitant liver disease); cimetidine; and omeprazole . Three patients had a hemorrhage at the time of a potentiating interaction (caused by alcohol, isoniazid, and phenylbutazone) . Warfarin's anticoagulant effect was inhibited by 3 antibiotics (griseofulvin, rifampin, and nafcillin); 3 drugs active on the central nervous system (barbiturates, carbamazepine, and chlordiazepoxide); cholestyramine; sucralfate; foods high in vitamin K; and large amounts of avocado . CONCLUSIONS: Many drugs and foods interact with warfarin, including antibiotics, drugs affecting the central nervous system, and cardiac medications . Many of these drug interactions increase warfarin's anticoagulant effect.

Am J Gastroenterol, 1994 Nov, 89(11), 2011 - 3
Erythromycin as a prokinetic agent: a prospective, randomized, controlled study of efficacy in nasoenteric tube placement; Stern MA et al.; OBJECTIVES: Erythromycin, a macrolide antibiotic, has been shown to mimic the effects of the polypeptide motilin in the gastrointestinal tract . To determine whether erythromycin ethylsuccinate elixir would facilitate the transpyloric passage of a standard nasoenteric feeding tube once the tube was placed into the stomach, 20 patients were randomized to receive erythromycin or standard therapy . METHODS: Twenty patients (ages 45-78), mean age 63 yr, all male, had 43-inch nasoenteric tubes placed and were randomized to receive erythromycin ethylsuccinate elixir (400 mg/5 ml per os every 8 h for three doses) through the feeding tube or to receive standard therapy that involved no drug intervention . RESULTS: Three placements resulted in immediate transpyloric passage . This represented 3/21 (14%) with immediate passage . One patient dropped out after initial tube placement . The remaining 17 patients had initial tube placement in the stomach; of these, eight were randomized to receive erythromycin and nine to receive standard therapy . Six of the eight nasoenteric tubes in the erythromycin group achieved transpyloric passage in 1 day . Zero of the nine nasoenteric tubes in the standard therapy group achieved transpyloric passage in 1 day (p = 0.0023, Fisher's exact test) . CONCLUSION: This study demonstrates that erythromycin ethylsuccinate elixir improves the success of transpyloric feeding tube passage in 1 day and is superior to the standard therapy, which consists of no drug intervention.

Drug Metab Dispos, 1994 Nov-Dec, 22(6), 947 - 55
Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel . Lack of prediction by the erythromycin breath test; Lown KS et al.; The CYP3A subfamily of cytochromes P450 metabolize many medications and environmental contaminants . CYP3A4 and, in 25% of patients, CYP3A5 seem to be the major CYP3A genes expressed in adult liver . Hepatic levels of CYP3A4 can be estimated by the erythromycin breath test and vary at least 10-fold among patients . CYP3A4 has also been shown to be present in small bowel where it is responsible for significant "first-pass" metabolism of orally administered substrates . However, it is not known whether there is significant interindividual variability in the intestinal expression of CYP3A4, or whether the liver and intestinal catalytic activities of CYP3A4 correlate within an individual . It is also not known whether CYP3A5 is expressed in the small intestine . To address these questions, we administered the erythromycin breath test to 20 patients and obtained biopsies from their small bowel . There was a 6-fold variation in CYP3A catalytic activity (midazolam hydroxylation), an 11-fold variation in CYP3A4 protein content, and an 8-fold variation in CYP3A4 mRNA content in intestinal biopsies . There was an excellent correlation between intestinal CYP3A4 protein level and catalytic activity (r = 0.86; p = 0.0001); however, neither parameter significantly correlated with hepatic CYP3A4 activity as measured by the erythromycin breath test result (r = 0.27; p = 0.24 and r = 0.33; p = 0.15, respectively) . We also found that CYP3A5 protein was readily detectable in biopsies from 14 (70%) of the patients, indicating that CYP3A5 is commonly expressed in human small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Saf, 1994 Nov, 11(5), 301 - 9
Antihyperlipidaemic agents . Drug interactions of clinical significance; Farmer JA et al.; The available antihyperlipidaemic drugs are generally safe and effective, and major systemic adverse effects are uncommon . However, because of their complex mechanisms of action, careful monitoring is required to identify and correct potential drug interactions . Bile acid sequestrants are the most difficult of these agents to administer concomitantly, because their nonspecific binding results in decreased bioavailability of a number of other drugs, including thiazide diuretics, digitalis preparations, beta-blockers, coumarin anticoagulants, thyroid hormones, fibric acid derivatives and certain oral antihyperglycaemia agents . Although the incidence is low, nicotinic acid may cause hepatic necrosis and so should not be used with drugs that adversely affect hepatic structure or function . With the HMG-CoA reductase inhibitors, relatively new agents for which clinical data are still being accumulated, the major problems appears to be rhabdomyolysis, associated with the concomitant use of cyclosporin, fibric acid derivatives or erythromycin, and mild, intermittent hepatic abnormalities that may be potentiated by other hepatotoxic drugs . Fibrates also have the potential to cause rhabdomyolysis, although generally only in combination with HMG-CoA reductase inhibitors, and are subject to binding by concomitantly administered bile acid sequestrants . The major interaction involving probucol is a possible additive effect with drugs or clinical conditions that alter the prolongation of the QTc interval, increasing the potential for polymorphic ventricular tachycardia.

J Fam Pract, 1994 Nov, 39(5), 437 - 40
Albuterol delivered by metered-dose inhaler to treat acute bronchitis; Hueston WJ; BACKGROUND . Previous research has suggested that cough associated with acute bronchitis is more likely to subside within 7 days when treated with albuterol than with an antibiotic . This study examines the effectiveness of aerosolized albuterol for the treatment of acute bronchitis in patients treated with erythromycin or placebo . METHODS . A double-blind, randomized placebo-controlled trial of albuterol delivered by metered-dose inhaler (MDI) was conducted in a primary care setting with healthy adult patients who presented with a productive cough of fewer than 30 days' duration . In addition to randomization for albuterol, patients were also randomized to receive erythromycin or placebo . Outcomes were assessed at follow-up after 7 days . RESULTS . Patients treated with albuterol MDI were less likely to be coughing after 7 days of treatment than were patients using a placebo inhaler (61% still coughing vs 91%, P = .02) . When analysis was stratified by cigarette smoking status and the use of erythromycin, the differences observed between albuterol MDI patients and controls persisted . CONCLUSIONS . Albuterol appears to reduce the likelihood that patients with acute bronchitis will be coughing after 7 days following initiation of treatment . This effect appears to be independent of cigarette smoking or the concomitant use of antibiotics.

Kansenshogaku Zasshi, 1994 Nov, 68(11), 1324 - 9
Evaluation of pertussis treatment with erythromycin ethylsuccinate and stearate according to age; Kawai H et al.; Although erythromycin estolate has been fully assessed for pertussis treatment, the evaluation of erythromycin ethylsuccinate and stearate, the main erythromycin preparations used in Japan and the US, is inadequate . We evaluated these preparations to establish an appropriate treatment for pertussis according to age . Sixty-six patients with culture-confirmed pertussis were treated with erythromycin administered at a dosage of 40-50 mg/kg/day (maximum, 1.2 g/day) . Negative culture was obtained in 39% (15/38) of patients aged 0-2 years within one week and in 71% (27/38) within two weeks, in 78% (7/9) of those aged 3-15 years within one week and in 100% (9/9) within two weeks . All 12 adult patients had a negative culture within one week . The efficacy of erythromycin for the eradication of B . pertussis was significantly lower in children aged 0-2 years than in older children . In conclusion, it is desirable to administer erythromycin for three weeks to children aged 0-2 years, two weeks to those aged 3-15 years and one week to adults.

Mol Microbiol, 1994 Nov, 14(3), 533 - 45
The mRNA for the 23S rRNA methylase encoded by the ermE gene of Saccharopolyspora erythraea is translated in the absence of a conventional ribosome-binding site; Bibb MJ et al.; Transcriptional analysis of the ermE gene of Saccharopolyspora erythraea, which confers resistance to erythromycin by N6-dimethylation of 23S rRNA and which is expressed from two promoters, ermEp1 and ermEp2, revealed a complex regulatory region in which transcription is initiated in a divergent and overlapping manner . Two promoters (eryC1p1 and eryC1p2) were identified for the divergently transcribed erythromycin biosynthetic gene eryC1, which plays a role in the formation of desosamine or its attachment to the macrolide ring . Transcription from eryC1p2 starts at the same position as that of ermEp1, but on the opposite strand of the DNA helix, suggesting co-ordinate regulation of genes for erythromycin production and resistance . ermEp1 initiates transcription at, and one nucleotide before, the ermE translational start codon . Site-directed and deletion mutagenesis, combined with immunochemical analysis, demonstrated that the ermEp1 transcript is translated in the absence of a conventional ribosome-binding site to give rise to the full-length 23S rRNA methylase . Deletion of the -35 region of ermEp1 reduced, but did not abolish, promoter activity, reminiscent of the 'extended -10' class of bacterial promoters which, like ermEp1, possess TGN motifs immediately upstream of their -10 regions and which initiate transcription seven nucleotides downstream of the -10 region.

Eur J Biochem, 1994 Oct 15, 225(2), 651 - 7
Effects of mifepristone (RU-486) on heme metabolism and cytochromes P-450 in cultured chick embryo liver cells, possible implications for acute porphyria; Cable EE et al.; Mifepristone (RU-486), a potent progesterone receptor antagonist and inducer of cytochromes P-450, is currently in use in Europe, particularly as a post-coital oral contraceptive . Soon it will be available in the United States, as well . Since progesterone has been implicated in the pathogenesis of acute attacks of porphyria, the use of RU-486 or related compounds might be considered in porphyric patients . However, as with other cytochrome P-450 inducers, RU-486 may have the ability to precipitate or exacerbate attacks of acute porphyria . The acute porphyrias in relapse are associated with an increase in activity of delta-aminolevulinic acid synthase, the first and normally rate-controlling enzyme in heme biosynthesis . We have used primary cultures of chick embryo liver cells to test the ability of RU-486 to induce delta-aminolevulinic acid synthase activity and mRNA, cytochromes P-450, porphyrin accumulation, and heme oxygenase . We found that RU-486, at concentrations observed in human plasma after a single oral dose, induced the mRNA and activity of delta-aminolevulinic acid synthase, both by itself and in the presence of deferoxamine, a potent iron chelator that inhibits ferrochelatase . RU-486 and deferoxamine together also produced significant accumulations of protoporphyrin . These results indicate that RU-486 may pose a risk in patients with known acute porphyria and should be used with caution . RU-486 increased the concentration of total cytochrome P-450, and the activity of erythromycin demethylase, an activity specifically catalyzed by cytochrome P-450 3A . Unlike several other porphyrogens (e.g . hydantoins, barbiturates), RU-486 does not produce accumulation of uroporphyrin or induction of heme oxygenase in chick embryo liver cells.

Kansenshogaku Zasshi, 1994 Oct, 68(10), 1256 - 63
{Serodiagnosis of Legionella pneumonia--data of our laboratory in the recent 3 years}; Yamashiro Y et al.; We had examined antibody titers against Legionella spp . of patients' sera which were mainly sent from other hospitals, performed with the indirect fluorescent antibody (IFA) method . The clinical status of the cases diagnosed as Legionella pneumonia serologically, were also studied . Out of 105 cases with clinically suspected Legionella pneumonia, 15 cases (14.3%) were seropositive . In 9 out of the 15 cases (60.0%) were caused by Legionella pneumophila serogroup 1 . Clinical outline of these 15 cases did not contradict those reported in the literature, and erythromycin was effective in many cases . Significant rises (more than four times) of the titer were observed 3 to 4 weeks after onset in most of cases . We would like to emphasize that this should be performed serodiagnosis of Legionella pneumonia.

J Pharmacol Exp Ther, 1994 Oct, 271(1), 574 - 9
EM574, an erythromycin derivative, is a potent motilin receptor agonist in human gastric antrum; Satoh M et al.; Erythromycin and its derivatives are known to induce phase III-like contractions, which are similar to those induced by motilin, in the human gastrointestinal tract during the interdigestive state, but few detailed in vitro studies have been reported . We evaluated EM574, an erythromycin derivative, as a motilin receptor agonist in the human gastric antrum in vitro, using contraction studies of muscle strips and isolated myocytes, receptor binding assay and tissue section autoradiography . EM574 stimulated contractions of muscle strips in a concentration-dependent manner (10(-7)-10(-5) M), and this contractile effect was unaffected by pretreatment with atropine or tetrodotoxin . Isolated myocytes contracted in response to EM574 with a peak shortening at 10(-7) M, which was comparable to the response to motilin . EM574 displaced specifically 125I-motilin bound to smooth muscle homogenates with a Kd value of 7.8 x 10(-9) M, compared with 4.5 x 10(-9) M for motilin . Film autoradiograms showed that 125I-motilin-binding sites were localized in the muscle layers, and that the labeling disappeared in the presence of a 1000 times molar concentration of EM574 . We conclude that EM574 directly stimulates smooth muscle cell contraction by acting on motilin receptors in the human gastric antrum in vitro.

Am J Gastroenterol, 1994 Oct, 89(10), 1769 - 74
Appraisal of medium- and long-term treatment of gastroparesis and chronic intestinal dysmotility; Camilleri M; OBJECTIVE: To evaluate the medium- and long-term treatment of patients with gastroparesis and chronic intestinal dysmotility (CID) . This assessment is timely, inasmuch as several treatment trials have been published within the past 2 yr, necessitating an appraisal of the outcome of treatments . METHODS: Literature review based on Medline Search using key words: gastroparesis, chronic intestinal pseudo-obstruction, enteral nutrition, feeding jejunostomy, prokinetics, gastric atony, gastrectomy, Roux-Y gastrectomy . RESULTS: Restoration of nutrition can be achieved orally, enterally, or parenterally, depending on the severity of the clinical syndrome . Combinations of antiemetics and prokinetics are useful for symptomatic and objective benefits . Intravenous erythromycin is chiefly beneficial in the acute presentation . The weight of current evidence favors cisapride as the prokinetic of choice in the medium and long term . Surgical approaches are restricted to providing a means for decompression, access to the small bowel for nutrition, and resection for localized disease or completion of gastrectomies for atony after gastric surgery . CONCLUSION: More rational choices of access for nutritional supplementation, selection of prokinetic agents, and indications for surgical treatment can be made on the basis of clinical experience and published studies; however, several unanswered questions remain and call for further outcome-based studies in patients with gastroparesis and CID.

J Infect Dis, 1994 Oct, 170(4), 906 - 11
Relative potency of 10 drugs with anti-Pneumocystis carinii activity in an animal model; Hughes WT et al.; Several drugs have been shown to have anti-Pneumocystis carinii activity in clinical trials . Because of the large number of patients required, no more than 3 drugs can be compared for efficacy in human studies . However, the experimental animal model for P . carinii pneumonitis is remarkably similar to the human disease and was used to compare 10 drugs for the relative potency against this infection . All drugs were compared at doses known to prevent the pneumonitis in > 80% of animals and at one-tenth of this dose . Drugs effective at the lowest dose were further tested at one-hundredth the original doses, and drugs ineffective were retested at 10 and 100 times the original dose . Trimethoprim-sulfamethoxazole was the most effective drug, with azithromycin-sulfamethoxazole and clarithromycin-sulfamethoxazole next most effective . Intravenous pentamidine and clindamycin-primaquine were the least effective . Atovaquone, sulfadoxine-pyrimethamine, erythromycin-sulfisoxazole, PS-15, and dapsone-trimethoprim had intermediate activity.

J Bacteriol, 1994 Oct, 176(20), 6192 - 8
Ribosomal protein gene sequence changes in erythromycin-resistant mutants of Escherichia coli; Chittum HS et al.; The genes for ribosomal proteins L4 and L22 from two erythromycin-resistant mutants of Escherichia coli have been isolated and sequenced . In the L4 mutant, an A-to-G transition in codon 63 predicted a Lys-to-Glu change in the protein . In the L22 strain, a 9-bp deletion removed codons 82 to 84, eliminating the sequence Met-Lys-Arg from the protein . Consistent with these DNA changes, in comparison with wild-type proteins, both mutant proteins had reduced first-dimension mobilities in two-dimensional polyacrylamide gels . Complementation of each mutation by a wild-type gene on a plasmid vector resulted in increased erythromycin sensitivity in the partial-diploid strains . The fraction of ribosomes containing the mutant form of the protein was increased by growth in the presence of erythromycin . Erythromycin binding was increased by the fraction of wild-type protein present in the ribosome population . The strain with the L4 mutation was found to be cold sensitive for growth at 20 degrees C, and 50S-subunit assembly was impaired at this temperature . The mutated sequences are highly conserved in the corresponding proteins from a number of species . The results indicate the participation of these proteins in the interaction of erythromycin with the ribosome.

Chest, 1994 Oct, 106(4), 1116 - 23
Erythromycin inhibits neutrophil chemotaxis in bronchoalveoli of diffuse panbronchiolitis; Oda H et al.; The efficacy of low dose long-term erythromycin (EM) therapy in the treatment of chronic lower respiratory tract disease, including diffuse panbronchiolitis (DPB), has been reported, but its therapeutic mechanism is still unclear . In 13 patients receiving oral EM therapy the accumulation of neutrophils in bronchoalveolar lavage (BAL) fluid was significantly reduced (p < 0.05), this reduction corresponds with an improvement in clinical symptoms . We sought to determine whether neutrophil chemotactic activity (NCA) in lavage fluid obtained from these 13 patients with DPB would respond to EM therapy . Pretreatment NCA in all patients was significantly elevated compared with levels in normal healthy nonsmoking volunteers (p < 0.001), and the level was greatly reduced after EM therapy (p < 0.001) . In addition, this reduction correlated with increased percentages of neutrophils in the BAL fluid (r = 0.737, p < 0.01) . Gel-filtration chromatography was also performed to characterize chemotactic factors . Pre-EM treatment BAL fluid revealed four NCA peaks (about molecular weight 15,000, 8,000, 1,500, and 300 daltons) in the elution profile, and chemotactic activity was reduced in all areas after EM therapy . These findings indicate that NCA in lavage fluid from patients with DPB consists of various components . Although it was not clear which component is predominantly affected, these results indicate that EM may inhibit the migration of neutrophils to inflammatory sites by reducing the intrapulmonary chemotactic gradient, thus, ultimately reducing pulmonary inflammation.

Eur J Clin Microbiol Infect Dis, 1994 Oct, 13(10), 866 - 71
Comparative studies of cefprozil in the management of skin and soft-tissue infections; Nolen T; Six multicenter clinical trials comparing cefprozil with cefaclor, amoxicillin-clavulanate or erythromycin in the management of skin and soft-tissue infections caused by susceptible bacteria demonstrate that cefprozil, given once or twice daily, is an effective chemotherapeutic agent in this context . Its pharmacokinetic behavior is compatible with once-daily or twice-daily administration, with a probability of improved patient compliance . Safety and tolerability compare favorably with other agents used in skin and soft-tissue infections.

J Biochem Toxicol, 1994 Oct, 9(5), 241 - 8
Differential modulation of hepatic cytochrome P-450 enzymes in rat and Syrian hamster by 4'-trifluoromethyl-2,3,4,5-tetrachlorobiphenyl; Bani MH et al.; The effects of a single injection (40 mg/kg) of 4'-trifluoromethyl-2,3,4,5-tetrachlorobiphenyl (CF3) on hepatic cytochrome P-450 monooxygenases were assessed in rat and syrian hamster . The CF3 treatment significantly increased the total amount of cytochrome P-450 in both species . In rats, CF3 treatment caused marked increases in ethoxyresorufin O-deethylase (EROD), arylhydrocarbon hydroxylase (AHH), and testosterone 7 alpha-hydroxylase activities but significantly reduced the activities of benzphetamine N-demethylase (BzND), erythromycin N-demethylase (ErND), testosterone 6 beta, 16 alpha, and 16 beta-hydroxylase, and formation of androstenedione . Administration of CF3 to hamsters strongly induced the activities of EROD, AHH, BzND, testosterone 15 alpha, and 16 alpha-hydroxylases, and androstenedione production, whereas ErND, testosterone 6 beta, and 7 alpha-hydroxylases were decreased . Administration of CF3 to rats induced the CYP1A family proteins and CYP2A1, while CF3 reduced the level of CYP2B1, and, to a lesser extent, of CYP6 beta 2 . In hamsters, CF3 treatment significantly induced the CYP1A2, CYP2A1, CYP2A8, and CYP2B1 isozymes, whereas the CYP6 beta 2 level was decreased . The ability of hepatic microsomes to activate aflatoxin B1 and benzo(a)pyrene was elevated by CF3 treatment in hamsters, while activation of aflatoxin B1 was decreased in microsomes from CF3-treated rats . These results showed differences in the CF3-induced pattern of rat and hamster cytochrome P-450 monooxygenases.

Proteins, 1994 Oct, 20(2), 197 - 201
Preliminary crystallographic analysis of an enzyme involved in erythromycin biosynthesis: cytochrome P450eryF; Cupp-Vickery JR et al.; Cytochrome P450eryF was overexpressed in Escherichia coli and purified in high yield . Crystals of the protein in the presence of the substrate, 6-deoxyerythronolide B, have been obtained by the hanging drop vapor diffusion method, using polyethylene glycol 4000 as a precipitant . The crystals belong to the orthorhombic space group P2(1)2(1)2(1) with unit cell dimensions of a = 54.16 A, b = 79.67 A, and c = 99.48 A and one molecule per asymmetric unit . A complete native data set has been collected to a resolution of 2.1 A, and anomalous dispersion difference Patterson maps have revealed the location of the single heme iron atom.

S Afr Med J, 1994 Oct, 84(10), 678 - 82
'Atypical' bacteria are a common cause of community-acquired pneumonia in hospitalised adults; Maartens G et al.; OBJECTIVES: To assess the proportion of cases of community-acquired pneumonia caused by 'atypical' bacteria, including the recently discovered Chlamydia pneumoniae, and to compare the clinical, radiographic and laboratory features of patients with and without 'atypical' bacteria . METHODS: A prospective serological study was carried out on consecutive adult pneumonia patients from July 1987 to July 1988 . Acute and convalescent sera were tested in batches for antibodies against Legionella pneumophila serogroup 1, C . pneumoniae, Chlamydia psittaci, Coxiella burnetii (phase-2 antigen) and Mycoplasma pneumoniae (IgG and IgM) . Records and chest radiographs were examined retrospectively . RESULTS . Acute and convalescent sera were available from 113 patients . The records of 4 patients could not be traced and 17 patients did not fulfil the inclusion criteria . Thirty-two of these 92 patients (35.9%) were found to be infected with 'atypical' bacteria . The two most common organisms were C . pneumoniae (20.7%) and L . pneumophila (8.7%) . There were no differences in the clinical and radiographic features of patients with and without 'atypical' bacteria . Clinicians prescribed erythromycin or tetracyclines with equal frequency in the two groups . CONCLUSIONS . 'Atypical' bacteria, especially C . pneumoniae, are a common cause of community-acquired pneumonia in adults in South Africa . This is the first demonstration of an aetiological role of C . pneumoniae in this country . We confirmed the finding of other studies that there are no clinical, radiographic or laboratory features characteristic of 'atypical' bacterial infection in hospitalised patients . This has major implications for therapy, as these organisms respond to erythromycin and tetracyclines, but not to beta-lactam antibiotics.

Br J Clin Pharmacol, 1994 Oct, 38(4), 363 - 7
The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone; Aranko K et al.; 1 . The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non-benzodiazepine hypnotic, was investigated in a double-blind, cross-over study . 2 . Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone . 3 . Erythromycin increased plasma zopiclone concentration by 4-fold at 0.5 h (P < 0.05) and by 2-fold at 1 h (P < 0.05) . There were increases of 3- and 2-fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05) . The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05) . The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001) . 4 . Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests . 5 . The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients.

Mol Microbiol, 1994 Oct, 14(1), 163 - 72
Repeated polyketide synthase modules involved in the biosynthesis of a heptaene macrolide by Streptomyces sp . FR-008; Hu Z et al.; Genes for biosynthesis of a Streptomyces sp . FR-008 heptaene macrolide antibiotic with antifungal and mosquito larvicidal activity were cloned in Escherichia coli using heterologous DNA probes . The cloned genes were implicated in heptaene biosynthesis by gene replacement . The FR-008 antibiotic contains a 38-membered, polyketide-derived macrolide ring . Southern hybridization using probes encoding domains of the type I modular erythromycin polyketide synthase (PKS) showed that the Streptomyces sp . FR-008 PKS gene cluster contains repeated sequences spanning c . 105kb of contiguous DNA; assuming c . 5 kb for each PKS module, this is in striking agreement with the expectation for the 21-step condensation process required for synthesis of the FR-008 carbon chain . The methods developed for transformation and gene replacement in Streptomyces sp . FR-008 make it possible to genetically manipulate polyene macrolide production, and may later lead to the biosynthesis of novel polyene macrolides.

Neuroendocrinology, 1994 Oct, 60(4), 452 - 6
Effect of erythromycin on pancreatic polypeptide release: role of the vagal nerve; Witteman BJ et al.; To determine whether long vagal cholinergic pathways are involved in erythromycin-induced pancreatic polypeptide release, erythromycin was administered as an intravenous bolus injection to 9 healthy volunteers (group A) and to 13 patients (group B) with impaired vagal function as a result of truncal vagotomy or accidental vagotomy after antireflux surgery . In 7 of these patients (group B1) an antrectomy was also performed, while in the other 6 patients (group B2) the antrum was not removed . Pancreatic polypeptide was measured by radioimmunoassay at 5-min intervals twice before and at 2, 5, 10, 15, 30, 45 and 60 min after a 3.5 mg/kg bolus injection of erythromycin . On another day, a standard meal was administered and plasma pancreatic polypeptide was measured at 10-min intervals for 1 h . Erythromycin injection resulted in a lower integrated pancreatic polypeptide response in the patients of group B1 (247 +/- 89 pmol/l x 15 min; p = 0.005) and group B2 (497 +/- 111 pmol/l x 15 min; p = 0.05) when compared to the healthy subjects of group A (1,136 +/- 227 pmol/l x 15 min) . The pancreatic polypeptide response to erythromycin in group B1 was reduced when compared to group B2, but the difference just failed to reach statistical significance (0.05 < p < 0.10) . In the first 30 min after ingestion of a meal (cephalic phase) pancreatic polypeptide release was also markedly lower in group B1 (1,461 +/- 304 pmol/l x 30 min; p < 0.005) and group B2 (1,452 +/- 215 pmol/l x 30 min; p < 0.005) when compared to group A (3,541 +/- 452 pmol/l x 30 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Clin Ter, 1994 Oct, 145(10), 277 - 81
{Effects of intravenous administration of clarithromycin on plasma levels of gastrin and group I pepsinogen}; Pustorino S et al.; Erythromycin and some of its derivatives have prokinetic gastrointestinal properties . In addition, erythromycin has been shown to stimulate isolated chief cells of the gastric mucosa, and to activate pepsin secretion . The above study was aimed at ascertaining in a group of dyspeptic patients whether clarithromycin, a structural analogue of erythromycin, is apt to modify certain functional parameters of gastric secretion, above all the patterns of gastrin and PG-I secretion . A 20-minute intravenous clarithromycin infusion (1.5 mg/kg) in fasting subjects has brought about a significant reduction (at 20 and 45 minutes from the start of infusion) of circulating gastrin (about 23%) and, after a meal, a 69% increase . No change of plasma PG-I level was observed either after placebo or after the active substance . These findings suggest that in vivo and at the doses used in our experiment clarithromycin has no influence on plasma PG-I release and is apt to modify the fasting and postprandial gastrin releasing pattern.

Br J Surg, 1994 Oct, 81(10), 1517 - 9
Hypotension induced by haemorrhage impairs lower oesophageal sphincter function; Caldwell MT et al.; The effect of haemorrhage-induced hypotension on lower oesophageal sphincter (LOS) tone was studied in 11 adult mongrel dogs . Mean(s.e.m.) blood loss of 760(66) ml, corresponding to 42 per cent of estimated blood volume, was associated with a significant fall in LOS tone (14.2(1.0) versus 7.2(0.6) sphinctometer units, P < 0.002) . This was associated with a reduction in mean(s.e.m.) arterial blood pressure (99(7) versus 53(3) mmHg, P < 0.002) and heart rate (113(6) versus 106(5) beats per min, P = 0.06) . Group 1 animals (n = 6) received autotransfusion, restoring LOS tone to prehaemorrhage values . Dogs in group 2 (n = 5) were given intravenous erythromycin 4 mg/kg, which also restored LOS tone . This effect was transient, lasting a mean(s.e.m.) of only 67(7) min . Infusion of an equivalent volume of 0.9 per cent saline following cessation of the erythromycin effect restored LOS tone to control values although the animals remained hypotensive . Reduction in LOS tone with haemorrhage may be part of a vagal reflex mediated by myocardial afferent C fibres and may explain the high incidence of pulmonary aspiration in shocked patients.

Parasite, 1994 Sep, 1(3), 211 - 8
Interaction of artemisinin and tetracycline or erythromycin against Plasmodium falciparum in vitro; Ye Z et al.; Antimalarial activities of tetracycline (TC) and erythromycin (EM), alone or in combination with artemisinin (Qinghaosu, QHS), were studied using chloroquine (CQ)-sensitive (D6) and -resistant (W2) strains of Plasmodium falciparum in vitro . The antimalarial potency of TC (IC50 = 9862 nM for the CQ-sensitive parasite, 32414 nM for the CQ-resistant one) or EM (IC50 = 45787 nM for the CQ-sensitive parasite, 33397 nM for the CQ-resistant one) was much less than that of QHS (IC50 ranging from 25 to 40 nM) . The CQ-resistant falciparum parasite displayed a cross-resistance to TC, while both the drug-sensitive and -resistant parasites exhibited similar responses to EM . However, antimalarial potency of EM appeared to be less than that of TC against the drug-sensitive parasite . When TC was combined with QHS, an additive interaction was observed against the CQ-sensitive falciparum parasite, while synergism was found with the CQ-resistant parasite . When EM was tested in combination with QHS, a potentiating interaction occurred with both the CQ-sensitive and resistant falciparum parasite . The above results indicated that the QHS combination with either TC or EM may be a promising antimalarial preparation with low recrudescence compared to artemisinin used alone in clinical practice.

J Infect Dis, 1994 Sep, 170(3), 689 - 92
Incubating syphilis in patients treated for gonorrhea: a comparison of treatment regimens; Peterman TA et al.; Dade County sexually transmitted disease clinic records were reviewed to estimate the relative effectiveness of gonorrhea treatment regimens for eradicating incubating syphilis . Records were searched to see if persons treated for gonorrhea returned with primary syphilis 3-45 days after treatment or secondary syphilis 15-90 days after treatment . The number of persons treated was adjusted for the prevalence of syphilis in the year of treatment . Between 1985 and 1992, 98,441 persons were treated for gonorrhea . Syphilis was diagnosed in an interval that suggested it was incubating at the time of the treatment for 5.6/10(4) (adjusted number) persons treated with spectinomycin alone (a regimen not expected to eradicate syphilis); 2.9/10(4) persons treated with spectinomycin plus tetracycline, doxycycline, or erythromycin; and 2.1/10(4) persons treated with ceftriaxone plus tetracycline, doxycycline, or erythromycin (P > .1) . Incubating syphilis was rare despite a syphilis epidemic . The effectiveness of a regimen for eradicating incubating syphilis should not be a major consideration when choosing gonorrhea therapy.

J Endod, 1994 Sep, 20(9), 427 - 31
Effectiveness of various medications on postoperative pain following root canal obturation; Torabinejad M et al.; This prospective study compared the effectiveness of nine medications and a placebo in controlling pain following obturation . A total of 588 patients who required root canal obturation were included . After obturation of root canals, each patient took one of the medications, salicylic acid (2 x 250 mg), acetaminophen (2 x 250 mg), ibuprofen (2 x 250 mg), ketoprofen (2 x 250 mg), acetaminophen (2 x 250 mg) plus codeine (2 x 250 mg), penicillin (2 x 250 mg), erythromycin base (2 x 250 mg), penicillin plus ibuprofen (2 x 250 mg), methylprednisolone (2 x 250 mg) plus penicillin (2 x 250 mg), or a placebo, every 6 h for 72 h . All medications were encapsulated in identical capsules . The patients registered their degree of discomfort on a visual analogue scale of 0 to 9 . Statistical analysis of the data showed that the incidence of postoperative pain after obturation is lower than that following complete cleaning and shaping (5.83% versus 21.76%) . In addition, there was no significant difference between the effectiveness of the various medications and placebo tablets in controlling postoperative pain following obturation.

Arch Dis Child, 1994 Sep, 71(2), F128 - 9
Erythromycin in neonatal postoperative intestinal dysmotility; Simkiss DE et al.; The motilin agonist erythromycin was used successfully in four infants receiving prolonged parenteral nutrition for severe intestinal dysmotility after gastrointestinal surgery . In a further child with a neuropathic intestinal pseudo-obstruction erythromycin induced a striking small intestinal manometric response, but was without effect in a child with an intestinal myopathy.

Chemosphere, 1994 Sep, 29(6), 1313 - 24
Effect of 1,2,4-trichlorodibenzo-p-dioxin on drug-metabolizing enzymes in the rat liver; Hanioka N et al.; The effects of 1,2,4-trichlorodibenzo-p-dioxin (1,2,4-TrCDD) on drug-metabolizing-enzymes have been studied in male Wistar rats . 1,2,4-TrCDD (0.1 mmol/kg per day) was administered by i.p . injection for 3 days . Among the cytochrome P-450 (P450)-mediated monooxygenase activities tested, 7-ethoxyresorufin O-deethylase, which is associated with CYP1A1, was remarkably induced by 1,2,4-TrCDD (0.1 mmol/kg) . The relative induction to control activity was 32.9-fold . Also, 1,2,4-TrCDD increased other CYP1A-mediated monooxygenase activities such as 7-ethoxycoumarin O-deethylase, 4-nitroanisole O-demethylase, 7-methoxyresorufin O-demethylase and caffeine N-demethylase from 5.7- to 1.9-fold . Western immunoblotting showed that the levels of CYP1A1 and CYP1A2 proteins in liver microsomes were increased by 1,2,4-TrCDD . On the other hand, 7-pentoxyresorufin O-depentylase activity was induced 2.6-fold whereas aniline 4-hydroxylase, nitrosodimethylamine N-demethylase and erythromycin N-demethylase activities were increased slightly (1.3-, 1.6- and 1.3-fold, respectively) by 1,2,4-TrCDD . However, aminopyrine N-demethylase was not significantly induced by 1,2,4-TrCDD . Of the Phase II drug-metabolizing enzymes, DT-diaphorase and glutathione S-transferase (GST) activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and those of UDP-glucuronyltransferase (UGT) towards 4-nitrophenol and 7-hydroxycoumarin were increased from 2.7 to 1.4-fold by 1,2,4-TrCDD . These results indicate that 1,2,4-TrCDD induces both Phase I and Phase II drug-metabolizing enzymes in the rat liver.

Arthritis Rheum, 1994 Sep, 37(9), 1265 - 82
Gastrointestinal motility disorders in scleroderma; Sjogren RW; After the skin, the gastrointestinal tract is the second most common target of systemic sclerosis . The major clinical manifestations include gastroesophageal reflux, small bowel bacterial overgrowth, malnutrition, and intestinal pseudoobstruction . Treatment is symptomatic and supportive . Gastroesophageal reflux can usually be adequately managed with prokinetic drugs, omeprazole, and judicious use of antireflux surgery . If Barrett's esophagus is present, periodic endoscopic monitoring for development of dysplastic changes or adenocarcinoma is indicated . Bacterial overgrowth usually responds to rotating antibiotics and prokinetic drugs . Malnutrition and intestinal pseudoobstruction remain the major problems and often home total parenteral nutrition is required . Intestinal pseudoobstruction occurs in two phases: an early, neuropathic phase may respond to prokinetic drugs (metoclopramide, cisapride, octreotide, and erythromycin) and dietary modification (low-residue diets, vitamin supplementation) . In the late myopathic phase, therapy is usually ineffective . Treatment consists of nutritional support . Careful manometric and radiographic localization of affected segments of stomach and small and large intestines may allow judicious surgical resection or venting procedures to reduce symptoms in this unfortunate group of patients.

Clin Pharmacol Ther, 1994 Sep, 56(3), 253 - 60
P450 3A activity and cyclosporine dosing in kidney and heart transplant recipients; Turgeon DK et al.; Interpatient differences in the kinetics of cyclosporine appear to result in part from interindividual differences in the catalytic activity of an enzyme termed P450 3A . We investigated the relationship between P450 3A activity, as measured by the erythromycin breath test (ERMBT), and the appropriate stable daily dose of cyclosporine as currently determined by physicians at our institution . The ERMBT was administered to kidney and heart allograft recipients who had attended at least two monthly clinic visits without having their daily cyclosporine dose changed . There was a significant positive correlation between the ERMBT result and the daily cyclosporine doses (in milligrams per kilogram) in both the heart (r = 0.68; p = 0.04; n = 9) and kidney (r = 0.68; p = 0.03; n = 10) recipients . To confirm our findings, we prospectively administered the ERMBT on multiple occasions to 20 patients who were undergoing kidney transplantation . Although the transplant physicians were blinded to the ERMBT results, the test predicted the stable daily doses of cyclosporine that they ultimately prescribed to the patients (r = 0.54; p = 0.015) . When data from all 39 patients were pooled and subjected to multiple regression analysis, the ERMBT was the only variable examined that significantly correlated with the stable daily cyclosporine dose (r = 0.63; p < 0.001; n = 39) . In the 20 patients prospectively studied, the prescribed daily dose of cyclosporine generally decreased during the months after surgery and the percentage changes in cyclosporine daily dose correlated with changes in P450 3A activity during this period (r = 0.47; p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Otolaryngol Head Neck Surg, 1994 Sep, 111(3 Pt 2), 348 - 54
Cardiovascular toxicity of antihistamines; Smith SJ; The efficacy of individual antihistamines is similar for most indications . The primary difference between traditional (first-generation) and nonsedating (second-generation) histamine1-receptor antagonists is the incidence and severity of adverse reactions . The first-generation drugs are associated with sedation, decreased psychomotor function, anticholinergic side effects, and other adverse reactions that are not observed with usual doses of second-generation agents . Since 1990 evidence has accumulated demonstrating that high doses of the second-generation drugs terfenadine and astemizole prolonged the cardiac QT interval and produced torsades de pointes, a rare but potentially lethal arrhythmia . Some first-generation agents also cause torsades de pointes . Concomitant administration of some drugs that inhibit the hepatic drug-metabolizing enzymes with either terfenadine or astemizole prevents the metabolism and increases the serum concentration of unchanged terfenadine and astemizole; this results in prolonged cardiac QT intervals and torsades de pointes . Interacting drugs include the macrolides (erythromycin and troleandomycin) and imidazole antifungals (ketoconazole and itraconazole) . Also discussed are other factors that increase the likelihood of torsades de pointes after administration of terfenadine or astemizole and the pathophysiology of torsades de pointes, current therapy, and ways to avoid its occurrence . Preliminary studies indicate that two other second-generation agents, loratadine and cetirizine (an investigational agent), do not produce torsades de pointes.

Drug Metab Dispos, 1994 Sep-Oct, 22(5), 688 - 92
cDNA-directed expression of human cytochrome P450 CYP3A4 using baculovirus; Buters JT et al.; A recombinant baculovirus containing the human CYP3A4 cDNA was constructed and used to express CYP3A4 in SF9 insect cells (0.46 +/- 0.13 nmol/mg protein, 103 +/- 29 nmol/liter, N = 15) . The enzyme represented approximately 2-3% of total cellular protein and could be purified by a two-column procedure to a specific content of 12.7 nmol/mg protein . Catalytic activity of the purified enzyme after reconstitution was optimum using molar ratios of CYP3A4 to cytochrome b5 to NADPH-P450 oxidoreductase of 1:3:20, respectively . The enzyme metabolized cortisol, erythromycin, testosterone, and (R)-warfarin . Recombinant baculovirus expresses the highest amounts of all expression systems published to date of catalytically intact CYP3A4 . This system is an excellent alternative for the isolation and characterization of P450 forms from human liver.

J Antimicrob Chemother, 1994 Sep, 34(3), 343 - 51
In-vitro activity of quinolones and macrolides against mycobacteria; Yew WW et al.; The activities of eight quinolones (ciprofloxacin, clinafloxacin, levofloxacin, ofloxacin, A-80556, sparfloxacin, temafloxacin and tosufloxacin) and three macrolides (azithromycin, clarithromycin and erythromycin) against 98 clinical isolates of Mycobacterium tuberculosis and 120 isolates of five different atypical mycobacterial species including 20 Mycobacterium kansasii, 25 Mycobacterium scrofulaceum, 25 Mycobacterium avium/intracellulare, 25 Mycobacterium chelonae and 25 Mycobacterium fortuitum were determined with the Middlebrook 7H9 broth macrodilution method . Sparfloxacin, clinafloxacin, levofloxacin, ciprofloxacin and ofloxacin were active against M . tuberculosis (MIC90 0.06-0.5 mg/L; MBC90 0.125-2.0 mg/L) . However, higher MIC90S and MBC90S of these quinolones were obtained for strains of multi-drug resistant M . tuberculosis . The macrolides tested had poor activity against M . tuberculosis isolates (MIC90 > 8.0 mg/L) . Furthermore, high MIC90S of the quinolones and macrolides (2.0 to 8.0 mg/L) were obtained for clinical isolates of atypical mycobacteria, with the exception of clarithromycin against M . kansasii (MIC90 = 1.0 mg/L) and sparfloxacin against M . scrofulaceum (MIC90 = 1.0 mg/L).

Scand J Gastroenterol, 1994 Sep, 29(9), 807 - 13
Effect of erythromycin administration on upper gastrointestinal motility in scleroderma patients; Fiorucci S et al.; BACKGROUND: Gastrointestinal involvement is frequent in patients with scleroderma . Erythromycin, a macrolide antibiotic, has been shown to accelerate gastric emptying in normal subjects and diabetic patients . The present study investigated the effects of acute erythromycin administration on gastric and gallbladder motility in patients with scleroderma and gastrointestinal involvement . METHODS: Twelve scleroderma patients and 14 healthy subjects were investigated . Each subject was investigated on 4 different days . Gastric and gallbladder emptying and gastric motility were determined by sonography and manometry, and the effect of 2 mg/kg/h erythromycin in fasted patients or after semisolid meal evaluated . RESULTS: The half-time of gastric emptying in response to semisolid meal was 121.3 +/- 14.0 min (SE) in scleroderma patients and 45.7 +/- 10.4 min in healthy subjects (P < 0.01) . The peak of gallbladder emptying occurred later in scleroderma patients (95.0 +/- 5.0 min) than in healthy subjects (45.0 +/- 8.0 min) (P < 0.01) . Erythromycin stimulated gastric and gallbladder motility in fasted subjects, as shown by manometry and sonography, and accelerated gastric and gallbladder emptying when administered immediately before the meal (P < 0.01) . CONCLUSIONS: Erythromycin accelerates gastric and gallbladder emptying in scleroderma patients and might be helpful in the treatment of gastrointestinal motor abnormalities in these patients.

Pharm Res, 1994 Sep, 11(9), 1330 - 6
Comparison of single and multiple dose pharmacokinetics using clinical bioequivalence data and Monte Carlo simulations; el-Tahtawy AA et al.; The purpose of this study was to evaluate the relative performance and usefulness of single dose (SD) and multiple dose (MD) regimens for bioequivalence (BE) determination . Drugs such as indomethacin, procainamide, erythromycin, quinidine, nifedipine were tested for BE under SD and MD dose regimens . Drugs characterized by low accumulation indices (AI) showed virtually no change in the 90% confidence interval (CI) of AUC and CMAX upon multiple dosing . On the other hand, drugs with higher AI appeared to have smaller CI at steady-state . For example, the CI range of AUC and CMAX of quinidine (AI of 1.54) decreased from 26 to 12 and from 22 to 12, respectively, upon multiple dosing . A Monte Carlo simulation study of SD and MD bioequivalence trials was performed . The probability of failing the bioequivalence test was evaluated for several situations defined by different levels of variability and correlation in ka constants, presence or absence of inter- and/or intra-individual variability in clearance (CL) and volume of distribution (V), and different degrees of accumulation . All the possible combinations of these factors were tested with SD and MD study designs . All simulations used 1000 data sets with 30 subjects in each data set for a total of 144 unique designs (total of 144,000 simulations of bioequivalence trials) . Upon multiple dosing, narrowing of CI ranges was observed for drugs simulated to have high AI high variability and a large difference in absorption constants (ka) between test and reference formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Clin Ter, 1994 Sep, 145(9), 223 - 9
{Allergy in pregnancy}; Di Lorenzo G et al.; During pregnancy, the ideal would be to abstain from the use of any drug, at least during the first three months . In fact, none of the drugs currently used for the therapy of allergies has been classified by the FDA and European Commission on the basis of controlled human and animal studies as completely negative from the point of view of untoward effects in pregnancy . The following are considered comparatively safe: disodium cromoglycate, diphenhydramine, chlorpheniramine, hydroxyzine, mebhydroline, brompheniramine, inhaled beta 2-agonists, xanthine bronchodilators, pseudoephedrine, and topical nasal treatment with beclomethasone dipropionate in the last trimenon . On the contrary, specific immunotherapy is inadvisable . In the case of anaphylaxis, epinephrine and ephedrine are drugs of choice, while in asthma monitoring of PEFR is essential for appropriate management . For rhinitis, DSCG and beclomethasone diproprionate appear to he comparatively safe . For urticaria, hydroxyzine or possibly ephedrine should be preferred . In case of a history of untoward drug effects, oral antibiotics should be preferred (erythromycin or micamycin); for atopic dermatitis the preference is for topical treatment with hydrocortisone.

Am J Ophthalmol, 1994 Aug 15, 118(2), 152 - 7
Bacillary angiomatosis of the conjunctiva; Lee WR et al.; A 70-year-old man had unilateral congestion of the right upper eyelid, which contained a nodular mass . A biopsy was performed, and histologic, immunocytochemical, and ultrastructural studies disclosed a pseudoneoplastic proliferation of endothelial cells and pericytes in a region containing clumps of bacteria . This combination of histologic features is characteristic of bacillary angiomatosis, which has been described in the skin, particularly in association with immunodeficient states, especially acquired immunodeficiency syndrome, but not in the conjunctiva . A second biopsy contained a diffuse polyclonal lymphocytic infiltrate in which large lymphocytes with irregular nuclei and mitotic figures were prominent . Systemic examination disclosed mild splenomegaly and a benign paraproteinemia . Treatment with topical gentamicin and systemic erythromycin brought about a complete resolution of the symptoms and signs within eight weeks, and there has been no sign of recurrence for the past two years.

Food Chem Toxicol, 1994 Aug, 32(8), 735 - 42
Effects of beta-carotene and canthaxanthin on liver xenobiotic-metabolizing enzymes in the rat; Astorg P et al.; The activities of several phase I and phase II xenobiotic-metabolizing enzymes have been measured in liver microsomes and cytosol of male rats that had been fed for 15 days with diets containing beta-carotene or canthaxanthin (300 mg/kg diet) or an excess of vitamin A (70,000 IU/kg diet), or to which beta-carotene had been administered by ip injections (7 x 10 mg/kg body weight) . Microsomal cytochrome P-450 and the associated NADH- and NADPH-cytochrome c reductases were assayed, as well as several phase I and phase II enzyme activities . Phase I activities were markers of the families 1, 2, 3 and 4 of P-450; phase II activities were microsomal UDP glucuronosyl transferases (UGT) and cytosolic glutathione S-transferase (GST) . Canthaxanthin accumulated in liver to a much higher level than did ingested or injected beta-carotene . Canthaxanthin increased the liver content of cytochrome P-450 (control value x 1.7), and the activity of NADH-cytochrome c reductase (x 1.5), and of some P-450-dependent enzymes (ethoxy-, methoxy-, pentoxy- and benzoxyresorufin O-dealkylases; x98, x15, x6.5 and x13, respectively), but not of others (erythromycin N-demethylase, nitrosodimethylamine N-demethylase and laurate omega-hydroxylase) . Phase II activities were also increased: UGT1 (x3.4), UGT2 (x1.2) and GST (x1.2) . This induction profile, characterized by the very strong increase of the activity associated with P4501A1, and the co-induction of UGT1, closely resemble that of a classical inducer, 3-methylcholanthrene . By contrast, neither beta-carotene (fed or injected), nor an excess of vitamin A induced any significant variation of the enzyme activities measured.

Toxicol Appl Pharmacol, 1994 Aug, 127(2), 222 - 32
Characterization of rat cytochrome P450 isozymes involved in the covalent binding of cyclosporin A to microsomal proteins; Sadrieh N et al.; Cyclosporin A (CsA) is an immunosuppressant drug which is extensively metabolized by the hepatic microsomal monooxygenases . Among other toxicities, CsA is nephrotoxic and hepatotoxic . In the present study, the NADPH-dependent cytochrome P450-supported metabolism of CsA to reactive metabolite(s) capable of covalently binding to proteins was studied . The covalent binding was inhibitable in vitro with classical cytochrome P450 inhibitors . The covalent binding of CsA metabolite(s) was induced six- to eightfold in liver microsomes from rats of both sexes treated with dexamethasone, suggesting that a P450 3A-related protein was involved in the covalent binding of CsA metabolite(s) . However, the isozyme responsible was not P450 3A1 or 3A2, since inhibitory monoclonal antibodies to these isozymes did not inhibit the covalent binding . The binding was, however, inhibitable in vitro with cytochrome P450 3A substrates and inhibitors such as erythromycin and triacetyloleandomycin . Greater amounts of CsA covalent binding occurred in liver microsomes from adult uninduced female rats than males or immature rats of either sex . Therefore, a female-specific isozyme of P450 present in adult female rat liver microsomes, which may or may not be identical to a dexamethasone-inducible isozyme, is also involved in the metabolism of CsA to form covalent binding metabolites . The covalent binding of CsA was 50% inhibited by glutathione . However, mannitol and superoxide dismutase did not affect the binding . This suggested that at least some of the metabolites of CsA involved in covalent binding were electrophilic in nature; however, hydroxyl radicals and superoxide anion radicals were not involved.

Res Commun Mol Pathol Pharmacol, 1994 Aug, 85(2), 181 - 92
Erythromycin inhibits cholinergic neuro-effector transmission in canine airway smooth muscle; Tagaya E et al.; To elucidate whether macrolide antibiotics affect cholinergic neuro-effector transmission in the airway, we studied canine isolated bronchial segments under isometric conditions in vitro . Addition of erythromycin (3 x 10(-4) M) attenuated the contractile responses to electrical field stimulation (EFS), so that the stimulus frequency required to produce a half-maximal contraction (ES50) increased from 1.3 +/- 0.3 to 5.1 +/- 0.5 Hz (p < 0.001) . This effect was concentration-dependent and not influenced by propranolol, indomethacin, ouabain or mechanical removal of the epithelium . In contrast, contractile responses to acetylcholine were not altered by erythromycin . These results suggest that erythromycin may inhibit neuro-effector transmission in the airway cholinergic motor pathway, probably involving the reduction of exocytotic release of acetylcholine from the nerve terminals.

Pharmacol Biochem Behav, 1994 Aug, 48(4), 983 - 90
Modulators of the adenylate cyclase system can alter electrophysiological taste responses in gerbil; Schiffman SS et al.; The adenylate cyclase system has been implicated in taste transduction . The purpose of this study was to determine whether application of modulators of the adenylate cyclase system to the tongue alter taste responses . Integrated chorda tympani (CT) recordings were made in gerbils to bitter, sweet, salty, sour, and glutamate tastants before and after a 4-min application of four types of modulators of the adenylate cyclase system . The four types of modulators tested were: a) NaF, a compound that promotes dissociation of GTP binding protein; b) forskolin, a powerful stimulant of adenylate cyclase; c) 8-bromoadenosine 3' :5'-cyclic monophosphate sodium salt (8BrcAMP) and N6,2'-O-dibutyryl-adenosine 3' :5'-cyclic monophosphate sodium salt (DBcAMP), two membrane permeable forms of cAMP; and d) 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride (H-7) and N-(2-{methylamino}ethyl)-5-isoquinolinesulfonamide dihydrochloride) (H-8), which are protein kinase inhibitors . The tast compounds tested were: NaCl (30 mM), monosodium glutamate-MSG (50 mM), sucrose (30 mM), HCl (5 mM and 10 mM), KCl (300 mM), quinine HCl (30 mM), MgCl2 (30 mM), erythromycin (0.7 mM and 1 mM), HCl (5 mM and 10 mM), and urea (2 M) . The main findings were as follows . NaF (20 mM) significantly inhibited responses to bitter compounds up to 35% and enhanced the response to sucrose by 30% . NaCl (20 mM), used as a control for NaF, inhibited most responses up to 78% with no enhancement of sucrose as seen with NaF . 8BrcAMP (1.16 mM) reduced the responses to bitter-tasting quinine HCl, MgCl2, and erythromycin but not to urea.(ABSTRACT TRUNCATED AT 250 WORDS)

J Vet Pharmacol Ther, 1994 Aug, 17(4), 317 - 22
Tiamulin selectively inhibits oxidative hepatic steroid and drug metabolism in vitro in the pig; Witkamp RF et al.; The simultaneous use of the antibiotic tiamulin with certain ionophoric antibiotics (monensin, salinomycin) may give rise to a toxic interaction in pigs and poultry . In the present study, effects of tiamulin on hepatic cytochrome P450 activities in vitro were studied using pig liver microsomes . When tiamulin was added to the incubation medium the N-demethylation rate of ethylmorphine and the hydroxylation of testosterone at the 6 beta- and 11 alpha-positions was strongly inhibited . Tiamulin inhibited these activities more than SKF525A or cimetidine, but less than ketoconazole . The microsomal N-demethylation rate of erythromycin and the hydroxylation of testosterone at the 2 beta-position were inhibited to a lesser degree, whereas the ethoxyresorufin-O-deethylation, aniline hydroxylation and testosterone hydroxylations at the 15 alpha- and 15 beta-positions were not affected by tiamulin . No in vitro complexation by tiamulin of cytochrome P450 resulting in a loss of CO-binding capacity could be demonstrated . Results from the present study suggest a selective inhibition of cytochrome P450 enzymes in pigs, probably belonging to the P4503A subfamily . The mechanism of this interaction is still unclear . However, interactions between tiamulin and those veterinary drugs or endogenous compounds which undergo oxidative metabolism by P450 enzymes must be considered . More research is needed to reveal which of the P450 enzymes are affected by tiamulin in order to improve the understanding and probably the predictability of this interaction.

Biochem Mol Biol Int, 1994 Aug, 33(6), 1135 - 43
Induction of hepatic microsomal cytochrome P450 by dexamethasone in rhesus monkey (Macaca mulatta); Ojha V et al.; Intraperitoneal administration of 150 mg dexamethasone (DEX) Kg-1 body wt for four days to rhesus monkeys resulted in statistically significant increases in the activities of hepatic tyrosine aminotransferase (3 fold), microsomal cytochrome P450 (2 fold) and erythromycin N-demethylase (4 fold), but no change in the activities of aminopyrine N-demethylase and NADPH cytochrome c reductase . Three peaks were obtained from control or DEX-treated monkey livers on fractionation of detergent solubilized microsomes by anion exchange chromatography on DE-52 . Peak II obtained from DEX-treated monkey microsomes on DE-52 demonstrated the highest specific activity of cytochrome P450 (5.84 nmol mg-1 protein) as compared to other peaks from the same microsomes or any of the peaks obtained from the control microsomes . Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the microsomes from control and experimental animals and peak II obtained after anion exchange chromatography of DEX-treated microsomes demonstrated the intensification of two polypeptides of 52.5 and 50 kDa . The results indicate that DEX is an inducer of cytochrome P450 and dependent erythromycin N-demethylase in non-human primate, Macaca mulatta.

Hepatology, 1994 Aug, 20(2), 309 - 16
Importance of cytochrome P-450IIIA activity in determining dosage and blood levels of FK 506 and cyclosporine in liver transplant recipients; Cakaloglu Y et al.; We have investigated the importance of cytochrome P-450IIIA enzyme activity in influencing dosage of the immunosuppressive drugs FK 506 and cyclosporine after liver transplantation . Cytochrome P-450IIIA enzyme activity in vivo was measured 1 yr postoperatively in 37 stable orthotopic liver graft recipients (21 receiving FK 506 and 16 given cyclosporine) by the erythromycin breath test and the production of monoethylglycinexylidide from lignocaine . A strong correlation existed between FK 506 dose and erythromycin breath test results (r = 0.583, p < 0.007), but no corresponding relationship with monoethylglycinexylidide production was observed . The FK 506 dose (14 to 196 micrograms/kg/day) also correlated closely with circulating predose levels of the drug in both plasma and blood (r = 0.538 and 0.731, p = 0.015 and < 0.001, respectively) . Although no correlation existed between cyclosporine dose (0.254 to 0.494 mg/kg/day) and trough blood levels, a relationship was demonstrated when erythromycin breath test results were included in the derived equation: Drug dose/cytochrome P-450IIIA activity alpha drug level (p = 0.011 vs . 0.175 without erythromycin breath test) . A corresponding enhancement was demonstrated with erythromycin breath test results to relate FK 506 dose and plasma levels (p = 0.006 versus 0.015 without erythromycin breath test results), although breath test results and FK 506 levels were highly discordant (p > 0.8) . The use of monoethylglycinexylidide test results as an alternative measure of cytochrome P-450IIIA activity provided no comparable increase in correlation for FK 506 or cyclosporine.(ABSTRACT TRUNCATED AT 250 WORDS)

Science, 1994 Jul 22, 265(5171), 509 - 12
Engineered biosynthesis of a complete macrolactone in a heterologous host; Kao CM et al.; Macrocyclic polyketides have been subjects of great interest in synthetic and biosynthetic chemistry because of their structural complexity and medicinal activities . With expression of the entire 6-deoxyerythronolide B synthase (DEBS) (10,283 amino acids) in a heterologous host, substantial quantities of 6-deoxyerythronolide B (6dEB), the aglycone of the macrolide antibiotic erythromycin, and 8,8a-deoxyoleandolide, a 14-membered lactone ring identical to 6dEB except for a methyl group side chain in place of an ethyl unit, were synthesized in Streptomyces coelicolor . The biosynthetic strategy utilizes a genetic approach that facilitates rapid structural manipulation of DEBS or other modular polyketide synthases (PKSs), including those found in actinomycetes with poorly developed genetic methods . From a technological viewpoint, this approach should allow the rational design of biosynthetic products and may eventually lead to the generation of diverse polyketide libraries by means of combinatorial cloning of naturally occurring and mutant PKS modules.

J Chromatogr A, 1994 Jul 15, 674(1-2), 153 - 63
Chemical profiling of pharmaceuticals by capillary electrophoresis in the determination of drug origin; Flurer CL et al.; Capillary electrophoresis has been utilized to detect trace components in bulk pharmaceutical products, with emphasis on the identification of differences among manufacturers that can be used for source verification in suspect/counterfeit cases . Micellar electrokinetic capillary chromatography with sodium dodecyl sulfate was used in the analyses of beta-lactam antibiotics . The aminoglycoside clindamycin phosphate and the macrolide erythromycin stearate were analyzed using borate buffers with direct UV detection . Methyl-beta-cyclodextrin was used as a buffer additive in the erythromycin studies . Determination of product potency using peak area ratios has been demonstrated for ampicillin and clindamycin phosphate.

J Biol Chem, 1994 Jul 15, 269(28), 18378 - 83
Substrate-regulated, cAMP-dependent phosphorylation, denaturation, and degradation of glucocorticoid-inducible rat liver cytochrome P450 3A1; Eliasson E et al.; The major rat glucocorticoid-inducible cytochrome P450 (CYP3A1) is known to be regulated at a transcriptional level by glucocorticoids and at a post-translational level by substrate-dependent stabilization . We have investigated mechanisms of substrate/ligand stabilization using primary hepatocytes, isolated liver microsomes from dexamethasone-treated rats, and purified enzymes . Treatment of hepatocytes with glucagon caused a 3-fold increase in CYP3A1 phosphorylation as well as an enhanced degradation rate of the enzyme . Specific CYP3A1 substrates or ligands, such as erythromycin, triacetyloleandomycin, and clotrimazole (CTZ) protected the enzyme from degradation in hepatocytes and inhibited in a concomitant manner (r = 0.99) glucagon-induced phosphorylation of the enzyme . In vitro experiments with purified CYP3A1 and isolated liver microsomes revealed one major site (Ser393) phosphorylated by the catalytic subunit of cAMP-dependent kinase, a reaction inhibited by ligands . Experiments in microsomes showed the presence of an endogenous cAMP-dependent kinase active on CYP3A1 . Addition of exogenous cAMP-dependent kinase increased the rate of microsomal CYP3A1 phosphorylation, a reaction further stimulated by NADPH, but inhibited by CTZ . The microsomal phosphorylation caused a pronounced denaturation of cytochrome P450, as revealed spectrophotometrically, whereas CTZ protected from this reaction . Similar effects were noted when the CYP3A1-dependent 6 beta-hydroxylation of testosterone was monitored . It is suggested that the cellular CYP3A1 level is regulated to a significant extent posttranslationally by substrate-regulated cAMP-dependent phosphorylation on Ser393, followed by denaturation and degradation in the endoplasmic reticulum.

Biochem Pharmacol, 1994 Jul 5, 48(1), 197 - 200
Comparison of levels of aldehyde oxidase with cytochrome P450 activities in human liver in vitro; Rodrigues AD; Microsomal suspensions and 9000 g supernatant (S-9) fractions were prepared from the liver tissue of six human multiorgan donors . The S-9 fractions were characterized for cytosolic aldehyde oxidase (AO) activity, using three different substrates {N1-methylnicotinamide (NMN), benzaldehyde and 6-methylpurine} . In addition, human liver NMN oxidase activity was compared with that detected in rat, dog and monkey liver S-9 fractions . As expected, the rank order of NMN oxidase activity was monkey > rat > dog, and in five out of six subjects the activity was lowest in humans (< 2.0 nmol/min/mg) . The variation in AO activity among the various human livers was greater for NMN oxidase (> 40 fold) than for 6-methylpurine and benzaldehyde oxidase (< or = 3.6 fold) activity . The corresponding microsomal preparations were characterized with respect to the levels of total cytochrome P450 (CYP) and six CYP-dependent mixed-function monooxygenase (MFO) activities . The variation was greatest for dextromethorphan O-demethylase (CYP2D6) and lowest for N,N-dimethylnitrosamine N-demethylase (CYP2E1) activity (147- vs . 1.4-fold) . The inter-sample variation for the total CYP, CYP3A (erythromycin N-demethylase), CYP1A2 (7-ethoxyresorufin O-deethylase), CYP2A6 (coumarin 7-hydroxylase) and CYP2C9/10 (tolbutamide 4-methyl hydroxylase) was 2.2- to 5.3-fold . Furthermore, the levels of AO activity did not correlate with total (spectrally detectable) CYP or any of the CYP form-selective MFO activities.

Biochem Pharmacol, 1994 Jul 5, 48(1), 173 - 82
Characterization of dextromethorphan N-demethylation by human liver microsomes . Contribution of the cytochrome P450 3A (CYP3A) subfamily; Gorski JC et al.; In an effort to identify the human cytochromes P450 involved in the N-demethylation of dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems . Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microsomes obtained from three human livers (Km: 0.52-0.71 mM; Vmax: 375-812 pmol/mg protein/min) . B-lymphoblastoid cells expressing CYP3A4 incubated with 0.4 mM dextromethorphan catalyzed the formation of 3-methoxymorphinan at a rate of 22 pmol product/mg protein/min . Midazolam, a prototypic substrate for CYP3A4 and CYP3A5, competitively inhibited dextromethorphan N-demethylation by two human liver microsomal samples with Ki values of 46 +/- 10 and 63 +/- 8 microM . At a dextromethorphan concentration of 0.4 mM, gestodene (100 microM) inhibited 3-methoxymorphinan formation by approximately 50% . Immunoinhibition of dextromethorphan N-demethylation using rabbit anti-CYP3A4 antibodies resulted in a 60% decrease in 3-methoxymorphinan formation at a dextromethorphan concentration of 0.4 mM . Additional inhibition studies using furafylline, coumarin, sulfaphenazole, mephenytoin, quinidine, and diethyldithiocarbamic acid, which are selective inhibitors of CYP1A2, CYP2A6, CYP2C8/9, CYP2Cmp, CYP2D6, and CYP2E1, respectively, demonstrated no substantial inhibition of dextromethorphan N-demethylation . Correlation analysis was performed using the rate of 3-methoxymorphinan formation at a concentration of 1 mM dextromethorphan and immunoquantified levels of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 and their associated characteristic catalytic activities . A significant correlation was observed between dextromethorphan N-demethylase activity and midazolam 1'- and 4-hydroxylase activity (r2 = 0.77 and 0.69 respectively, N = 19, P < 0.01); the exclusion of those samples containing both CYP3A4 and CYP3A5 increased the correlation significantly (r2 = 0.87 and 0.91 respectively, N = 12, P < 0.01) . In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2 = 0.94, N = 12, P < 0.01), testosterone 6 beta-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01) . Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation . No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed . In conclusion, dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans.(ABSTRACT TRUNCATED AT 400 WORDS)

Rinsho Ketsueki, 1994 Jul, 35(7), 699 - 703
{Pure red cell aplasia induced by erythromycin and furosemide effects on in vitro erythroid colony forming unit (CFU-E)}; Fujiwara H et al.; A 84-year-old man was treated with antibiotics including erythromycin and a diuretic (furosemide) because of acute heart failure and pneumonia . During the treatment, he developed moderate anemia (Hb 8.7g/dl) . His anemia improved after the treatment . He again developed marked anemia (Hb 6.3g/dl) during the second treatment with erythromycin and furosemide and received blood transfusions . Bone marrow aspiration study revealed severe erythroid hypoplasia (0.2%) . He was referred to our hospital, but he was not treated because his hemoglobin levels and reticulocyte count increased (80%) and his bone marrow showed increased erythroblasts (41.5%) . His anemia gradually improved without any treatment . We diagnosed the case as drug-induced pure red cell aplasia (PRCA) . We cultured bone marrow cells obtained from the present case and four normal healthy volunteers by a plasma clot method to determine the effects of two drugs on the number of erythroid colony forming unit (CFU-E) . Furosemide strongly inhibited the CFU-E colony formation in the patient, but the inhibition effect of erythromycin was moderate . Furthermore, CFU-E was markedly suppressed by a combination of erythromycin and furosemide in both patient and control materials . These results indicate that both furosemide and erythromycin were related to the occurrence of PRCA in this patient.

Dig Dis Sci, 1994 Jul, 39(7), 1399 - 404
Effect of erythromycin on antroduodenal motility in children with chronic functional gastrointestinal symptoms; Di Lorenzo C et al.; To evaluate the effects of erythromycin on antroduodenal motility in children with chronic functional gastrointestinal symptoms, we studied 35 consecutive subjects referred for diagnostic motility studies . We recorded fasting motility for > 4 hr, then infused in random order either 1 or 3 mg/kg erythromycin intravenously over 1 hr and continued the study for another hour . Erythromycin induced phase III in 18 of 20 children who had phase III during fasting compared to only one of 15 who did not (P < 0.001) . The antral motility index increased after erythromycin (1596 +/- 323 vs 436 +/- 242 mm Hg/30 min before erythromycin, P < 0.005) but the duodenal motility index did not change . The antral motility index was greater in children receiving 3 mg/kg than in those receiving 1 mg/kg (1968 +/- 391 vs 1226 +/- 285 mm Hg/30 min, P < 0.01), but duodenal motility indices did not differ . Only one child receiving the lower dose erythromycin complained of abdominal pain, nausea, or vomiting vs 9 of 19 the children receiving the higher dose (P < 0.02) . In summary, in children with chronic functional gastrointestinal disorders, erythromycin rarely induced phase III in patients who did not have it during fasting . When different doses erythromycin are compared, 1 and 3 mg/kg are equally efficacious in inducing phase III episodes; the lower dose is associated with fewer side effects and the higher dose produces a higher antral motility index.

Arch Pediatr Adolesc Med, 1994 Jul, 148(7), 727 - 32
The association of Chlamydia pneumoniae infection and reactive airway disease in children; Emre U et al.; OBJECTIVE: To determine the possible association of Chlamydia pneumoniae infection and reactive airway disease in children . DESIGN: Prospective observational study . SETTING: Pediatric emergency department in Children's Medical Center of Brooklyn (NY), Kings County Hospital Center . PARTICIPANTS: One hundred eighteen children with acute episodes of wheezing and 41 age- and sex-matched healthy controls, aged 5 to 16 years . INTERVENTIONS: Children with cultures positive for C pneumoniae were treated with antibiotics . MEASUREMENTS/MAIN RESULTS: Cultures for C pneumoniae and serum samples for antibody testing were obtained from subjects and healthy controls . We isolated C pneumoniae from 13 (11%) children with wheezing and from two (4.9%) controls . Seven (58.3%) of 12 children with positive cultures had no detectable antibody to C pneumoniae and only three (25%) children had serologic evidence of acute infection . Six children had positive cultures on multiple occasions, ranging from 1 to 5 months . The children with wheezing were treated with erythromycin or clarithromycin, a new macrolide antibiotic approved for use in adults; all eventually had a negative culture . Nine (75%) of these children demonstrated clinical and laboratory improvement of the reactive airway disease after the eradication of chlamydial infection . CONCLUSIONS: Infection with C pneumoniae can trigger acute episodes of wheezing in children with asthma . Treatment of C pneumoniae infection may improve the course of reactive airway disease in these patients.

Obstet Gynecol, 1994 Jul, 84(1), 61 - 3
Azithromycin and erythromycin in the treatment of cervical chlamydial infection during pregnancy; Bush MR et al.; OBJECTIVE: To compare azithromycin and erythromycin in regard to side effects, intolerance, and cure rate in a pregnant population with chlamydial cervicitis . METHODS: Thirty women were randomized to receive either erythromycin, 500 mg orally four times a day for 7 days, or azithromycin, 1 g orally as one dose . All subjects completed questionnaires identifying the incidence of nausea, vomiting, diarrhea, abdominal pain, and anorexia . Post-treatment cultures were taken from all subjects . RESULTS: All subjects receiving erythromycin reported two or more gastrointestinal side effects, versus none in the azithromycin group (P < .001) . Five of 15 subjects in the erythromycin treatment arm were intolerant to the 500-mg dose given four times a day, compared to none in the azithromycin group (P < .025), so the dosage was lowered to 250 mg four times a day to complete the course . Repeat cervical testing demonstrated similar cure rates for both medications: 100 and 93% (14 of 15) for azithromycin and erythromycin, respectively . CONCLUSION: These data suggest that azithromycin is a valid treatment option in pregnant patients who cannot tolerate erythromycin because of side effects.

Infection, 1994 Jul-Aug, 22(4), 242 - 6
Early- and late-onset pelvic inflammatory disease among women with cervical Chlamydia trachomatis infection at the time of induced abortion--a follow-up study; Sorensen JL et al.; After termination of a double-blind, randomized study on erythromycin in the prevention of post-abortion infection, 34 women (14 treated with erythromycin, 20 not treated with erythromycin) harbouring Chlamydia trachomatis were followed up within 6 weeks and again 2 to 24 months after the abortion in order to detect an early- and late-onset pelvic inflammatory disease (PID) . For statistical analysis survival analysis by Kaplan-Meir estimates and Mantel-Cox test were carried out . Untreated women with C . trachomatis infection at the time of abortion had a cumulative risk of 72% of developing early and/or late PID, if observed for 24 months . This cumulative risk was significantly reduced to 8% if the C . trachomatis infection was treated at the time of the abortion . Screening for and treatment of C . trachomatis is warranted, especially in women < or = 25 years old, to avoid early and late-onset PID after induced first trimester abortion.

Cir Pediatr, 1994 Jul, 7(3), 115 - 20
{Intestinal pseudo-obstruction secondary to systemic neuropathies and myopathies}; Garcia Aroca J et al.; The term intestinal pseudo-obstruction, is applied to a group of clinical disorders in which there are obstructive symptoms, in the absence of a mechanical agent, secondary to a disorder of intestinal motility . In this report, we show manometric studies done in four patients, with acute intestinal pseudo-obstructions, secondary to von Recklinghausen's neurofibromatosis (VRNF), in two patients, and in one patient with Duchenne's muscular dystrophy (DMD) and in another with Werdnig-Hoffmann's disease (WHD) . We studied 24 hours antroduodenal motility, specially during phase 3 of the migratory motor complex (CMM), which showed a neuropathic disorder in one case of von Recklinghausen's disease and a myopathic disorder in patients with Duchenne's muscular dystrophy and Werdnig-Hoffmann's disease . We analysed results and conclusions and specially the kinetic action of erythromycin.

J Endod, 1994 Jul, 20(7), 345 - 54
Effectiveness of various medications on postoperative pain following complete instrumentation; Torabinejad M et al.; The root canals of 588 consecutive nonsurgical patients with varying levels of pain were completely instrumented in 10 endodontic practices and 4 endodontic graduate programs . The participants were sequentially assigned to one of nine medications and a placebo . The severity of pain was assessed by the visual analog scale for 72 h following instrumentation . Among all of the parameters studied, three factors (preoperative pain, apprehension, and types of medication) were found to be significant in determining postinstrumentation pain . An association was found between the intensity of pre-and postoperative pain . As the intensity of preoperative pain increased, the chances for more severe postoperative pain increased (p < 0.0001) . In addition, an association between the presence of apprehension before any treatment and postoperative pain was also noted (between 0.012 < p < 0.047) . Examination of the time-effect curves for various medications in patients with no mild pain showed no statistical significant difference between the effectiveness of different medications and placebo . However, a multiple comparison of the effectiveness of various medications and placebo on patients in moderate and severe preoperative pain showed that ibuprofen, ketoprofen, erythromycin base, penicillin, and methylprednisolone plus penicillin were more effective than placebo within the first 48 h following complete instrumentation.

Mol Microbiol, 1994 Jul, 13(2), 349 - 55
Analysis of five tylosin biosynthetic genes from the tyllBA region of the Streptomyces fradiae genome; Merson-Davies LA et al.; The tyllBA region of the tylosin biosynthetic gene cluster of Streptomyces fradiae contains at least five open reading frames (ORFs) . ORF1 (tylI) encodes a cytochrome P450 and mutations in this gene affect macrolide ring hydroxylation . The product of ORF2 (tylB) belongs to a widespread family of proteins whose functions are speculative, although tylB mutants are defective in the biosynthesis or addition of mycaminose during tylosin production . ORFs 3 and 4 (tylA1 and tylA2) encode delta TDP-glucose synthase and delta TDP-glucose dehydratase, respectively, enzymes responsible for the first two steps common to the biosynthesis of all three deoxyhexose sugars of tylosin via the common intermediate, delta TDP-4-keto, 6-deoxyglucose . ORF5 encodes a thioesterase similar to one encoded in the erythromycin gene cluster of Saccharopolyspora erythraea.

Antimicrob Agents Chemother, 1994 Jul, 38(7), 1548 - 54
Effects of dirithromycin and erythromycylamine on human neutrophil degranulation; Abdelghaffar H et al.; Dirithromycin and, to a lesser extent, erythromycylamine and erythromycin directly induced the release of three intragranular enzymes (lysozyme, lactoferrin, and beta-glucuronidase) from unstimulated human neutrophils . Macrolide-induced enzyme release was dependent upon the incubation time (30 to 180 min) and drug concentration . Dirithromycin was the most effective . At 120 min, release of lysozyme, beta-glucuronidase, and lactoferrin by macrolide (100 micrograms/ml)-treated cells, expressed as a percentage of total enzyme content, was, respectively, 58% +/- 8.3%, 52% +/- 10.7%, and 35% +/- 5.1% (dirithromycin); 42% +/- 3.9%, 28% +/- 5.8%, and 10% +/- 2.2% (erythromycylamine); and 35% +/- 4.0%, 19% +/- 4.3%, and 10% +/- 5.2% (erythromycin) (mean +/- standard error of the mean of three to eight experiments) . The lowest macrolide concentrations which induced significant enzyme release were 10, 100, and 25 micrograms/ml, respectively, for dirithromycin, erythromycylamine, and erythromycin . Furthermore, we obtained evidence of a link between the prodegranulation effects of dirithromycin and erythromycylamine and the intragranular location of these drugs . Indeed, cell-associated drug levels increased for up to 60 min and then plateaued and declined substantially . Increasing the pH from 7 to 9 resulted in a parallel increase in drug uptake and the prodegranulation effect . Finally, when macrolide-treated neutrophils were disrupted by sonication and centrifuged, a correlation was found between lysozyme and beta-glucuronidase activities (both granule markers) and pellet-associated macrolide levels . Taken together, our results suggest that dirithromycin and erythromycylamine concentrate within neutrophil granules and then induce degranulation.

Res Commun Mol Pathol Pharmacol, 1994 Jul, 85(1), 67 - 72
Influence of mercury and cadmium intoxication on hepatic microsomal CYP2E and CYP3A subfamilies; Alexidis AN et al.; The effects of subchronic mercuric acetate and of acute mercuric acetate and cadmium chloride administration to rat hepatic microsomal protein and total cytochrome P450, as well as on p-nitrophenol hydroxylase (CYP2E) and erythromycin N-demethylase (CYP3A) activities were examined . It was found that Hg2+ and Cd2+ intoxication resulted in a significant decrease of total cytochrome P450 content . Acute Hg2+ and Cd2+ exposure decreased microsomal protein level . These metals also reduced CYP2E1 activity, while they did not seem to alter CYP3A1-mediated drug metabolism . This effect on CYP2E1 may be connected to free radical generation during Hg2+ and Cd2+ intoxication . Investigation is in progress using more P450 markers for elucidation of the effect of Hg2+ and Cd2+ on P450 activities.

Ital J Gastroenterol, 1994 Jul-Aug, 26(6), 306 - 17
The aminopyrine breath test; Perri F et al.; The metabolic basis and clinical application of the aminopyrine breath test (ABT) as a measure of liver function is reviewed in this article . Several papers have been published in the 20 years that have elapsed since the test was validated in man by Hepner and Vesell . Nevertheless, even if the aminopyrine breath test has been shown to be a non-invasive, reliable and semiquantitative liver function test with diagnostic and prognostic accuracy, it is not yet extensively used in clinical practice, probably because it is not widely known to clinicians . The aminopyrine breath test, like other newer tests (phenacetin, caffeine and erythromycin breath tests), allows the effects of drugs on hepatic cytochrome P-450 to be explored both in normal subjects and in liver patients . This interesting field of application is sure to expand the appeal of the aminopyrine breath test in the future.

G Ital Cardiol, 1994 Jul, 24(7), 853 - 68
{Sampling study on practitioners' attitude to the prevention of infectious endocarditis}; Crociani P et al.; BACKGROUNDS AND METHODS . The opinions and the experience of Veneto practitioners about prevention of infective endocarditis were detected through a sample survey among the 386 practitioners of Health and Social Unit Nr 16, 17, and 36 of Veneto Region . The interview was carried out through a questionnaire, sent by mail, asking for: 1) general information on the practitioner's profession; 2) information about the previous experience in diagnosis and care of heart diseases, particularly of infective endocarditis, of atrial septal defect ostium secundum type without pulmonary hypertension, of unstable angina, and moderate mitral stenosis; 4) attitudes in the prevention of infective endocarditis . Of 386 practitioners surveyed, 186 (48.2%) responded . More than 60% of the responders held a diploma of specialization and 7% were cardiologists, half of the responders had worked in public hospitals . The 63.8% of the practitioners had patients over sixty in a percentage of 15-44% . In 1990 only 5.9% of the practitioners observed new cases of infective endocarditis, while half of them stated that some of their patients had suffered from this disease in the past . RESULTS . The assessment of the level of severity for every heart disease is ranged between 0 (the minimum) and 10 (the maximum) . The statistical analysis showed that the minimum arithmetic mean (+/- SD) is given for atrial septal defect without pulmonary hypertension with 4.6 +/- 2 . Then for moderate mitral stenosis with 7.1 +/- 1.6, unstable angina pectoris with 7.4 +/- 2 and the maximum mean is given for infectious endocarditis with 8 +/- 1.7 . ANOVA statistical analysis applied on the four paired series of assessment of severity carried out a high significant difference (F of Snedecor = 328.2; P < 0.001) among assessments, and among practitioners (F = 1.71; P < 0.01) . High significant linear correlation (at least P < 0.01) is observed among the severity of the four heart diseases . Vice versa not significant association is showed between severity for every heart diseases and the experience of the interviewed . CONCLUSIONS . Most practitioners would prescribed prophylaxis for infective endocarditis to patients with rheumatic valve disease (91% of the responders), with previous episodes of infective endocarditis (90.4%), with prosthetic valve (67.6%) or with degenerative valve disease (57.3%) . On the contrary most practitioners would not prescribe the prevention for infective endocarditis to patients with coronary heart disease (84.9%), with coronary bypass (71.4%), with mitral valve prolapse without insufficiency (60.6%), with dilatative cardiomyopathy (67%) or with obstructive cardiomyopathy (57.8%) . A prevailing trend in case of congenital heart disease and mitral valve prolapse with insufficiency was not observed . The 86.6% of practitioners would prescribe the prophylaxis for infective endocarditis in case of dental extraction, but only the 64.4% would prescribe it in case of any potentially haemorrhagic oral or dental procedure . The 61.7% of the responders would not prescribe the prevention for infective endocarditis to patients receiving the prophylaxis for rheumatic fever . The practitioners would use in the following order: amoxicillin (77.3%), erythromycin (76.9%), penicillin V (76.3%) and ampicillin-gentamycin (61.3%) . On the contrary, most responders would prescribe neither tetracycline (73%) nor spiramycin (69.8%) . There is no prevailing trend to the employ of oral cephalosporins . The 90.3% of the practitioners think that infective endocarditis can be a quite interesting and useful subject for an up-to-date course.

Eur Respir J, 1994 Jul, 7(7), 1275 - 80
The levels of clarithromycin and its 14-hydroxy metabolite in the lung; Honeybourne D et al.; Clarithromycin is a new macrolide that has a longer half-life than erythromycin and is claimed to reach higher tissue concentrations . We aimed to investigate whether, following oral administration, the drug and its 14-hydroxy metabolite reach levels in lung tissue that are likely to be clinically effective against common respiratory pathogens . Ten patients undergoing diagnostic bronchoscopy received seven doses of clarithromycin, 500 mg b.i.d . orally . Bronchoscopy was performed at a mean time of 4.25 h after the last dose . At bronchoscopy, bronchial biopsies and bronchoalveolar lavage were performed . Clarithromycin and its 14-OH metabolite were measured in serum, bronchial biopsies, epithelial lining fluid (ELF) and alveolar cells . Mean levels of clarithromycin were 4.0 mg.l-1 in serum, 16.8 mg.kg in bronchial biopsies, 20.5 mg.l-1 in ELF and 372.7 mg.l-1 in alveolar cells . The equivalent levels of 14-OH metabolite were 0.7, 2.7, 1.9 and 38.6 mg.l-1, respectively . We conclude that there is considerable concentration of clarithromycin and its 14-OH metabolite in alveolar cells, and to a lesser extent in bronchial tissue and ELF; this implies efficacy against susceptible organisms at these sites.

Chem Pharm Bull (Tokyo), 1994 Jul, 42(7), 1522 - 4
Biosynthesis of erythromycin: origin of the methyl protons; Kajiwara M et al.; 13C-Nuclear magnetic resonance (13C-NMR) spectroscopy has been used to locate deuterium atoms incorporated biosynthetically into erythromycin from {3-13CD3}- and {3-13C}sodium propionate and L-{13CD3}- and L-{13C}methionine in Saccharopolyspora erythraea JCM 4748 . The alpha-shifts of deuterated methyl groups were clearly observed in broad-band deuterium and proton-decoupled 13C-NMR spectra . The seven propionate-derived methyl groups and the four methionine-derived methyl groups were shown to undergo no exchange of methyl protons during the biosynthesis of erythromycin.

J Formos Med Assoc, 1994 Jul, 93(7), 642 - 4
Azithromycin in the treatment of pneumonia caused by Chlamydia pneumoniae: report of a case; Wang JH et al.; We report a 67-year-old male with pneumonia in which Chlamydia pneumoniae was identified by serologic studies as the causative agent . After initial treatment failure with amoxicillin + clavulanic acid, pneumonia was successfully treated with the administration of oral azithromycin, 500 mg per day, for three days . Azithromycin is a new macrolide which has a long half-life and superior action to erythromycin . It provides a new and alternative choice in the treatment of Chlamydia pneumoniae infection in the future.

Transplantation, 1994 Jun 27, 57(12), 1736 - 41
Prediction of interpatient and intrapatient variation in OG 37-325 dosing requirements by the erythromycin breath test . A prospective study in renal transplant recipients; Turgeon DK et al.; OG 37-325 (nva-cyclosporine, cyclosporine G) is structurally similar to cyclosporine A (CsA) . We hypothesized that OG 37-325 may, therefore, be metabolized by P450 3A, an enzyme recently shown to metabolize CsA . To test this hypothesis, we employed the erythromycin breath test (ERMBT) to measure P450 3A activity on multiple occasions in twenty OG 37-325-treated renal transplant recipients . When stable dosing was achieved, there was a measured 6-fold variation in the ratio of 12-hr whole-blood parent compound trough concentration (ng/ml, HPLC) to daily OG 37-325 dose (mg/kg) ({OG 37-325}/dose) . In support of our hypothesis, there was an inverse correlation between the ERMBT result and the {OG 37-325}/dose ratio (r = -0.71, P < 0.001, n = 20); that is, patients with higher P450 3A activity generally required higher OG 37-325 doses to attain target blood levels . We also found that intrapatient variation in the {OG 37-325}/dose ratio observed over the course of the study correlated with changes in the ERMBT results (r = -0.67, P = 0.002) . Inter- and intrapatient differences in {OG 37-325}/dose ratio were not predicted by patient age, serum cholesterol, blood hematocrit, or traditional liver chemistries . We conclude that P450 3A is generally rate limiting in the elimination of OG 37-325 in adult renal transplant recipients . Therefore, most drug interactions observed with CsA should also be expected with OG 37-325 . We also conclude that intrapatient changes in OG 37-325 dosing requirements largely result from changes in P450 3A activity . The ERMBT may therefore provide useful information concerning patient compliance and may also serve as a useful guide to OG 37-325 dosing adjustments.

Tidsskr Nor Laegeforen . 1994 Jun 10;114(15):1696.
{Acute hypothermia and adverse effects on the central nervous system during erythromycin therapy}; Hassel B; Acute hypothermia and central nervous symptoms were observed in a 1 1/2 year-old child treated with erythromycin . The symptoms were mild hypothermia, ataxia, somnolence and apparent fatigue . Withdrawal of erythromycin led to reversal of the symptoms . Such side effects of antibiotics may be misinterpreted as involvement of the central nervous system in the infection for which the drug was given.

Proc Natl Acad Sci U S A, 1994 Jun 7, 91(12), 5612 - 6
Anti-peptidyl transferase leader peptides of attenuation-regulated chloramphenicol-resistance genes; Gu Z et al.; The chloramphenicol (Cm)-inducible cmlA gene of Tn1696 specifies nonenzymatic resistance to Cm and is regulated by attenuation . The first eight codons of the leader specify a peptide that inhibits peptidyl transferase in vitro . Functionally similar, but less inhibitory, peptides are encoded by the leaders of Cm-inducible cat genes . However, the cat and cmlA coding sequences are unrelated and specify proteins of unrelated function . The inhibition of peptidyl transferase by the leader peptides is additive with that of Cm . Erythromycin competes with the inhibitory action of the peptides, and erythromycin and the peptides footprint to overlapping sites at the peptidyl transferase center of 23S rRNA . It is proposed that translation of the cmlA and cat leaders transiently pauses upon synthesis of the inhibitor peptides . The predicted site of pausing is identical to the leader site where long-term occupancy by a ribosome (ribosome stalling) will activate downstream gene expression . We therefore propose the inducer, Cm, converts a peptide-paused ribosome to the stalled state . We discuss the idea that cooperativity between leader peptide and inducer is necessary for ribosome stalling and may link the activation of a specific drug-resistance gene with a particular antibiotic.

Am Fam Physician, 1994 Jun, 49(8), 1825 - 9, 1832
Chlamydial cervicitis: complications and new treatment options; Majeroni BA; Chlamydial cervicitis has the potential for serious gynecologic complications, including pelvic inflammatory disease, infertility and ectopic pregnancy . In the pregnant patient, this infection is associated with premature rupture of membranes and increased fetal morbidity and mortality . In addition, infants infected by passage through an infected cervix are at risk for respiratory complications and conjunctivitis . Chlamydial cervicitis may, however, be asymptomatic, and no single risk factor has been identified that reliably predicts infection . Current recommendations are to screen all pregnant women and patients in high-risk populations, such as those attending clinics for sexually transmitted diseases . Screening tests for chlamydial cervicitis are limited by expense and technical difficulties in obtaining and handling specimens . Chlamydial cervicitis can be treated effectively with several antibiotics, including doxycycline, ofloxacin and erythromycin . Newer antibiotics such as azithromycin offer the potential of effective single-dose treatment.

J Pediatr, 1994 Jun, 124(6), 956 - 61
Frequency and significance of isolation of Ureaplasma urealyticum and Mycoplasma hominis from cerebrospinal fluid and tracheal aspirate specimens from low birth weight infants; Heggie AD et al.; To investigate the pathogenicity of Ureaplasma urealyticum and Mycoplasma hominis in preterm infants, we conducted a study to determine (1) frequency of isolation from cerebrospinal fluid and tracheal aspirate specimens and (2) clinical outcomes and effect of erythromycin treatment in ureaplasma-colonized infants . From the cerebrospinal fluid of 920 infants, U . urealyticum was isolated from 2 (0.2%) and M . hominis from none . From tracheal aspirate specimens from 224 infants, U . urealyticum was recovered from 37 (17%) and M . hominis from 4 (2%) . Demographic characteristics and clinical outcomes were compared in very low birth weight infants (< 1500 gm) who were culture-positive or -negative for U . urealyticum . Although infants with positive results were less mature than their cohorts with negative results, there were no substantive differences in clinical outcomes between the two groups . Initiation of erythromycin treatment of infants with positive ureaplasma culture results at a mean age of 16.4 days did not appear to alter the clinical outcome . We conclude that in preterm infants (1) infection of the cerebrospinal fluid by U . urealyticum is infrequent, (2) ureaplasma organisms are frequently present in tracheal aspirate specimens but do not appear to be related to the presence or the subsequent development of respiratory disease, and (3) initiation of erythromycin treatment at 1 to 3 weeks of age does not alter the clinical course.

Dig Dis Sci, 1994 Jun, 39(6), 1309 - 12
Effect of single dose of oral erythromycin on gastric and gallbladder emptying . Simultaneous assessment by ultrasound; Arienti V et al.; To evaluate the effects of a single oral dose of erythromycin on gastric and gallbladder emptying, 10 volunteers, without a known history of gastrointestinal disease, were investigated . Erythromycin stearate (500 mg) or placebo was given on separate mornings 30 min before a standard solid meal in a randomized, double-blind, crossover study . Gastric and gallbladder emptying rates were simultaneously evaluated by means of real-time ultrasonography . Gastric antral area and gallbladder volume were determined before the meal and 30, 60, 120, 180, 240, and 300 min after commencing eating . Erythromycin, compared to placebo, significantly accelerates and increases the degree of both gastric and gallbladder emptying . As previously reported for intravenous and chronic oral assumption, also a single dose of oral erythromycin is able to accelerate gastric and gallbladder emptying in normal human subjects.

Minerva Pediatr, 1994 Jun, 46(6), 269 - 73
{Lung infections in children . IV . Pneumonia due to Chlamydia pneumoniae}; Della Santa L et al.; Chlamydia pneumoniae is the third strain of Chlamydia and transmission is presumed to be by droplet spread from symptomatic patients . The authors show a literature scientific review on subject-matter emphasizing several sporadic and epidemic case of illness in every age, first months excepted . The described cases are few and therefore clinical characteristics are shadowy . Certain clinical features are suggesting of severe pneumonia with fever and pharyngitis without exudate . In the childhood and in the adolescence the clinical evolution is favourable . Tetracyclines or erythromycin is recommended for therapy.

Clin Infect Dis, 1994 Jun, 18(6), 995 - 8
Erythromycin-induced QT prolongation and polymorphic ventricular tachycardia (torsades de pointes): case report and review; Brandriss MW et al.; Although uncommon, ventricular arrhythmias associated with erythromycin use have been reported previously, usually in the presence of heart disease and/or situations causing abnormal cardiac electrophysiology (such as bradycardia, hypokalemia, and the administration of other cardioactive drugs) . We report a case of QT prolongation and polymorphic ventricular tachycardia (torsades de pointes) that was precipitated by the intravenous administration of erythromycin . In contrast to most other previously described patients, our patient did not demonstrate significant heart disease or other apparent factors contributing to the genesis of the arrhythmia.

Infect Control Hosp Epidemiol, 1994 Jun, 15(6), 411 - 5
Management of healthcare workers exposed to pertussis; Weber DJ et al.; The epidemiology of pertussis has changed in recent years . First, pertussis in adults is far more common than previously thought . Second, in many instances, the disease in adults is atypical or asymptomatic . Third, adult pertussis occurs despite a prior history of full immunization and, indeed, in persons with a prior history of natural disease . Large outbreaks of pertussis have occurred in healthcare facilities through failure to recognize and isolate infected infants and children, failure to recognize and treat disease in staff members, and failure to institute control measures rapidly . Appropriate use of work restriction and erythromycin prophylaxis may decrease the likelihood of institutional outbreaks.

J Clin Pharmacol, 1994 Jun, 34(6), 635 - 43
Effects of motion sickness and antimotion sickness drugs on gastric function; Stewart JJ et al.; This study examined the effects of motion sickness and antimotion sickness drugs on gastric emptying (GE) . Drugs were tested in normal and motion sick subjects . To induce motion sickness, subjects performed head movements while seated in a rotating chair . Gastric emptying of liquid (300 mL) was determined by nuclear medicine techniques, whereas gastric electrical activity, the electrogastrogram (EGG), was monitored from surface (cutaneous) electrodes positioned over the abdominal area . Gastric emptying was severely inhibited at the peak of motion sickness symptoms, but returned to normal 15 minutes later when symptoms abated . In normal (non-motion sick) subjects intramuscular (IM) scopolamine (0.1 mg) and IM promethazine (25 mg) inhibited GE, whereas erythromycin ethylsuccinate (EES) suspension (200 mg) given orally increased GE . When administered to motion sick subjects, IM scopolamine and IM promethazine added slightly, but not significantly, to the inhibition of GE already present . Oral EES did not significantly alter GE in motion sick subjects . Although EGG frequency remained within normal limits (approximately 2.5-3.5 cpm) after liquid ingestion in both normal and motion sick subjects, EGG amplitude was differentially affected in the two groups . Electrogastrogram amplitude increased twofold to fourfold after liquid ingestion in normal, but not in motion sick subjects . The results suggest that (1) maximal inhibition of GE is coincident with peak motion sickness symptoms, (2) both IM scopolamine and IM promethazine inhibit GE in normal subjects, but do not add significantly to the inhibition of GE already established during motion sickness, (3) orally administered erythromycin enhances GE in normal, but not in motion sickness subjects, and (4) the normal stimulatory effect of liquid ingestion on gastric motility does not occur in motion sick subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

J Otolaryngol, 1994 Jun, 23(3), 216 - 20
Bacillary angiomatosis: a new entity in acquired immunodeficiency syndrome; Hnatuk LA et al.; Since the recognition of the acquired immunodeficiency syndrome (AIDS) in 1981, previously rare infections and neoplasms have become increasingly common . Bacillary angiomatosis, undescribed in the medical literature prior to 1983, is now second in frequency only to Kaposi's sarcoma with respect to the cutaneous manifestations associated with human immunodeficiency virus (HIV) infection . Caused by Rochalimaea henselae, bacillary angiomatosis is easily treated, when diagnosed early, with erythromycin . We present two cases of bacillary angiomatosis that presented to Toronto General Hospital and review this new and clinically interesting entity . The incidence of bacillary angiomatosis will undoubtedly increase as the HIV epidemic accelerates . Since bacillary angiomatosis commonly affects the head and neck region, it is important for the otolaryngologist to become increasingly proficient in its diagnosis and treatment . The current AIDS crisis demands that the otolaryngologist become aware not only of bacillary angiomatosis, but also of the other cutaneous head and neck manifestations of HIV infection.

Nippon Jibiinkoka Gakkai Kaiho, 1994 Jun, 97(6), 1070 - 8
{Histopathological studies on paranasal mucosa from patients treated with erythromycin}; Iino Y et al.; Low-dose and long-term administration of erythromycin (EM therapy) has been reported to be very effective for patients with intractable chronic sinusitis including sinobronchial syndrome . However, we sometimes encounter patients whose sinusitis is extremely resistant to EM therapy . Therefore, the present study was carried out to determine the correlation between the clinical efficacy of EM therapy and the histopathological features of the ethmoidal mucosa and nasal polyps of patients treated with erythromycin . Patients with significant lymphocytic infiltration in the submucosal area responded well to EM therapy . Furthermore, patients with neutrophilic infiltration within and beneath the ciliary epithelium tended to show improvement with this therapy . On the other hand, EM therapy was minimally effective in patients whose subepithelial layer showed marked eosinophilic infiltration . In patients showing excellent and good clinical results, histological changes in the paranasal mucosa after therapy were as follows: a decrease in the number of inflammatory cells, reduced interstitial edema, increased fibrosis and normalization of the secretory glands . From these results, we conclude that erythromycin may suppress chronic inflammation except for an allergic reaction characterized by marked eosinophilic infiltration.

Biol Mass Spectrom, 1994 Jun, 23(6), 369 - 75
Confirmatory analysis for spiramycin residue in bovine muscle by liquid chromatography/particle beam mass spectrometry; Sanders P et al.; To ensure that residues of veterinary drugs, above their respective maximum residue limits, do not reach the human food supply, European Community regulations specify requirements for detection, quantification and confirmation analytical methods and control procedures . The European Community member states base meat controls on these protocols . A liquid chromatographic/mass spectrometric analysis of spiramycin in calf muscle is presented as a confirmatory method for this compound . A particle beam interface was used, with negative ion chemical ionization mass spectrometry, using methane as the reagent gas . Samples (2 g muscle were prepared by liquid/liquid extraction followed by solid-phase extraction clean-up . On-line liquid chromatography/mass spectrometry of extracts was carried out on a C-18 bonded silica column . The specificity required for a regulatory confirmation procedure was achieved by monitoring five fragment ions with m/z 304, 330, 475, 683 and 684 . Variation of the relative ion abundances was less than 20% at the maximum limit of residue, 50 micrograms kg-1 . The method specificity was tested for three related compounds: neospiramycin, erythromycin and tylosin . The detection limit based on ion chromatogram peaks areas obtained with control samples was determined to be 20 micrograms kg-1.

J Invest Dermatol, 1994 Jun, 102(6), 970 - 5
Multiple cytochrome P450 isozymes in murine skin: induction of P450 1A, 2B, 2E, and 3A by dexamethasone; Jugert FK et al.; Cytochrome P450s (P450s) are a supergene family of enzymes responsible for the metabolism of a wide range of endogenous and foreign compounds . P450 isozymes possess overlapping substrate specificity . Systemic administration of dexamethasone, a widely used topical agent in dermatologic practice, to animals is known to result in the induction of multiple P450 isozymes in liver . In this study the effect of topical application of dexamethasone to mice on P450-dependent monooxygenase activities, expression of P450 isozymes, and P450 mRNA levels in skin was assessed . The treatment of mice with dexamethasone resulted in significant induction of 7-ethoxyresorufin O-deethylase (2.3 times), 7-pentoxyresorufin O-depentylase (19.2 times), para-nitrophenol hydroxylase (7.5 times), and erythromycin N-demethylase (2.2 times) activities; the monooxygenases catalyzed preferentially by P450 isozymes 1A1, 2B1, 2E1, and 3A, respectively . Immunoblot analysis of cutaneous microsomes, employing antibodies directed against purified P450s 1A1/2, 2B1/2, 2E1, and 3A, showed that dexamethasone treatment results in an increased immunoreactivity (1.8-13.9 times) . In immunohistochemical staining of skin with antibody against P4502B1/2, topical application of dexamethasone resulted in an increased reactivity towards microsomal protein in the suprabasal layer of the epidermis and with the cells of the hair follicles . Whereas constitutive expression of mRNAs for CYP1A1 and CYP2E1 was evident in murine skin, any change in the levels of these mRNAs following treatment with dexamethasone was not apparent . The results of our study indicate that the application of dexamethasone to murine skin results in the induction of several families of P450 isozymes, suggesting that murine skin contains multiple inducible P450 isozymes capable of participating in the metabolism of a wide range of xenobiotics and endogenous compounds.

Arch Dermatol, 1994 Jun, 130(6), 748 - 52
Inhibition of a model of in vitro granuloma formation by tetracyclines and ciprofloxacin . Involvement of protein kinase C; Webster GF et al.; BACKGROUND AND DESIGN: Granulomatous inflammation is a common component of many diseases . In this study the ability of commonly used antibiotics to inhibit an in vitro model of granuloma formation were studied . The effect of protein kinase C inhibition in this system was also investigated . RESULTS: Ampicillin, cephalothin, metronidazole, rifampin, isoniazide, erythromycin, and clindamycin were inactive in inhibiting granuloma formation . Tetracycline, doxycycline, minocycline, and ciprofloxacin produced dose-dependent inhibition of the granuloma model in concentrations between 10(-4) and 10(-6) mol/L . The approximate order of descending potency was doxycycline equals minocycline greater than tetracycline greater than ciprofloxacin . The same drugs were tested for the ability to inhibit protein kinase C . Drugs inactive in the granuloma model had no effect on protein kinase C activity . The tetracyclines and ciprofloxacin all caused a dose-dependent inhibition of protein kinase C activity in the same order of relative potency as was found for inhibition of granuloma formation . CONCLUSIONS: These data demonstrate a previously unappreciated activity of the tetracyclines and ciprofloxacin . Inhibition of granuloma formation helps to account for the activity of these drugs in the severest forms of inflammatory acne.

Zhonghua Nei Ke Za Zhi, 1994 Jun, 33(6), 376 - 8
{Clinical study of erythromycin action on gallbladder motility in patients with non-ulcer dyspepsia}; Liu YG et al.; Thirty-two patients of non-ulcer dyspepsia (NUD) with gallbladder hypokinesia treated by oral erythromycin administration 0.125g three times daily for two weeks . Before and after oral erythromycin administration, gallbladder volumes were determined by ultrasound, and plasma motilin concentration were determined by radioimmunoassay . The results showed that before and after oral erythromycin administration, maximal percentage emptying of gallbladder were 48.24 +/- 8.30ml vs 69.74 +/- 10.78ml (P < 0.01), plasma motilin were 361.28 +/- 87.92ng/L vs 394.97 +/- 134.27ng/L (P > 0.05) . It is indicated that erythromycin could reduce fasting and postprandial residual gallbladder volumes and increases maximal percentage emptying of gallbladder . It suggests that erythromycin might have an agonist action on the motilin receptor as an agonist action on the motilin receptor as an exogenously administrated motilin.

Antibiot Khimioter, 1994 Jun, 39(6), 36 - 8
{Azithromycin in the treatment of syphilis}; Mashkilleison AL; The results of the use of azithromycin (sumamed) in the treatment of 100 patients with fresh syphilis were analyzed . The antibiotic was used in accordance with two treatment schemes: 500 mg daily for 10 days and 500 mg every two days . The total course dose was 5 g in both the cases . The results of the treatment with azithromycin were compared with those of the treatment with erythromycin (30 g) and penicillin (300,000 U every 3 hours for 16-28 days depending on the disease stage) . The results were estimated by the rate of the elimination of Treponema pallidum and syphilids as well as by the time course of the seroreactions . The analysis provided a conclusion that the therapeutic efficacy of sumamed in the treatment of patients with fresh manifest syphilis was high: by comparison with penicillin and erythromycin it more rapidly eliminated the clinical signs of syphilis and in the majority of the cases induced negativation of the cutaneous serological reactions within the first 4 months of the treatment.

Zhonghua Liu Xing Bing Xue Za Zhi, 1994 Jun, 15(3), 177 - 8
{The investigation on drug resistance to N . gonorrhoeae in Benxi district}; Guo R; The sensitivity of 95 strains of N . gonorrhoeae to antibiotics was determined . In 1990, among 18 strains of N . gonorrhoeae, 7 (38.90%) were resistant to Penicillin G, 3 (16.66%) to Gentamicin, 8 (44.44%) Kanamycin, 8 (44.44%) Midecamycin . In 1992, among 77 strains of N . gonorrhoeae, 61 (79.22%) were resistant to Penicillin G, 38 (49.35%) to Gentamicin, 62 (80.52%) to Kanamycin, 54 (70.13%) to Midecamycin, 56 (72.72%) to Ampicillin 60 (77.92%) to Erythromycin, 22 (28.57%) to Cefazolin, 18 (23.37%) to Cefotaxime . The results showed that Cefazolin and Cefotaxime were the most effective antibiotics, Gentamicin was the next.

Biochem Pharmacol, 1994 May 18, 47(10), 1883 - 95
Involvement of cytochrome P450 3A enzyme family in the major metabolic pathways of toremifene in human liver microsomes; Berthou F et al.; The anti-estrogen toremifen-Fc-1157a or 4-chloro-1,2-diphenyl-1-{4-{2(N,N-dimethylamino)ethoxy}-phenyl}-1- butene is now used for the treatment of breast cancer . This drug is extensively metabolized by cytochrome P450 dependent hepatic mixed function oxidase in man, yielding mainly the N-demethyl-(DMTOR), 4-hydroxy-(4OH-TOR) and deamino-hydroxy-(TOR III) toremifene metabolites . The specific forms of cytochrome P450 involved in these oxidation reactions were examined in 32 human liver microsomal preparations previously characterized with respect to their contents of several known P450 enzymes . Toremifene was demethylated with an apparent Km of 124 microM while it was hydroxylated with an apparent Km of 139 microM . The metabolic rates were 71 +/- 56, 13 +/- 9 and 15 +/- 4 pmol/min/mg microsomal protein, respectively, for DMTOR, 4-OH-TOR and TOR III . The N-demethylation activity was strongly correlated with estradiol 2-hydroxylation (r = 0.75), nifedipine oxidation (r = 0.86), tamoxifen N-demethylation (r = 0.73), testosterone 6 beta-hydroxylation (r = 0.78) and erythromycin N-demethylation (r = 0.84), all these monooxygenase activities known to be supported by CYP3A4 isoform . Furthermore, the CYP3A content of liver microsomal samples, measured by western blot analysis using a monoclonal anti-human CYP3A4 antibody, was strongly correlated with DMTOR formation (r = 0.80) . Compounds such as cyclosporin, triacetyl-oleandomycin and testosterone inhibited the N-demethylation of toremifene metabolism at 80, 89 and 56% vs control, respectively, while the formation of TOR III was inhibited at 78, 82 and 73% vs control and the 4-hydroxylation pathway was inhibited no more than about 50% vs control . Prior incubation of microsomes with 100 microM gestodene, known to be a selective mechanism-based inhibitor of CYP3A4 in the presence of NADPH, led to 76 +/- 6 and 76 +/- 5% (N = 5 samples) reductions in the N-demethylation and formation of TOR III, respectively . Polyclonal antibody directed against human CYP3A enzymes inhibited formation of DMTOR and TOR III by 60 and 46%, respectively . The metabolism of toremifene was not activated by alpha-naphthoflavone . Finally, the use of yeasts genetically engineered for expression of human P4501A1, 1A2, 2C9 and 3A4 allowed us to demonstrate that DMTOR and TOR III formations are mediated by P4501A and 3A4 enzymes and by contrast these enzymes are not involved in the 4-hydroxylation pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Biochem Pharmacol, 1994 May 18, 47(10), 1767 - 76
Caffeine metabolism by human hepatic cytochromes P450: contributions of 1A2, 2E1 and 3A isoforms; Tassaneeyakul W et al.; Caffeine (CA) N1-, N3- and N7-demethylase, CA 8-hydroxylase and phenacetin O-deethylase activities were measured in microsomes from 18 separate human livers which had been characterized previously for a range of cytochrome P450 (CYP) isoform-specific activities and immunoreactive CYP protein contents . Correlations between the high affinity components of the three separate CA N-demethylations were highly significant (r = 0.77-0.91, P < 0.001) and each of the three high affinity CA N-demethylations correlated significantly (r = 0.64-0.93, P < 0.05-0.001) with the high affinity phenacetin O-deethylase, 2-acetylaminofluorene N-hydroxylation and 2-amino-1-methyl-6-phenylimidazo{4,5-b}pyridine (PhIP) and 2-amino-3-methylimidazo{4,5-f}quinoline (IQ) mutagenicity (all predominantly CYP1A2-mediated reactions) . Consistent with these observations, cDNA-expressed human CYP1A2 catalyzed the N1-, N3- and N7-demethylation of CA and apparent Km values were similar (0.24-0.28 mM) for all three reactions and comparable to those observed previously with human liver microsomes . The low affinity components of CA N1- and N7-demethylation correlated significantly (r = 0.55-0.85, P < 0.05-0.001) with immunoreactive CYP2E1 content and the CYP2E1-specific activities 4-nitrophenol and chlorzoxazone hydroxylation . Diethyldithiocarbamate, a selective inhibitor of CYP2E1, inhibited the low affinity CA N1- and N7-demethylation, with IC50 values of 23 microM and 11 microM, respectively . The apparent Km values for CA N1- and N7-demethylation by cDNA-expressed CYP2E1 (namely 28 and 43 mM, respectively) were of a similar order to those calculated for the low affinity microsomal activities . Significant correlations (r = 0.87-0.97, P < 0.001) were observed between CA 8-hydroxylation and immunoreactive CYP3A content and the CYP3A-mediated reactions benzo(a)pyrene hydroxylation, omeprazole sulfoxidation and aflatoxin B1 mutagenesis . Effects of alpha-naphthoflavone, erythromycin, troleandomycin and nifedipine on microsomal CA 8-hydroxylation were generally consistent with CYP3A involvement . Taken together with previous data, the results indicate a major involvement of CYP1A2 in the high affinity component of all three human hepatic CA N-demethylations . In contrast, CYP2E1 appears to be the main enzyme involved in the low affinity components of CA N1- and N7-demethylation while CA 8-hydroxylation is catalysed predominantly by a CYP3A isoform(s).

Ann N Y Acad Sci, 1994 May 2, 721, 123 - 32
Correlation of the avermectin polyketide synthase genes to the avermectin structure . Implications for designing novel avermectins; MacNeil DJ et al.; Streptomyces avermitilis produces a series of eight potent anthelmintic compounds called avermectins (AVM) . AVM are pentacyclic, macrocyclic lactone compounds containing an oleandrose disaccharide . Labeling studies have shown that AVM is a polyketide derived from the condensation of 12 acyl units (five propionates and seven acetates) to an isobutyl or 2-methylbutyryl starter unit . The genes required for AVM biosynthesis have been cloned, and deletion mapping has located the AVM gene cluster to a 95-kb region . Partial DNA sequencing of this region indicates two 30-kb segments encode large, multifunctional peptides of the AVM polyketide synthase (PKS) . The PKS proteins contain at least 49 domains with homology to the domains in fatty acid synthase and erythromycin PKS . These domains are arranged as 12 modular repeats that each encode a PKS unit with various subsets of the FAS-like functions . The predicted functions required to form the side groups on the AVM macrocyclic ring were compared to the functions found in the 12 PKS units . This comparison suggests that each PKS unit is specific for condensation and reduction of one acyl unit . If the various domains can be manipulated without disrupting the PKS, it may be possible to synthesize a variety of AVM derivatives.

Br J Dermatol, 1994 May, 130(5), 665 - 8
Bacillary angiomatosis in a patient with lymphocytic leukaemia; Torok L et al.; A 78-year-old man, who suffered from chronic lymphocytic leukaemia and diabetes mellitus, but was human immunodeficiency virus (HIV)-negative, developed disseminated angiomatous papules following a cat scratch . Bacillary angiomatosis was diagnosed by light and electron microscopic demonstration of the causative bacteria in the vascular lesions . The lesions resolved completely when he was treated with erythromycin . This case demonstrates that bacillary angiomatosis can be an important cutaneous manifestation of immunodeficiency in individuals who are not infected with the human immunodeficiency virus.

J Reprod Med, 1994 May, 39(5), 412 - 4
Primary syphilis and nonimmune fetal hydrops in a penicillin-allergic woman . A case report; ElTabbakh GH et al.; The incidence of congenital syphilis is on the rise . Penicillin continues to be the drug of choice for it during pregnancy . A penicillin-allergic woman with primary stage syphilis who was treated initially with erythromycin presented with fever and nonimmune fetal hydrops secondary to an intrauterine syphilitic infection . Following desensitization and penicillin therapy the fetal hydrops disappeared, the pregnancy continued to term, and the patient delivered a small-for-gestational-age but other-wise normal infant who continued to do well up to 1 year of age.

Clin Pharmacokinet, 1994 May, 26(5), 374 - 95
Pharmacokinetics of anti-infective agents in paediatric patients; Butler DR et al.; Various differences in drug disposition exist between children and adults . For example, the volume of distribution (Vd) for many drugs is larger in children than in adults . Other parameters, including excretion and elimination may be altered in children compared with adults . The penicillins and cephalosporins are used commonly for the treatment of infection in paediatric patients . The increased Vd in children contributes to the increased elimination half-life of these agents . Clearance of the acylureido-penicillins is increased in children with cystic fibrosis, a disease that decreases the elimination half-life for these drugs . Aminoglycosides distribute into extracellular fluid and their pharmacokinetic profile is affected by changes in Vd . The Vd for aminoglycosides is slightly higher in children than in adults . Children with cystic fibrosis, burns, or cancer have higher clearance rates and larger Vd values for aminoglycosides . Few data in the literature address the pharmacokinetics of other anti-infective agents, including vancomycin, teicoplanin, erythromycin, metronidazole, chloramphenicol, and cotrimoxazole (trimethoprim-sulfamethoxazole), in children . Similarly, there is little information regarding the pharmacokinetic profile of antivirals and antifungals in children . Dosage guidelines are available to enable the clinician to initiate anti-infective therapy in children . Subsequent dosage requirements may change based on the patient's current clinical condition . Although several studies have investigated the pharmacokinetics of anti-infectives in neonates and adults, data for children are limited . Therefore, further studies are required so that the ever growing arsenal of anti-infectives can be administered appropriately to children.

S D J Med, 1994 May, 47(5), 161 - 4
Erythromycin induced Torsades de Pointes: case report and review of the literature; Rezkalla MA et al.; We report a case of an 82 year old woman with bilateral pneumonia who developed repeated episodes of polymorphic ventricular tachycardia with QT prolongation (Torsades de Pointes) after intravenous infusion of erythromycin . After discontinuation of erythromycin, the QT interval returned to normal and there was no recurrence of this arrhythmia . The association of intravenous erythromycin and this potentially fatal ventricular arrhythmia has been described in 15 similar cases reported in the literature . Both in vitro and in vivo studies have shown that erythromycin exerts electrophysiologic effects on the cardiac muscle similar to that of class IA antiarrhythmic drugs and that cross sensitivity may exist between this class of drugs and erythromycin . The definition, pathophysiology, etiology, clinical and electrocardiographic feature, and prevention and treatment of "Torsades de Pointes" are described in this article.

Neth J Med, 1994 May, 44(5), 178 - 81
Systemic infection with Nocardia asteroides cured with amoxicillin/clavulanic acid, erythromycin and ultrasound-guided transcutaneous aspiration; Stella PR et al.; A case is presented of systemic nocardiosis . The patient was completely cured by unconventional antibiotic therapy and simple transcutaneous needle aspiration.

Ann Pharmacother, 1994 May, 28(5 Suppl), S15 - 7
Pharmacology and pharmacokinetics of paclitaxel; Kuhn JG; There remain several pharmacologic considerations relating to paclitaxel that are being, or need to be, explored . Some of the more important of these include the following issues: Further elaboration of the metabolic fate of paclitaxel . A multicenter study is currently being planned to determine the complete metabolic fate of paclitaxel, using radiolabeled (14C) drug . Establishing criteria for optimal dosing and scheduling, particularly in patients with organ dysfunction . Evaluation of the optimal use of paclitaxel in combination with other drugs, and the potential interactions of these drugs, which may result in different response and toxicity patterns . Several aspects of drug-drug interactions are being considered . Interactions between paclitaxel and other drugs that are highly protein bound . Interactions with the P-450 enzyme system, in which antineoplastic agents that are currently used in combination with paclitaxel, such as cisplatin and doxorubicin, have been shown to modulate these enzymes . Interactions at the level of hepatic metabolism between paclitaxel and the H2-antagonists used as a premedication to prevent hypersensitivity reactions . Different compounds of this class, including cimetidine, ranitidine, and famotidine, have variable modulatory effects on P-450 enzymes . The choice of a specific agent may therefore affect response and toxicity patterns, although to date, no clinically significant drug interactions have been observed . Interactions between paclitaxel and other drugs used as supportive therapy that may inhibit P-450 enzymes . One such drug is erythromycin, which has been shown in a rat model to block significantly the excretion of doxorubicin through the MDR mechanism (unpublished data, J.G . Kuhn).(ABSTRACT TRUNCATED AT 250 WORDS)

Infect Immun, 1994 May, 62(5), 1696 - 704
Construction and characterization of a fimA mutant of Porphyromonas gingivalis; Hamada N et al.; Although fimbriae of Porphyromonas gingivalis have been implicated as playing a major role in adherence to gingival tissue surfaces, no conclusive genetic evidence has yet been obtained . The fimA gene, the determinant for the major fimbrial subunit protein, was cloned and sequenced (D . P . Dickinson, M . A . Kubiniec, F . Yoshimura, and R . J . Genco, J . Bacteriol . 170:1658-1665, 1988) . We undertook to inactivate the fimA gene by a homologous recombination technique and examined the fimA mutant for changes in surface properties, including production of fimbriae, adherence to human gingival fibroblasts and epithelial cells, hemagglutinating activity, and surface hydrophobicity . To inactivate the fimA gene, we disrupted a fimA clone by insertion of a DNA segment containing an erythromycin resistance (Emr) gene . This was then delivered into P . gingivalis ATCC 33277 from an Escherichia coli K-12 strain, SM10 lambda pir, by using a mobilizable suicide vector, pGP704; recombination at the fimA locus led to the isolation of a fimA mutant . Disruption of the fimA locus and disappearance of FimA production were confirmed by Southern hybridization with a fimA-specific DNA probe and Western immunoblotting with a monoclonal antibody against the FimA protein, respectively . The fimA mutant constructed failed to express long (0.5- to 1.0-micron) fimbriae from the bacterial surface and had a diminished adhesive capacity to tissue-cultured human gingival fibroblasts and epithelial cells . Observation of the bacteria adhering to human gingival fibroblasts by scanning electron microscopy revealed that the wild-type strain had dramatic local changes in the appearance of the microvilli at the point of contact with large bacterial clumps, whereas the fimA mutant did not . In contrast, neither the hemagglutinating activity nor the surface hydrophobicity was changed in the fimA mutant . These data thus constitute the first direct genetic evidence demonstrating that the FimA protein of P . gingivalis is essential for the interaction of the organism with human gingival tissue cells through a function(s) encoded by the fimA gene.

Pathol Biol (Paris), 1994 May, 42(5), 399 - 405
{Electron microscopic studies of the action of erythromycin, doxycycline and ofloxacin on the growth cycle of Chlamydia trachomatis}; Dailloux M et al.; The aim of this work is to realise an ultra structural study of the action of antibiotics (doxycycline, erythromycin and ofloxacin) on the intracellular growth cycle of chlamydia . All assays were done on McCoy cells . Antibiotics were added to the culture medium two hours after inoculation with C . trachomatis . 24 and 48 hours, cells were removed and treated by standard procedure for transmission electron microscopy . No difference between control-cells and cells treated with doxycycline, erythromycin (0.015 mg/l) and ofloxacin (0.15 mg/l), was observed in the inclusions (number and size) . However 48 hours, the quantity of elementary bodies (E.B.) was lower in treated culture . The organisms were not morphologically different from those seen in untreated culture . At higher concentrations of doxycycline and erythromycin (0.03 mg/l - 0.06 mg/l), the inclusions were smaller . Reticulate bodies (RB) were each in separate inclusion indicating that no fission has taken place . At 48 hours, no infectious forms (EB) were observed . Small or large RBs appeared with an apparent normal cytoplasmic membrane within an inflated cell wall . With ofloxacin (0.3 - 0.6 mg/l), inclusions contained enlarged and sometimes empty bacterial cells . Doxycycline and erythromycin (0.03 mg/l) inhibit the division of RBs and there maturation to EBs Ofloxacin (0.3 mg/l) induces the production of large abnormal forms which may not be able to revert towards viable bacteria.

Biochem Pharmacol, 1994 Apr 29, 47(9), 1643 - 53
Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily; Gorski JC et al.; The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5 . Under initial rate conditions and high substrate concentration (400 microM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1'- and 4-hydroxylation of midazolam, respectively . Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1'- and 4-hydroxylation, respectively . Six fetal hepatic microsomal samples showed 10-fold variation in both 1'-hydroxymidazolam and 4-hydroxymidazolam formation rates . The rates of formation of 4-hydroxymidazolam and 1'-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were highly correlated (r2 = 0.99 and 0.97, P < 0.01, respectively) . The rates of formation of 1'-hydroxymidazolam and 4-hydroxymidazolam from midazolam (400 microM) by adult samples that contained only CYP3A4 were correlated significantly (P < 0.01) with the ability of the samples to N-demethylate erythromycin (r2 = 0.95 and 0.92, respectively) . 6 beta-hydroxylate testosterone (r2 = 0.96 and 0.96, respectively), and the CYP3A4 content of the samples (r2 = 0.89 and 0.86, respectively) . Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ratio of 1'-hydroxymidazolam to 4-hydroxymidazolam compared with samples containing only CYP3A4 or CYP3A7 (P < 0.001) . Purified CYP3A5 in a reconstituted system, consisting of dilauroylphosphatidylcholine, cytochrome b5, and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1'-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4 . In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1'- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.

Biochem Pharmacol, 1994 Apr 20, 47(8), 1295 - 307
An evaluation of cytochrome P450 isoform activities in the female dark agouti (DA) rat: relevance to its use as a model of the CYP2D6 poor metaboliser phenotype; Barham HM et al.; The female dark agouti (DA) rat lacks CYP2D1, the equivalent enzyme in the rat to human CYP2D6 (debrisoquine hydroxylase), and shows impaired metabolism of a number of CYP2D6 substrates . However, from the data available in the literature it is not entirely clear whether the enzyme deficiency in the DA rat is restricted to CYP2D1, and whether factors such as age and substrate concentration are important determinants of interstrain differences in the activity of this enzyme . Given that the female DA rat is used as a model of the human CYP2D6 poor metaboliser phenotype, there is a need for a systematic evaluation of the P450 activities in the DA rat, and of its suitability as a model of the PM phenotype . In the present study metoprolol was used as a probe substrate to investigate CYP2D1 activity since both the alpha-hydroxylation and O-demethylation of this drug are catalysed by CYP2D6 in man . Formation of alpha-hydroxymetoprolol (AHM) and O-demethylmetoprolol (ODM) was 10- and 2.5-fold lower in liver microsomes from female DA rats compared with microsomes from age-matched female Wistar rats, the latter representing the extensive metaboliser strain . Kinetic analysis suggested that in both strains of rat both the alpha-hydroxylation and O-demethylation of metoprolol were catalysed by more than one enzyme . By using quinine as a specific inhibitor of the enzyme, CYP2D1 was identified as an intermediate affinity site in the Wistar strain and was shown to have impaired activity in the DA strain . The activities of lower and higher affinity sites were similar in the two strains . Thus, the only difference between the two strains with respect to both routes of metoprolol metabolism appeared to be in the activity of CYP2D1 . Interstrain differences were found to be highly dependent on the choice of substrate concentration, being more marked at lower concentrations . We have also investigated the metabolism of a number of probe compounds for some of the other P450 isoforms commonly involved in drug metabolism to determine the selectivity of the deficiency in the DA strain . p-Nitrophenol hydroxylation and erythromycin N-demethylation were catalysed at higher rates by DA than by Wistar liver microsomes, indicating higher levels of activity of CYP2E1 and CYP3A in the former strain . Felodipine oxidation, tolbutamide hydroxylation and both the hydroxylation and N-demethylation of S-mephenytoin were catalysed at similar rates by microsomes from the two strains, indicating similar activities of enzymes in the CYP2C and CYP3A families.(ABSTRACT TRUNCATED AT 400 WORDS)

Acta Paediatr Jpn, 1994 Apr, 36(2), 198 - 201
Erythromycin improves gastrointestinal motility in extremely low birthweight infants; Kubota M et al.; Erythromycin (EM) was administered to five extremely low birthweight infants (ELBWI) with delayed enteral feeding to evaluate the clinical effect on severely impaired gastrointestinal motility . Five patients studied responded well to EM administration without any adverse effects during the course . Four patients were given 15-30 mg/kg per day EM intravenously as a loading and thereafter 3-5 mg/kg per day as a maintenance dose . One patient responded well without loading . The infants could be fed enterally 4, 5, 6, 4 and 2 days after the initiation of EM administration, respectively . Erythromycin administration is a safe and useful way to facilitate gastrointestinal motility in ELBWI who require prolonged ventilator support with an increased risk for nutrient deprivation.

Z Lebensm Unters Forsch, 1994 Apr, 198(4), 307 - 12
{Fluorimetric determination of erythromycin residues in foods of animal origin after derivatization with FMOC and HPLC separation}; Zierfels G et al.; A high-performance liquid chromatographic (HPLC) method for the determination of the macrolide antibiotic erythromycin in eggs, milk, swine muscle, kidney and liver was developed . The drug was extracted from the matrix with acetonitrile . The raw extract was purified by liquid-liquid partitioning and fractionation by reversed-phase HPLC for additional cleanup . Erythromycin was reacted in a pre-column procedure with 9-fluorenylmethylchloroformate (FMOC) to enable fluorimetric detection (excitation 255 nm, emission 315 nm) after isocratic separation on an analytical RP-18 HPLC column . Mean recoveries ranged from 99% at fortification levels of 0.03 mg/kg in egg to 38% at 0.06 mg/kg in liver . With the exception of liver all detection limits were below 0.01 mg/kg and precision for all other matrices and tested concentrations (0.015-0.09 mg/kg) better than 20% (coefficient of variation).

Neth J Med, 1994 Apr, 44(4), 131 - 5
Erythromycin-induced torsades de pointes and ventricular fibrillation in a patient with Legionella pneumonia; de Koning J et al.; Several case reports of erythromycin-induced torsades de pointes (TDP) arrhythmia have been reported in the literature . However, this potentially lethal side-effect of a frequently prescribed drug is not generally known . We report a patient who developed TDP followed by ventricular fibrillation during rapid infusion of erythromycin lactobionate . Although the patient used diuretics, probably predisposing her to arrhythmias due to hypokalaemia, several ECG abnormalities predisposing to TDP, all related to erythromycin infusion, occurred during observation in the ICU, establishing the precipitating role of erythromycin . The diagnosis was made only after QT prolongation, TDP and ventricular fibrillation were observed during rapid intravenous infusion of erythromycin lactobionate, one of the reasons no doubt being the assumed lack of serious side-effects of this frequently prescribed drug.

Am J Physiol, 1994 Apr, 266(4 Pt 1), G576 - 84
Neural control of small intestinal giant migrating contractions; Otterson MF et al.; We investigated the neural mechanisms of control of giant migrating contractions (GMCs) in five conscious dogs . After control recordings, a Thiry-Vella loop was prepared from the middle segment, and the remaining two segments were reanastomosed . GMCs were stimulated by intravenous administration of fentanyl and erythromycin lactobionate, oral administration of loperamide and erythromycin stearate, and gastric or intraluminal administration of cider vinegar in the loop . In the intact state, the agents stimulated GMCs in all three segments, and they propagated uninterruptedly from the point of their origin to the terminal ileum . The propagation velocity of GMCs increased, whereas that of migrating motor complexes (MMCs) decreased distally . After Thiry-Vella loop formation, the agents stimulated GMCs independently in the three segments, and they propagated only to the end of the segment in which they started . In the intact small intestine, the GMCs produced ascending and descending inhibition of spontaneous phase II contractions but did not interrupt the caudad propagation of the ongoing MMC . After Thiry-Vella loop formation, the ascending inhibition was unaltered, but the descending inhibition occurred only in the segment containing the GMC . We conclude that the propagation of GMCs in the small intestine is controlled by the enteric nerves . The extrinsic nerves control the ascending inhibition produced by GMCs, whereas the enteric nerves control the descending inhibition.

Mol Gen Genet, 1994 Apr, 243(2), 225 - 33
Erythromycin, lincosamides, peptidyl-tRNA dissociation, and ribosome editing; Menninger JR et al.; Inaccurate protein synthesis produces unstable beta-galactosidase, whose activity is rapidly lost at high temperature . Erythromycin, lincomycin, clindamycin, and celesticetin were shown to counteract the error-inducing effects of streptomycin on beta-galactosidase synthesized in the antibiotic-hypersensitive Escherichia coli strain DB-11 Met- . Newly synthesized beta-galactosidase was more easily inactivated by high temperatures when synthesized by bacteria partially starved for arginine, threonine, or methionine . Simultaneous treatment with erythromycin or lincomycin yielded beta-galactosidase that was inactivated by high temperatures less easily than during starvation alone, an effect attributed to stimulation of ribosome editing . When synthesized in the presence of canavanine, beta-galactosidase was inactivated by high temperature more easily but this effect could not be reversed by erythromycin . The first arginine in beta-galactosidase occurs at residue 13, so the effect of erythromycin during arginine starvation is probably to stimulate dissociation of erroneous peptidyl-tRNAs of at least that length . Correction of errors induced by methionine starvation is probably due to stimulation of dissociation of erroneous peptidyl-tRNAs bearing peptides at least 92 residues in length . All the effects of erythromycin or the tested lincosamides on protein synthesis are probably the result of stimulating the dissociation from ribosomes of peptidyl-tRNAs that are erroneous or short.

Postgrad Med, 1994 Apr, 95(5), 195 - 8, 201-4
Diabetic gastroparesis . What to do when gastric emptying is delayed; Clark DW et al.; Diagnostic evidence or symptoms of gastroparesis develop in about 20% to 30% of patients with long-standing diabetes . Diabetic gastroparesis is likely caused by autonomic neuropathy involving the nerves that regulate gastric motor function . The following are necessary for diagnosis: thorough history taking and physical examination to eliminate factors that might further delay gastric emptying; esophagogastroduodenoscopy or barium contrast studies to exclude structural abnormalities; and a radionuclide gastric emptying study . The three main agents available for therapy in the United States are metoclopramide (Maxolon, Octamide, Reglan), erythromycin, and cisapride (Propulsid) . All have been shown to offer benefit in improving gastric emptying and symptoms, although use of metoclopramide is limited by a significant incidence of side effects . Surgical intervention should be avoided if possible.

Am J Gastroenterol, 1994 Apr, 89(4), 550 - 5
Effect of erythromycin on gastric and gallbladder emptying and gastrointestinal symptoms in scleroderma patients is maintained medium term; Fiorucci S et al.; OBJECTIVES: Scleroderma patients frequently present esophageal and gastric emptying abnormalities and small bowel dysfunction . Erythromycin, a macrolide antibiotic, has been found to accelerate gastric and gallbladder emptying in both healthy subjects and diabetic patients . Our objective was to investigate the effects of 4-wk oral erythromycin administration on the gastric and gallbladder emptying, gastrointestinal symptoms (early satiety, abdominal pain, nausea, bloating, vomiting, and constipation), and motilin plasma levels of patients with scleroderma . METHODS: 12 scleroderma patients were investigated before and after 4-wk treatment with 250 mg oral erythromycin three times a day . The effect of a single i.v . dose of 2 mg/kg/h erythromycin on gastric and gallbladder emptying before starting the oral treatment was also evaluated . Gastric and gallbladder emptying after a solid meal were evaluated by sonography . RESULTS: Single i.v . administration of erythromycin before the meal reduced gastric emptying T1/2 from 121.3 +/- 14.0 to 45.5 +/- 7.3 min (p < 0.01) and accelerated gallbladder emptying without affecting the peak . Four-week oral administration of erythromycin reduced gastric emptying T1/2 from 121.3 +/- 14.0 min to 46.5 +/- 8.3 min (p < 0.01) . Peak gallbladder emptying was also significantly accelerated, while total emptying remained unchanged (p < 0.01) . Furthermore, 4-wk erythromycin administration reduced both motilin plasma levels (from 223.4 +/- 53.8 to 145.4 +/- 67.2 pmol/L, p < 0.01) and symptoms of nausea, vomiting, and abdominal pain (p < 0.01), and increased bowel movements in a subset of scleroderma patients with intestinal pseudo-obstruction . CONCLUSIONS: Erythromycin stimulates gastrointestinal motility in patients with scleroderma . Administered medium-term, it accelerates gastric and gallbladder emptying and alleviates gastrointestinal symptoms.

Minerva Pediatr, 1994 Apr, 46(4), 147 - 52
{Pulmonary infections in children . II - Mycoplasma pneumonia}; Della Santa L et al.; The authors show a literary review on Mycoplasma pneumonia which represents a fifth of human pneumonia . M . pneumoniae is the major cause of illness in school-age children (5-9 years) and young adults and the peak incidence of illness occurs in this age . The infection appears mainly as an interstitial pneumonitis and the onset of illness is gradual, influence-like with few clinical symptoms and typical roentgenographic and bronchoscopic findings . Cold hemagglutinins appear in approximately 50% of patients . A severe prognosis can be associated with extrarespiratory symptoms; Erythromycin (as others macrolides) is the drug of choice.

Eur J Clin Microbiol Infect Dis, 1994 Apr, 13(4), 313 - 5
Bordetella pertussis as a cause of chronic respiratory infection in an AIDS patient; Colebunders R et al.; A 60-year-old heterosexual man with AIDS was admitted to hospital with dyspnea, a severe paroxysmal non-productive cough of two months' duration, low-grade fever and exhaustion . Bordetella pertussis was cultured from a bronchoalveolar lavage specimen . After erythromycin therapy (500 mg q.i.d . for two weeks) all respiratory symptoms resolved progressively over a four-week period . Bordetella pertussis should be added to the long list of pathogens that may cause respiratory disease in persons with HIV infection.

Pediatr Infect Dis J, 1994 Apr, 13(4), 287 - 93
Serum concentrations of erythromycin after intravenous infusion in preterm neonates treated for Ureaplasma urealyticum infection; Waites KB et al.; Erythromycin is receiving renewed attention as an alternative for treatment of neonatal infections caused by Ureaplasma urealyticum because of recently proved abilities of this organism to produce systemic disease in this population . Although erythromycin has been used clinically for almost 40 years, very little is known about its activity in the preterm neonate . Fourteen neonates, birth weights < or = 1500 g and < or = 15 days of age, from whom U . urealyticum was isolated from the lower respiratory tract were randomized to receive erythromycin lactobionate either 25 or 40 mg/kg/day in four divided doses at 6-hour intervals scheduled for a total of 10 days . Blood samples collected at multiple time points after initial and steady state doses were assayed for erythromycin by liquid chromatography . Minimal inhibitory concentrations (MICs) of erythromycin for the U . urealyticum isolates were determined . MICs ranged from 0.031 to 2 micrograms/ml; MIC90 = 2 micrograms/ml . Serum erythromycin concentrations met or exceeded most MICs, with peak values of 3.05 to 3.69 and 1.92 to 2.9 micrograms/ml for the 40- and 25-mg/kg/day dosage groups, respectively . Pharmacokinetic parameters were calculated after the initial dose and at steady state for both dosage groups and compared . No adverse effects thought to be related to administration of erythromycin were observed . These preliminary findings showed that erythromycin is well-tolerated, has favorable pharmacokinetic activity in the preterm neonate and should be further investigated for treatment of ureaplasmal infections.

Antimicrob Agents Chemother, 1994 Apr, 38(4), 738 - 41
In vitro and in vivo activities of sparfloxacin against Mycoplasma pneumoniae; Kaku M et al.; The in vitro and in vivo activities of sparfloxacin against Mycoplasma pneumoniae were compared with those of erythromycin, levofloxacin, ofloxacin, and minocycline . The MICs of sparfloxacin, erythromycin, levofloxacin, ofloxacin, and minocycline for 90% of the 43 M . pneumoniae strains tested were 0.063, 0.016, 0.5, 1, and 0.5 microgram/ml, respectively . In the experimental pulmonary M . pneumoniae infection model in Syrian golden hamsters, sparfloxacin was as effective as erythromycin when orally administered at 15 mg/kg twice daily for 5 days and more effective than erythromycin when orally administered at 10 mg/kg once daily for 5 days . Sparfloxacin was more effective than levofloxacin and ofloxacin in both dosing regimens . The peak concentrations of sparfloxacin in hamster sera after administration of single oral doses of 15 mg/kg were almost the same as those in human sera after administration of single oral doses of 200 mg (the usual clinical dose), and the half-life of sparfloxacin in hamster serum was shorter than that in human serum after administration of a single oral dose of 200 mg . These results suggest that sparfloxacin may be clinically useful for the treatment of M . pneumoniae infections.

West J Med, 1994 Apr, 160(4), 321 - 5
Possible interactions with terfenadine or astemizole; Zechnich AD et al.; Concurrent use of terfenadine or astemizole with erythromycin or ketoconazole can prolong the QT interval and produce potentially fatal ventricular arrhythmias . We examine the frequency and patterns of concurrent prescribing and suggest methods to reduce the incidence of serious drug interactions . By retrospectively reviewing Oregon Medicaid prescription claims data over 22 months, we determined the frequency of concurrent prescribing of terfenadine or astemizole with macrolide antibiotics or ketoconazole . From 1991 to 1992, terfenadine use increased by 29%, with a seasonal peak in June of each year . Terfenadine was one of the most prescribed medications from March through July 1992 . During the 22 months reviewed, there were 122 episodes of concurrent use of terfenadine or astemizole with macrolide antibiotics or ketoconazole . Most of these episodes (94%) involved terfenadine . The frequency of concurrent use increased more than threefold from 1991 to 1992 . Although patients received prescriptions from different physicians in 48% of these episodes, they used different pharmacies only 3% of the time . We demonstrate that terfenadine use is extensive and increasing, thus increasing the possibility of serious interactions, and many physicians may remain unaware of this potential . Effective prospective screening by pharmacists could dramatically reduce the incidence of concurrent prescribing . Physicians must be aware of the potential for these drug interactions, avoid prescribing these medications concurrently, and consider these interactions in the evaluation of syncope and cardiac arrhythmias.

Can J Physiol Pharmacol, 1994 Apr, 72(4), 397 - 401
Mechanism-based inactivation of hepatic cytochrome P450 2C6 and P450 3A1 following in vivo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine to rats: differences from previously observed in vitro results; Kimmett SM et al.; Using progesterone 21-hydroxylase as a selective substrate for P450 2C6 in phenobarbital-treated male rats, and androstenedione and progesterone 6 beta-hydroxylases as well as erythromycin N-demethylase as selective markers for P450 3A1 in dexamethasone-treated female rats, we have shown that these P450 isozymes undergo mechanism-based inactivation after in vivo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC) . These results differ from our previous studies where no inactivation was observed after in vitro administration of 4-ethyl DDC to rat hepatic microsomes . We show that the differences between the in vivo and in vitro effects of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) analogues are due to the presence of residual 4-ethyl DDC in the in vitro experiments causing time-independent competitive inhibition and obscuring observation of mechanism-based inactivation.

Biochem Biophys Res Commun, 1994 Mar 30, 199(3), 1400 - 6
Evidence for multiple inducible cytochrome P450 isozymes in SENCAR mouse skin by pyridine; Agarwal R et al.; Pyridine, an amphipathic solvent, is widely used in industry and is also a constituent of tobacco and its smoke . Since, in addition to inhalation and ingestion, pyridine is also readily absorbed through skin, we assessed the effect of skin application of pyridine on monooxygenase activities and cytochrome P450 (CYP) isozymes and CYP mRNA levels in the skin of SENCAR mice . Compared to controls, a single topical application of pyridine (30 or 50 mg/100 g body weight) resulted in induction of cutaneous 7-ethoxyresorufin O-deethylase, 7-pentoxyresorufin O-depentylase, and erythromycin N-demethylase activities . Pyridine treatment also resulted in an increase in reactivity with monoclonal antibodies directed against CYP 1A1, 2B1 and 3A . In Northern blot analysis, treatment of pyridine also showed a significant increase in mRNA for Cyp1a-1 in the skin . These data indicate that murine skin contains multiple inducible CYP isozymes, and that pyridine results in the induction of at least three families of CYP in murine skin.

J Biol Chem, 1994 Mar 18, 269(11), 8524 - 8
Limited proteolysis and active-site studies of the first multienzyme component of the erythromycin-producing polyketide synthase; Aparicio JF et al.; The domain structure of the 6-deoxyerythronolide B synthase 1 component of the erythromycin-producing polyketide synthase from Saccharopolyspora erythraea has been investigated using limited proteolysis and active-site labeling . Trypsin, elastase, endoproteinase Glu-C, and endoproteinase Arg-C were used to cleave the multienzyme, and the sizes of the resulting fragments were assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis . The location of fragments within the primary structure was established by N-terminal sequence analysis . The cleavage pattern followed domain boundaries previously predicted on the basis of sequence alignments, but many predicted interdomain regions were not cleaved, even under the harshest conditions used . Initial proteolysis generated three large fragments: an N-terminal fragment (about 60 kDa) housing an acyltransferase-acyl carrier protein di-domain; a central fragment (about 90 kDa) containing a ketosynthase-acyltransferase di-domain; and a C-terminal fragment (about 220 kDa) containing the remaining six domains of the multienzyme, including the third acyltransferase . The intact multienzyme behaves as a dimer of molecular mass 660 kDa on gel filtration; and the C-terminal fragment remains dimeric . However, the N-terminal and central fragments appear to be monomeric species . After proteolysis of the multienzyme, the N-terminal di-domain was found to be specifically labeled after incubation with {14C}propionyl-CoA, providing the first evidence for its proposed role as a "loading domain" for the propionate starter unit . In contrast, the other two fragments were specifically acylated by {14C}methylmalonyl-CoA, indicating that both the other two acyltransferases remain enzymatically active after proteolysis.

Arch Intern Med, 1994 Mar 14, 154(5), 524 - 8
Bacillary angiomatosis . Clinical and histologic features, diagnosis, and treatment; Cotell SL et al.; Bacillary angiomatosis is a relatively new infection affecting primarily patients with human immunodeficiency virus or others with impaired host defenses . It presents most commonly with multiple red skin lesions, but visceral involvement may also occur, including involvement of the liver and spleen . Because of the dermatologic manifestations, bacillary angiomatosis may be mistaken for Kaposi's sarcoma . The diagnosis is made by identification of the characteristic histologic findings or genetic amplification by means of polymerase chain reaction . The causative agent was recently identified as Rochalimaea henselae, although Rochalimaea quintana may also play a role . Therapy with erythromycin or doxycycline is usually effective.

Pharmacoeconomics, 1994 Apr, 5(4), 343 - 50
Drug prices and third party payment: do they influence medication selection?
Hux JE, Naylor CD.
The growing burden of prescription drug costs has focused attention on factors which influence physicians' prescribing decisions . We hypothesised that third party coverage of prescription costs would elicit selection of expensive drugs, but that this tendency could be moderated by price reminders . In a mailed survey, primary care physicians throughout Ontario (n = 1072) were provided with the clinical scenario of a patient with an infectious exacerbation of chronic obstructive pulmonary disease, and asked to select diagnostic tests as well as 1 of 6 antibiotics . Two antibiotics were expensive (ciprofloxacin and cefaclor; average price $Can52.23), and 4 inexpensive {amoxicillin, cotrimoxazole (trimethoprim/sulfamethoxazole), erythromycin and tetracycline; average price $Can2.80} . Neither expensive drug is considered first line therapy for the condition described . Questionnaires differed in the presence or absence of drug benefit coverage and price information . The response rate was 71% . With third party cost coverage and prices shown, 18% of respondents selected an expensive antibiotic . This increased to 38% when the prices were omitted {odds ratio 2.72; 95% confidence interval (CI) 1.61, 4.60; p less than 0.001}, and decreased to 8% when the patient was said to have no drug benefits coverage (odds ratio 0.40; 95% CI 0.19, 0.84; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Br J Hosp Med, 1994 Mar 16-Apr 5, 51(6), 295 - 6
Intravenous clarithromycin; Winter J; Clarithromycin is a new macrolide with advantages over older macrolides such as erythromycin . The intravenous formulation has just been registered . This article reviews its activity experience with the drug and the indications for its use.

Pharmacotherapy, 1994 Mar-Apr, 14(2), 229 - 34
Impact of compliance and side effects on the clinical outcome of patients treated with oral erythromycin; Anastasio GD et al.; STUDY OBJECTIVE . To determine the relationship among compliance, side effects, and self-reported outcome for patients in an erythromycin trial . DESIGN . A retrospective analysis of data from a multicenter, prospective, single-blind, randomized trial . SETTING . Five metropolitan ambulatory care offices . PATIENTS . The 252 adults (> 18 yrs) were prescribed oral erythromycin 1.0 g/day (base equivalent) for infectious disorders . INTERVENTION . Subjects received erythromycin for 10 days and reported compliance, drug efficacy, and side effects in a daily diary . Compliance was measured by tablet count . RESULTS . A negative correlation was found between gastrointestinal symptom severity score and percentage of tablets taken (p < 0.001) . A significant positive correlation was seen between compliance and outcome (p < 0.001) . Subjects who took greater than 80% of the drug achieved the treatment goal more frequently than those taking 80% or less (94% vs 59%, p < 0.001) . CONCLUSIONS . Side effects of erythromycin adversely affected compliance . Compliance had a positive effect on self-reported outcome.

Pediatr Dermatol, 1994 Mar, 11(1), 69 - 71
Treatment of kerions; Honig PJ et al.; Therapy for kerions was evaluated by randomly assigning 30 patients to one of four treatment groups: group A griseofulvin, group B griseofulvin plus erythromycin, group C griseofulvin plus prednisone, and group D griseofulvin, erythromycin, and prednisone . Data indicate that antibiotic and steroid therapy, in addition to griseofulvin, may reduce scaling and pruritus, but does not reduce the time it takes for kerions to flatten.

Gut, 1994 Mar, 35(3), 333 - 7
Pharmacological modulation of gastric emptying rate of solids as measured by the carbon labelled octanoic acid breath test: influence of erythromycin and propantheline; Maes BD et al.; The *C (13C or 14C) labelled octanoic acid breath test was recently developed to measure the gastric emptying rate of solids . This study aimed to investigate whether it is sensitive enough to detect pharmacologically induced changes in the gastric emptying rate . Nine healthy volunteers were studied in basal condition, after intravenous administration of 200 mg erythromycin, and after peroral administration of 30 mg propantheline . Erythromycin significantly enhanced gastric emptying in all subjects, with an increase of the gastric emptying coefficient (p = 0.0043) in eight of nine and a fall in both the gastric half emptying time (p = 0.0020) and the lag phase (p = 0.0044) in all nine . Propantheline significantly reduced the gastric emptying rate, with a decreased gastric emptying coefficient (p = 0.0007) and an increased gastric half emptying time (p = 0.0168) in all subjects, but no change in the lag phase (p = 0.1214) . Further mathematical analysis showed that breath sampling at 15 minutes intervals over a four hour period is recommended to guarantee accuracy and the discriminative value of the breath test in various gastric emptying patterns . In conclusion the *C labelled octanoic acid breath test is sufficiently sensitive to show pharmacologically induced changes of gastric emptying rates of solids.

Am J Obstet Gynecol, 1994 Mar, 170(3), 829 - 32
A randomized, prospective trial comparing amoxicillin and erythromycin for the treatment of Chlamydia trachomatis in pregnancy; Silverman NS et al.; OBJECTIVE: Our purpose was to evaluate the efficacy of amoxicillin as an alternative therapy to erythromycin for the treatment of cervical chlamydial infections during pregnancy . STUDY DESIGN: A randomized, prospective trial of two treatment regimens for Chlamydia trachomatis was performed in a cohort of pregnant women enrolled for care in an inner-city, university-based prenatal clinic, with an alternate-therapy crossover arm for primary treatment failures . Pregnant women diagnosed with chlamydial infection by McCoy cell culture of cervical swabs were assigned to receive either 500 mg of amoxicillin three times daily or 500 mg of erythromycin four times daily for 7 days . Patients' partners were treated with doxycycline . Compliance information was obtained by a standardized questionnaire at a posttherapy follow-up visit . Patients with positive follow-up cultures were crossed over into the alternate treatment arm and recultured at a later visit . RESULTS: During the study period 74 women consented to participate in this trial; 36 were treated with amoxicillin and 38 with erythromycin . Initial cure rates of 82.3% (28/34) for the amoxicillin group and 84.6% (27/32) for erythromycin were obtained before crossover (p = 0.91); four patients in each group were lost to follow-up . Overall cure rates after crossover were 84.6% (33/39) for amoxicillin and 84.2% (32/38) for erythromycin (p = 0.83) . In the amoxicillin group 12.8% of patients reported side effects compared with 31.6% treated with erythromycin (p = 0.09), although seven erythromycin-treated patients compared with none of those in the amoxicillin arm stopped therapy because of side effects (p = 0.02) . CONCLUSION: Amoxicillin offers a reasonable alternative to erythromycin for the treatment of Chlamydia trachomatis in pregnancy, on the basis of both cure rates and patient compliance.

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