Am J Trop Med Hyg, 1992 Sep, 47(3), 378 - 82 Activity of azithromycin (CP-62,993) and erythromycin against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro; Gingras BA et al.; Several antibiotics, including the macrolide erythromycin and the azalides azithromycin (CP-62,993) and CP-63,956, that inhibit protein synthesis on 70S ribosomes demonstrated antimalarial effects in vitro against two strains of Plasmodium falciparum, one sensitive to chloroquine and the other resistant . In 48-hr incubations, erythromycin was 10-fold less potent than the azalides against the chloroquine-resistant strain . Erythromycin and the azalides were essentially equipotent against the chloroquine-sensitive strain . An additive effect occurred with the azalides in combination with chloroquine against both strains, but this was not seen with erythromycin. Cancer Res, 1992 Aug 15, 52(16), 4379 - 84 Role of cytochrome P-450 from the human CYP3A gene family in the potentiation of morpholino doxorubicin by human liver microsomes; Lewis AD et al.; The cytotoxicity of the morpholino derivative of doxorubicin (MRA) can be potentiated 50- to 100-fold by human liver microsomes and NADPH (J . Natl . Cancer Inst., 81: 1034, 1989) . This metabolic potentiation is inhibited by carbon monoxide or hypoxia, indicating that it is cytochrome P-450-dependent . The potentiation is also inhibited by the cytochrome P-450 inhibitors, SKF-525A and cimetidine . The metabolism by the microsomes is substrate-specific, varying markedly with alterations of either the morpholino or anthracycline ring substituents . No potentiation occurred with doxorubicin itself, or the cyanomorpholinyl, methoxypiperidinyl, N-hydroxyethyl or the O-bridged cyanomorpholinyl analogues of doxorubicin . We utilized a panel of human liver microsomes and cytochrome P-450 type-specific antibodies to further identify the isoform(s) of cytochrome P-450 that potentiated the cytotoxicity of MRA . The potentiation correlates well with the benzyloxyresorufin assay (r2 = 0.98) and aflatoxin B1 metabolism (r2 = 0.98), both assays that are relatively specific for CYP3A proteins . Correlations were also observed for the expression of protein(s) cross-reacting with an antibody against rat cytochrome P-450 CYP3A1 (r2 = 0.97) and MRA metabolism . This antibody against the rat cytochrome P-450 CYP3A isoform(s) inhibited more than 90% of the potentiation of the cytotoxicity by human liver microsomes . Antibodies against the CYP1A2, CYP2C6, and CYP2B2 isoforms produced no inhibition, nor did their expression by Western blotting correlate with MRA potentiation . Complete inhibition of the potentiation of MRA by human liver microsomes was found when the CYP3A substrates cyclosporin A and erythromycin were used in the reaction system . These data indicate that the CYP3A isoform(s) of cytochrome P-450 play a major role in the metabolism of MRA in vitro to a more active species. Acta Neurol Scand, 1992 Aug, 86(2), 120 - 3 Absence of interaction between oxcarbazepine and erythromycin; Keranen T et al.; When erythromycin (ERY) is co-administrated with the antiepileptic carbamazepine (CBZ), a drug interaction may cause an increase in CBZ plasma concentrations, which can result in CBZ related toxic symptoms . This cross-over study was designated to investigate whether ERY influences the pharmacokinetics of the new antiepileptic oxcarbazepine (OXC) and its metabolites . In 8 healthy volunteers there were no significant differences in AUC, peak plasma concentrations or time to peak concentration when OXC was administered either with or without ERY . The results of this study suggest that OXC may offer an important advantage over CBZ especially when concomitant therapy with ERY is required. Cryobiology, 1992 Aug, 29(4), 454 - 69 Thawed human hepatocytes in primary culture; Dou M et al.; In drug metabolism studies, isolated and cultured human hepatocytes provide a useful model for overcoming the difficulty of extrapolating from animal data . In vitro studies with human hepatocytes are scarce because of the lack of livers and suitable methods of storage . After developing a new method for cryopreservation of human hepatocytes, we evaluated the effects of deep freezing storage on their viability, morphology, and functional and toxicological capabilities in classical culture conditions . Freshly isolated human hepatocytes were cryopreserved in medium containing 10% Me2SO and 20% fetal calf serum, using a Nicool ST20 programmable freezer (-1.9 degrees C/min for 18 min and -30 degrees C/min for 4 min) . Cells were stored in liquid nitrogen . Viability of thawed human hepatocytes was 50-65% as assessed by erythrosin exclusion test prior to purification on a Percoll density gradient . Morphological criteria showed that thawed human hepatocytes require an adaptation period to the medium after seeding . Functional assessments showed that human hepatocytes which survive freezing and thawing preserve their protein synthesis capabilities and are able to secrete a specific protein, anionic peptidic fraction, which is involved in the hepatic uptake of bile-destined cholesterol . We then studied Midazolam biotransformation to test metabolic functions, and erythromycin toxicity by Neutral Red test (cell viability) and 3-(4,5-dimethylthiazol-2-yl)-diphenyl tetrazolium bromide test (cell metabolism) . All of these experiments indicated that thawed human hepatocytes should be used 38 h after seeding for optimum recovery of their functions: membrane integrity, protein synthesis, and stabilization of drug metabolism enzymes. Biopharm Drug Dispos, 1992 Aug, 13(6), 437 - 43 Studies on the intravenous pharmacokinetics in rabbit and in vitro protein binding of two new salts of erythromycin: erythromycin maltobionate and erythromycin fumarate; Basu SK et al.; Pharmacokinetics in rabbits following intravenous administration and in vitro protein binding were studied for two new salts of erythromycin (erythromycin maltobionate and erythromycin fumarate) . Serum erythromycin levels following intravenous injection were described by two compartment model kinetics, and values for the distribution volume of the central compartment, the peripheral compartment and overall distribution volume were calculated . The elimination half-lives of erythromycins in serum were 83 min, 168 min, and 103 min for erythromycin maltobionate, erythromycin fumarate, and erythromycin lactobionate (reference standard), respectively . The erythromycin salts were highly (c . 90 per cent) protein bound, but the binding was found to be reversible . Differences in the pharmacokinetic parameters after administration of equivalent doses of the salts, indicate possible variation in efficacies of different salts. Eur J Surg, 1992 Aug, 158(8), 407 - 11 Erythromycin accelerates delayed gastric emptying of solids in patients after truncal vagotomy and pyloroplasty; Xynos E et al.; OBJECTIVE--To find out if erythromycin (a motilin agonist) accelerated gastric emptying after vagotomy and in normal subjects . DESIGN--Double blind controlled study . SETTING--Two referral centres . SUBJECTS--15 patients who had previously undergone vagotomy and who did (n = 8) or did not (n = 7) have symptoms of gastric stasis and 10 normal controls . INTERVENTIONS--A standard meal containing 185 x 10(5) Bq -99mTc was eaten after either erythromycin 200 mg or 40 ml placebo (normal saline) had been given intravenously . Subjects were then scanned by gamma camera . MAIN OUTCOME MEASURES--Measurement of: the length of time from completion of the meal to the onset of gastric emptying; the length of time from completion of the meal until half of the meal had left the stomach; the length of the time from the onset of gastric emptying until half of the meal had left the stomach; and the percentage of the meal that was left in the stomach at 60 and 120 min after the end of the meal . RESULTS--Gastric emptying was significantly delayed in those patients with symptoms compared with normal subjects and patients without symptoms . Erythromycin accelerated the first two phases of gastric emptying in all patients and normal subjects, but did not affect the length of time from the onset of gastric emptying until half the meal had left the stomach . CONCLUSION--Erythromycin could be a useful gastrokinetic agent in patients with symptoms of gastric stasis after vagotomy. Biochem Pharmacol, 1992 Jul 22, 44(2), 275 - 83 Effect of age and gender on the activity of human hepatic CYP3A; Hunt CM et al.; Many pharmacokinetic investigations in the elderly population reveal decreased clearance of lipophilic drugs metabolized by the cytochrome P450 enzymes; however, few studies have evaluated aging-dependent or gender-related changes in specific cytochrome P450 enzymes . The clearance of quinidine, midazolam, triazolam, erythromycin, and lidocaine declines with age; these drugs are metabolized by the isoform, CYP3A . To determine whether these metabolic effects are due to changes in CYP3A, the effects of age and gender on CYP3A activity were examined . The activity of the human hepatic cytochrome P450, CYP3A, was quantified in vitro as erythromycin N-demethylation in microsomes prepared from forty-three resected human liver specimens obtained from patients, age 27 to 83, with normal liver function . Erythromycin N-demethylation varied 5-fold in human liver microsomes . CYP3A activity was 24% higher in females than males (P = 0.027) . CYP3A activity did not correlate with age, smoking status, ethanol consumption or percent ideal body weight . Large interindividual differences and a small female-specific increase in CYP3A activity were obtained . However, CYP3A activity was unaffected by age over the range of 27-83 years, suggesting that the aging-related alteration in the clearance of CYP3A substrates is secondary to changes in liver blood flow, size, or drug binding and distribution with aging. Diagn Microbiol Infect Dis, 1992 Jul, 15(5), 473 - 8 Evaluation of the E-Test for susceptibility testing of pneumococci; Jacobs MR et al.; The E-Test (AB Biodisk, Sweden) is an antibiotic gradient strip that is applied to an inoculated agar plate and results in an elliptical zone of inhibition that intercepts the graded strip, producing a quantitative (microgram per milliliter) result . Pneumococci (100) were used in this study, 38 penicillin-susceptible {minimal inhibitory concentrations (MICs), less than or equal to 0.12 micrograms/ml}, 42 intermediately resistant (MICs, 0.12-1.0 micrograms/ml), and 20 resistant (MICs, greater than 1 microgram/ml) . E-Test strips were evaluated on Mueller-Hinton agar plates with 5% sheep blood . Agar dilution MICs were determined by the National Committee for Clinical Laboratory Standards (NCCLS) method . Penicillin MICs for the E-Test tended to be slightly lower (one log2 dilution) than reference MICs due to the continuous scale from which E-Test MICs were read . All but two penicillin-susceptible isolates were correctly categorized by the E-Test method . Of the 62 penicillin-resistant strains, 59 had E-Test MICs of greater than or equal to 0.12 micrograms/ml, with 88% of these strains having E-Test MICs within one doubling dilution of the reference MICs . However, using the current NCCLS breakpoint MICs, many of the penicillin-resistant strains with reference MICs of 2 micrograms/ml were categorized as intermediate by the E-Test, with MICs of 0.38-1 microgram/ml . For chloramphenicol, erythromycin, and tetracycline, correlation of the two methods was excellent . E-Test chloramphenicol MICs provided clearer separation of susceptible and resistant strains than did the reference method . We conclude that the E-Test is a reliable method for determination of MICs of the antibiotics evaluated for pneumococci. Carcinogenesis, 1992 Jul, 13(7), 1191 - 8 Effects of cytochrome P450 inducers on I-compounds in rat liver and kidney DNA; Li D et al.; I-compounds are covalent DNA modifications presumably derived from endogenous electrophiles . To investigate the possible role of cytochrome P450 in I-compound metabolism, groups of female Sprague-Dawley rats (225-250 g) were treated i.p . with vehicle or cytochrome P450 inducers, i.e . 80 mg/kg phenobarbital (PB), 20 mg/kg 3-methylcholanthrene (MC) or 50 mg/kg pregnenolone-16 alpha-carbonitrile (PCN), once daily for 4 days . DNA synthesis rate was measured via {3H}methylthymidine incorporation . DNA adducts and I-compounds in liver and kidney were analyzed 1 and 8 days after the last treatment . Total liver and kidney microsomal cytochrome P450 content and activities of representative drug-metabolizing enzymes for PB, MC and PCN, i.e . benzphetamine N-demethylase, ethoxycoumarin O-deethylase (ECD) and erythromycin N-demethylase, were also determined in all groups . PCN caused significant depletion of total non-polar I-compounds at 1 day, compared to controls . Levels of several individual I-spots in liver were differentially reduced by each of the three inducers at 1 day . Most I-spots were restored to control levels at 8 days . Kidney I-compounds were not affected by PB or PCN, but MC reduced the level of one non-polar individual I-compound at 1 day . Except for the expected DNA adduct formation from MC, there were no qualitative changes in profiles of postlabeled modified nucleotides . Total cytochrome P450 content in liver microsomes and activities of individual P450 enzymes were significantly increased by treatment with each of the inducers at 1 day . This was, however, not the case at 8 days in PB- and PCN-treated livers . MC-treated rats, on the other hand, displayed elevated levels of liver cytochrome P450 and ECD at 8 days . In kidney, PB and PCN did not elicit induction of P450 and individual enzymes, but MC increased total P450 content and ECD activity at 1 day, and ECD activity alone at 8 days . These results suggest a major role for cytochrome P450 enzymes in the metabolism of I-compounds. Am J Physiol, 1992 Jul, 263(1 Pt 1), G24 - 8 Effect of erythromycin on gastric myoelectrical activity in normal human subjects; Chen J et al.; While a great deal of attention has been paid to the effect of erythromycin (Ery) on gastric contractility, its effect on gastric myoelectrical activity, which controls gastric motility, remains unknown . In this study, Ery (6 mg/kg) was infused intravenously in 14 normal human subjects (placebo controlled) . Gastric myoelectrical activity was recorded using the surface electrogastrographic method . The electrogastrogram (EGG) recordings were analyzed using spectral analysis methods . It was found that the presence of the 2-4 cycles/min activity (normal slow wave frequency range) in the EGG was 51 +/- 19% in the first hour of the intravenous Ery infusion, which was significantly smaller (P less than 0.001, t test) than that (72 +/- 20%) during the corresponding control period (intravenous saline) . This difference was, however, not quite significant (P = 0.067, t test) in the second hour after the infusions . The average score for nausea during Ery was 4.5 (0 for no nausea, 10 for the most severe nausea) . We conclude that 1) intravenous Ery induces irregularities in the cutaneous EGG in normal human subjects; and 2) the noninvasive cutaneous EGG is an attractive method both for the investigation of the effects of pharmacological and prokinetic agents such as Ery on gastric myoelectrical activity in humans and for correlating clinical responses to changes in the EGG. Am Rev Respir Dis, 1992 Jul, 146(1), 196 - 203 Erythromycin reduces neutrophils and neutrophil-derived elastolytic-like activity in the lower respiratory tract of bronchiolitis patients; Ichikawa Y et al.; Diffuse panbronchiolitis (DPB) is a disease of adults characterized by chronic inflammation of the respiratory bronchioles and the infiltration of chronic inflammatory cells . The clinical efficacy of erythromycin therapy has been demonstrated in DPB patients, but the mechanism of action of this drug is unknown . We investigated the localization of neutrophils in lung biopsy specimens, as well as the cell population and elastolytic-like and chemotactic activity of bronchoalveolar lavage (BAL) fluid, before and after treatment with erythromycin or ampicillin in 11 DPB patients (six biopsy-proven and five clinically diagnosed) and one follicular bronchiolitis patient . These bronchiolitis patients had a high percentage of neutrophil and a high neutrophil-derived elastolytic-like activity in BAL fluid compared with chronic bronchitis patients and normal control subjects . The number of neutrophils and the neutrophil-derived elastolytic-like activity in BAL fluid decreased significantly after treatment with erythromycin along with a significant improvement in pulmonary function studies, although there was no significant change in the chemotactic activity of BAL fluid . No significant reduction in BAL fluid neutrophilia was found in the ampicillin-treated patients . These results suggest an important role for the neutrophil in the pathogenesis or development of bronchiolitis, and also suggest that erythromycin may be useful for the treatment of bronchiolitis through its direct action upon host phagocytic cells. Gastroenterology, 1992 Jul, 103(1), 72 - 9 Effect of erythromycin on gastric motility in controls and in diabetic gastroparesis; Tack J et al.; The effect of three doses of erythromycin on interdigestive gastrointestinal motility and on plasma motilin levels was studied in healthy volunteers and patients with diabetic gastroparesis . Abnormalities of interdigestive motility were observed in 40% of the patients . In healthy volunteers, 40 mg erythromycin elicited a premature phase 3 that started in the stomach . In contrast to the spontaneous gastric phase 3, this erythromycin-induced phase 3 was not accompanied by a motilin peak . In patients with diabetic gastroparesis, 40 mg erythromycin induced a premature phase 3 in three patients, no response in one patient, and a burst of antral contractions in another patient . Doses of 200 and 350 mg erythromycin elicited a burst of antral phase-3-like contractions in both volunteers and patients, which was not accompanied by a motilin peak . This phase-3-like activity did not migrate to the small intestine and was not followed by a phase 1, but by a prolonged period of antral contractile activity . The number and amplitude of antral contractions after 200 or 350 mg erythromycin were significantly higher than after 40 mg . The motor patterns induced by different doses of erythromycin offer potential therapeutic applications. Gastroenterology, 1992 Jul, 103(1), 114 - 9 Intravenous erythromycin overcomes small intestinal feedback on antral, pyloric, and duodenal motility; Fraser R et al.; The retardation of gastric emptying caused by intraduodenal lipid is associated with suppression of antral contractions and stimulation of localized pyloric contractions . Similar patterns of motility have been described in patients with gastroparesis . The effect of erythromycin on the antropyloroduodenal motor responses to intraduodenal lipid was investigated . In 17 volunteers an intraduodenal lipid infusion (10% Intralipid) was given at 1 mL/min for 50 minutes . Either erythromycin (3 mg/kg) or saline was administered IV for 15 minutes, beginning 20 minutes after the start of the intraduodenal lipid infusion . Antral, pyloric, and duodenal motility were measured with a sleeve/sidehole manometric assembly . Intraduodenal lipid stimulated localized pyloric contractions . Erythromycin suppressed localized phasic (P less than 0.003) and tonic (P less than 0.002) pyloric pressure waves and stimulated antral (P less than 0.003) and duodenal pressure waves (P less than 0.02) . After erythromycin antral pressure waves were usually of high amplitude (greater than 50 mm Hg) and often associated with duodenal pressure waves . It was concluded that erythromycin overcomes the effects of intraduodenal lipid on antral, pyloric, and duodenal motility . These effects probably contribute to the gastrokinetic properties of erythromycin. J Am Podiatr Med Assoc, 1992 Jul, 82(7), 382 - 5 Ciprofloxacin in the treatment of Mycobacterium fortuitum infection of the peroneal tendons . A case report; Binning TA et al.; In the case reported, M . fortuitum was sensitive in vitro to amikacin, erythromycin, tobramycin, and ciprofloxacin . Because the patient did not respond to long-term therapy with amikacin and erythromycin, an experimental antibiotic, ciprofloxacin, was tried . Only after extensive surgical debridement and 2 1/2 months of oral ciprofloxacin therapy was the infection eradicated and wound healing obtained . The authors conclude that a wound that has reopened, but remains indolent, exudes a clear, serous drainage and responds poorly to antibiotics should suggest a possible mycobacterial infection . Combination antibiotic therapy is recommended because of the high rate of relapse and development of resistance to drugs . Extensive surgical debridement of all infected tissue remains the primary treatment . The therapeutic value of ciprofloxacin and other newer antibiotics in the treatment of mycobacterial infection is promising. Nihon Kyobu Shikkan Gakkai Zasshi, 1992 Jul, 30(7), 1315 - 21 {An autopsy case of Marfan syndrome with bronchiectasis and multiple bullae}; Saito H et al.; We report an autopsy case (27-year-old male) with Marfan syndrome, who died of chronic respiratory failure due to bronchiectasis and multiple bullae in both lungs . He had suffered from expectoration of massive amounts of sputum since the age of 15 years . At this time, chest roentgenogram had revealed bronchiectatic changes in the bilateral lower lung fields . Seven years later at the age of 22 years, the formation multiple bullae in both lungs were added to the bronchiectatic changes on chest roentgenogram . Administration of erythromycin (400 mg/day) was started in February, 1987, and the massive sputum volume markedly decreased according to appearance of bullous formation . He was admitted to our department because of deterioration with chronic respiratory failure and right heart failure at 26 years in December, 1989 . Although various therapy was performed, he died of chronic respiratory failure in February, 1990 . Autopsy findings were as follows: (1) cyclindrical bronchiectatic changes in bilateral lower lobes and (2) extensive multiple bullae in the subpleural areas with bronchiectatic changes in the middle and bilateral lower lobes, with no bronchiectatic changes in the bilateral upper lobes . Several pulmonary disorders accompanying Marfan syndrome have been reported, especially in children . However, the present case demonstrated that fetal pulmonary involvement by Marfan syndrome may not present until adulthood, and affect both airways and lung parenchyma. Nihon Kyobu Shikkan Gakkai Zasshi, 1992 Jul, 30(7), 1285 - 9 {Contents of chemical mediators in sputum in a case of mycoplasma pneumoniae bronchiolitis resembling bronchial asthma}; Takahashi N et al.; A case of Mycoplasma pneumoniae bronchiolitis with hypoxemia is presented . A 41-year-old man was admitted to hospital because of fever, productive cough and dyspnea with wheezing of one month duration . On admission, bronchial asthma was suspected on the basis of reversible airflow obstruction and sputum eosinophilia . However, despite treatment with bronchodilators, his condition did not improve . Chest film and computed tomogram revealed small nodular shadows and tramlines in the bilateral lower lung fields, and pulmonary function tests indicated peripheral airway obstruction . Serologic titer for Mycoplasma pneumoniae was 1:160 . A diagnosis of bronchiolitis due to Mycoplasma pneumoniae was made . Improvement of lung function and roentgenographic findings was observed following administration of erythromycin and doxycycline . The concentrations of prostanoids in sputum were markedly higher than in cases of bronchial asthma, and decreased as he improved . These observations suggest that Mycoplasma bronchiolitis should be considered in the differential diagnosis of wheezing, and that measurement of prostanoids in sputum may be useful in the differentiation of infective bronchiolitis and bronchial asthma. Am J Physiol, 1992 Jul, 263(1 Pt 1), G52 - 9 Effects of erythromycin in the dog upper gastrointestinal tract; Holle GE et al.; The effects of erythromycin on motor and electrical behavior of the antrum, pylorus, and duodenum were determined in chronically instrumented, awake dogs . Erythromycin infusion resulted in an abrupt, powerful increase in motility . The motility index increased 18-fold in the antrum, 15-fold in the pylorus, and 8-fold in the duodenum . Bradyarrhythmia with a 30% decrease in slow-wave frequency occurred in all animals . Retrograde giant contractions in association with retching and vomiting occurred in 88% of the dogs . Neostigmine was less potent than erythromycin in increasing motility . Hexamethonium given intra-arterially during erythromycin infusion abolished motility for 7.2 +/- 2.9 min and intra-arterial atropine did so for 51 +/- 25 min . Hexamethonium or atropine restored the electrical slow-wave frequency . The results provide evidence that erythromycin action involves cholinergic pathways including ganglionic transmission. EMBO J, 1992 Jul, 11(7), 2717 - 26 Yeast mitochondrial DNA mutators with deficient proofreading exonucleolytic activity; Foury F et al.; The MIP1 gene which encodes yeast mitochondrial DNA polymerase possesses in its N-terminal region the three motifs (Exo1, Exo2 and Exo3) which characterize the 3'-5' exonucleolytic domain of many DNA polymerases . By site directed mutagenesis we have substituted alanine or glycine residues for conserved aspartate residues in each consensus sequence . Yeast mutants were therefore generated that are capable of replicating mitochondrial DNA (mtDNA) and exhibit a mutator phenotype, as estimated by the several hundred-fold increase in the frequency of spontaneous mitochondrial erythromycin resistant mutants . By overexpressing the mtDNA polymerase from the GAL1 promoter as a major 140 kDa polypeptide, we showed that the wild-type enzyme possesses a mismatch-specific 3'-5' exonuclease activity . This activity was decreased by approximately 500-fold in the mutant D347A; in contrast, the extent of DNA synthesis was only slightly decreased . The wild-type mtDNA polymerase efficiently catalyses elongation of singly-primed M13 DNA to the full-length product . However, the mutant preferentially accumulates low molecular weight products . These data were extended to the two other mutators D171G and D230A . Glycine substitution for the Cys344 residue which is present in the Exo3 site of several polymerases generates a mutant with a slightly higher mtDNA mutation rate and a slightly lower 3'-5' exonucleolytic activity . We conclude that proofreading is an important determinant of accuracy in the replication of yeast mtDNA. Riv Eur Sci Med Farmacol, 1992 Jul-Aug, 14(4), 261 - 4 {Clinical-therapeutic considerations in pertussis}; Catania S et al.; One-hundred and seventy-one cases of pertussis were observed at the Institute of Infections Diseases and at the 2nd Division of Infectious Diseases of the Policlinico Umberto I in Rome from January 1, 1987 to June 30, 1991 . All subjects were treated according to a therapeutic protocol consisting of macrolides (erythromycin or myocamicin) at doses of 40-50 mg/die, betamethasone 0.1 mg/kg/die, specific immunoglobulin G at doses of 0.5 ml/kg repeated after 24 hours (new born babies and babies still unweaned) and oxygen therapy during the paroxystic fits . In 20 patients who were over the first year of life and who had serious asphyxiated fits, bronchodilators (trimetochinol or salbutamol) were added to the previous therapeutic scheme . Our data show both efficacy of therapeutic protocol and importance of early starting the treatment to shorten the length of disease, the strength of asphyxiated fits, and the risk of contagion. Biochem Pharmacol, 1992 Jun 23, 43(12), 2655 - 8 Investigation of the mechanism by which cyclophosphamide alters cytochrome P450 in male rats; McClure MT et al.; The effects of administration of the cytotoxic agent cyclophosphamide on cytochrome P450 have been examined in the liver microsomes of male rats . Microsomes were prepared after cyclophosphamide administration 1, 4 or 7 days prior to killing . The coadministration of cyclophosphamide with N-acetylcysteine has also been investigated . The microsomes were assayed for NADPH cytochrome P450 reductase, aminopyrine demethylase, erythromycin demethylase and androstenedione hydroxylase activities . Activities were generally unchanged 1 and 4 days after cyclophosphamide administration and were significantly decreased at 7 days . N-Acetylcysteine did not alter the effects of cyclophosphamide at 7 days . The effect of cyclophosphamide in vitro has also been examined . Microsomes from untreated animals were subjected to the above assays following in vitro metabolic activation of cyclophosphamide in a reconstituted system in the presence and absence of N-acetylcysteine . All enzyme activities were significantly reduced by the cyclophosphamide metabolites . The presence of N-acetylcysteine prevented this inactivation . The results of these investigations suggest that cyclophosphamide inactivates hepatic cytochrome P450 in vitro and in vivo via different mechanisms. Presse Med, 1992 Jun 20, 21(23), 1072 - 8 {Disorders of gastric emptying}; Jian R; Disorders of gastric emptying are observed in many clinical situations . Their symptoms are diverse and correlate poorly with the objective abnormalities of gastric emptying . The underlying mechanism consists of abnormalities of basal electrical rhythm, fundic compliance, post-prandial antral motricity and, above all, antro-pyloro-duodenal co-ordination, associated to varying degrees . Among possible causes 3 clinical situations predominate: diabetes mellitus, functional gastrointestinal disorders (idiopathic dyspepsia) and sequelae of gastric surgery where retention of solids and accelerated evacuation of liquids may coexist in the same patient . Treatment of gastric incontinence rests, almost exclusively, on dietary measures, but several drugs, such as metoclopramide, domperidone and cisapride, are available to treat gastric stasis . Other compounds, notably motilin agonists (erythromycin and its derivatives) are currently being evaluated and will reinforce this therapeutic armentarium in a not too distant future. Presse Med, 1992 Jun 20, 21(23), 1064 - 9 {Pneumopathies caused by Chlamydia pneumoniae}; Bruaire JP et al.; Among the atypical pneumonias observed between March 1990 and March 1991, 6 were diagnosed as being caused by Chlamydia pneumoniae of the TWAR strain . The serological diagnosis was obtained by a microimmunofluorescence test . All 6 patients had anti-TWAR antibody levels higher than 512; they were treated with a macrolide administered by the oral route and were cured without sequelae or recurrences . Four cases received a ten day course of roxithromycin 300 mg/day and one case received erythromycin 2 g/day also for 10 days . The sixth case received a short course of azithromycin 500 mg once daily for three days . In 2 other patients presenting with clinical and radiological signs of pneumonia the diagnosis of C . pneumoniae infection could not be made despite an antibody level equal or higher than 512, since the serological results showed cross-reactions between C . pneumoniae, C . trachomatis and C . psittaci antibody responses. FEBS Lett, 1992 Jun 15, 304(2-3), 225 - 8 Identification of DEBS 1, DEBS 2 and DEBS 3, the multienzyme polypeptides of the erythromycin-producing polyketide synthase from Saccharopolyspora erythraea; Caffrey P et al.; The ery A region of the erythromycin biosynthetic gene cluster of Saccharopolyspora erythraea has previously been shown to contain three large open reading frames (ORFs) that encode the components of 6-deoxyerythronolide B synthase (DEBS) . Polyclonal antibodies were raised against recombinant proteins obtained by overexpression of 3' regions of the ORF2 and ORF3 genes . In Western blotting experiments, each antiserum reacted strongly with a different high molecular weight protein in extracts of erythromycin-producing S . erythraea cells . These putative DEBS 2 and DEBS 3 proteins were purified and subjected to N-terminal sequence analysis . The protein sequences were entirely consistent with the and DEBS 3 proteins were purified and subjected to N-terminal sequence analysis . The protein sequences were entirely consistent with the translation start sites predicted from the DNA sequences of ORFs 2 and 3 . A third high molecular weight protein co-purified with DEBS 2 and DEBS 3 and had an N-terminal sequence that matched a protein sequence translated from the DNA sequence some 155 base pairs upstream from the previously proposed start codon of ORF1. Gene, 1992 Jun 15, 115(1-2), 97 - 103 Biosynthesis of the erythromycin macrolactone and a rational approach for producing hybrid macrolides; Donadio S et al.; The three eryA genes involved in the formation of the polyketide portion of the macrolide antibiotic erythromycin in Saccharopolyspora erythraea, appear to be organized in a single transcriptional unit on the basis of the results of gene disruption experiments . An insertion sequence-like element of lower G + C content separates eryAI from eryAII . The organization of the enzymatic domains present in the eryA-encoded multifunctional polypeptides, determined by computer-assisted analysis, is presented . This has enabled the determination of a putative dehydratase domain . A rational approach for producing novel macrolides by introducing selected changes in polyketide synthase genes is outlined . The isolation of a lactone intermediate resulting from an early synthesis step in macrolactone formation is also presented. Gene, 1992 Jun 15, 115(1-2), 75 - 84 Resistance to macrolides and lincosamides in Streptomyces lividans and to aminoglycosides in Micromonospora purpurea; Cundliffe E; Ribosomal (r) resistance to gentamicin in clones containing DNA from the producing organism Micromonospora purpurea is determined by grmA, and not by kgmA as originally reported . The kgmA gene originated in Streptomyces tenebrarius and is identical to kgmB . Both grmA and kgm encode enzymes that methylate single specific sites within 16S rRNA, although the site of action of the grmA product has not yet been determined . In either case, the methylated nucleoside is 7-methyl G . Inducible resistance to lincomycin (Ln) and macrolides in Streptomyces lividans TK21 results from expression of two genes: lrm, encoding an rRNA methyltransferase and mgt, encoding a glycosyl transferase (MGT), that specifically inactivates macrolides . The lrm product monomethylates residue A2058 within 23S rRNA (Escherichia coli numbering scheme) and confers high-level resistance to Ln with much lower levels of resistance to macrolides . Substrates for MGT, which utilises UDP-glucose as cofactor, include macrolides with 12-, 14-, 15- or 16-atom cyclic polyketide lactones (as in methymycin, erythromycin, azithromycin or tylosin, respectively) although spiramycin and carbomycin are not apparently modified . The enzyme is specific for the 2'-OH group of saccharide moieties attached to C5 of the 16-atom lactone ring (corresponding to C5 or C3 in 14- or 12-atom lactones, respectively) . The lrm and mgt genes have been cloned and sequenced . The deduced lrm product is a 26-kDa protein, similar to other rRNA methyltransferases, such as the carB, tlrA and ermE products, whereas the mgt product (deduced to be 42 kDa) resembles a glycosyl transferase from barley.(ABSTRACT TRUNCATED AT 250 WORDS) Gene, 1992 Jun 15, 115(1-2), 151 - 7 The evolutionary role of secondary metabolites--a review; Maplestone RA et al.; It is argued that organisms have evolved the ability to biosynthesise secondary metabolites ('natural products') due to the selectional advantages they obtain as a result of the functions of the compounds . Pleiotropic switching, the simultaneous expression of sporulation and antibiotic biosynthesis genes in Streptomyces, is interpreted in terms of the defense roles of antibiotics . The clustering together of antibiotic biosynthesis, regulation, and resistance genes, and in particular the staggering complexity shown in the case of the gene cluster for erythromycin A biosynthesis, implies that these genes have been selected as a group and that the antibiotics function in antagonistic capacities in nature. Gene, 1992 Jun 15, 115(1-2), 119 - 25 Complex organization of the Streptomyces avermitilis genes encoding the avermectin polyketide synthase; MacNeil DJ et al.; The avermectin (Av) polyketide synthase (PKS) and erythromycin (Er) PKS are encoded by modular repeats of DNA, but the genetic organization of the modules encoding Av PKS is more complex than Er PKS . Sequencing of several related DNA fragments from Streptomyces avermitilis that are part of the Av biosynthetic gene cluster, revealed that they encode parts of large multifunctional PKS proteins . The Av PKS proteins show strong similarity to each other, as well as similarity to Er PKS proteins {Donadio et al., Science 252 (1991) 675-679} and fatty acid synthases . Partial DNA sequencing of the 65-kb region containing all the related sequence elements in the avr genes provides evidence for twelve modular repeats encoding FAS-like domains . The genes encoding the Av PKS are organized as two sets of six modular repeats which are convergently transcribed. Acta Crystallogr C, 1992 Jun 15, 48 ( Pt 6), 1145 - 8 Structure of a protected C3-C10 subunit of erythromycin and its C8 epimer; Lynch VM et al.; (1) (2S,3R,4R,6R)-3,4-O-Carbonyl-7,7-dimethylenedithio-2,4,6-trimet hylnonane-1,3,4-triol, C15H26O4S2, M(r) = 334.49, triclinic, P1, a = 6.460 (2), b = 8.917 (3), c = 15.616 (5) A, alpha = 83.60 (3), beta = 83.41 (2), gamma = 89.52 (2) degrees, V = 888.0 (5) A3, Z = 2, Dx = 1.25 g cm-3, mu = 2.980 cm-1, lambda (Mo K alpha) = 0.7107 A, F(000) = 360, T = 298 K, R = 0.0465 for 1832 reflections {Fo greater than or equal to 4 sigma (Fo)} . (2) (2S,3R,4R,6S)-3,4-O-Carbonyl-7,7-dimethylenedithio-2,4,6-trimet hylnonane-1,3,4-triol, C15H26O4S2, M(r) = 334.49, monoclinic, P21, a = 8.1849 (8), b = 8.9456 (14), c = 12.0258 (14) A, beta = 100.878 (8) degrees, V = 864.7 (2) A3, Z = 2, Dx = 1.28 g cm-3, mu = 3.060 cm-1, lambda (Mo K alpha) = 0.7107 A, F(000) = 360, T = 298 K, R = 0.0569 for 2001 reflections {Fo greater than or equal to 4 sigma (Fo)} . The two diastereomers differ in configuration at C6 . For (1) there are two unique molecules in the unit cell . These two molecules differ in conformation by a rotation about the bond C7-C8 . The molecules are hydrogen bonded into infinite chains along b . The hydroxyl O atom of molecule (2), O10', acts as both a donor and an acceptor in hydrogen-bonding interactions with the carbonyl O atom, O14, and the hydroxyl H atom, H10, of molecule (1).(ABSTRACT TRUNCATED AT 250 WORDS) Mech Ageing Dev, 1992 Jun, 64(1-2), 189 - 99 Hepatic cytochrome P-4503A (CYP3A) activity in the elderly; Hunt CM et al.; Elderly patients exhibit decreased clearance of multiple drugs biotransformed by the hepatic cytochromes P-450 . The cytochromes P-450 are a superfamily of enzymes, which comprise a central component of phase I drug metabolism . Distinct isoforms metabolize specific drugs . In human liver microsomes, the glucocorticoid-inducible cytochrome P-450IIIA, CYP3A, catalyzes the N-demethylation of erythromycin . To examine the activity of hepatic CYP3A in elderly males and females, erythromycin N-demethylation was examined, as reflected by the recently described {14C}erythromycin breath test in 24 healthy volunteers, age 70-88 . The {14C}erythromycin breath test was measured in normal elderly males and females to: (a) determine persistence of the gender-related dimorphism (evident in younger subjects) of CYP3A activity in the elderly population, (b) examine the effect of % ideal body weight, age, diet, and medication use on the activity of human hepatic CYP3A, and (c) compare breath test results obtained in normal geriatric volunteers with published results obtained in younger subjects, to determine aging-related alterations in CYP3A enzyme activity . Erythromycin N-demethylation varied fivefold among these patients . Similar to earlier studies examining erythromycin N-demethylation in younger subjects, CYP3A activity was found to vary with gender in the geriatric cohort . {14C}Erythromycin N-demethylation at 60 min was 3.14% +/- 0.75 (n = 13) in females and 2.15% +/- 0.77 (n = 11) in males (P = 0.005) . In evaluating the role of % ideal body weight and % dietary fat using multivariable linear regression analyses, {14C}erythromycin N-demethylation, was found to decline significantly as % ideal body weight increased (P = 0.001) . This was not confounded by gender . {14C}Erythromycin N-demethylation was not related to dietary fat intake (P less than 0.13) . {14C}Erythromycin N-demethylation in the elderly volunteers was similar to values reported for subjects aged 20-60 . Performance of a new non-invasive test of the human hepatic glucocorticoid-inducible CYP3A in a geriatric cohort suggests that: (a) the gender-related heterogeneity in function of the glucocorticoid inducible human CYP3A persists during normal aging, (b) that the activity of CYP3A may decrease in obesity, and (c) that the activity of CYP3A is stable throughout normal ageing. Clin Infect Dis, 1992 Jun, 14(6), 1208 - 12 Infection caused by Mycobacterium chelonae: a diagnostic and therapeutic problem in the neutropenic patient; McWhinney PH et al.; Mycobacterium chelonae, a rapidly growing species, is a significant cause of fever in neutropenic patients . We describe three febrile neutropenic patients at the Royal Free Hospital from whom this organism was isolated on several occasions . The condition of the first patient improved as the neutrophil count recovered . The second patient developed pulmonary disease and required surgical resection of a pulmonary lesion . The third patient, who had rapidly progressive, diffuse pulmonary disease, responded to an antibiotic regimen including erythromycin and ciprofloxacin . Both our findings and reports in the literature suggest that neutropenia may be a major risk factor for disseminated infection due to M . chelonae and that treatment is effective only after the recovery of the neutrophil count. Gastroenterology, 1992 Jun, 102(6), 2071 - 6 Effect of oral erythromycin on gallbladder motility in normal subjects and subjects with gallstones; Catnach SM et al.; The action of the motilin receptor agonist erythromycin on human gallbladder contraction, measured by ultrasound, both in normal subjects and those with gallstone disease was studied . In 17 normal subjects, oral erythromycin administration (500 mg; vs . placebo) reduced fasting gallbladder volume at 2 hours (26.2 vs . 19.0 mL; P less than 0.001), and postprandial residual gallbladder volume (9.0 vs . 4.4 mL; P less than 0.001) and the rate constant of gallbladder emptying following the meal was significantly increased . Erythromycin also reduced fasting and residual gallbladder volumes in 13 patients with gallstone disease: in 6 who underwent cholecystolithotomy, fasting volume was 29.5 vs . 22.3 mL (P less than 0.05) and residual volume was 17.7 vs . 6.5 mL (P less than 0.05), and in 7 with gallstones in situ, fasting volume was 23.8 vs . 14.3 mL (P less than 0.05) and residual volume was 17.2 vs . 5.0 mL (P less than 0.05) . In 7 of 8 subjects with gallstones and impaired gallbladder emptying, the gallbladder emptied normally following administration of erythromycin, and in 3 of the other 5 gallstone subjects gallbladder emptying was increased . In 6 normal subjects given erythromycin three times weekly for 1 month, the effect was maintained (fasting volume, 18.8 mL, P less than 0.001; residual volume, 3.7 mL, P less than 0.001) . Oral erythromycin significantly reduces fasting and postprandial residual gallbladder volumes in both normal subjects and subjects with gallstones and reverses the gallbladder motility defect found in a proportion of subjects with gallstones . This effect is maintained for a month in normal subjects. Dig Dis Sci, 1992 Jun, 37(6), 949 - 54 Pneumatosis cystoides intestinalis in intestinal pseudoobstruction . Resolution after therapy with metronidazole; Tak PP et al.; A 66-year-old man with chronic idiopathic intestinal pseudoobstruction was admitted for pneumatosis cystoides intestinalis, complicated by pneumoperitoneum . The latter conditions resolved after treatment with metronidazole . There was no favorable effect of the prokinetic agents cisapride and erythromycin . To the authors' knowledge, this is the first reported case of successful treatment of pneumatosis cystoides intestinalis with metronidazole in primary chronic intestinal pseudoobstruction. Methods Find Exp Clin Pharmacol, 1992 Jun, 14(5), 367 - 72 Absorption of various erythromycin esters and salts in mice after intragastric intubation; Vainio PJ et al.; Erythromycin base and its different salts and esters were given intragastrically to mice . Serum concentrations of erythromycin and its 2'-esters were determined by the bacterial growth inhibition method . Acetyl and propionyl erythromycin were the best absorbed 2'-esters, and differed significantly from butyryl erythromycin and erythromycin base . Erythromycin estolate yielded a larger area under the concentration curve than acistrate or stearate . Among the syrup preparations, erythromycin acistrate was significantly better absorbed than 2'-ethylsuccinyl erythromycin . Absorption of 2'-esters decreased with increasing number of esterified carbon atoms and increasing hydrophobicity and increasing log P value (the logarithm of octanol-water partition coefficient) . In addition to sufficient lipophilicity, the optimum absorption of erythromycin esters seems to require a high hydrophilicity. P N G Med J, 1992 Jun, 35(2), 95 - 100 Compliance profiles of paediatric patients in an outpatient department; Kiyingi KS et al.; A cross-sectional study was carried out in paediatric patients with acute illnesses attending an outpatient clinic at Angau Memorial Hospital, Lae . The aim of the study was to estimate the level of compliance to previously prescribed medication . 45 sick children were included in this study . Their parents or guardians were interviewed and their health record books carefully examined for details of prescribed and administered medication . Poor compliance to prescribed medication was observed in 38% of cases . A number of reasons for the poor compliance were documented . In a second, closely related study designed to determine the reliability of oral medicine ingestion, 348 children were enlisted . In 7% of them oral medicine ingestion was not satisfactory . These results emphasize the need to carefully consider each sick child individually, especially with regard to optimizing compliance, whenever drugs are prescribedPIP: Health practitioners interviewed the parents or the guardians of 45 patients at the Children's Outpatient Department (COPD) of Angau Memorial Hospital in Lae in Morobe Province in Papua New Guinea to determine compliance levels in these children (Study 1) . They also monitored and recorded adequacy of oral treatment among 348 pediatric patients given oral medication in the COPD (Study 2) . In Study 1, 62% of the patients had good compliance with prescribed medication . Even though compliance was better for those who received injectable medications than it was for those who received oral medications (72% vs . 52%), the difference was not significant . Referred patients were more compliant than review patients (76% vs, 54%), but this difference was also not significant . Clinic staff explained the illness and medicine usage to most parents or guardians with poor compliance (82% and 76%, respectively) . Of the 13 parents or guardians who had received instructions about medicine usage, 69% (9) claimed to have understood medicine usage . Respiratory infections were the leading disease of patients with poor compliance (about 77%) . The antibiotics included intramuscular procaine penicillin, oral amoxicillin, oral erythromycin, and oral chloramphenicol . The most common reasons for noncompliance, in descending order, were distance to the clinic for repeat injectable medication, forgetfulness, confusion, and prescription not filled . In Study 2, poor compliance stood at 7%, yet none of these patients refused medication . Poor compliance was due to spitting out the medicine or vomiting within 5 minutes of ingestion . Health practitioners need to consider each child individually to optimize drug compliance . They should take into consideration side effects of the drug, distance from home to the clinic when repeated injections are indicated, and symptoms of the disease such as vomiting . J Vet Pharmacol Ther, 1992 Jun, 15(2), 188 - 93 Effect of erythromycin on L-threonine transport in rabbit jejunum in vitro; Navarro H et al.; Several antibiotics characterized by different molecular structures are known to affect some intestinal activities . Some of them have been described as inhibitors of the intestinal sugar and amino acid transport with different mechanisms . Erythromycin (EM) is a macrolide antibiotic acting as a motilin agonist and thus stimulating the gastrointestinal motor activity . Since several substances which increase the motor activity of the gastrointestinal tract may produce effects on the intestinal absorption of nutrients, the present study has been carried out to determine whether erythromycin affects the L-threonine intestinal absorption . The results obtained indicate that erythromycin diminishes the L-threonine intestinal transport, probably at the mucosal border level . Two groups of experiments carried out, with Na(+)-deprived medium and ouabain-enriched medium, might indicate that erythromycin action could be due to either a direct or an indirect action on the Na(+)-dependent L-threonine transport located in the brush border. Kansenshogaku Zasshi, 1992 Jun, 66(6), 736 - 42 {Two cases of diffuse panbronchiolitis receiving long-term erythromycin (EM) therapy with acute exacerbation due to EM-resistant pneumococcus}; Yoshimoto E et al.; The first case was a 73-year-old woman with chief complaints of fever, cough, purulent sputum and dyspnea . EM therapy was begun in December 1983 due to a diagnosis of diffuse panbronchiolitis (DPB) . Subsequently, P . aeruginosa was persistently detected, while in February 1991 at the time of an acute exacerbation of the DPB P . aeruginosa and S . pneumoniae were detected by TTA . The second case was a 65-year-old man with chief complaints of fever, cough and purulent sputum . DPB was diagnosed and EM therapy was begun in December 1985 . In January 1991, pneumonia developed, at the time when S . pneumoniae was detected by TTA . In both cases, rapid disappearance of S . pneumoniae from the sputum and alleviation of symptoms were obtained with carbapenem antibiotic administration . Both strains were resistant to EM, Tetracycline (TC), Minocycline (MINO) and Clindamycin (CLDM) . Particularly, S . pneumoniae of case 2 showed low sensitivity to Ampicillin (ABPC), Cefotiam (CTM) and Cefoxitin (CFX) as well . These cases showed acute exacerbations due to EM-resistant pneumococcus during long-term therapy with EM, and are of interest in that they may shed light on the relation between long-term EM therapy and the emergence of resistant pneumococcus. J Chromatogr, 1992 May 27, 600(1), 99 - 108 Determination of erythromycin ethylsuccinate by liquid chromatography; Cachet T et al.; A method is described for the determination of erythromycin ethylsuccinate by liquid chromatography . A C18 reversed-phase column (25 cm x 4.6 mm I.D.) was used with acetonitrile-0.2 M tetrabutylammonium sulphate (pH 6.5)-0.2 M phosphate buffer (pH 6.5)-water {x:5:5:(90-x)} as mobile phase . The proportion of acetonitrile (x) has to be adapted to the type of stationary phase used . For RSil C18 LL, 42.5% was used . The column was heated at 35 degrees C, the flow-rate was 1.5 ml/min and UV detection was performed at 215 nm . The main component, erythromycin A ethylsuccinate, was separated from all other components which were present in commercial samples . The main impurities were erythromycin A and the ethylsuccinate esters of erythromycin B and C . The amide N-ethylsuccinyl-N-demethylerythromycin A was shown to be present in all the samples examined . The method was successfully applied to the analysis of specialities. Diagn Microbiol Infect Dis, 1992 May-Jun, 15(4 Suppl), 133S - 137S Multicenter double-blind study of the efficacy and tolerance of roxithromycin versus erythromycin ethylsuccinate in acute orodental infection in adults . Odontogenic Infections Study Group; Deffez JP et al.; A total of 194 patients with orodental infection were randomized either to roxithromycin 150 mg twice daily plus placebo or to erythromycin 1 g twice daily plus placebo for a mean duration of 8 days . The infections consisted of cellulitis, pericoronitis, and adenopathy, or any two in combination . In the 176 cases in which efficacy was evaluable, outcome was satisfactory in 94% and 91% of cases treated with roxithromycin and erythromycin, respectively (p = 0.45) . Patients were evenly distributed with respect to demographic characteristics, diagnosis, and concomitant treatment . Surgery was performed in 63%, primarily for abscess formation in cellulitis (p less than 0.001); 18% of patients with an abscess did not undergo surgery . The success rate was identical irrespective of whether surgery was performed, including in those with an abscess . Tolerance was evaluated in 1986 patients . Unwanted effects, elicited by direct questioning, were reported in approximately 20% of cases per group (19% for roxithromycin and 21% for erythromycin) . They consisted of mild gastrointestinal upsets which caused treatment to be withdrawn in eight cases (four per group) . Thus, roxithromycin and erythromycin twice daily for orodental infection are similar in both efficacy and tolerance. Int J STD AIDS, 1992 May-Jun, 3(3), 161 - 7 Congenital syphilis; Boot JM et al.; PIP: In the US and northern Europe, the prevalence of pregnant syphilitic women is estimated at .1-.6%, while in South Africa it was 7.6% in 1982 . In 1978, there 108 cases in the US which increased to 268 reported cases in 1985 . The increase of congenital syphilis (CS) by 25% from 1985 to 1988 was attributed to the spread of crack cocaine in the US . The rate was 10.5 cases/100,000 live births in the US during this period, a 21% increase . In contrast, in the Netherlands there were 2.5 cases/100,000 live births during 1982-85 . Clinical symptoms appear 3 weeks after birth, but some are present at birth such as hepatosplenomegaly, bloated abdomen, cutaneous lesions, and nasal discharge turning into purulent rhinitis . Anemia occurs in 90% of children with CS . Generalized lymphadenopathy, splenomegaly with hepatomegaly, and syphilitic hepatitis may also occur . Syphilitic skeletal abnormalities include osteochondritis, periostitis, osteomyelitis, and osteitis . Meningovascular syphilis produces nervous system effects . CS complications include nephrotic syndrome and acute glomerulonephritis . Ocular abnormalities are caused by treponemes found in the cornea, sclera, uvea, retina and the optic nerve . Chorioretinitis and iridocyclitis are common ocular lesions . The pathogen Treponema pallidum can be diagnosed by dark field microscopy, by immunofluorescence, or by histopathological examination of silver-stained preparations . Pregnancy women with syphilis are treated with penicillin although failures have been reported after single or 2 or 3 in administrations of 2.4 MU benzathine penicillin and after giving tetracycline in 3rd trimester pregnancy . The CDC recommendation for treating infants with CS is iv 50,000 U/kg penicillin G every 8-12 hours for 10-14 days or im 50,000 U procaine penicillin once daily for 10-14 days . Single administration of 50,000 U/kg benzathine penicillin is recommended for newborn children whose mothers have been treated with erythromycin . Mol Pharmacol, 1992 May, 41(5), 981 - 8 Imprinting of hepatic microsomal cytochrome P-450 enzyme activities and cytochrome P-450IIC11 by peripubertal administration of testosterone in female rats; Cadario BJ et al.; The influence of peripubertal exposure to physiological doses of testosterone on the adult androgen responsiveness of hepatic microsomal cytochrome P-450 was investigated . Male and female Sprague-Dawley rats were sham-operated or gonadectomized before puberty, at 25 days of age . They were injected subcutaneously with testosterone enanthate (5 mumol/kg/day) during the pubertal time period, on days 35-49 . Responsiveness to this same dose of testosterone was tested by administering the compound during adulthood, on days 81-89 . The females provided a model that had not been exposed to neonatal androgen imprinting, in contrast to the males . Testosterone 2 alpha-hydroxylase activity and cytochrome P-450IIC11, which are normally expressed only in adult males, were expressed in the gonadectomized females administered testosterone during puberty with no further exposure to the hormone for the next 40 days . The levels found were similar to those in the gonadectomized male group . When the combined pubertal and adult testosterone regimen was used, a synergistic effect was produced; the 2 alpha-hydroxylase activity reached control male levels in both gonadectomized and sham-operated females and, in addition, cytochrome P-450IIC11 attained control male levels in the gonadectomized females . Testosterone 6 beta-hydroxylase and erythromycin N-demethylase activities were used as indicators of the cytochrome P-450IIIA subfamily . These activities were significantly increased only in the females treated with testosterone during both the pubertal and adult periods, reaching control male levels of 6 beta-hydroxylation . A similar effect, but in the opposite direction, was found with testosterone 7 alpha-hydroxylase, an enzyme activity indicative of cytochrome P-450IIA1 . A decrease in this enzyme was produced in the females administered testosterone during both time periods, resulting in levels equivalent to those found in control males . In general, a highly significant interaction was found between the pubertal and adult treatment periods for the females, indicating a chronic effect of the pubertal exposure . The experiments with castrated males did not result in synergistic interactions, although there was some evidence of an additive effect . The results of this study support the hypothesis that the peripubertal period is a time during which testosterone imprinting of both increased basal levels and adult androgen responsiveness of some hepatic cytochrome P-450 enzymes can occur in the female rat. South Med J, 1992 May, 85(5), 524 - 7 Erythromycin therapy for gastroparesis; Klutman NE et al.; Gastroparesis from numerous causes has been treated with a number of prokinetic agents . We report the successful use of erythromycin as a prokinetic agent in the treatment of two cases of idiopathic gastroparesis in which treatment with metoclopramide or domperidone or both had failed . We also review information about erythromycin's mechanism of action, previous therapeutic uses, administration (doses, duration, and route), and role as an alternative to other prokinetic agents . When treatment with other agents is unsuccessful, erythromycin is a viable alternative therapy for gastroparesis. Chest, 1992 May, 101(5), 1450 - 2 Actinobacillus actinomycetemcomitans pneumonia with chest wall involvement and rib destruction; Yuan A et al.; There are four cases of Actinobacillus actinomycetemcomitans pulmonary infections reported in the English literature prior to 1990 . We report a case of A actinomycetemcomitans pulmonary infection with invasion of overlying soft tissue, rib, and sternum . This manifestation has not been previously reported . The clinical manifestation is similar to that of Actinomyces israelii, which may be misinterpreted as malignancy initially . The portal of entry of A actinomycetemcomitans may be via hematogenous spread or aspiration . The diagnosis depends on culture after prolonged incubation of the involved tissue obtained by aspiration or biopsy . Elevated serum antibody is helpful for diagnosis of active infection . A actinomycetemcomitans is susceptible to most antibiotics, but is frequently resistant to penicillin, vancomycin, clindamycin, and erythromycin . Isolation of the organism and an in vitro drug sensitivity testing are important in managing the patient . Our patient recovered after a three-month regimen of penicillin. Arch Biochem Biophys, 1992 May 1, 294(2), 454 - 60 In vitro metabolism of FK-506 in rat, rabbit, and human liver microsomes: identification of a major metabolite and of cytochrome P450 3A as the major enzymes responsible for its metabolism; Vincent SH et al.; The metabolism of the immunosuppressant FK-506 was shown to be catalyzed primarily by cytochrome P450 isozymes of the P450 3A subfamily . Antibodies against rat P450 3A inhibited FK-506 metabolism by 82% in rat liver microsomes and by 35-56% in liver microsomes from humans, dexamethasone-induced rats, and erythromycin-induced rabbits . Poor species cross-reactivity of the antibodies, metabolic switching, and/or some metabolism by P450 isozymes other than P450 3A may be responsible for the incomplete inhibition observed . Besides anti-rat P450 3A, antibodies against rat P450 1A also appeared to have some inhibitory effect implicating these particular cytochrome P450 isozymes as having a minor role in FK-506 metabolism . The formation of 13-desmethyl FK-506, identified here as a major metabolite of FK-506 in all types of microsomes examined, was inhibited completely by anti-P450 3A in liver microsomes from dexamethasone-induced rats and erythromycin-induced rabbits but only partially in human and control rat liver microsomes. Nihon Kyobu Shikkan Gakkai Zasshi, 1992 May, 30(5), 802 - 7 {A clinical study of the long-term therapeutic effects of low-dose erythromycin in diffuse panbronchiolitis--with special reference to changes in tumor-associated carbohydrate antigens in serum}; Mukae H et al.; We investigated the long-term (3-30 months) therapeutic effects of low-dose (300-600 mg/day) erythromycin in 26 patients with diffuse panbronchiolitis (DPB) . Significant improvements of pulmonary functions especially in %VC and PaO2 as well as respiratory symptoms were shown . However, erythromycin treatment was not associated with a significant change in surface phenotypes on peripheral blood lymphocytes (CD4, CD8, CD4/CD8) . It is well known that serum levels of tumor-associated carbohydrate antigens such as SLX (sialylated Lewis X-i) and CA19-9 (sialylated Lewis(a)) are significantly elevated in patients with DPB . In the present study, 68.4% (13/19) of DPB patients showed marked elevation of SLX and 52.9% (9/17) showed marked elevation of CA19-9 levels in serum . These positive ratios were significantly decreased by erythromycin treatment to 31.6% (6/19) in SLX and 23.4% (4/17) in CA19-9 . The mean values of each marker were also significantly decreased after erythromycin administration from 54.9 +/- 26.9 U/ml to 39.5 +/- 22.1 U/ml for SLX and from 70.5 +/- 77.4 U/ml to 28.8 +/- 37.4 U/ml for CA19-9. J Gen Intern Med, 1992 May-Jun, 7(3), 261 - 72 Optimal management strategies for HIV-infected patients who present with cough or dyspnea: a cost-effective analysis; Freedberg KA et al.; OBJECTIVE: To determine the effectiveness and costs of alternative management strategies for patients infected with the human immunodeficiency virus (HIV) who present with pulmonary symptoms . DESIGN: Decision analysis comparing initial testing (arterial blood gas analysis, induced sputum analysis, or bronchoscopy with bronchoalveolar lavage) with empiric antibiotics (trimethoprim-sulfamethoxazole or erythromycin) . Subsequent steps in management are detailed based on the results of initial management . Patients were stratified by initial CD4 lymphocyte count (less than 200/mm3, 200-500/mm3, or greater than 500/mm3) and results of chest radiography . SETTING: Hypothetical . MEASUREMENTS AND MAIN RESULTS: The estimated levels of effectiveness among strategies were relatively similar, but costs varied markedly . If potentially reasonable strategies are defined as those that have incremental cost-effectiveness ratios below $50,000 per quality-adjusted life year (QALY), the recommended strategies would be: for patients at highest risk for Pneumocystis carinii pneumonia (PCP), with a probability of PCP above 30% (CD4 less than 200/mm3 and abnormal chest radiograph or prior history of PCP), begin with induced sputum analysis ($34,174/QALY); for intermediate-risk patients, with a probability of PCP between 6% and 30% (CD4 less than 200/mm3, regardless of chest radiograph; or CD4 200-500/mm3, regardless of chest radiograph findings), begin with arterial blood gas analysis ($4,593 to $8,310/QALY); for low-risk patients, with a probability of PCP below 6% (CD4 greater than 500/mm3, regardless of chest radiograph findings), begin with one week of erythromycin, followed by induced sputum examination if symptoms persist ($675 to $3,306/QALY) . For highest-risk patients, if empiric trimethoprim-sulfamethoxazole was considered entirely to be outpatient therapy, it was preferred management if the probability of PCP was above 38% . CONCLUSIONS: The authors conclude that preferred management strategies are determined more by differences in costs than by differences in levels of effectiveness, and that they vary depending on the probability of PCP in definable patient subgroups. Curr Genet, 1992 May, 21(6), 431 - 6 Interaction of the yeast pleiotropic drug resistance genes PDR1 and PDR5; Meyers S et al.; The network of genes which mediates multiple drug resistance in yeast includes, among others, the PDR1 gene, which encodes a putative regulator of gene expression, and PDR5, a locus whose amplification leads to resistance . We demonstrate that disruption of PDR5 causes marked hypersensitivity not only to cycloheximide but also to sulphometuron methyl and the mitochondrial inhibitors chloramphenicol, lincomycin, erythromycin and antimycin . Genetic analysis of double mutants containing an insertion in PDR5 (pdr5:Tn5), which renders cells hypersensitive to cycloheximide, and a pdr1 mutation, which confers resistance to this inhibitor, indicates that the expression of resistance requires a functional PDR5 gene . The same interdependency is observed for chloramphenicol, but not for oligomycin, lincomycin, erythromycin or sulphometuron methyl . Northern analysis of PDR1 and PDR5 transcripts reveals that the 5.2 kbp PDR5 transcript is overexpressed in pdr1 (resistant) mutants, but underexpressed in a disruption of PDR1 . These observations provide strong experimental support for our former proposal that the PDR5 gene is a target for regulation by the PDR1 gene product. Lakartidningen, 1992 Apr 22, 89(17), 1473 - 6 {TWAR infection is a common diagnosis in outpatient clinics}; Falck G et al.; Infections caused by Chlamydia pneumoniae were first described in 1985 . The infection can cause common cold, sore throat, hoarseness, cough, headache, fatigue and sometimes influenza-like illness . Examination can indicate serous otitis media, sinusitis, laryngitis, bronchitis and pneumonia . The course can be long and relapsing . The recommended drugs for treatment are tetracycline or erythromycin for at least two weeks . Five verified cases are described in the article, four of them with symptoms from the upper respiratory tract only . It is concluded that Chlamydia pneumoniae is a not unusual cause of upper airway diseases . Up to now the diagnosis can best be verified by micro immunofluorescence . The authors call for a rapid and reliable test for use in physician's office . It is proposed that infections caused by Chlamydia pneumoniae be termed TWAR. Intern Med, 1992 Apr, 31(4), 508 - 12 An outbreak of Legionnaires' pneumonia in a nursing home; Maesaki S et al.; An outbreak of Legionnaires' pneumonia occurred at a nursing home in December 1990 . A 79-year-old female and a 73-year-old male clerk who were staying at the nursing home developed pneumonia with only a 5-day interval . Legionella pneumophila serogroup I was isolated from transtracheal aspirate of the former and sputum of the latter . After treatment with a combination of erythromycin and rifampicin both patients improved . Serological surveillance of inpatients and staff of the nursing home was performed in February 1991 . Seven out of 51 samples (14.0%) showed a titer higher than 1:128 of anti-Legionella pneumophila serogroup I antibody determined by indirect immunofluorescence; two of these seven complained of respiratory symptoms . Molecular epidemiology analyzed by restriction endonuclease digestion of isolated L . pneumophila showed an identical pattern which suggested a common origin. Kansenshogaku Zasshi, 1992 Apr, 66(4), 441 - 7 {Determination of the neutrophil chemotactic factor in bronchoalveolar lavage fluid in patients with diffuse panbronchiolitis}; Oda H et al.; It is well known that erythromycin (EM) therapy is effective on chronic lower respiratory tract disease, including diffuse panbronchiolitis (DPB) . In this study we investigated the relationship between clinical findings and neutrophil chemotactic activity (NCA) in bronchoalveolar lavage fluid (BALF) in patients with DPB receiving orally EM therapy . The NCA in post-EM therapy BALF was significantly reduced (p less than 0.001) compared with that in BALF before EM therapy (30.17 +/- 7.84% vs 53.05 +/- 10.65%) . On the respiratory function before and after EM therapy, DPB patients (20 cases) showed significant improvement of %VC, FEV1.0, RV/TLC (p less than 0.001, each) and V25 (p less than 0.05) . And on the post-EM therapy blood gas, PaO2 and AaDO2 level were confirmed to be significantly improved (p less than 0.001) . In addition, we examined the correlation between the improvement ratio of clinical finding and the reduction of NCA in BALF after EM therapy in 10 patients with DPB . We found the significant correlation between the improvement ratio of PaO2 and the reduction NCA in BALF of those patients (p less than 0.05) . There were no significant relationships between the improvement ratio in other parameters as stated above and the reduction of NCA in BALF . These findings indicate that EM restrains the NCA in BALF of patients with DPB and impairs the accumulation of neutrophils in respiratory tract, ultimately contributes to the improvement of clinical symptoms such as sputum and clinical findings such as PaO2 in patients with DPB. J Gen Microbiol, 1992 Apr, 138 ( Pt 4), 779 - 86 Purification and characterization of TDP-D-glucose 4,6-dehydratase from anthracycline-producing streptomycetes; Thompson MW et al.; TDP-D-glucose 4,6-dehydratase, which converts TDP-D-glucose to TDP-D-4-keto-6-deoxyglucose, was purified to near-homogeneity from the daunorubicin and baumycin-producing organism Streptomyces sp . C5 (968-fold purification with a 41% recovery), and from the daunorubicin producer Streptomyces peucetius ATCC 29050 (1000-fold purification with a 37% recovery) . The TDP-D-glucose 4,6-dehydratases from Streptomyces sp . C5 and S . peucetius were determined by SDS-PAGE and HPLC gel filtration to be homodimers with subunit relative molecular masses of 39,000 and 36,000, respectively . For the enzymes from both organisms, negligible activity was observed in the absence of added NAD+, or when ADP-glucose, ADP-mannose, GDP-mannose, UDP-glucose or UDP-galactose was substituted for TDP-D-glucose as substrate . For the enzyme from Streptomyces sp . C5, the K'm values for NAD+ and TDP-D-glucose were 19.2 microM and 31.3 microM, respectively . The V'max for TDP-D-glucose was 309 nmol min-1 (mg protein)-1 . For the S . peucetius enzyme, the K'm values for NAD+ and TDP-D-glucose were 20.1 microM and 34.7 microM, respectively . V'max values were 180 nmol min-1 (mg protein)-1 for NAD+ and 201 nmol min-1 (mg protein)-1 for TDP-D-glucose . TDP was a good inhibitor of TDP-D-glucose 4,6-dehydratase from both organisms . The N-terminal amino acid sequence of the TDP-D-glucose 4,6-dehydratase from S . peucetius and from the erythromycin producer, Saccharopolyspora erythraea, were similar, whereas the enzyme from Streptomyces sp . C5 contained a different N-terminal amino acid sequence from either of the other two enzymes. J Clin Gastroenterol, 1992 Apr, 14(3), 255 - 9 Effects of erythromycin on gut transit in pseudo-obstruction due to hereditary coproporphyria; Vassallo MJ et al.; We studied gastrointestinal transit in a 57-year-old man with chronic intestinal pseudo-obstruction along with peripheral and autonomic neuropathy due to hereditary coproporphyria and we evaluated the effects of acute and chronic therapy with erythromycin . Noninvasive scintigraphic studies of regional transit of solid residue through the gut were obtained before treatment, during the acute i.v . administration of 500 mg, every-8-h doses of erythromycin for 24 h and after 15 weeks of oral therapy (500 mg, three times daily) . During acute i.v . administration, symptoms and transit measurements dramatically improved; however, all parameters and symptoms returned to pretreatment levels during chronic oral therapy . We conclude that hereditary coproporphyria with associated autonomic neuropathy results in significant delay in small bowel and colonic transit; chronic administration of 500 mg three times a day oral erythromycin was not associated with maintenance of the improvement in regional transit and symptoms observed following acute i.v . administration of the drug at the same dose. Arch Surg, 1992 Apr, 127(4), 475 - 7 Graft involvement by Legionella in a liver transplant recipient; Tokunaga Y et al.; Legionella pneumophila, serogroup 1, was identified by direct immunofluorescence in the lung and liver graft from a 2 1/2-month-old infant who underwent orthotopic liver transplantation because of fulminant hepatic failure secondary to neonatal hepatitis . The patient died of respiratory failure owing to this infection 22 days after transplantation despite treatment with erythromycin lactobionate . To our knowledge, this represents the first reported case of hepatic infection with Legionella in liver transplant recipients. Antibiot Khimioter, 1992 Apr, 37(4), 28 - 31 {Pleiotropic nature of mutation of resistance to 2,3,5-triphenyl- tetrazolium chloride of Francisella tularensis}; Pavlovich NV et al.; Natural strains of F . tularensis were characterized by sensitivity to 2,3,5-triphenyl tetrazolium chloride (TTC) . Development of TTC resistance in the cells of F . tularensis was accompanied by changes in the biological properties of the culture, i.e . the colony morphology, antigenic structure, virulence and immunogenicity for laboratory animals . Moreover, there was a direct correlation between the levels of TTC resistance and resistance to chloramphenicol, erythromycin, tetracycline, furazolidone and rifampicin . The antibiotic resistant mutants of F . tularensis were in turn more resistant to TTC than the initial strains . This could be useful in isolation of polymarked strains of F . tularensis for genetic studies and investigation of the nature of the phenomenon of virulence in F . tularensis. Clin Ther, 1992 Mar-Apr, 14(2), 185 - 91 Efficacy of erythromycin in the treatment of inner city pregnant women with cervical Chlamydia trachomatis infection; Cohen I; In this retrospective study, the efficacy of screening for and treating cervical Chlamydia trachomatis infection was evaluated in a pregnant population at increased risk for chlamydial infection . Over a 2 1/2-year period, 5.75% (338) of the 5,875 women tested were found to be infected with this organism . Of the 323 women patients available for follow-up, 76% (244) were successfully treated and 24% (79) remained infected throughout their pregnancies . Forty (12%) patients became infected during pregnancy, while 26 (8%) were reinfected during pregnancy, despite treatment with erythromycin . Twenty-seven (8%) patients had their first antenatal visit and cervical swab less than a week before delivery . The gestational age at which the first cervical chlamydial swab was obtained was significantly more advanced in patients who remained infected (30.23 +/- 6.2 weeks) than those who were successfully treated (22.15 +/- 7.66 weeks; P = 0.00001) . The data suggest that in a pregnant population considered to be at increased risk for C trachomatis infection: (1) there is a subgroup of patients with a high risk of remaining infected or becoming reinfected with C trachomatis during pregnancy despite treatment with erythromycin and (2) repeated prenatal testing and treatment of those infected is necessary to detect and eradicate maternal chlamydial infection. Sex Transm Dis, 1992 Mar-Apr, 19(2), 105 - 10 Gonococcal infection of the newborn in Florida, 1984-1989; Desenclos JC et al.; An increase in neonatal gonococcal infections was recorded in Florida between 1984 and 1988 . By reviewing Florida sexually transmitted disease surveillance case records between 1984 and 1989, 68 cases of neonatal gonococcal infections were identified state-wide . Those 68 cases included 55 (81%) cases of gonococcal ophthalmia neonatorum, 4 genital infections, 1 nasal infection, 1 ear infection, 1 skin infection, and 1 scalp infection . At birth, positive culture results were demonstrated in 3 gastric and 2 respiratory aspirate cultures . A case-control study using birth certificates as the source of information showed that mothers of infected infants were more likely to be younger, black (odds ratio {OR} = 6.2; 95% confidence interval {CI} 2.3, 16.2), and less educated (less than a high school education, OR = 2.9, CI 1.0,8.8) in comparison to mothers of control subjects . Although mothers of infected newborns were less likely to have received prenatal care than were mothers of control subjects, this difference was not statistically significant . Maternal substance abuse was documented among 19% of the mothers of the infected infants . The rate of clinical gonococcal ophthalmia neonatorum in Florida hospitals from which cases had been reported was 1.7 per 10,000 live births, and tended to be higher in hospitals using erythromycin than in hospitals using any other prophylactic eye treatment . This study suggests that the rate of neonatal gonococcal infection, in particular ophthalmia neonatorum, may have increased in Florida among high-risk populations between 1984 and 1988, and underscores the need for targeted prevention efforts and surveillance. J Rheumatol, 1992 Mar, 19(3), 494 - 6 Acute colchicine intoxication--possible role of erythromycin administration; Caraco Y et al.; A 29-year-old patient with familial Mediterranean fever and amyloidosis involving the kidney, liver, and gastrointestinal tract received longterm colchicine, 1 mg daily . In the last year she developed diarrhea and abdominal pain, that coincided with toxic colchicine blood levels . After 2 weeks of oral erythromycin therapy she was hospitalized for acute, life threatening colchicine toxicity, with fever, diarrhea, abdominal pain, myalgia and lower extremity parasthesias and later convulsions and alopecia . Pancytopenia evolved into rebound leukocytosis, disturbed liver function and hypoglycemia . After a long stormy course she improved . Colchicine toxicity with combined liver and renal impairment and the role of erythromycin in her colchicine toxicity are discussed. J Nurse Midwifery, 1992 Mar-Apr, 37(2 Suppl), 74S - 86S Pharmaceutical preparations . A review of drugs commonly used during the neonatal period; Faucher MA et al.; Certified nurse-midwives, whose responsibility includes care of the newborn in the first days of life, should be well versed in the commonly used pharmaceutical preparations in the neonatal period . This article reviews therapeutic uses and the pharmacodynamics of vitamin K, as well as the neonatal eye preparations for prophylaxis of infections (silver nitrate, tetracycline, and erythromycin ophthalmic ointments) . Preparations used in caring for the umbilical cord, as well as the commonly prescribed antibiotics ampicillin and gentamicin, are discussed . The narcotic antagonist naloxone is also reviewed, along with commonly used medications for colic and thrush . The etiology and clinical conditions that require the application of these medications are considered. Biopharm Drug Dispos, 1992 Mar, 13(2), 77 - 82 Effect of dehydration on the disposition kinetics of erythromycin in rabbits; Ahmad M et al.; The effect of water deprivation on the physiologic, biochemical, and disposition parameters of erythromycin was investigated in rabbits . The packed cell volume, plasma glucose, and total lipid concentration increased significantly in dehydration . The pharmacokinetic parameters of erythromycin after intravenous administration also changed, suggesting a need for monitoring toxicity of erythromycin in the water-deprived population. Am J Obstet Gynecol, 1992 Mar, 166(3), 794 - 802 Erythromycin therapy in preterm premature rupture of the membranes: a prospective, randomized trial of 220 patients; Mercer BM et al.; OBJECTIVES: The use of prophylactic antibiotics in the management of preterm premature rupture of the membranes has not been adequately studied . The purpose of this study was to evaluate the efficacy of oral erythromycin therapy in the prolongation of latency and reduction of infectious morbidity after preterm premature rupture of membranes . STUDY DESIGN: In this randomized, prospective, double-blind, placebo-controlled study, 220 women at 20 to 35 weeks' gestation were evaluated . Subjects received oral erythromycin 333 mg (n = 106) or indistinguishable placebo (n = 114) every 8 hours from randomization to delivery . RESULTS: Prolongation of latency was identified with erythromycin therapy (p = 0.02), particularly for those destined to have chorioamnionitis (p = 0.003) and those with oligohydramnios (p = 0.01) . No decrease in the incidence of maternal or neonatal infectious morbidity was seen . CONCLUSIONS: Oral erythromycin delays, but does not prevent, the onset of clinical infection when administered to women with preterm premature rupture of membranes . This regimen does not decrease neonatal morbidity and mortality. Transplantation, 1992 Mar, 53(3), 596 - 602 Cyclosporine metabolism by P450IIIA in rat enterocytes--another determinant of oral bioavailability? Kolars JC, Stetson PL, Rush BD, Ruwart MJ, Schmiedlin-Ren P, Duell EA, Voorhees JJ, Watkins PB. Cyclosporine is converted to its major metabolites (M-17, M-1, and M-21) in human liver by enzymes belonging to the P450IIIA subfamily . These enzymes are also present in rat and human enterocytes; however, the possibility that CsA is metabolized in enterocytes has not been previously investigated . We therefore directly compared metabolism of 3H-CsA in microsomes prepared from liver and jejunal enterocytes . M-17, M-1, and M-21 were the major CsA metabolites produced by enterocyte microsomes . This metabolism appeared to be catalyzed by P450IIIA, because pretreatment of rats with the P450IIIA inducer dexamethasone significantly increased the rate of CsA metabolism in enterocyte microsomes and preincubation of enterocyte microsomes with anti-P450IIIA IgG inhibited the production of CsA metabolites by greater than 95% . To determine if enterocyte P450IIIA metabolizes CsA in vivo, rats were pretreated with the P450IIIA inducer dexamethasone, the P450IIIA inhibitor erythromycin, or vehicle alone . At laparotomy, 2 mg/kg of 3H-CsA was injected into a sealed loop of jejunum, and after collection of the mesenteric venous blood draining this segment for 45 min, the production of M-17 and M-1 was measured . In the control group, a mean of 3.9% of the recovered radioactivity was found as M-1 and M-17 . In the rats pretreated with dexamethasone, a mean of 8.4% of the radioactivity was found as M-1 and M-17 (P less than 0.05 relative to control) and this decreased to 2.3% in the group pretreated with erythromycin (P = 0.08 relative to control) . We conclude that P450IIIA in jejunal enterocytes readily metabolizes CsA . Furthermore, the metabolism of CsA by enterocytes in vivo is substantial and likely contributes to "first pass metabolism" of orally administered CsA . Our observations provide novel hypotheses to explain some important drug interactions and interpatient differences in CsA dosing requirements. Am J Med, 1992 Mar, 92(3), 249 - 53 Gastrointestinal side effects of intravenous erythromycin: incidence and reduction with prolonged infusion time and glycopyrrolate pretreatment; Bowler WA et al.; OBJECTIVE: To determine the frequency of gastrointestinal toxicity due to intravenous (IV) erythromycin and to attempt to decrease this toxicity by prolonging the infusion time of erythromycin and/or pretreating with the peripheral anticholinergic, glycopyrrolate 0.1 mg IV . DESIGN: Randomized, double-blind, placebo-controlled trial . SETTING: General medical wards of a tertiary medical center . PATIENTS: A total of 51 hospitalized patients 18 years of age or older who were prescribed IV erythromycin lactobionate (EMLB) 500 mg every 6 hours by their attending physicians . INTERVENTIONS: Each of eight consecutive infusions of EMLB was randomly assigned to one of four groups: control--30-minute infusion/placebo pretreatment; 60/P--60-minute infusion/placebo pretreatment; 30/G--30-minute infusion/glycopyrrolate pretreatment; and 60/G--60-minute infusion/glycopyrrolate pretreatment . MAIN OUTCOME MEASURES: Each infusion was accompanied by a questionnaire in which patients rated the magnitude of nausea and vomiting on a scale of 1 (no toxicity) to 9 (severe toxicity) . Scores for both nausea and vomiting were added together for a total toxicity score ranging from 2 to 18 . A total score of greater than 8 was defined as clinically important . RESULTS: The 51 patients received a total of 356 infusions with gastrointestinal toxicity occurring in 27 of 51 (53%) patients . Among patients under the age of 40, 22 of 33 (67%) experienced toxicity compared with only five of 18 patients (28%) over the age of 40 (p = 0.018) . Clinically important toxicity was seen in 19 of 51 patients (37%), including five who withdrew during the study because of severe nausea and vomiting . In this group, the combination of a 60-minute erythromycin infusion and glycopyrrolate pretreatment decreased clinically important toxicity by 79% from 47% to 10%, a statistically and clinically significant 37% (95% CI, 14% to 60%) difference (p = 0.007) . CONCLUSIONS: Gastrointestinal toxicity associated with the IV infusion of erythromycin is common and is more likely to occur in younger patients . A 1-hour infusion of erythromycin combined with pretreatment with glycopyrrolate, 0.1 mg IV, is effective in reducing this toxicity. J Pharmacol Exp Ther, 1992 Mar, 260(3), 1441 - 9 Selective inhibition of rat hepatic microsomal cytochrome P-450 . I . Effect of the in vivo administration of cimetidine; Chang T et al.; Cimetidine is considered to be a general inhibitor of cytochrome P-450 enzymes, but there is indirect evidence that certain cytochrome P-450 enzymes are not inhibited by cimetidine . The purpose of this study was to determine whether cimetidine, when administered in vivo to adult male Wistar rats, selectively inhibits hepatic microsomal cytochrome P-450 enzymes . Uninduced, phenobarbital (PB)-induced and dexamethasone (DEX)-induced rats were sacrificed 90 min after treatment with a single i.p . dose of cimetidine HCI (150 mg/kg) or saline . Hepatic microsomes were prepared, and aminopyrine N-demethylase (APND), pentoxyresorufin O-dealkylase (PROD), erythromycin N-demethylase (EMND) activities and oxidation of testosterone were determined . In addition, immunoinhibition studies with a polyclonal antibody monospecific for cytochrome P-450IIC11 were performed . Cimetidine treatment inhibited APND, PROD and EMND activities to a greater extent in microsomes from uninduced rats than in those from PB- or DEX-induced rats, suggesting that the induced cytochrome P-450 enzymes were less affected by cimetidine than were those in uninduced rats . Cimetidine treatment inhibited testosterone 2 alpha-hydroxylase activity by 65, 73 and 46%, respectively, in microsomes from uninduced, PB-induced and DEX-induced rats . The antibody completely inhibited testosterone 2 alpha-hydroxylase activity in the three groups of microsomes, indicating that this activity is specific for cytochrome P-450IIC11 in all these cases . Neither cimetidine treatment nor the antibody inhibited microsomal testosterone 2 beta-, 6 beta-, 7 alpha- or 16 beta-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS) Clin Pharmacol Ther, 1992 Mar, 51(3), 229 - 38 The erythromycin breath test selectively measures P450IIIA in patients with severe liver disease; Lown K et al.; There are significant interpatient differences in the activity of a major drug metabolizing enzyme termed P450IIIA . Because P450IIIA uniquely catalyzes the N-demethylation of erythromycin, we have proposed that the P450IIIA activity of a patient may be determined from the rate of 14CO2 production in the breath after an intravenous infusion of a test dose of {14C-N-methyl}erythromycin . However, direct evidence that this erythromycin breath test selectively measures P450IIIA and not other major human liver P450s in patients has been lacking . We therefore administered the erythromycin breath test to nine patients with severe liver disease who were awaiting liver transplantation . Microsomes were prepared from liver samples obtained during surgery and the concentration of P450IA2, P450IIC8, P450IIC9, P450IIE1, and P450IIIA were determined immunochemically . We found a significant correlation between patients' erythromycin breath test results and their liver P450IIIA levels (r2 = 0.56, p = 0.02) . In contrast, there was no correlation at all between the erythromycin breath test result and the microsomal levels of any of the other four P450s assayed . The correlation of the erythromycin breath test and P450IIIA did not appear related to the extent of liver disease because neither correlated with prothrombin time or albumin or bilirubin levels . These data provide the best evidence to date that the erythromycin breath test is a specific assay of in vivo P450IIIA activity in patients. Gastroenterology, 1992 Mar, 102(3), 823 - 8 Erythromycin accelerates gastric emptying by inducing antral contractions and improved gastroduodenal coordination; Annese V et al.; Erythromycin has been shown to act as a motilin agonist by binding to motilin receptors on gastrointestinal smooth muscle and to improve the severely impaired gastric emptying in patients with diabetic gastroparesis . To elucidate the motor pattern that accounts for this accelerated emptying, the effect of 200 mg erythromycin vs . placebo on postprandial motility of the stomach and the upper small intestine was examined in 13 normal subjects . Erythromycin significantly increased the amplitude of the antral contractions during the 2-hour postprandial study period (maximal difference in mean amplitude of distal antral contractions between erythromycin and placebo recorded from 80 to 90 minutes after meal: 123 +/- 17 vs . 44 +/- 12 mm Hg; P less than 0.005) . The total number of antral contractions was not affected, but the contractions could be recorded manometrically higher up in the stomach after erythromycin than after placebo (9-12 vs . 3-6 cm above the pylorus) . Antroduodenal coordination was significantly improved during the first postprandial hour, and the first normal phase 3 of the migrating motor complex, indicating the reappearance of fasting motility, occurred earlier after erythromycin than after placebo (128.3 +/- 14.3 vs . 173.4 +/- 16.1 minutes; P less than 0.05) . These changes in postprandial motility induced by erythromycin may well account for its accelerating effect on gastric emptying. Alcohol Alcohol, 1992 Mar, 27(2), 143 - 52 Benzodiazepine metabolism in ethanol-treated male rats: use of pair-fed and age-matched controls; Mason SR et al.; The effects of chronic moderate (15%) ethanol consumption and ageing on rat hepatic cytochrome P450 monooxygenase activities were examined using diazepam, nordazepam, d-benzphetamine, erythromycin, ethylmorphine and nitrosodimethylamine (NDMA) as substrates . In addition, the effects of moderate ethanol alone on the oxidation of metoprolol, morphine and temazepam were examined . Cytochrome P450 specific content increased significantly only in the 6-week ethanol-treated rats, and no changes in percentage liver to body weights were apparent in any of the ethanol-treated animals compared with pair-fed controls . Only cytochrome P450IIIA enzyme activities displayed age-related decreases, these being identified in the pair-fed animals . C3-hydroxylation of diazepam and nordazepam (36% of controls) and N-demethylation of erythromycin and ethylmorphine (58% and 64% of controls) were decreased in 6-week ethanol-treated animals, these effects being less pronounced in the 12, 24 and 48-week ethanol-treated groups . The decrease seen for diazepam and d-benzphetamine N-demethylation caused by ethanol consumption was approximately 80% of control groups for the duration of the treatment . NDMA and morphine N-demethylations were increased to 120% of control activities and metoprolol alpha-hydroxylase was increased to 140% of control activities at 6 weeks, whilst metoprolol O-demethylase activity remained unaltered . NDMA N-demethylase activity showed a two-fold induction at 24 and 48 weeks of ethanol treatment, compared with corresponding pair-fed control groups . These results support previous findings from this laboratory showing that the same or similar P450IIIA family isozymes are involved in the C3-hydroxylation of diazepam and nordazepam.(ABSTRACT TRUNCATED AT 250 WORDS) Drug Metab Dispos, 1992 Mar-Apr, 20(2), 316 - 21 Involvement of the cytochrome P-450IID subfamily in minaprine 4-hydroxylation by human hepatic microsomes; Marre F et al.; 4-Hydroxylation of minaprine was measured on microsomal fractions prepared from 25 different human liver samples . In vitro formation of 4-hydroxyminaprine exhibited a large interindividual variability . Indeed, minaprine 4-hydroxylase activity ranged between 0.033 and 0.421 nmol/min/mg microsomal protein . Two samples presented a particularly low enzyme activity . Minaprine 4-hydroxylation followed Michaelis-Menten kinetics with KM and Vmax values of 5.26 microM and 0.478 nmol/min/mg microsomal protein, respectively, for one particular representative sample . The effects of various compounds (substrates or inhibitors of cytochrome P-450 isoforms) on 4-hydroxyminaprine formation were investigated . Selective substrates for P-450IA {benzo(a)pyrene, theophylline, and phenacetin}, IIC (hexobarbital), IIE (aniline), and IIIA (erythromycin, nifedipine, and troleandomycin) cytochrome subfamilies did not inhibit 4-hydroxyminaprine formation . The nonspecific cytochrome P-450 inhibitor, cimetidine, slightly inhibited minaprine 4-hydroxylation . The classical substrates of the P-450IID cytochrome subfamily (debrisoquine, propranolol, and sparteine) inhibited minaprine 4-hydroxylation, as did the known P-450IID specific inhibitor, quinidine . These compounds inhibited minaprine 4-hydroxylase with Ki values of 16.5 (debrisoquine), 14.4 (propranolol), 61.9 (sparteine), and 0.146 microM (quinidine) . 4-Hydroxyminaprine formation rate was shown not to be correlated with the activity of both erythromycin N-demethylase (r = 0.29, non-significant) and aniline hydroxylase (r = -0.15, NS) . In contrast, minaprine 4-hydroxylase was well correlated with both debrisoquine 4-hydroxylase activity (r = 0.501, p less than 0.05) and immunoquantified cytochrome P-450IID6 (r = 0.579, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) Eur J Biochem, 1992 Feb 15, 204(1), 39 - 49 6-Deoxyerythronolide-B synthase 2 from Saccharopolyspora erythraea . Cloning of the structural gene, sequence analysis and inferred domain structure of the multifunctional enzyme; Bevitt DJ et al.; Sequencing of the eryA region of the erythromycin biosynthetic gene cluster from Saccharopolyspora erythraea has revealed another structural gene (ORF B), in addition to the previously characterised ORF A, which appears to encode a component of 6-deoxyerythronolide-B synthase, the enzyme that catalyses the first stage in the biosynthesis of the polyketide antibiotic erythromycin A . The nucleotide sequence of ORF B, which lies immediately adjacent to ORF A, has been determined . The predicted gene product of ORF B is a polypeptide of 374417 Da (3568 amino acids), which is highly similar to the product of ORF A and which likewise contains a number of separate domains, each with substantial amino acid sequence similarity to components of known fatty-acid synthases and polyketide synthases . The order of the predicted active sites along the chain from the N-terminus is 3-oxoacyl-synthase--acyltransferase--acyl-carrier-protein-- 3-oxoacyl-synthase--acyltransferase--dehydratase--enoylreductase-- oxoreductase--acyl-carrier-protein . The position of the dehydratase active site has been pinpointed for the first time for any polyketide synthase or vertebrate fatty-acid synthase . The predicted domain structure of 6-deoxyerythronolide-B synthase is strikingly similar to that previously established for vertebrate fatty-acid synthases . This analysis of the sequence supports the view that the erythromycin-producing polyketide synthase contains three multienzyme polypeptides, each of which accomplishes two successive cycles of polyketide chain extension . In this scheme, the role of the ORF B gene product is to accomplish extension cycles 3 and 4. Mol Cell Biochem, 1992 Feb 12, 109(2), 185 - 8 Impairment of contractile response to carbachol and muscarinic receptor coupling in gastric antral smooth muscle cells isolated from diabetic streptozotocin-treated rats and db/db mice; Soulie ML et al.; This work explored the role of the cholinergic pathway, assessed at a post-synaptic level by the use of isolated smooth muscle cells, in the impairment of antral motility associated with diabetic gastroparesis . Contractile response to carbachol--but not to erythromycin, a motilin receptor agonist--was abolished in antral smooth muscle cells isolated from (i) rats previously rendered diabetic by a single i.v . dose of streptozotocin (STZ, 60 mg/kg) and (ii) db/db spontaneously diabetic mice . Insulin treatment of STZ-rats was able to prevent the impairment of the carbachol contractile response, but not to reverse it once established . In STZ-rats, impairment of contractile response was not associated with a change in density of {3H}-N-methyl-scopolamine ({3H}-NMS) binding sites (approximately 1.5 fmol/mg protein) . Displacement curve of the {3H}-NMS binding by carbachol was shifted to the right in diabetic rats as compared to controls . The addition of GTP-gamma-S induced a shift to the right of the displacement curve in control but not in diabetic animals . These results strongly suggest that diabetes is associated with an early and specific alteration of the muscarinic control of contraction of antral smooth muscles at a post-synaptic level, associated with an alteration of the GTP-binding proteins coupled to muscarinic receptors. Pediatrics, 1992 Feb, 89(2), 210 - 4 Cost-effectiveness of erythromycin versus mupirocin for the treatment of impetigo in children; Rice TD et al.; A new topical antibiotic, mupirocin, has been found to be as effective as erythromycin for the treatment of impetigo, but concerns about its expense have been raised . This controlled clinical trial sought to compare the cost-effectiveness of erythromycin (E) and mupirocin (M) . Ninety-three children, aged 3 months to 16 years, were randomly assigned to receive 10 days of oral erythromycin (n = 46) or topical mupirocin (n = 47) . Costs and effects were measured through structured interviews . Cost per case differed significantly by group (E = $56.85; M = $62.30; P less than .05) due chiefly to extra visits and medication changes needed by those treated with mupirocin . Erythromycin and mupirocin were equally effective . The likelihood of side effects (E = 43%, M = 22%) approached significance (P less than .07); those treated with erythromycin were willing to pay more for a different medicine to avoid the side effects experienced (P less than .05) . Working parents and school-age children were more likely to alter their daily activities when the patient was taking erythromycin (P less than .04) . Compliance and parental satisfaction did not differ by treatment group; however, parents of children treated with erythromycin were more likely to prefer the alternate drug regimen . It is concluded that the type of medication prescribed can be based on parental preference because the increased cost of mupirocin is offset by increased side effects and number of schooldays and workdays lost with erythromycin. Am J Dis Child, 1992 Feb, 146(2), 177 - 81 Prevention of secondary transmission of pertussis in households with early use of erythromycin; Sprauer MA et al.; To examine the effectiveness of erythromycin therapy and prophylaxis for pertussis, 17 households with one secondary case or more were compared with 20 households without secondary cases following a community-wide pertussis outbreak in Maricopa County, Arizona, in 1988 . There were no significant differences between the two household groups in age distribution of members, size, crowding, race, proportion of children aged 7 months to 18 years with three or more diphtheria and tetanus toxoids and pertussis vaccine doses, or in the age distribution, vaccination status, or medical care of patients with primary cases . However, median intervals from onset of illness in primary cases to initiation of erythromycin therapy (for cases) and prophylaxis (for contacts) were 11 and 16 days, respectively, in households without secondary spread, vs 21 and 22 days, respectively, in households with secondary spread . These results provide additional evidence that erythromycin is effective in the medical management of pertussis and should be initiated promptly to minimize secondary spread. J Bacteriol, 1992 Feb, 174(3), 725 - 35 Characterization of Saccharopolyspora erythraea cytochrome P-450 genes and enzymes, including 6-deoxyerythronolide B hydroxylase; Andersen JF et al.; Previous studies of erythromycin biosynthesis have indicated that a cytochrome P-450 monooxygenase system is responsible for hydroxylation of 6-deoxyerythronolide B to erythronolide B as part of erythromycin biosynthesis in Saccharopolyspora erythraea (A . Shafiee and C . R . Hutchinson, Biochemistry 26:6204-6210 1987) . The enzyme was previously purified to apparent homogeneity and found to have a catalytic turnover number of approximately 10(-3) min-1 . More recently, disruption of a P-450-encoding sequence (eryF) in the region of ermE, the erythromycin resistance gene of S . erythraea, produced a 6-deoxyerythronolide B hydroxylation-deficient mutant (J . M . Weber, J . O . Leung, S . J . Swanson, K . B . Idler, and J . B . McAlpine, Science 252:114-116, 1991) . In this study we purified the catalytically active cytochrome P-450 fraction from S . erythraea and found by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis that it consists of a major and a minor P-450 species . The gene encoding the major species (orf405) was cloned from genomic DNA and found to be distinct from eryF . Both the orf405 and eryF genes were expressed in Escherichia coli, and the properties of the proteins were compared . Heterologously expressed EryF and Orf405 both reacted with antisera prepared against the 6-deoxyerythronolide B hydroxylase described by Shafiee and Hutchinson (1987), and the EryF polypeptide comigrated with the minor P-450 species from S . erythraea on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels . In comparisons of enzymatic activity, EryF hydroxylated a substrate with a turnover number of 53 min-1, whereas Orf405 showed no detectable activity with a 6-deoxyerythronolide B analog . Both enzymes showed weak activity in the O-dealkylation of 7-ethoxycoumarin . We conclude that the previously isolated 6-deoxyerythronolide B hydroxylase was a mixture of two P-450 enzymes and that only the minor form shows 6-deoxyerythronolide B hydroxylase activity. Yeast, 1992 Feb, 8(2), 83 - 93 IMP2, a nuclear gene controlling the mitochondrial dependence of galactose, maltose and raffinose utilization in Saccharomyces cerevisiae; Donnini C et al.; The IMP2 gene of Saccharomyces cerevisiae is involved in the nucleo-mitochondrial control of maltose, galactose and raffinose utilization as shown by the inability of imp2 mutants to grow on these carbon sources in respiratory-deficient conditions or in the presence of ethidium bromide and erythromycin . The negative phenotype cannot be scored in the presence of inhibitors of respiration and oxidative phosphorylation, indicating that the role of the mitochondria in the utilization of the above-mentioned carbon sources in imp2 mutants is not at the energetical level . Mutations in the IMP2 gene also confer many phenotypic alterations in respiratory-sufficient conditions, e.g . leaky phenotype on oxidizable carbon sources, sensitivity to heat shock and sporulation deficiency . The IMP2 gene has been cloned, sequenced and disrupted . The phenotype of null imp2 mutants is indistinguishable from that of the originally isolated mutant. Int J Dermatol, 1992 Feb, 31(2), 131 - 3 Erythromycin versus cefadroxil in the treatment of skin infections; Heskel NS et al.; Erythromycin is often overlooked for the treatment of skin and skin structure infections . We evaluated the efficacy and safety of erythromycin particles in tablets and of cefadroxil in 164 patients with skin infections; both treatments were given as 500 mg twice daily . One hundred percent of erythromycin and 96% of cefadroxil patients were clinically cured or improved, and 98% of susceptible pathogens were eradicated in both groups . Only three erythromycin patients and one cefadroxil patient left the study early because of GI-related adverse events . Erythromycin, therefore, was as effective and safe as cefadroxil in the treatment of mild-to-moderate skin infections. Eur Respir J, 1992 Feb, 5(2), 234 - 8 Erythromycin inhibits Cl secretion across canine tracheal epithelial cells; Tamaoki J et al.; We studied the effect of the macrolide antibiotic erythromycin on bioelectrical properties of canine cultured tracheal epithelium under short-circuit conditions in vitro . Addition of erythromycin to the submucosal but not to the mucosal side dose-dependently decreased short-circuit current (Isc), the maximal decrease from the baseline value and the concentration required to produce a half-maximal effect (IC50) being 5.6 +/- 1.0 microA.cm-2 (mean +/- SE, p less than 0.001) and 18 microM, respectively . In contrast, other antibiotics including ampicillin, cephazolin and tetracycline were without effect . The erythromycin-induced decrease in Isc was not altered by amiloride, but it was abolished by bumetanide, diphenylamine-2-carboxylate2, and substitution of Cl in the bathing medium with gluconate (p less than 0.001, in each case) . The effect of erythromycin on epithelial Isc was attenuated by pretreatment of cells with indomethacin but not with AA-861 a lipoxygenase inhibitor . Incubation of cells with erythromycin inhibited the release of prostaglandins E2 and F2 alpha from tracheal epithelial cells . These results indicate that erythromycin may selectively inhibit Cl secretion across airway epithelium through the inhibition of prostaglandin synthesis and suggest that this action possibly reflects its clinical efficacy in the