Erythromycin

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 treatment of airway hypersecretion.

Ann Pharmacother, 1992 Feb, 26(2), 190 - 2
Lovastatin-induced rhabdomyolysis in the absence of concomitant drugs; Wallace CS et al.; OBJECTIVE: Presentation of a case of lovastatin-induced rhabdomyolysis in the absence of other medications known to potentiate this adverse effect . METHODOLOGY: Case report . RESULTS: A 60-year-old black man developed rhabdomyolysis after receiving lovastatin for 14 months . Rhabdomyolysis developed in the absence of other medications previously reported to cause this adverse effect when administered concomitantly with lovastatin . Adverse drug reaction causality algorithms categorized this reaction as either possible or probable . CONCLUSIONS: Rhabdomyolysis is an uncommon adverse effect associated with lovastatin therapy . Although reported cases of lovastatin-induced rhabdomyolysis were associated with the coadministration of cyclosporine, erythromycin, gemfibrozil, or nicotinic acid, this adverse effect may occur in the absence of these agents.

Ann Pharmacother, 1992 Feb, 26(2), 188 - 9
Pleurocerebral Nocardia in a patient with human immunodeficiency virus; Idemyor V et al.; OBJECTIVE: To report a case of Nocardia asteroides pneumonia and subsequent brain abscess in an immunocompromised host . SETTING: Private, community, teaching hospital . PATIENT: A man readmitted to the hospital for a third time with a fatal brain abscess, after responding to (misdirected) therapy in previous admissions . INTERVENTIONS: Treatment with cefuroxime, erythromycin, trimethoprim/sulfamethoxazole at different times . RESULTS: Patient's condition deteriorated and he died after one month of intravenous trimethoprim/sulfamethoxazole therapy . CONCLUSIONS: Because it is an infection of the immunocompromised host, it may be considered an AIDS-defining illness . Several other similar cases have been reported in the literature.

Gene, 1992 Feb 1, 111(1), 51 - 60
Organization of the enzymatic domains in the multifunctional polyketide synthase involved in erythromycin formation in Saccharopolyspora erythraea; Donadio S et al.; Localization of the enzymatic domains in the three multifunctional polypeptides from Saccharopolyspora erythraea involved in the formation of the polyketide portion of the macrolide antibiotic erythromycin was determined by computer-assisted analysis . Comparison of the six synthase units (SU) from the eryA genes with each other and with mono- and multifunctional fatty acid and polyketide synthases established the extent of each beta-ketoacyl acyl-carrier protein (ACP) synthase, acyltransferase, beta-ketoreductase, ACP, and thioesterase domain . The extent of the enoyl reductase (ER) domain was established by detecting similarity to other sequences in the database . A segment containing the putative dehydratase (DH) domain in EryAII, with a potential active-site histidine residue, was also found . The finding of conservation of a portion of the DH-ER interdomain region in the other five SU, which lack these two functions, suggests a possible evolutionary path for the generation of the six SU.

Curr Opin Obstet Gynecol, 1992 Feb, 4(1), 43 - 7
Drug therapy during pregnancy; Niebyl JR; A randomized prospective trial has shown that folic acid started before conception and continued for the first trimester reduces the risk of recurrence of neural tube defects by 72% in women with a previously affected child . Carbamazepine exposure in utero is associated with a 1% risk of spina bifida . Long-term follow-up of antenatal exposure to phenobarbital and carbamazepine in two groups of infants shows no neurologic differences between the two groups . Magnesium sulfate is more effective in prevention of recurrent eclamptic seizures than phenytoin . During pregnancy, the need for thyroxine increases in many women . Vitamin B6 and ginger are both effective for nausea and vomiting in early pregnancy . Low-dose aspirin does not change the course of preeclampsia when it is started after the diagnosis is made . Angiotensin-converting enzyme inhibitors cause significant disturbances of fetal and neonatal renal function . Prophylactic beta-adrenergic agents fail to prevent prematurity in twins . Oral tocolysis with magnesium chloride or ritodrine is no more effective than observation alone . The risk of primary pulmonary hypertension in the newborn after indomethacin tocolysis is increased with prolonged therapy . Lithium causes polyhydramnios from fetal diabetes insipidus in utero . Treatment of Ureaplasma urealyticum infection with erythromycin during pregnancy does not eliminate the organism from the lower genital tract and does not improve perinatal outcome.

Antibiot Khimioter, 1992 Feb, 37(2), 11 - 4
{Various properties of erythromycin basicity}; Bureiko SF et al.; Erythromycin (Er) as a weak base showed some specific properties when dissolved in aqueous solutions . The basic ability of Er had a tendency to become weaker during storage in the room settings and especially at high temperatures . The temperature gradient within the ranges of 10 to 25 degrees C was dpH/dt = -0.03 (for 2 x 10(-3) M Er solution) . However, the basic properties of the Er base partly renewed when Lewis' bases such as dimethyl carboxide, dimethylformamide and dimethyl sulfoxide were added to Er aqueous solutions previously stored for days or weeks . In chloroform solutions, either the thermodynamics or the kinetics of Er protonization showed no abnormalities as compared to nitric bases . It was supposed that in aqueous solutions of Er base there was transformation linked with intramolecular or extramolecular interactions which provoked shielding of the tertiary basic atom of nitrogen due to formation of the nitrogen linkage.

J Antimicrob Chemother, 1992 Feb, 29(2), 173 - 8
Effect of erythromycin on ciliary motility in rabbit airway epithelium in vitro; Tamaoki J et al.; The effect of erythromycin on ciliary beat frequency (CBF) of rabbit tracheal epithelium was studied by a microphoto-oscillation technique in vitro . Addition of erythromycin dose-dependently increased CBF, the maximal increase from the baseline value and EC50 being 23.3 +/- 4.5% (P less than 0.001) and 6.8 +/- 0.9 mg/L, respectively . This effect was not influenced by autonomic receptor antagonists, blockers of arachidonic acid metabolism, Ca(2+)-free medium, or inhibition of protein kinase C and protein kinase A activities.

Kansenshogaku Zasshi, 1992 Feb, 66(2), 194 - 200
{Effect of erythromycin on intrapulmonary influx of neutrophils by intratracheal injection of lipopolysaccharide}; Sakito O et al.; Recently, "low dose and long term" erythromycin (EM) treatment has been reported as effective on chronic lower respiratory tract disease, including diffuse panbronchiolitis (DPB) . However the effective mechanism of EM is still obscure . In this study, we investigated the effect of EM on intrapulmonary influx of neutrophils by intratracheal injection of lipopolysaccharide (LPS), and the following results were obtained . 1) The intrapulmonary influx of neutrophils was significantly suppressed (p less than 0.001) in mice intraperitoneally injected with EM at 5 mg per animal 2 hr before intratracheal injection of LPS (control group: 6.5 +/- 0.8 x 10(5) vs EM-treated group: 1.7 +/- 0.3 x 10(5)), but not 10 hr before lung challenge . This inhibition was observed at 6 hr after lung challenge, and became maximum with 84% suppression at 24 hr . 2) The intrapulmonary influx of neutrophils was not affected when EM was injected intraperitoneally daily for 3, 7, or 14 days, and lung challenge was performed 24 hr after the final administration of EM . 3) The number of neutrophils in the peripheral blood was not affected by EM . These results suggest that EM treatment impairs the capacity for pulmonary inflammation by reducing, at least in part, the migration of neutrophils to inflammatory sites.

J Surg Res, 1992 Feb, 52(2), 140 - 6
Erythromycin stimulates ileal motility by activation of dihydropyridine-sensitive calcium channels; Armstrong DN et al.; Erythromycin, a macrolide antibiotic, is a potent stimulant of small bowel motor activity (MA) which may motility either via the peptide motilin receptor or neural mechanisms . We hypothesized that erythromycin stimulates directly stimulates smooth muscle cells by a calcium-mediated event . Thus, we evaluated the effect of neuronal blockade with tetrodotoxin, muscarinic blockade with atropine, and opiate blockade with naloxone on erythromycin-stimulated MA in isolated perfused segments of rabbit terminal ileum . We also tested the effect of nonspecific calcium channel blockade (verapamil and cadmiun) and specific blockade (dihydroxypyridine and nichol) on erythromycin-stimulated MA . MA was measured with a multichannel continuous perfusion manometry catheter . Erythromycin caused a concentration-dependent increase in MA (ED100 5 x 10(-4) M) . Tetrodotoxin, atropine, and naloxone did not effect erythromycin-stimulated MA (P greater than 0.05) . Both verapamil (10(-7) M) and cadmium (10(-2)-10(-4) M) inhibited erythromycin-stimulated MA . Selective blockade of "l" type calcium channels using dihydropyridine (10(-6) M) and "t" channels with nickel (10(-2)-10(-4) M) both reversed erythromycin-stimulated MA . Since the isolated segments of terminal ileum were free of exogenous humoral and neural effects, these studies indicated that erythromycin directly stimulated MA in the terminal ileum . Furthermore, since tetrodotoxin, atropine, and naloxone did not inhibit this increase in MA, erythromycin acted by a mechanism which was independent of the intrinsic nervous and opiate systems . In conclusion, these data are consistent with the model that erythromycin stimulates ileal motility by a mechanism involving activation of dihydroxypyridine and nickel-sensitive calcium channels.

FASEB J, 1992 Jan 6, 6(2), 752 - 8
Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture; Maurice M et al.; The expression of several forms of cytochrome P450 including P450 1A2, 2D6, 2E1, and 3A was investigated in human hepatocytes maintained in primary culture for 96 h in the absence or presence of 50 microM of various imidazole derivatives . These included ketoconazole, clotrimazole, miconazole, fluconazole, secnidazole and metronidazole . In addition, the typical inducers rifampicin and beta-naphthoflavone were used for comparison . Western and Northern blot analysis of microsomes and RNA prepared from these cultures as well as de novo synthesis experiments revealed that, among the imidazole derivatives tested, only clotrimazole was a strong rifampicin-like inducer of P450 3A . The expression of the other forms of P450 tested was not affected by the treatments . Analysis of the inhibition of 13 monoxygenase activities, including ethoxyresorufin and phenacetin O-deethylases, coumarin 7 alpha-, lauric acid 11- and 12-, mephenytoin 4-, debrisoquin 4-, and aniline hydroxylases, benzphetamine, aminopyrine, mephenytoin and erythromycin demethylases, and cyclosporin oxidase (representative of 10 different forms of P450 in human liver microsomes) revealed that ketoconazole was a strong and selective in vitro inhibitor of P450 3A (cyclosporin oxidase) with a Ki less than 1 microM . Clotrimazole and miconazole were also strong inhibitors of P450 3A-mediated activities in contrast to the other imidazole derivatives.

Am J Physiol, 1992 Jan, 262(1 Pt 1), G50 - 5
Erythromycin contracts rabbit colon myocytes via occupation of motilin receptors; Hasler WL et al.; Erythromycin stimulates gastroduodenal motility via action on motilin receptors . We evaluated erythromycin as a colonic muscle motilin agonist using in vitro rabbit colon studies . Isolated myocytes contracted to erythromycin with a half-maximal effective concentration of 2 pM and peak shortening of 22.4 +/- 2.5% at 1 nM, which was superimposable with the response to motilin . 125I-labeled motilin binding to colon muscle homogenates was saturable and specific with a dissociation constant (Kd) of 0.39 nM and maximal binding (Bmax) of 41 +/- 3 fmol/mg protein . Motilin displaced specifically bound 125I-motilin, with a Kd of 0.31 nM . Erythromycin displaced 125I-motilin but was less potent, with an inhibitory constant of 84.0 nM . Bmax values from displacement studies were similar to the Scatchard data . Motilin receptor protection from alkylation by N-ethylmaleimide preserved contraction to motilin and erythromycin but not acetylcholine or cholecystokinin, whereas protection with erythromycin preserved contraction to motilin but not other agonists . In conclusion, erythromycin binds to colon muscle motilin receptors present in densities similar to reported values for the upper gut . Furthermore, erythromycin contracts colonic myocytes via specific action on motilin receptors . Thus erythromycin may have colonic motor-stimulating properties by action on motilin receptors.

Am J Med, 1992 Jan, 92(1), 61 - 8
Erythromycin ototoxicity: prospective assessment with serum concentrations and audiograms in a study of patients with pneumonia; Swanson DJ et al.; BACKGROUND AND METHODS: The incidence and risk factors for erythromycin-induced ototoxicity are unknown . We conducted a prospective, nested case-control study of assessment of auditory function in patients receiving erythromycin versus other antibiotics (control group) for community-acquired pneumonia . Sequential audiograms were performed during antibiotic therapy for both cases and controls by an audiologist unaware of the identity of the therapy administered . Erythromycin serum concentrations were obtained for all patients receiving erythromycin . RESULTS: Symptomatic ototoxicity (tinnitus or hearing loss) confirmed by audiograms was documented in five of 30 patients receiving erythromycin and none of 15 receiving other antibiotics . Ototoxicity was significantly related to high peak concentration and high AUC 0-infinity as a function of decreased total systemic clearance . Ototoxicity occurred only in those patients who received 4 g/day versus 2 g/day or no erythromycin (p = 0.05) . Ototoxicity resolved in all patients within 6 to 14 days after discontinuation of therapy . CONCLUSIONS: Erythromycin ototoxicity is dose- and serum concentration-dependent . Patients receiving erythromycin, especially at a total daily dose of 4 g, should be monitored regularly for subjective evidence of sensorineural hearing dysfunction . Ototoxicity is reversible if the diagnosis is made early in the course.

Chest, 1992 Jan, 101(1), 281 - 3
Fibrosing alveolitis responsive to corticosteroids following Legionnaires' disease pneumonia; Hurter T et al.; Two male patients ages 54 and 58 years had persisting pneumonia with dry cough, dyspnea, weight loss, and fever up to 39 degrees C that did not respond to erythromycin treatment . There was extensive restrictive impairment of ventilation and loss of diffusing capacity for carbon monoxide . Histologic examination of the basal pulmonary infiltrates showed fibrosing alveolitis . Serologic titers indicated that the patients had suffered from Legionella pneumophila infection . We believe that Legionella had caused the fibrosing alveolitis since there was absence of any other causative agents or factors . Both patients responded to corticosteroid treatment with rapid clinical improvement but delayed radiologic regression.

Gastroenterology, 1992 Jan, 102(1), 97 - 101
Effect of motilin on gastric emptying in patients with diabetic gastroparesis; Peeters TL et al.; Erythromycin markedly accelerates gastric emptying, possibly because it acts as a motilin agonist . In the present study, the effect of an equipotent dose of motilin was tested . In six patients with severe diabetic gastroparesis, gastric emptying of liquids and solids was examined scintigraphically after motilin or placebo in a double-blind crossover study . Motilin (10 pmol.kg-1.min-1) or saline was infused over a 90-minute period starting 5 minutes before breakfast . Motilin markedly accelerated emptying . For liquids, the half-emptying time was reduced from 51 +/- 6 to 22 +/- 11 minutes (P less than 0.01) and for solids from 111 +/- 4 to 51 +/- 12 minutes (P less than 0.01) . The mean increase in plasma motilin levels was 1315 +/- 342 pg/mL, corresponding to an effective infusion rate of about 4 pmol.kg-1.min-1 . In the control experiments, basal motilin levels (173 +/- 17 pg/mL) were within the normal range but increased steadily postprandially, reaching 321 +/- 25 pg/mL at the end of the study period, probably reflecting gastric distension . The postprandial increase in pancreatic polypeptide level was blunted compared with accepted normal values but was more pronounced during motilin infusion, i.e., 650 +/- 217 vs . 279 +/- 66 pg/mL (P less than 0.01), probably because of the improved emptying . Our data show that motilin accelerates gastric emptying in diabetic gastroparesis and support the hypothesis that erythromycin's effect is mediated through motilin receptors.

Skin Pharmacol, 1992, 5(2), 124 - 8
Assay of erythromycin in tape strips of human stratum corneum and some preliminary results in man; van Hoogdalem EJ; The antibiotic erythromycin is used topically in the treatment of acne vulgaris . In order to evaluate the in vivo cutaneous absorption behavior of erythromycin in man, an analytical procedure for erythromycin in stratum corneum tape strips was developed . Erythromycin was extracted from tape strips using solid-phase extraction, followed by alkaline diethyl ether extraction . Reconstituted extracts were analyzed by RP-HPLC with electrochemical detection . This procedure proved to be adequate in a pilot experiment in man, topical erythromycin appearing to be distributed over the stratum corneum, its upper layers displaying an inward decreasing gradient.

Acta Otolaryngol Suppl, 1992, 492, 55 - 7
Acute laryngitis in adults: results of erythromycin treatment; Schalen L et al.; Previous studies of acute laryngitis in adults have shown high nasopharyngeal isolation rates of B . catarrhalis and H . influenzae . Phenoxymethylpenicillin had no effect on the clinical course . In the present study, 106 patients with acute laryngitis were treated with erythromycin 0.5 g x 2 V or placebo . During the first week the isolation rate of B . catarrhalis was reduced from 60 to 10% in the erythromycin group compared to 34 to 27% in the placebo group (p less than 0.01) . The elimination of H . influenzae, isolated in 19% at the acute visit, did not differ between the two groups . As compared to controls, erythromycin treated patients reported significantly lower scores of subjective voice disturbance after 1 week and cough after 2 weeks . Laryngological examination and voice evaluation failed to reveal any differences between the groups.

Nihon Kyobu Shikkan Gakkai Zasshi, 1992 Jan, 30(1), 100 - 5
{A case of psittacosis with migratory infiltrates}; Yamato H et al.; A 56-year-old man with fever, headache, cough and sputum was admitted to another clinic . Chest X-ray examination revealed infiltrates in the upper lobe of the right lung . Cefem and aminoglycoside therapy was not effective, and the infiltrates migrated from the right upper lobe to the right middle and lower lobes and then to the left lung . He was transferred to our clinic, and laboratory data showed that CRP was 6+; ESR, 119 mm/1 h; WBC, 3000/mm3; and CAR, 512 . The tentative diagnosis of atypical pneumonia was based on the positive agglutination test for Legionella pneumophila, and treatment with erythromycin, minocycline and rifampicin resulted in alleviation of symptoms and resolution of the infiltrates in the lungs . Complement fixation titer for Chlamydia was 128 at admission and was elevated to 512 after 2 weeks . Indirect fluorescent antibody for Legionella was negative . Transient liver dysfunction was also observed.

J Gynecol Obstet Biol Reprod (Paris), 1992, 21(4), 385 - 92
{Mycoplasmas and pregnancy . Preliminary study}; Segonds C et al.; The prevalence of genital mycoplasmas was studied among 191 pregnant women followed up at Diaconesses Hospital, Paris . Ureaplasma urealyticum was recovered from 65% of patients, alone (54%) or in association with Mycoplasma hominis (11%) . The relationship to pregnancy outcome, the effect of erythromycin treatment, the interest of biological markers of infection (mycoplasmal quantitation and serologic tests, C-reactive protein) and the role of other known genital pathogens were investigated . Vaginal infection with Ureaplasma urealyticum according to biological criteria (i.e . vaginal concentration greater than 10(3) CCU/ml or coisolation of Mycoplasma hominis) was significantly associated with an increased risk of: 1 . premature rupture of the fetal membranes; 2 . prematurity in cases of preterm labor . Erythromycin treatment was able to prevent only the risk of prematurity . On the other hand, we didn't show any influence of mycoplasmal colonization on birth weight, if expressed with regard to gestational age . An immune response to Ureaplasma urealyticum was demonstrated in 15% of patients; rare fourfold antibody rises were detected specially in the case of a second trimester spontaneous abortion and of an intrauterine death (both were untreated patients) and probably attest an infectious process . A randomized trial with a larger study sample must be undertaken to corroborate these preliminary data.

Toxicology, 1992, 73(2), 179 - 89
Protective effect of diosmetin on in vitro cell membrane damage and oxidative stress in cultured rat hepatocytes; Villa P et al.; Primary cultures of rat hepatocytes were used to study the effects of the flavonoids diosmin and its main metabolite diosmetin on the cell membrane damage caused by erythromycin estolate (EE) and oxidative stress caused by tert-butylhydroperoxide (TBHP) . The damage was evaluated by the leakage of intracellular enzymes lactate dehydrogenase, aspartate-aminotransferase and the residual cell content of a lysosomal marker acid phosphatase (AP) . After treating the cells for 40 h with diosmetin EE induced less enzyme leakage . The content of AP was kept higher by diosmetin pretreatment after 6 h exposure to EE . Diosmin at the same concentrations had barely any effect . Diosmetin, but not diosmin, also protected against TBHP toxicity and this was related to lower lipid peroxidation and higher glutathione content caused by pretreatment with the flavonoid . When the cells were treated simultaneously with TBHP and diosmetin after 21 h of culture, the protection by the flavonoid was even higher . In fact the antioxidant activity of diosmetin was considerably greater than that of diosmin . After 40 h exposure to both flavonoids diosmin but not diosmetin was detectable in the cell membrane fraction, suggesting that the latter's protective effect is associated with its metabolites.

Arzneimittelforschung, 1992 Jan, 42(1), 73 - 6
Effect of food on absorption and hydrolysis of erythromycin acistrate; Jarvinen A et al.; Effect of food on absorption of erythromycin acistrate (2'-acetyl erythromycin stearate, Erasis; CAS 96128-89-1) was studied in 14 healthy volunteers in a randomized cross-over design . The subjects were given 400 mg erythromycin acistrate enteric coated tablets b.i.d . for 4 days . On the 1st and 4th days the tablets were taken after an overnight fast or immediately after a light or a heavy breakfast . Erythromycin (E), 2'-acetyl-erythromycin (2AE), anhydroerythromycin and anhydro-2'-acetyl-erythromycin concentrations in plasma were analyzed chemically by HPLC . After a single dose the lag time of absorption (tlag) was significantly longer after both types of breakfasts as compared to fast . The tmax of E and 2AE were also somewhat delayed by food although tmax of 2AE after a heavy breakfast only differed statistically significantly from that of the fasting state . Food significantly delayed the absorption especially in some subjects since no drug was observed during the 12-h observation period in 2 and 5 of the subjects after a light and heavy breakfast, respectively . At steady state the delaying effect of food on absorption had almost disappeared . No significant differences were observed in Cmax- or AUC0-12-values between the fasting and the fed states both after a single dose or at steady state . It is concluded, that food does not affect the mean bioavailability of erythromycin acistrate neither the mean rate of absorption but in some subjects the absorption from enteric coated tablets might be significantly delayed.

Clin Infect Dis, 1992 Jan, 14(1), 204 - 7
Legionnaires' disease and acute renal failure: case report and review; Shah A et al.; The case of a 26-year-old man with pneumonia due to Legionella pneumophila associated with acute renal failure is presented, and the English-language literature on legionnaires' disease is reviewed . For this review, acute renal failure was defined as rapid deterioration in renal function indicated by a rise in levels of blood urea nitrogen and creatinine with or without the presence of oliguria . Our patient experienced renal failure and underwent hemodialysis . His condition gradually improved after treatment of legionnaires' disease with erythromycin . Biopsy of the kidney showed acute tubulointerstitial nephritis . Immunofluorescence microscopy demonstrated the presence of L . pneumophila serogroup 1 . The laboratory findings suggested rhabdomyolysis . To our knowledge, this is the first case report of a patient with legionnaires' disease who recovered from acute renal failure and in whom the presence of L . pneumophila was demonstrated, and we believe it is the first case in which morphology of the kidney demonstrated the presence of L . pneumophila in a patient with legionnaires' disease, rhabdomyolysis, and renal failure.

Naunyn Schmiedebergs Arch Pharmacol, 1992 Jan, 345(1), 71 - 7
Motilin and erythromycin enhance the in vitro contractile activity of the sphincter of Oddi of the Australian brush-tailed possum; Baker RA et al.; Erythromycin has been shown to interact with gastrointestinal smooth muscle in a similar manner to motilin, and has been postulated as a motilin receptor agonist . We report that in isolated preparations from the biliary tract of thirty one Australian Brush-tailed Possums (Trichosurus vulpecula) erythromycin acts in a similar manner to motilin . In all muscle strips from the sphincter of Oddi, prepared in both the circular and longitudinal orientation, both synthetic porcine motilin (10(-10) M-10(-6) M) and erythromycin (lactobionate) (10(-8) M-10(-4) M) stimulated contractile activity in a concentration dependent manner, via a direct effect on the smooth muscle (the response was unaffected by tetrodotoxin, omega conotoxin GVIA or atropine) . In strips prepared from the gallbladder neither agonist affected the contractile activity in 7 of 8 animals . Motilin was approximately 1000 fold more potent in stimulating contractile activity than erythromycin in both sphincter of Oddi circular strips {pD2 for peak response to motilin 8.67 (mean) +/- 0.06 (SEM) compared with erythromycin 5.67 +/- 0.09} and sphincter of Oddi longitudinal strips {pD2 for peak response to motilin 8.64 (mean) +/- 0.28 (SEM) compared with erythromycin 5.45 +/- 0.23} . The concentration response curves for motilin and erythromycin were similar and both agonists required the presence of extracellular calcium to elicit responses (responses were diminished by verapamil and abolished in calcium free Krebs solution) . Our results support the hypothesis that erythromycin mimics the action of motilin in stimulating the sphincter of Oddi in vitro.

Microsurgery, 1992, 13(6), 348 - 9
Free flap failure due to venous occlusion secondary to previous intravenous cannulation: a case report; Beckingham IJ et al.; A case of failure of a free radial forearm flap is presented . It is surmised that this was due to venous thrombosis in the cephalic vein which showed evidence of recanalization of an old thrombus . The patient had received intravenous erythromycin some months previously.

Bull Soc Pathol Exot, 1992, 85(4), 276 - 8
{The reappearance of chancroid in Algeria}; Boudghene-Stambouli O et al.; After 35 observations of the chancroid observed in the department of dermato-venereology of the University Hospital of Tlemcen (West Algeria) from August 1988 to December 1991, we are led to analyze the flare of this sexual transmitted disease . The principal affected subjects are single male no older than 30 years, having had sexual intercourse with prostitutes (30/35) . Less than 10 days (19/29) after the sexual contacts, the ulcer appears, and most often unique (25/35), mildly painful, accompanied frequently by adenopathies (31/35) . The contamination took place mainly in Bel Abbes--city located at 90 km from Tlemcen--(12 cases), in Tlemcen (4 cases) and Morocco (5 cases) . The treatment based on sulfonamides, erythromycin and tetracycline or doxycycline, has been constantly efficient . No concomitant HIV infection has been revealed . The chancroid is the first STD observed in our department in 1991, and also, the first cause for genital ulcerPIP: During August 1988 to December 1991 in western Algeria, the dermato-venereology department of the University Hospital in Tlemcen observed 35 cases of chancroid, all of whom were male . About 50% of the cases (18) occurred in 1991 . Predominant characteristics of the chancroid cases included contact with prostitutes (30 cases), single (29), and age ranging from 20 to 30 years (70%) . Leading sites where contamination occurred were Bel Abbes (90 km from Tlemcen) (12 cases), Tlemcen (4 cases), and Morocco (5 cases) . The mean incubation period was 15 days (range, 3 days to 5 months) . The genital ulcer appeared within 10 days in 19 men . More than 50% of the men made a visit to the clinic before 20 days of the chancroid's evolution . The ulcer appeared only once in 25 cases . It was accompanied by moderate pain in 13 cases . Gland enlargement occurred in all but 4 cases . None of the cases tested positive for syphilis or for HIV . 25 patients were successfully treated with 4 doses of co-trimoxazole per day for 10-15 days . Erythromycin was used to successfully treat five patients at a dose of 2 g/d for 10 days . The 10-day treatment for the last five cases consisted of 200 mg doxycycline per day, 2 g oxytetracycline per day, and 1 g intramuscular streptomycin . This combination treatment was also effective .

Ter Arkh, 1992, 64(3), 32 - 4
{The causes of prolonged fever in patients with infiltrative lung processes}; Shchennikov EL et al.; The authors analyze the causes of lingering fever in patients with pulmonary infiltrations . The given phenomenon is most often caused by pneumonias provoked by unusual causative agents (Legionella, Rickettsia, Mycoplasma) . In such cases, administration of erythromycin is effective . In rare cases, lingering fever is induced by blocked pulmonary suppurations, pleural exudates in pneumonia patients, and infiltrative tuberculosis . Besides, there were cases, in which fever was of drug etiology.

Int J Clin Pharmacol Res, 1992, 12(2), 71 - 9
Effect of midecamycin acetate on gastrointestinal motility in humans; Sifrim D et al.; The effect was studied on gastrointestinal motor activity of three different macrolides (erythromycin, roxithromycin and midecamycin acetate), administered by mouth in therapeutic doses . This placebo-controlled study was performed in 12 normal human subjects by means of intraluminal pressure measurements in the gastric antrum, duodenum and upper jejunum . In each subject, three manometries were done for 5 h in the interdigestive period and for 3 h postprandially . In the interdigestive period, midecamycin acetate did not affect the characteristics of the gastric migrating motor complex (MMC) and did not increase the number of antral contractions or the gastric motility index as compared to the placebo . Erythromycin and roxithromycin increased the number of antral contractions (24.5 +/- 11 versus 15.2 +/- 7 and 28.4 +/- 12 versus 14.9 +/- 5.9 respectively) and the motility index (4.05 +/- 0.5 versus 3.17 +/- 0.6 and 4.38 +/- 0.2 . versus 3.64 +/- 0.7 respectively) as compared to the placebo . In the postprandial period, the number of antral contractions was not significantly increased by any of the three antibiotics . The postprandial antral motility index was not significantly increased by midecamycin acetate . In contrast, the postprandial antral motility indexes after erythromycin (4.4 +/- 0.5) and after roxithromycin (4.3 +/- 0.2) were significantly greater than after the placebo . In the upper small intestine, erythromycin elicited an increased number of phase-III-like activity events and roxithromycin shortened the MMC cycle length . Midecamycin acetate had no effect on interdigestive upper jejunal motility . The postprandial jejunal motor activity was not altered by any of the three antibiotics neither during the interdigestive nor the postprandial periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Drugs Exp Clin Res, 1992, 18(3), 105 - 11
The influence of seaprose on erythromycin penetration into bronchial mucus in bronchopulmonary infections; Braga PC et al.; In bronchopulmonary infections antibiotics can be combined with other drugs, called mucoactive drugs, that act to reduce the abnormal viscoelasticity of the mucus enabling a deeper penetration of more antibiotic into the mucus . Seaprose is a protease that interacts with the polymeric fibrillar structure of the bronchial mucus to shorten the long chains of mucoproteins, DNA and other macromolecules, thus reducing the viscosity of the mucus . In order to assess whether the combination of seaprose (60 mg/8 h) plus erythromycin (500 mg/8 h) allows higher antibiotic levels in sputum than erythromycin (500 mg/8 h) plus placebo, the pharmacokinetic behaviour in sputum and in blood of these two treatments was investigated in a double-blind study in two groups of twenty patients each with bronchopulmonary infections . Serum and sputum levels were determined for each patient at the first and seventh day of the two drug regimens . Statistically significant differences for peak, AUC and MRT, were observed for erythromycin between the first and last dose in the group of patients treated with seaprose plus erythromycin; moreover significant differences for these parameters were observed between the two groups . These findings indicate the presence of a pharmacokinetic synergism between seaprose and erythromycin which allows erythromycin to penetrate bronchial secretion more easily and in higher amounts, performing a sterilizing action with therapeutic advantages.

Scand J Infect Dis, 1992, 24(4), 531 - 3
Rat bite fever in a Greek child; Konstantopoulos K et al.; Rat bite fever was diagnosed in a 10-year-old boy in a rural area of south-west Greece . The clinical presentation was typical for this disease and the relevant causative agent (Streptobacillus moniliformis) was isolated from blood cultures of the febrile patient . Erythromycin treatment was efficient . Although extremely rare in continental Europe, this infection must be taken into account as a potential hazard of a rat bite.

Drug Metab Dispos, 1992 Jan-Feb, 20(1), 31 - 7
Characterization of human liver cytochromes P-450 involved in theophylline metabolism; Sarkar MA et al.; Theophylline is metabolized in the liver by one or more cytochrome P-450 enzymes . To assess the amounts and types of these human cytochromes P-450, we incubated theophylline with microsomes prepared from 22 different human livers in the presence of NADPH, and measured simultaneous rates of 1- and 3-N-demethylations to 3-methylxanthine (3-MX) and 1-methylxanthine (1-MX), respectively; and 8-hydroxylation to 1,3-dimethyluric acid (1,3-DMU) . Under optimal conditions, 3-MX, 1-MX, and 1,3-DMU formation proceeded with mean Km values of 2.05, 1.93, and 5.34 mM and Vmax values of 2.28, 2.48, and 23.4 pmol/mg/min, respectively . Formation of 3-MX and 1-MX correlated best with amounts of the immunoreactive protein HLd (P-450IA2) (p less than 0.05), whereas formation of 1,3-DMU correlated with the microsomal content of HLp (P-450IIIA3) and HLj (P-450IIE1) . In immunoinhibition experiments, incubations conducted with a polyclonal anti-rat P-450c/d antibody, the formation of all the three theophylline metabolites (p less than 0.05) was significantly inhibited . However, addition of isoform-specific anti-rat-P-450d antibodies to the microsomal mixture significantly inhibited 1-N-demethylation, selectively, with little (if any) inhibition of 3-N-demethylation or 8-hydroxylation . Nonspecific cytochrome P-450 inhibition was ruled out by showing that erythromycin N-demethylation, an activity catalyzed by HLp, was unaffected by either anti-P-450c/d (P-450IA1/IA2) or anti-P-450d . Anti-rat-P-450p antibodies failed to block formation of theophylline metabolism, but did inhibit erythromycin N-demethylase.(ABSTRACT TRUNCATED AT 250 WORDS)

Drugs Exp Clin Res, 1992, 18(10), 427 - 30
The efficacy of clarythromycin (A-56268, TE-031) in the treatment of genital chlamydial infection; Calzolari E et al.; The authors report the preliminary results of an experience of treatment with clarythromycin in Chlamydia trachomatis endocervicitis/endourethritis; 100% of 51 outpatients treated had negative ELISA results 7-10 days after the end of treatment with clarythromycin 500 mg . b.i.d . for 7 days . Among 64 female outpatients with chlamydial cervicitis treated with erythromycin 1 g b.i.d . for 7 days, 88% were negative at ELISA at the same intervals after therapy . The authors conclude that the efficacy of clarythromycin in this experience makes it use worthy of other and more extensive studies.

Pneumoftiziologia, 1992 Jan-Mar, 41(1), 56 - 7
{Acute rhinopharyngitis, acute interstitial pneumonia and parieto-frontal brain abscess with H . influenzae type B}; Mihancea N et al.; The paper deals with a parietal frontal cerebral abscess caused by HITB biotype I in a girl aged 8 months . First a meningitis is suspected, then a tuberculous meningitis unsuccessfully treated with ampicillin, biseptol, respectively INH, rifampicin, pyrazinamide, prednisone, phenobarbital and chloramphenicol . The patient died through a central respiratory standstill on the 17th day of disease . The anatomopathological examinations revealed a giant parietal frontal cerebral abscess . H.influenzae, (serum type B, biotype I) resistant to ampicillin, chloramphenicol, Kanamycin, rifampicin and tetracycline but sensitive to erythromycin and neomycin was also found . A pharyngeal infection with HITB was presumably the origin of the abscess.

Intensive Care Med, 1992, 18(8), 469 - 73
Possible risk for cardiac arrhythmia related to intravenous erythromycin; Haefeli WE et al.; OBJECTIVE: To evaluate the incidence of prolongation of the rate-corrected electrocardiographic QT interval (QTc) and of ventricular arrhythmia associated with intravenous administration of erythromycin lactobionate . DESIGN: A consecutive series of 7 critically ill patients treated with intravenous erythromycin for severe pneumonia . SETTING: A medical intensive care unit of a university hospital . MEASUREMENTS AND RESULTS: Registration of QTc duration before and after intravenous administration of erythromycin as a short infusion . Blood chemistry, hemodynamic variables, arrhythmias, and co-medications were recorded . Evaluation of at least 10 ECG intervals by 2 experienced investigators who were blinded as to the time of drug administration . If several measurements were performed in the same patient, only the mean value was used for further analysis . During 12 of 13 drug administrations studied in 7 patients QTc prolongation was observed . The extent of QTc prolongation was significantly correlated with the infusion rate (mg/min, r = 0.765, p = 0.05) . In 3 patients ventricular arrhythmia occurred in close temporal relation to the erythromycin infusion; two of them developed ventricular fibrillation shortly after the first and second dose of erythromycin, respectively, and died within 3 h . CONCLUSION: In critically ill patients erythromycin-induced QTc prolongation is a frequent pharmacologic effect correlated with erythromycin infusion rate . To avoid changes in electrocardiographic intervals and thereby possibly potentially life-threatening ventricular arrhythmia administration with the lowest possible infusion rate and close cardiac rhythm monitoring are advisable in these patients.

Chemotherapy, 1992, 38(6), 433 - 40
Uptake of flurithromycin by human polymorphonuclear phagocytes: partial characterization of the entry mechanism; Fietta A et al.; The ability of flurithromycin and erythromycin to enter human polymorphonuclear phagocytes were studied and compared by a velocity centrifugation gradient technique . Both macrolides were markedly concentrated by human cells and attained cellular to extracellular concentration ratios (C/E) > or = 10 . The incorporation was rapid and essentially complete after 60 min incubation . When PMNs were pretreated with formaldehyde, or incubated at low temperatures (4-25 degrees C) or at low pH, the transport ratios of both molecules were reduced . Sodium fluoride and 2,4-dinitrophenol, which decreased erythromycin uptake, did not affect flurithromycin penetration . Perturbation of cell membrane by phorbol myristate acetate, but not by formyl methionyl leucyl peptide, affected C/E ratios of both antibiotics . The addition of amino acids or nucleosides did not influence their transfer into PMNs.

East Afr Med J, 1991 Dec, 68(12), 999 - 1005
Neonatal Borrelia infections (relapsing fever): report of 5 cases and review of the literature; Melkert PW et al.; Tick borne relapsing fever is an endemic disease in Sengerema district, Mwanza region, Tanzania, East Africa . Five cases of neonatal relapsing fever occurring in this endemic area are described . Two neonates showed signs of septicaemia, clumping of spirochetes (Borrelia index is uncountable) in the thick blood smear and they died the day of admission . Two neonates showed severe spirochetaemia (Borrelia index: 3) . The neonate treated with low dose penicillin died, the other neonate, treated with erythromycin, survived . One neonate had only a mild spirochetaemia (Borrelia index is 0.5) and responded well to penicillin treatment . Jaundice was seen in four of the five cases, three of them died . Only twenty cases of neonatal relapsing fever were previously reported . Findings are discussed in comparison with those of former reports on relapsing fever in the literature . Based on the fact that in a relatively short time (1 year), 5 cases of neonatal relapsing fever were diagnosed in an endemic area in East Africa, we conclude that neonatal relapsing fever is probably underdiagnosed.

Kansenshogaku Zasshi, 1991 Dec, 65(12), 1527 - 32
{Evaluation of DNA-probe assay for the clinical diagnosis of Mycoplasma pneumoniae infections}; Nara N et al.; DNA probe-assay using the Gen-Probe kit was carried out to detect Mycoplasma pneumoniae infections . Fifteen children visited Ota General Hospital complaining of dry cough and high grade fever . Throat swabs of the patients were examined to detect M . pneumoniae ribosomal RNA by Gen-Prove kit . Five out of 15 patients were positive for DNA probe assay of M . pneumoniae . Clinical and laboratory data including serological examinations were compatible with M . pneumoniae infection in these cases . Following the improvement of clinical symptoms and signs by receiving erythromycin or minocycline, the positivity for DNA probe assay turned to negative . Among the ten patients, who were negative for DNA probe assay, 2 cases were suspected of M . pneumoniae infection on the basis of clinical and laboratory findings . One patient had already taken antibiotics . Therefore, in these two patients, there was a possibility that the bacterial numbers were too small to be detected by DNA-probe assay . The data described above support that DNA-probe assay is useful for the diagnosis of M . pneumoniae infections in the early stage . DNA-probe assay is also valuable to follow up the clinical course of the patients.

Am J Physiol, 1991 Dec, 261(6 Pt 1), G1079 - 84
Variation of slow-wave frequency and locking during the migrating myoelectric complex in dogs; Caenepeel P et al.; Slow waves determine rhythm and polarity of spike bursts . We measured the variation of slow-wave frequency (swf) and locking (swl) in the canine jejunum during the various phases of the migrating myoelectric complex (MMC) and during induced phase III (erythromycin 125 micrograms/kg iv bolus or somatostatin 2.5 micrograms.kg-1.h-1 iv infusion), blocked phase III (atropine 20 micrograms/kg iv bolus), and so-called stationary phase III activity (cisapride 150 micrograms/kg iv bolus) . The EMG of 4 dogs, implanted with 10 bipolar electrodes, was recorded on a polygraph . Our results indicate that swf and swl change during the MMC from a stepwise swf gradient with slow waves locked in plateaus during phase I to a continuous swf gradient without or with significantly reduced phase locking during phase III . The length of the first swf plateau decreases significantly from 42 +/- 12 cm post Treitz during phase I to 11 +/- 4 cm during spontaneous phase III . Atropine block of phase III activity prevents phase unlocking and development of a continuous swf gradient . Our hypothesis is that phase unlocking may be one of the induction mechanisms of spike-burst activity.

Biochem Pharmacol, 1991 Nov 6, 42(11), 2085 - 90
The inhibition of drug oxidation by anhydroerythromycin, an acid degradation product of erythromycin; Stupans I et al.; The inhibition of steroid 6 beta-hydroxylase activity by anhydroerythromycin, an acid breakdown product of erythromycin, has been studied and compared to the effects of erythromycin using liver microsomes from control and dexamethasone pretreated rats and human liver microsomes . Both anhydroerythromycin and erythromycin were found to be demethylated, thus both fulfil the prerequisites for possible metabolite-cytochrome P450 complex information . The formation of a metabolite-cytochrome P450 complex was demonstrated for anhydroerythromycin by preincubating NADPH fortified microsomes with anhydroerythromycin . This complex formation could be reversed by incubating the microsomes in 50 microM potassium ferricyanide . Anhydroerythromycin was a more potent inhibitor of androst-4-ene-3,17-dione (androstenedione) 6 beta-hydroxylation than erythromycin . Kinetic analysis shows that there are probably two cytochromes P450 involved in androstenedione 6 beta-hydroxylation in control rat microsomes both of which are inhibited by anhydroerythromycin . There are at least two forms of cytochrome P450 responsible for androstenedione 6 beta-hydroxylation in microsomes from dexamethasone pretreated rats but only the high affinity form is inhibited by anhydroerythromycin . "Atypical" kinetics were observed in human microsomes but inhibition of androstenedione 6 beta-hydroxylation was observed with 5 microM anhydroerythromycin at all androstenedione concentrations used . Inconsistencies have been observed in the literature with respect to clinical interactions observed with erythromycin . Since anhydroerythromycin appears to be a more potent inhibitor of androstenedione 6 beta-hydroxylation than erythromycin, we speculate that the variable blood levels of anhydroerythromycin found after dosing with erythromycin may explain these discrepancies.

J Steroid Biochem Mol Biol, 1991 Nov, 39(5A), 741 - 9
Effects of ethinylestradiol and testosterone implants on hepatic microsomal cytochrome P450 monooxygenases of birth gonadectomized male and female Dark Agouti rats; Reilly PE et al.; Monooxygenases in the cytochrome P450 IIIA subfamily are induced by a number of their xenobiotic substrates and by testosterone, an endobiotic substrate of importance in their regulation . 17 alpha-Ethinylestradiol (EE) is also metabolized by these enzymes and in this study Dark Agouti rats were used to examine the effects of subcutaneous implantation of controlled release silastic capsules containing EE to determine if this steroid also induces these enzymes . Data were compared with results obtained from equivalent groups of animals implanted with capsules containing testosterone propionate (TP) . Liver microsomes prepared from male and female rats were used to identify intrinsic gender differences in the monooxygenases studied and gender differences in the responses to the implanted steroids were also determined . Effects due to imprinting of growth hormone secretion patterns were controlled by using male and female birth gonadectomized animals . Results obtained from groups with blank implants showed there were no effects due to the silastic implant material itself on the monooxygenases studied . The specific activities of erythromycin N-demethylation in liver microsomes of both EE and TP implanted male and female birth gonadectomized animals were enhanced relative to corresponding blank implanted controls consistent with both steroids having an effect to induce activity attributable to cytochrome P450 IIIA isoforms . Immunoinhibition studies using microsomes from EE treated female rats with erythromycin as substrate provided further evidence for this steroid having this induction effect . The specific activity of ethylmorphine N-demethylation was however not increased in microsomes prepared from the EE implanted female animals and was decreased in the corresponding male preparations . These findings distinguished the response to this steroid from that to TP and suggested induction by this estrogen of an isoform(s) having a more limited range of substrates than has characteristically been found in this subfamily . EE treatment also caused an increase in diazepam C3 hydroxylase consistent with an effect to induce P450 IIIA activity but this was found only in microsomes from birth gonadectomized female animals . This was in contrast to the effect of TP treatment which produced increases in this monooxygenase in both male and female animals . Another gender specific effect of EE was a striking decrease in morphine N-demethylase activity seen only in birth gonadectomized male rats . This again contrasted with the effect of TP which caused a marked increase in this activity in liver microsomes of both male and female birth gonadectomized animals consistent with the proposal that testosterone is important in the regulation of this activity.(ABSTRACT TRUNCATED AT 400 WORDS)

J Fam Pract, 1991 Nov, 33(5), 476 - 80
A comparison of albuterol and erythromycin for the treatment of acute bronchitis; Hueston WJ; BACKGROUND . Based on observations that pulmonary function tests of patients with acute bronchitis resemble those of patients with asthma, it was hypothesized that a bronchodilator may be an effective form of treatment for patients with acute bronchitis . METHODS . Albuterol was compared with erythromycin in a prospective, randomized, double-blinded fashion . Participants were patients who presented to family physicians with a history of having a productive cough of less than 30 days' duration, no history or evidence of pneumonia, and no other pulmonary or cardiac disease . Patients completed a 7-day symptom diary and returned to their physician after 1 week of therapy for reexamination . RESULTS . Patients treated with albuterol were less likely to be coughing after 7 days of treatment than patients treated with erythromycin (41% vs 88%, P less than .05) . This was true for both smokers and nonsmokers and in patients with purulent-appearing sputum . Trends toward an earlier improvement in cough and an improved feeling of well-being also were observed in the albuterol group . No differences between groups were found as to the length of time before patients returned to work, the length of time until patients resumed normal activities, or the overall improvement in patient well-being . Minor side effects were equal in both groups . CONCLUSIONS . Oral albuterol may be more effective than commonly used antibiotics in relieving the symptoms of acute bronchitis.

J Med Virol, 1991 Nov, 35(3), 180 - 6
Effects of purine nucleoside analogues with a cyclobutane ring and erythromycin A oxime derivatives on duck hepatitis B virus replication in vivo and in cell culture and HIV-1 in cell culture; Hung LF et al.; The effects on duck hepatitis B virus (DHBV) replication of specific analogues of two classes of chemical compounds not previously tested against hepadnaviruses are described . One is erythromycin A-9-methyloxime (EMO) and other oxime derivatives of erythromycin A, and the other is purine nucleoside analogues (cyclobut A and cyclobut G) with cyclobutane rings . Viral replication was assessed by measuring serum levels of DHBV DNA in infected ducklings and DHBV DNA in infected primary duck hepatocyte cultures . Administration of EMO 15 mg/kg of body weight IM to infected ducklings resulted in a rapid fall in DHBV DNA levels during therapy and a return to pretreatment levels after EMO administration was stopped . There was local toxicity at injection sites with muscle necrosis in some animals . When 100 mg/kg EMO was administered by gastric tube no such viral response was observed . The difference in virus response to EMO 15mg/kg IM and 100 mg/kg by gastric tube was not due to failure to achieve comparable blood and tissue levels of EMO administered by the different routes . The results suggest an indirect effect dependent on IM injection of EMO rather than a direct antiviral effect of the compound . Administration of cyclobut G or cyclobut A at 70 mg/kg IM led to a rapid reduction of DHBV DNA to undetectable levels in serum, and in only 1 of 4 animals did DHBV DNA became detectable again within 10 days after stopping the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

J Biomed Mater Res, 1991 Nov, 25(11), 1409 - 14
Effect of hand mixing tobramycin on the fatigue strength of Simplex P; Davies JP et al.; In a recent study, we showed that the presence of gentamicin in Palacos R or erythromycin plus colistin in Simplex P bone cement did not significantly decrease the fatigue strength of the cement . {J.P . Davies, D.O . O'Connor, D.W . Burke, and W.H . Harris, "Influence of antibiotic impregnation on the fatigue life of Simplex P and Palacos R acrylic bone cements, with and without centrifugation," J . Biomed . Mater . Res., 23, 379-397 (1989)} However, the commercially prepared Palacos R with Gentamicin and AKZ (Simplex P with colistin and erythromycin) which were tested are not approved by the FDA for use in the United States . Because of this, many surgeons in the United States hand mix tobramycin with the cement in the operating room if a case calls for the use of antibiotic-impregnated cement . In this study, we determined the effect of adding 1.2 g of tobramycin to one pack (40 g) of Simplex P powder on the fatigue strength of the cement . The effect of centrifugation on the fatigue strength of Simplex P with the tobramycin added was also assessed . Simplex P was prepared according to the manufacturer's instructions with and without the addition of 1.2 g tobramycin per 40-g pack and with and without centrifugation . Fifteen specimens of each of the four cement preparations were tested in fully reversed tension-compression fatigue at +/- 15 MPa, 2 Hz . The fatigue strength of the uncentrifuged and centrifuged Simplex P was not significantly reduced by the tobramycin . Centrifugation significantly increased the fatigue life of Simplex P both with and without the addition of tobramycin . The fatigue life of the Simplex P with tobramycin was increased by a factor of 8 by centrifugation.

Cornea, 1991 Nov, 10(6), 478 - 82
The effect of tarsorrhaphy on normal healing of corneal epithelial defects in a rabbit model; Anderson C et al.; The presumed benefits of occlusive patching are patient comfort and enhancement of corneal healing . However, there is little experimental evidence to document a beneficial effect of eyelid occlusion on corneal healing . We produced corneal abrasions by mechanical debridement within a 4 mm trephine-marked area on 1 eye each of 23 New Zealand albino rabbits . Homatropine 5% solution and erythromycin ointment were instilled . Then we divided the animals into three groups . The abraded eyes of the first group (7 rabbits) were sutured shut by a temporary tarsorrhaphy . The eyes of the second group (7 rabbits) were left open until 12 h postinjury, when they were sutured shut in a similar fashion . The abraded eyes of the control group (9 rabbits) were left open for the entire observation period . We monitored fluorescein staining patterns of the epithelial defects photographically at a set focal length at 12-h intervals . By 48 h, corneal staining had resolved in 87% of eyes . We performed computerized planimetry on the photographs of wound size for each time point . There was no statistically significant difference in the rate of healing of corneal abrasions in the occluded versus of the unoccluded eyes.

Int J STD AIDS, 1991 Nov-Dec, 2(6), 447 - 8
Donovanosis (granuloma inguinale) in pregnancy; O'Farrell N; PIP: Although the availability of antibiotics has reduced the general incidence of donovanosis, the disease remains prevalent in India, Papua New Guinea, parts of southern Africa, and the West Indies . Clinical variants of this sexually transmitted disease include ulcerogranulomatous, hyertrophic, necrotic, and cicatrical . Described here is the case of a 20-year-old Zulu female who developed donovanosis with hypertrophic and ulcerogranulomatous lesions during the third trimester of pregnancy . When the patient presented at 36 weeks, she reported a 10-week history of vaginal ulceration and a 6-week history of swelling in the inguinal region . The ulcerative lesion, located at the introitus, had raised edges 2 cm in diameter, while the dry keloidal-like lesion 2 x 4 cm was present in the inguinal region . This is the first reported case of a combination of two variants of donovanosis in one individual . Histologic examination revealed mildly acanthotic surface squamous epithelium with underlying granulation tissue containing plasma cells, lymphocytes, pockets of neutrophils, and scattered histiocytic cells . Donovan bodies with the typical safety pin appearance were demonstrated by a Giemsa stained tissue smear . Treatment with 500 mg of erythromycin twice daily for 2 weeks resolved the disease . Both the incidence and severity of donovanosis appear to increase during late pregnancy, presumably because of depression of lymphocyte proliferative responses .

Nucleic Acids Res, 1991 Oct 25, 19(20), 5749 - 54
A synthetic alanyl-initiator tRNA with initiator tRNA properties as determined by fluorescence measurements: comparison to a synthetic alanyl-elongator tRNA; Picking WL et al.; Two synthetic tRNAs have been generated that can be enzymatically aminoacylated with alanine and have AAA anticodons to recognize a poly(U) template . One of the tRNAs (tRNA(eAla/AAA)) is nearly identical to Escherichia coli elongator tRNA(Ala) . The other has a sequence similar to Escherichia coli initiator tRNA(Met) (tRNA(iAla/AAA)) . Although both tRNAs can be used in poly(U)-directed nonenzymatic initiation at 15 mM Mg2+, only the elongator tRNA can serve for peptide elongation and polyalanine synthesis . Only the initiator tRNA can be bound to 30S ribosomal subunits or 70S ribosomes in the presence of initiation factor 2 (IF-2) and low Mg2+ suggesting that it can function in enzymatic peptide initiation . A derivative of coumarin was covalently attached to the alpha amino group of alanine of these two Ala-tRNA species . The fluorescence spectra, quantum yield and anisotropy for the two Ala-tRNA derivatives are different when they are bound to 70S ribosomes (nonenzymatically in the presence of 15 mM Mg2+) indicating that the local environment of the probe is different . Also, the effect of erythromycin on their fluorescence is quite different, suggesting that the probes and presumably the alanine moiety to which they are covalently linked are in different positions on the ribosomes.

Arch Neurol, 1991 Oct, 48(10), 1086 - 8
Acute hemorrhagic leukoencephalitis . A successful recovery; Seales D et al.; A 50-year-old woman developed acute hemorrhagic leukoencephalitis approximately 7 days after the onset of a benign respiratory infection . Mycoplasmal pneumonia was suspected because of Coomb's positive hemolysis, cold agglutinins, and sensitivity to erythromycin base but was not proved . Acute hemorrhagic leukoencephalitis was demonstrated by brain biopsy 24 hours after admission . The patient recovered without lasting sequelae following reduction of increased intracranial pressure by mannitol, hyperventilation, and phenobarbital and prolonged immunosuppression by plasmapheresis, steroids, and cyclophosphamide.

South Med J, 1991 Oct, 84(10), 1214 - 6
Erythromycin ototoxicity: a call to heighten recognition; Whitener CJ et al.; Bilateral sensorineural hearing loss developed in a 64-year-old woman treated with intravenous erythromycin lactobionate for bacteremic pneumococcal pneumonia . Discontinuance of the antibiotic led to prompt correction of the hearing deficit . Reversible hearing loss is an infrequently described adverse effect attributed to high-dose erythromycin therapy . Possible risk factors, including age, gender, and hepatic and renal function, may contribute to the development of erythromycin ototoxicity.

Xenobiotica, 1991 Oct, 21(10), 1363 - 70
Maintenance of monooxygenase activities and detection of cytochrome P-450-mediated cytotoxicity in Mongolian gerbil hepatocyte cultures; Fentem JH et al.; 1 . Hepatocytes were isolated from untreated and phenobarbitone (PB)-treated Mongolian gerbils by lobe perfusion . Yields were approx . 20 x 10(6) cells/g liver and viability was 95 +/- 1% . 2 . PB treatment significantly increased the total cytochrome P-450 content, and the 7-ethoxycoumarin O-deethylase, p-nitrophenol hydroxylase and coumarin 7-hydroxylase activities, relative to those of untreated gerbils, measured in homogenates of freshly isolated hepatocytes . 3 . After 24 h in culture the cytochrome P-450 content of hepatocyte homogenates from both untreated and PB-treated gerbils was 40-45% that of the corresponding values of freshly isolated hepatocytes . This decrease was accompanied by selective losses of cytochrome P-450-dependent enzyme activities . 4 . Erythromycin and benzphetamine N-demethylase, and p-nitrophenol hydroxylase, activities were well maintained over 24 h in culture, whilst 7-ethoxycoumarin O-deethylase and coumarin 7-hydroxylase activities were poorly maintained . In general, the stability of the monooxygenase activities measured was improved by BP treatment of gerbils . 5 . The toxicity of coumarin, precocene I and precocene II to gerbil hepatocyte cultures was dose-dependent . Precocene II was significantly more toxic to hepatocytes cultured from PB-treated, compared with untreated, gerbils . 6 . Gerbil hepatocyte cultures would seem to be appropriate for investigating species differences in metabolism-mediated cytotoxicity.

Ulster Med J, 1991 Oct, 60(2), 168 - 72
Evidence of Chlamydia infection in a Belfast antenatal population; Roberts RN et al.; Chlamydia trachomatis is an important cause of postpartum endometritis and neonatal conjunctivitis . However, the prevalence of chlamydial genital infection varies considerably from one population group to another . A study was thus conducted to determine the incidence of C trachomatis infection of the cervix in an unselected group of women attending a Belfast antenatal clinic . One hundred and six patients were screened for evidence of current cervical infection with C trachomatis or serological evidence of past infection . C trachomatis was identified in 2.9%, and there was evidence of past infection in 18.9% . No significant risk factors were identified from gynaecological, contraceptive or sexual histories . C trachomatis infection was treated with erythromycin and there were no perinatal complications ascribed to chlamydia.

Antimicrob Agents Chemother, 1991 Oct, 35(10), 2016 - 9
Differential modulation of cytokine production by macrolides: interleukin-6 production is increased by spiramycin and erythromycin; Bailly S et al.; Antibiotics do not act alone but act in conjunction with the host defense system . In particular, it has been shown that some antibiotics can modify cytokine production . We compared the in vitro effects of three macrolides (roxithromycin, spiramycin, and erythromycin) actively concentrated by leukocytes on interleukin-1 alpha, (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha production by human monocytes stimulated with lipopolysaccharide . Our results show that the three macrolides tested have different effects on production of these cytokines . Spiramycin and, to a lesser extent, erythromycin increased total IL-6 production without affecting IL-1 alpha, IL-1 beta, or tumor necrosis factor alpha production, whereas roxithromycin had no effect . To our knowledge, this is the first time that an antibiotic has been shown to increase IL-6 production.

Eur J Clin Microbiol Infect Dis, 1991 Oct, 10(10), 807 - 12
The pharmacokinetics of azithromycin and their clinical significance; Lode H; The usefulness of erythromycin is limited by its poor pharmacokinetic profile which is characterised by low blood levels and poor gastric acid stability . Erythromycin's short half-life means that a four-times daily dosage schedule is required for effective treatment . In comparison, the azalide structure of azithromycin confers a much improved pharmacokinetic profile . The bioavailability of azithromycin is approximately 37% in humans (25% for erythromycin) . Serum concentrations decline in a polyphasic manner and the relatively short serum half-life (11-14 hours recorded 8-24 hours after last dose) is an indication of the initial rapid distribution of drug into the tissues . The low serum levels recorded 24 hours or more after the end of administration are thought to reflect the slow release of azithromycin from tissues . Tissue concentrations exceed serum concentrations by as much as 100-fold following a single 500 mg oral dose . Macrophages and polymorphonuclear leucocytes concentrate azithromycin at levels greater than those found in tissues themselves . During multiple dosing, tissue half-life increases with duration of administration and the tissue to serum ratio further increases . High concentrations of drug are found in tissues such as tonsil, lung, prostate, liver and lymph nodes with relatively low concentrations in fat and muscle . Significantly, the sustained high levels of drug in the tissues appears to correlate with good in vivo activity . Two 1.5 g regimens have been investigated in clinical trials: 500 mg on day 1, followed by 250 mg daily on days 2 to 5; or 500 mg daily for three days.(ABSTRACT TRUNCATED AT 250 WORDS)

J Bacteriol, 1991 Oct, 173(20), 6325 - 31
Transformation system for Amycolatopsis (Nocardia) mediterranei: direct transformation of mycelium with plasmid DNA; Madon J et al.; A new procedure for transformation of Amycolatopsis (Nocardia) mediterranei LBG A3136 was developed . The method makes use of polyethylene glycol and alkaline cations and enables direct transformation of the A . mediterranei mycelium with high efficiency: more than 10(6) transformants per microgram of DNA were obtained . Transformation of A . mediterranei is stimulated by the ionophore antibiotic valinomycin and abolished by arsenate and p-chloromercuribenzenesulfonate . pMEA123, a vector based on the indigenous plasmid pMEA100 and containing the erythromycin resistance gene, was constructed.

Rev Infect Dis, 1991 Sep-Oct, 13(5), 857 - 64
Chronic tenosynovitis of the hand due to Mycobacterium nonchromogenicum: use of high-performance liquid chromatography for identification of isolates; Ridderhof JC et al.; Six cases of chronic tenosynovitis of the hand due to the Mycobacterium terrae complex were identified . All isolates from the six cases were identified as Mycobacterium nonchromogenicum by high-performance liquid chromatography and by testing for susceptibility to ofloxacin and to 5% NaCl . Ethambutol, sulfonamides (or trimethoprim-sulfamethoxazole), erythromycin, and streptomycin are the drugs most active against isolates of the M . terrae complex, and therapy with some combination of these agents plus surgical debridement offers the best current treatment of this disease . This study supports the contention arising from previous case reports of pulmonary disease that M . nonchromogenicum is the pathogenic member of the M . terrae complex.

Schweiz Rundsch Med Prax, 1991 Sep 10, 80(37), 941 - 5
{Diagnostic accuracy in bacterial infections in an emergency ward: results of a retrospective study}; Buser U et al.; Accuracy of the initial diagnosis and the appropriate choice of antibiotics were evaluated in a group of patients with presumed bacterial infections admitted to the medical ward after initial examination at the emergency ward . A bacterial infection was initially suspected and treated with antibiotics in 88 (33%) of 265 patients admitted consecutively . An inaccurate diagnosis of bacterial infection was made in 2.6% of all patients and in 8% of the patients treated with antibiotics . In one patient (0.4%) the presence of a bacterial infection was overlooked . Penicillins, co-trimoxazole, erythromycin and aminoglycosides represented 93% of the antibiotics chosen . 28% of all empiric antibiotic regimens had to be modified due to the result of sensitivity testing, side effects or clinical failure.

J Antimicrob Chemother, 1991 Sep, 28(3), 455 - 9
Erythromycin and the treatment of Coxiella burnetii pneumonia; Perez-del-Molino A et al.; Erythromycin is commonly used for the empirical treatment of community-acquired pneumonia, but there is some concern about its usefulness when Q fever is suspected because of in-vitro studies showing a lack of efficacy against Coxiella burnetii . This study was undertaken to assess the clinical value of the antibiotic in this setting . Nineteen patients with Q fever pneumonia treated with a variety of antibiotics considered ineffective against C . burnetii, were reviewed . Eleven patients who received erythromycin had a rapid clinical improvement and each became afebrile by the fourth day of treatment . However, only two of eight patients who received other antibiotics improved (both of them had been treated with beta-lactams) . Both groups were comparable regarding to age and previous duration and severity of disease . Those patients who did not respond to other antibiotics improved promptly after erythromycin was started . This study suggests that erythromycin is an adequate treatment for Q fever pneumonia.

Thorax, 1991 Sep, 46(9), 663 - 6
Radiographic appearance of nosocomial legionnaires' disease after erythromycin treatment; Domingo C et al.; Radiographic features of 71 patients (48 men, 23 women) with nosocomial Legionella pneumophila pneumonia were assessed and compared with those of other nosocomial series of L pneumophila pneumonia . Sixteen patients were assessed retrospectively and 55 prospectively . Chest radiographs were assessed at the onset of the illness, 10 days later, and at 3 months . Erythromycin was given to 67 patients at the time of the diagnosis and to the remaining four at a later stage . Forty eight patients were over the age of 60 . On the initial chest radiograph 53 of the 71 patients had unilateral shadowing (23 of them in the right lung); 35 had unilobar shadowing and the remaining 36 had more than one affected lobe . Pleural effusion was present in 24 cases and cavitation in 2 . One patient had evidence of a pericardial effusion . At 10 days 21 patients had evidence of radiographic progression (14 ipsilateral), but 28 had improved . At 3 months 36 patients had an abnormal radiograph, 30 showing residual scarring, 15 loss of volume, six pleural shadows and two cavitation . Our series shows a lesser incidence of unilateral shadowing and pleural effusion than other nosocomial series and a lesser tendency to progression, but more patients had radiographic abnormalities at long term follow up.

Nippon Geka Gakkai Zasshi, 1991 Sep, 92(9), 1208 - 11
{Effect of motilin agonist, EM-523 on gastrointestinal motility}; Mizumoto A et al.; In this study, we investigated the effect of EM-523, one of the erythromycin derivatives, on gastrointestinal motility in conscious dogs, in which force transducers were chronically implanted in the gastrointestinal tract . As a result, intravenous administration of EM-523 (1-10 micrograms/kg) induced phase III-like contractions in the stomach, and the EM-523-induced contractions migrated along the entire small intestine . EM-523 also stimulated the lower esophageal sphincter and the gallbladder motility, quite similar to exogenous motilin . Furthermore, we have investigated the effects of EM-523 both in postoperative ileus dogs and truncally vagotomized dogs . The dogs 1 to 4-day after the operation showed continuous and irregular contractions in the entire gastrointestinal tract, instead of typical interdigestive contractions . In these conditions, EM-523 induced strong phasic contractions in the stomach and duodenum, although these contractions did not always migrate along the small intestine . In the vagotomized dogs, spontaneous phase III contractions tended to be weaker than those in the normal dogs . EM523 induced phase III-like contractions in vagotomized dogs as in the normal dogs, and the contractile activities were improved . These results indicated that EM-523 may be useful as a gastroprokinetic drug for postoperative ileus and the patients with vagotomy.

Changgeng Yi Xue Za Zhi, 1991 Sep, 14(3), 156 - 62
Mycoplasma pneumoniae pneumonia: clinical analysis of 45 cases; Juang YC et al.; Mycoplasma pneumoniae (M . Pneumoniae) is a primarily pathogen of the respiratory tract . The clinical characteristics, laboratory findings, and roentgenographic patterns of 45 patients with serologically proven M . pneumoniae pneumonia admitted to Chang Gung Hospital from 1981 to 1989 have been reviewed . There were 23 males and 22 females . Forty-one (91%) were below 40 years old and 13 patients (29%) were below 5 years old . Fever, cough and chest rales were the most common symptoms and signs . A transient mild elevation of liver enzymes was seen in 33% of the patients, most of whom were below the age of ten (73%) . A leukocyte count over 15,000/cu mm was not rare (16%) . Roentgenographic features included unilateral infiltration (84%), lower lobe predominance (60%), and either confluent (56%) or patchy (33%) consolidation . Pleural effusion occurred in 24% of the patients . Complete resolution of chest roentgenography took from 8 to 42 days with a mean of 20 days . The response of fever to treatment with erythromycin took from 1 to 6 days with a mean of 3 days . There were no life threatening pulmonic or extrapulmonic complications.

Public Health Rep, 1991 Sep-Oct, 106(5), 490 - 3
Prevalence of Chlamydia trachomatis infection in pregnant patients; Much DH et al.; Chlamydia is a sexually transmitted disease of epidemic proportions, infecting an estimated 4 million people a year . It results not only in infertility and ectopic pregnancy but also in infant morbidity and mortality . Ectopic pregnancy is responsible for 11 percent of maternal deaths . About 60 percent of infected women can transmit the bacteria at birth to their infants . Early detection and treatment of chlamydia in both men and women, especially prenatal women, is critical . Chlamydia trachomatis infection of the cervix was found in 8.1 percent of a group of 1,004 pregnant women at a hospital prenatal clinic by means of a direct fluorescent antibody test . The prevalence of C . trachomatis was only 0.7 percent in 277 pregnant women receiving prenatal care from private practitioners . All patients between 27 and 30 weeks gestation who tested positive were treated with oral erythromycin . Their partners were treated with tetracycline . The outcome of pregnancy in patients treated for chlamydial infection was compared with a control group of noninfected mothers from the same population . The frequency of premature rupture of the membranes, prematurity, and low Apgar scores among the treated women were not significantly different from those in the control group . There was a significant difference, however, between the two groups in the incidence of low mean birth weight infants and the presence of meconium . Children can acquire a chlamydial infection at birth from contact with infected cervico-vaginal secretions . If not detected and treated, these infected infants may develop conjunctivitis, bronchiolitis, and pneumonia . It is suggested, therefore, that all patients at prenatal clinics be screened for chlamydial cervicitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Arq Neuropsiquiatr, 1991 Sep, 49(3), 352 - 6
{AIDS and myopathy: report of a case and review of the literature}; Rodrigues KM et al.; Report of an unusual case of myopathy in an HIV infected patient, responsive only to the immunosuppressor drug methotrexate . The patient was a 39 year old homosexual male with no past history of HIV-related manifestations . One month prior to admission he noticed that his left thigh was swollen and painful . Two weeks later both arms became enlarged and tender . A few days before admission he noticed intermittent fever and progressive dyspnea . Upon admission, oral thrush, dyspnea and global enlargement of both arms was noted . There was no articular involvement . Fiberoptic bronchoscopy revealed Pneumocystis carinii pneumonia (PCP) . Serology for HIV was positive . Tests for antinuclear antibodies were negative . Serum CPK level was 1019 IU . Capillaroscopy was compatible with vasculitis . Muscle biopsy revealed multifocal myonecrosis . PCP was successfully treated with standard doses of TMP/SMZ . Although indomethacin, prednisone and dexamethasone were administered in succession, there was relentless progression of myopathy and persistence of fever . Six days after administration of methotrexate, the patient defervesced, volume of arms and legs diminished . CPK levels returned to normal after a second course of methotrexate . Upon reduction of the dose thigh enlargement recrudesced . The patient remained asymptomatic on weekly doses of methotrexate . He died five months later of acute respiratory failurePIP: Myopathy may be associated with the syndrome of seroconversion in individuals infected by the human immunodeficiency virus (HIV) or may represent the initial symptom of AIDS . In 1990, 39-year old white, single homosexual who was admitted 1 month prior had experienced an episode of edema and pain in the left thigh that faded with the use of nonhormonal antiinflammatory drugs . 15 days later both forearms became enlarged accompanied by pain and erythema . Erythromycin and cefalexine were used without success . Intermittent fever started to appear before admission accompanied by dyspnea when straining . Examination showed tachypnea, oral candidiasis, and enlargement of both upper arms with pain and local erythema without articular involvement . Neurological examination revealed hypotonia and generalized hyperreflexia with intact muscle strength . Serology was positive for HIV, rheumatic activity tests were negative, and muscle biopsy indicated multifocal myonecrosis . Creatinine phosphokinase was 1019 IU (decrease to 44 IU after treatment), aldolase was 19 IU (decrease to 5.6 IU), and glutamic-pyruvic transminase was 50 IU (decrease to 22 IU) . Radiography of the thorax indicated interstitial infiltration . Fiberoptic bronchoscopy indicated Pneumocystis carinii pneumonia . Sulfamethoxazole and trimetropim treatment cured the dyspnea and hypoxemia, but the enlargement of both arms progressed . Capillaroscopy indicated vasculitis that was treated without success with indomethacin (150 mg/day), for 7 days; prednisone (40-80 mg/day) for 10 days; and dexamethasone (280 mg/day) for 2 days . 6 days after methotrexate (50 mg/dose/week) treatment the fever disappeared and the enlargement in the extremities receded, but a lower dose of 7.5 mg caused the return of fever and edema in the right thigh . The myopathy remained asymptomatic for 5 months with a weekly dose of 15 mg of methotrexate .

Pediatr Dermatol, 1991 Sep, 8(3), 189 - 93
Eosinophilic pustular folliculitis (Ofuji disease) in childhood: a review of four cases; Giard F et al.; Four children under 2 years of age were treated at our hospital in the last three years with a recurrent vesiculopustular eruption of the scalp, variably extending to the face and limbs . All cases followed a cyclical pattern . Three of the children had a moderate response to topical steroids, and one went into remission after a two-month course of erythromycin . Ethnic origin may be an important predisposing factor . Histologically, all patients showed a moderate mixed inflammatory infiltrate with numerous eosinophils centered around hair follicles . Peripheral white blood cell count showing leukocytosis with eosinophilia was observed in those cases measured, but no consistent immunologic abnormalities could be identified.

J Hosp Infect, 1991 Sep, 19 Suppl A, 39 - 46
The tolerance and toxicity of clarithromycin; Wood MJ; In a programme of Phase II and III trials, 3437 patients received clarithromycin . Twenty percent of these patients reported adverse events, and three-quarters of these were thought to be possibly or probably linked with the drug . Only 1% of these were severe and most of the adverse events (11% of patients) were digestive system upsets . There was no significant relationship between the dosage of clarithromycin and the incidence of adverse events . Comparison between clarithromycin and the other antibiotics used in controlled trials showed similar side effects reported for beta-lactam agents and clarithromycin but adverse events were reported less frequently with clarithromycin (19%) than with erythromycin (29%) and other macrolides . This was particularly noticeable for adverse events of the digestive system (9% with clarithromycin vs 20% with erythromycin) . No significant haematological, hepatic or renal toxicity due to clarithromycin was reported . There may be slight elevation of theophylline levels during concomitant clarithromycin administration.

J Hosp Infect, 1991 Sep, 19 Suppl A, 21 - 7
Clarithromycin in the treatment of community-acquired lower respiratory tract infections; Anderson G; Clarithromycin is a macrolide with in-vitro activity against the organisms usually responsible for community-acquired pneumonia and acute exacerbations of chronic bronchitis . Three double-blind controlled studies each in pneumonia and chronic bronchitis are reviewed . In pneumonia clarithromycin is as effective as erythromycin and in acute-on-chronic bronchitis is as effective as ampicillin . In an open study of 46 patients with pneumonia due to Legionella pneumophila, resolution occurred in 93% with no deaths . The incidence of adverse events was 20% in 3437 patients . These were rarely severe . Clarithromycin is better tolerated than erythromycin and its twice daily dosage is likely to lead to better patient compliance.

Biochem Pharmacol, 1991 Aug 8, 42(5), 1093 - 7
Modulation of rat hepatic cytochromes P450 by chronic methapyrilene treatment; Wrighton SA et al.; The antihistaminic compound methapyrilene (MP) when chronically administered has been shown to be a rat-specific hepatocarcinogen . To examine the effects of chronic MP treatment on the hepatic microsomal cytochromes P450 . Fischer 344 rats were gavaged for 10 weeks (5 days on, 2 days off) with either vehicle or 50, 100, or 150 mg MP/kg body weight . Chronic MP treatment was found to have a significant effect on several microsomal enzymatic activities . Small (17-28%) but significant (P less than 0.05) decreases were observed for total P450 levels and the activities of erythromycin N-demethylase (catalyzed by P450IIIA), N-nitrosodimethylamine demethylase (catalyzed by P450IIE1) and pentoxyresorufin O-dealkylase (catalyzed by P450IIB1) . In addition, a relatively large decrease (approximately 80%) was observed for the activity of benzphetamine N-demethylase (representative of P450IIC11) and an induction of about 40% was observed for ethoxyresorufin O-dealkylase (catalyzed by P450IA) . The metabolism of testosterone by microsomes isolated from the rats chronically treated with MP indicated that several reactions were compromized . Specifically, testosterone 2 alpha-hydroxylase, indicative of P450IIC11, was reduced greatly (86%), whereas testosterone 6 beta-hydroxylase, reflecting P450IIIA, and testosterone 7 alpha-hydroxylase, indicative of P450IIIA1, were affected only slightly by MP treatment (approximately 25%) . Immunoblot analyses of the various microsomal samples were performed to determine if chronic MP treatment had direct effects on the level of expression of the cytochromes P450 . Decreases in the levels of P450IIIA, IIE1, and IIC11, determined by immunoblot analyses, closely paralleled those observed for their marker catalytic activities . Further studies will be required to determine the mechanism by which MP affects the levels of the cytochromes P450 (i.e . increased degradation or decreased synthesis).

J Pediatr Gastroenterol Nutr, 1991 Aug, 13(2), 201 - 3
Childhood protein-losing enteropathy associated with Helicobacter pylori infection; Cohen HA et al.; Helicobacter pylori was found in a gastric biopsy specimen of a child with protein-losing gastropathy . Through erythromycin therapy, clinical and ultrasonographic recovery was associated with the disappearance of the pathogen on repeated biopsy . The association of H . pylori with protein-losing gastropathy has been reported only once in children, to our knowledge . Although the causative correlation between the pathogen and the disease has not been proven yet, we suggest that future cases of protein-losing gastropathy be studied for the presence of H . pylori and followed up by ultrasonographic investigation and urea breath test . Appropriate treatment should be given to suspected cases.

FEMS Microbiol Lett, 1991 Aug 1, 66(2), 169 - 75
The melanophore aggregating response of isolated fish scales: a very rapid and sensitive diagnosis of whooping cough; Karlsson JO et al.; Pertussis toxin (PT) has been found to block noradrenaline-induced pigment aggregation in fish melanophores, and, based on this, a rapid and highly sensitive assay for PT was developed . Some preliminary results have also indicated that it may be possible to detect PT-like activity in saliva samples from patients with clinically suspected pertussis . In the present study the diagnostic value of the fish melanophore method was evaluated in 70 patients suspected of having pertussis; culture, serology and physician diagnosis were used as reference methods . In 60 of the patients, pertussis was verified by at least one of the reference methods . The melanophore test showed PT-like activity in saliva samples from 58 of the patients . Three patients with reference-verified pertussis showed no PT-like activity in the test; among these, one patient had been immunized and had also been treated with erythromycin during 3 days immediately prior to visiting the hospital . The melanophore test has three major advantages: it allows detection of pertussis in the early and curable stage of the disease; it takes only 2 h to perform; and it requires no sophisticated equipment.

Z Gesamte Inn Med, 1991 Aug, 46(10-11), 349 - 54
{The potentials of erythromycin derivatives in the treatment of gastrointestinal motility disorders}; Peeters TL; In low dosages erythromycin imitates the effect of motilin on the gastrointestinal motility . In vitro experiments show that erythromycin is a motilin agonist: it displaces motilin which is bound to its receptor; it directly acts on smooth musculature and it possesses the same animal and tissue specificity . Structural changes cause adequate changes in the binding affinity and in the contractile activity . Several motilides such as erythromycin derivatives with prokinetic properties have no antibiotic activity, but they cause a distinct increase of the prokinetic activity . Motilides may be defined as a new group of prokinetic substances: the motilinomimetics . Erythromycin normalises the delayed evacuation of the stomach of solid and fluid food in diabetic, idiopathic and postvagotomy gastroparesis . For the treatment of gastrooesophageal reflux disease, gastritis, pathological overgrowth of the small intestine, hypokinesia of the gallbladder and the chronic obstipation erythromycin appears as a promising medicament . The substances with a stronger effect may become even still more useful medicaments . A better understanding of the relation between motilin and motilides may lead to new knowledge about the regulation of the gastrointestinal motility.

Arch Ophthalmol, 1991 Aug, 109(8), 1141 - 6
Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids; Talamo JH et al.; A 193-nm excimer laser system was used to create deep stromal ablations in seven New Zealand white rabbits and shallow ablations in three . Eyes were randomized for treatment with topical mitomycin C, steroids, and erythromycin; topical steroids and erythromycin; or topical erythromycin only . All treatment regimens were instituted twice daily for 14 days . All eyes reepithelialized normally within 3 to 5 days . During 10 weeks of follow-up, all eyes developed moderate reticular subepithelial haze without significant differences among treatment groups . Results of light, fluorescence, and electron microscopic examination showed anterior stromal scarring and markedly reduced new subepithelial collagen formation in the group treated with mitomycin C, corticosteroids, and erythromycin . Focal abnormalities of Descemet's membrane and endothelial abnormalities were present in all treatment groups . Combination therapy with topical steroids, mitomycin C, and erythromycin to control the corneal wound healing response after refractive laser surgery appears promising and warrants further study.

Am J Obstet Gynecol, 1991 Aug, 165(2), 375 - 81
Comparative efficacy of clindamycin versus erythromycin in eradication of antenatal Chlamydia trachomatis; Alger LS et al.; Antenatal Chlamydia trachomatis infections are associated with both maternal and neonatal morbidity . Erythromycin, the only drug recommended for treatment during pregnancy, is often poorly tolerated, thus preventing successful cure . We have done a prospective, randomized, double-blind, placebo-controlled trial to compare the efficacy of clindamycin with that of erythromycin base in eradication of antenatal chlamydia . A total of 126 patients with documented cervical infection were enrolled before 24 weeks' gestation to receive clindamycin (450 mg), erythromycin (333 mg), or placebo orally four times daily for 14 days . Partners received doxycycline, 100 mg, twice daily for 7 days . Both clindamycin and erythromycin were effective agents with cure rates of 92.7% and 83.8%, respectively . Erythromycin therapy was associated with significantly more gastrointestinal complaints than was placebo therapy (23.1% (9/39) vs . 2.4% (1/41), p less than 0.02) whereas clindamycin was not . Patients who experienced side effects were more likely to be poorly compliant (p less than 0.03) and patients with moderate-to-good compliance were more likely to be cured than were women who were poorly compliant (p less than 0.002) . Results of test of cure cultures performed immediately on completion of therapy did not differ significantly from those taken 4 weeks later.

Am J Clin Pathol, 1991 Aug, 96(2), 196 - 200
A case of acquired factor X deficiency with in vivo and in vitro evidence of inhibitor activity directed against factor X; Mulhare PE et al.; A 67-year-old woman had symptoms of an upper respiratory tract infection for which she received a five-day course of erythromycin . Epistaxis and gross hematuria subsequently developed, and the patient was found to have a selective Factor X deficiency . She received supportive therapy and prothrombin complex concentrates (Factors II, VII, IX, and X), with subsequent resolution of her transient Factor X deficiency . Her hospital course, however, was complicated by the development of multiple cerebral infarctions . This is the tenth reported case of transient Factor X deficiency not associated with amyloidosis . In seven of the previous cases, as in this patient, the deficiency was associated with a preceding upper respiratory infection . This is the only case, however, with evidence of inhibitory activity in the plasma that was directed toward Factor X.

Arzneimittelforschung, 1991 Aug, 41(8), 839 - 43
{The biological availability of cefadroxil given simultaneously with N-acetylcysteine}; Barkworth MF et al.; A preliminary study revealed that similarly to the antibiotics amoxillin, thiamphenicol, erythromycin and doxycycline, the oral cephalosporin cefadroxil (CAS 66592-87-8) can be administered simultaneously with the mucolytic n-acetylcysteine (CAS 616-91-1) . In the present study 12 healthy male volunteers received in a randomised cross-over design a single oral dose of 1000 mg cefadroxil or a single oral dose of 1000 mg cefadroxil (Bidocef) plus 200 mg n-acetylcysteine . The two study days were separated by a wash-out period of one week . To determine the pharmacokinetic profile of cefadroxil, plasma and sputum were analysed by HPLC at defined intervals . Regarding the bioavailability of cefadroxil, the free combination is bioequivalent to the individual component . After administration of cefadroxil plus n-acetylcysteine, a higher cefadroxil concentration was found in the sputum compared to an administration of cefadroxil alone . However, the difference was not statistically significant . According to the results, simultaneous administration of the oral cephalosporin cefadroxil and the mucolytic n-acetylcysteine is possible without changes in the bioavailability of cefadroxil being observed.

J Chemother, 1991 Aug, 3(4), 240 - 4
Impact of rokitamycin, a new 16-membered macrolide, on serum theophylline; Cazzola M et al.; Side effects have been observed when 14-membered macrolides, erythromycin and troleandromycin, have been prescribed concurrently in patients receiving therapeutic doses of theophylline . Rokitamycin is a new 16-membered macrolide antibiotic . We have evaluated its effect on theophylline serum concentrations in 12 adult patients suffering from chronic obstructive pulmonary disease . Initially, six patients were treated for four consecutive days with theophylline as sustained-release formulation in the amount of 600 mg daily; six other patients received for four consecutive days a short term intravenous infusion of 240 mg aminophylline, given over a period of 30 min twice daily . On the last day, blood samples were taken for theophylline determination . Theophylline concentrations were measured serially for 12 hours after oral formulation and 4 hours after aminophylline by enzyme immunoassay technique . Subsequently, while theophylline and aminophylline treatments were continued at the same dosage, each patient received in addition rokitamycin tablets, 400 mg every 12 hours . After seven days of this combined medication, the serial assays of serum theophylline were repeated at the same time intervals as before . Concomitant administration of therapeutic doses of rokitamycin did not affect significantly the steady-state pharmacokinetics of oral theophylline and did not alter the (pseudo-) steady-state pharmacokinetics of intravenous aminophylline, showing that the two drugs may be coadministered without any theophylline dose adjustment.

J Antimicrob Chemother, 1991 Aug, 28(2), 301 - 7
Treatment of chlamydial conjunctivitis in newborns and adults with erythromycin and roxithromycin; Stenberg K et al.; A randomized single-blind study of the effects of erythromycin and roxithromycin on chlamydial conjunctivitis was performed on a group of patients, comprising 28 newborns and 27 adults . Treatment used was either 200 mg of erythromycin ethylsuccinate or 50 mg of roxithromycin daily, divided into two doses for the neonatal group or for the adult group, 1000 mg of erythromycin stearate or 300 mg of roxithromycin daily divided into two doses . All patients were treated for ten days . Clinically nine of the neonates and 13 of the adults had unilateral conjunctivitis, whilst the remaining cases were bilateral . At follow-up one month after commencing therapy, all but one (erythromycin-treated) of the 28 neonates and three (two of whom were erythromycin-treated) of the 27 adults were cured . However, 16 (nine neonates and seven adults) were culture-positive for Chlamydia trachomatis in samples from eye and/or nasopharynx . The culture-positive group comprised ten cases (four neonates and six adults) who had been treated with erythromycin and six (five neonates and one adult) with roxithromycin . No major side effects of the therapy were seen . The study indicates that there was no difference in the clinical cure rate for the two drugs either in neonates or in adults . However, the isolation rate of chlamydiae in the adult group differed, with 12 (92%) of the 13 roxithromycin-treated cases becoming culture-negative, whilst this was true for only eight (57%) of the 14 erythromycin-treated cases (P less than 0.007).

Br J Pharmacol, 1991 Jul, 103(3), 1709 - 12
The cyclosporin-erythromycin interaction: impaired first pass metabolism in the pig; Freeman DJ et al.; 1 . The pharmacokinetic interaction between cyclosporin (CsA) and erythromycin has been studied in the weanling pig model . 2 . Blood CsA and metabolite-1 (M1) concentrations were monitored by high performance liquid chromatography in portal, hepatic and jugular venus blood before and after treatment with erythromycin stearate for 7 days . 3 . Erythromycin significantly increased maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC) of CsA in the peripheral circulation . This was accompanied by a significant reduction in the hepatic extraction ratio calculated from portal and hepatic Cmax and AUC data . 4 . The extraction ratio appears to be concentration-dependent in that values derived from Cmax (high concentrations) were greater than those from AUC (average concentrations) . 5 . Time to Cmax (tmax) and t1/2 of CsA were essentially unchanged and no significant changes were observed in peripheral M1 kinetics apart from a small increase in tmax . 6 . The pharmacokinetic changes observed in the pig suggest that the CsA-erythromycin interaction is caused by inhibition of hepatic metabolism and the impact of inhibition is greatest during first-pass when CsA concentrations are at their highest.

Drug Des Deliv, 1991 Jul, 7(4), 309 - 19
Controlled release microspheres based on Eudragit L100 for the oral administration of erythromycin; Morishita I et al.; The use of Eudragit L100, a copolymer based on methacrylic acid and methacrylic acid methyl ester, in preparing erythromycin microspheres is described . The microspheres were simply prepared in liquid paraffin by solidifying an Eudragit L100 in ethanol solution . When gelatin was incorporated in the solidifying solution, the resultant microspheres were more spherical and had a smooth surface . The size of the microspheres could be controlled by varying the Eudragit L100 concentration in ethanol, and erythromycin was incorporated with 60-70% efficiency . The degradation of erythromycin by acid was markedly protected when the erythromycin microspheres were coated with the polymer . The in vitro release rate of erythromycin from the microspheres was also modified by the coating process . The feasibility of preparing formulations of erythromycin for oral administration, which release the drug at a controlled rate, and protect the drug from gastric acid, is thus demonstrated.

Br J Obstet Gynaecol, 1991 Jul, 98(7), 725 - 7
A maternal death caused by AIDS . Case report; Kell PD et al.; PIP: Physicians at a district general hospital in London, England admitted a 26 year old pregnant political refugee from Uganda complaining of shortness of breath, fever, and a productive cough for 1 week . She was at 10 weeks gestation and had not yet sought prenatal care . 6 years earlier she had a child and her pregnancy and delivery were normal . They diagnosed an interstitial pneumonia based on an X ray, arterial gases, and quick breathing and administered intravenous (IV) ampicillin and erythromycin for 3 days . Her condition deteriorated nevertheless, so they had her blood tested for HIV . She tested positive and suspected pneumocystosis (later confirmed) and began treatment with IV Septrin and hydrocortisone . She worsened, and by the 10th day of this treatment she was receiving 60% oxygen . They changed her treatment to IV pentamidine and oral rifampicin and isoniazid . By this time, her white blood cell count was 28.7x109/1 and hemoglobin concentration 8.2g/dl . Her condition would not allow her to undergo general anesthesia so an abortion requested by the patient was not performed . Additional treatment included continuous infusion of eflornithine, but she died despite it . This case poses 2 questions . Could she have lived if there had not been a delay in HIV diagnosis? Research shows that CD4 lymphocytes cell counts fall considerably during pregnancy in HIV positive women . So some advocate prophylaxis earlier in these women than other immunocompromised patients . Was it indeed her pregnancy that contributed to the severity of her illness and its inability to respond to treatment? Some researchers find pregnancy accelerates the progress of HIV infection, but researchers do not yet know if it also accelerates the progress of opportunistic infections . If so, terminating pregnancy may be considered .

Clin Exp Dermatol, 1991 Jul, 16(4), 300 - 2
Cutaneous Mycobacterium kansasii infection--treatment with erythromycin; Groves RW et al.; A 20-year-old woman developed cutaneous Mycobacterium kansasii infection following steroid infiltration of two plaques of lichen simplex . The organism was resistant to many standard antituberculous drugs and following sensitivity studies treatment with erythromycin was begun . This has been effective and well tolerated . Treatment of atypical mycobacteria with drugs not traditionally associated with antituberculous activity is being increasingly reported and, so far, resistance has not been a problem . Erythromycin has good tissue penetration with excellent activity against M . kansasii and should be considered in the therapy of similar cases.

Xenobiotica, 1991 Jul, 21(7), 895 - 904
Comparison of the effects of inducers of cytochrome P450 on Mongolian gerbil and rat hepatic microsomal monooxygenase activities; Fentem JH et al.; 1 . Basal cytochrome P450 content (nmol/mg protein) was higher in gerbil (1.10 +/- 0.01) than in rat (0.81 +/- 0.05) hepatic microsomes . Pretreatment of gerbils with phenobarbitone and beta-naphthoflavone increased P450 contents by 200% and 60% respectively . 2 . 7-Ethoxycoumarin O-deethylase, coumarin 7-hydroxylase and 4-nitrophenol hydroxylase activities were generally higher in gerbil liver microsomes, whereas erythromycin N-demethylase, and 7-ethoxyresorufin and 7-pentoxyresorufin O-dealkylase activities were higher in rat microsomes . Microsomal benzphetamine N-demethylase activities were similar in both species . 3 . Induction of specific cytochrome P450 isozymes increased similar monooxygenase activities of rat and gerbil microsomes . Phenobarbitone, beta-naphthoflavone, isoniazid and pregnenolone 16 alpha-carbonitrile principally increased benzphetamine N-demethylase, 7-ethoxyresorufin O-deethylase, 4-nitrophenol hydroxylase and erythromycin N-demethylase activities respectively . 4 . Constitutive 7-ethoxyresorufin and 7-pentoxyresorufin O-dealkylase activities were markedly lower in gerbil microsomes compared with rat microsomes, and pretreatment of gerbils with cytochrome P450 inducers did not significantly increase these activities . 5 . Hepatic microsomal coumarin 7-hydroxylase activities were approximately 30-200 times greater (depending on the inducer) in the gerbil than in rat . The gerbil, due to is high coumarin 7-hydroxylase activity, would appear to be a more appropriate species than rat for investigations of coumarin metabolism and toxicity relevant to humans.

Biochimie, 1991 Jul-Aug, 73(7-8), 1101 - 7
The use of synthetic tRNAs as probes for examining nascent peptides on Escherichia coli ribosomes; Picking W et al.; The polyuridylic acid-dependent syntheses of polycysteine and polyserine were carried out on Escherichia coli ribosomes using two new synthetic tRNA species . The peptides were initiated with N-acetyl or N-acyl coumarin derivatives of either Ser-tRNA or Phe-tRNA . The properties of the resulting nascent peptides were compared to those of nascent polyphenylalanine chains synthesized under similar conditions . This was accomplished by following changes in the fluorescence properties of the probes covalently linked to the amino-terminus of each of the nascent polypeptides as they were formed on the ribosomes . Nascent polycysteine and polyserine peptides appeared quite different from those of polyphenylalanine, as indicated by the anisotropy of fluorescence from the amino terminal probe . In contrast to serine and cysteine peptides, the synthesis of all the polyphenylalanine peptides was insensitive to inhibition by erythromycin, even though these peptides were initiated with N-acyl serine . The results support the hypothesis that nascent polyphenylalanine peptides have atypical physical and chemical properties and demonstrate the utility of using modified tRNAs to study ribosome function and the synthesis of proteins.

Dtsch Med Wochenschr, 1991 Jun 28, 116(26), 1013 - 7
{Tertiary syphilis with liver gummata}; Fischbach W et al.; Sonography revealed multiple echo-poor lesions in the liver of a 51-year-old man with nonspecific symptoms (fatigue, drop in performance, pressure sensation in the upper abdomen), increased blood sedimentation rate (68/110 mm) and evidence of cholestasis (gamma-GT 126 U/l, alkaline phosphatase 444 U/l, leucine-aminopeptidase 64 U/l) . Under the diagnosis of liver metastases the primary tumour was looked for . These investigations and a fine-needle biopsy having proved unsuccessful, laparoscopy was performed . The biopsies so obtained showed whitish yellow, tight elastic structures indicating gummas of the liver in tertiary syphilis . Treponema-specific IgM antibodies in serum characterized active syphilis requiring treatment . Administration of antibiotics (penicillin 1 mega U daily i.m.; because of allergy replaced after four days by erythromycin 2 g daily for six weeks) resulted in complete normalization of all biochemical findings and, some time later, regression of the gummas . The patient has now been symptom-free for three years . This case illustrates the need even to-day of including syphilis in the differential diagnosis of unclear space-occupying lesions of the liver.

Biochem Pharmacol, 1991 Jun 15, 41(12), 1911 - 9
Identification of the cytochrome P450 IIIA family as the enzymes involved in the N-demethylation of tamoxifen in human liver microsomes; Jacolot F et al.; The antiestrogen tamoxifen (Tam or Nolvadex, ICI)-Z-1-{4-{2-(dimethylamino) ethoxy}phenyl}-1,2-diphenyl-1-butene is widely used in treatment of hormone-dependent breast cancer . The drug is extensively metabolized by cytochrome P450 dependent hepatic mixed function oxidase in man, yielding mainly the N-desmethyl metabolite (DMT) . This study has been carried out to determine the P450 enzyme involved in the N-oxidative demethylation of Tam in microsomal samples from 25 human livers (23 adults, two children) . This metabolic step was inhibited by carbon monoxide up to 75% . Tam was demethylated into DMT with an apparent Km of 98 +/- 10 microM; rates varied between 37 and 446 pmol/min/mg microsomal protein . These metabolic rates were strongly correlated with 6 beta-hydroxylation of testosterone (r = 0.83) and erythromycin N-demethylase (r = 0.75), both activities known to be associated with P450 IIIA enzyme . To further assess whether or not the Tam demethylation pathway is catalysed by the same P450, the inhibitory effect of TST on this reaction was determined . The competitive inhibition had an apparent Ki of 100 +/- 10 microM . Drugs such as erythromycin, cyclosporin, nifedipine and diltiazem were shown to inhibit in vitro the metabolism of tamoxifen . Furthermore the P450 IIIA content of liver microsomal samples, measured by Western blot technique using a monoclonal P450NF (nifedipine) antibody, was strongly correlated with DMT formation (r = 0.87) . Tam N-demethylase activity was inhibited by more than 65% with polyclonal anti-human anti-P450NF . All these in vitro observations establish that a P450 enzyme of the IIIA sub-family is involved in the oxidative demethylation of tamoxifen in human liver.

Biochem Pharmacol, 1991 Jun 15, 41(12), 1813 - 20
Inducing effect of oxfendazole on cytochrome P450IA2 in rabbit liver . Consequences on cytochrome P450 dependent monooxygenases; Gleizes C et al.; Male New Zealand rabbits were dosed with either 0.9, 4.5 or 22.5 mg/kg/day of oxfendazole by gastric intubation for 10 days . Oxfendazole administered at the therapeutic dose (4.5 mg/kg) and at the highest dose (22.5 mg/kg) increased 1.54- and 2.36-fold the total liver microsomal cytochrome P450 and more particularly the isoenzyme P450IA2 (95 and 184% increases) as demonstrated by western blotting . Increases in ethoxyresorufin O-deethylation and hydroxylations of benzopyrene and acetanilide occurred in livers of the same animals without any change in N-demethylation of aminopyrine, benzphetamine or erythromycin . Because of the unchanged level of mRNA specific to cytochrome P450IA2, as shown by northern blot analysis of poly mRNA, an enzyme stabilization rather than a transcriptional activation of IA2 genes should be involved in the P450IA2 regulation mechanisms . Oxfendazole bound strongly to cytochrome P450, giving rise to a type II spectrum, and inhibited noncompetitively the ethoxyresorufin O-deethylase and acetanilide hydroxylase activities, this confirmed that oxfendazole interacts only with the P450IA2 family . On the basis of a comparison of the enzymatic activities induced by various imidazole drugs, it was concluded that oxfendazole, like omeprazole and albendazole, behaved as a 3-methylcholanthrene-type inducer . These three benzimidazoles did not all belong to the same category of cytochrome P450 inducers as the antifungal drugs miconazole, clotrimazole and ketoconazole.

Eur J Biochem, 1991 Jun 15, 198(3), 713 - 22
The synthesis of polyphenylalanine on ribosomes to which erythromycin is bound; Odom OW et al.; Erythromycin binds to the large subunit of Escherichia coli ribosomes at a specific site that is very close to the amino acid of aminoacyl-tRNA bound into the peptidyltransferase center, and to the site to which puromycin is bound, the P and A sites, respectively, of the classical two-site model of ribosome function . Both erythromycin and puromycin affect fluorescence from fluorescent derivatives of aminoacyl-tRNAs, while both puromycin and aminoacyl-tRNAs affect fluorescence of fluorescent derivatives of erythromycylamine . The results demonstrate unequivocally that erythromycin, deacylated tRNA, a peptidyl-tRNA analogue and puromycin can be bound simultaneously to the same ribosome . Nascent peptides of more than a few amino acids in length block binding of erythromycin to the ribosomes but, unlike most other peptides, long polyphenylalanine chains can be synthesized on ribosomes to which erythromycin is bound . It is suggested that this refractory synthesis in the presence of erythromycin reflects the atypical physical and structural properties of polyphenylalanine.

J Clin Psychopharmacol, 1991 Jun, 11(3), 203 - 6
Effect of erythromycin on tricyclic antidepressant metabolism; Amsterdam JD et al.; Macrolide antibiotics such as erythromycin have been found to impair the hepatic metabolism of carbamazepine . In addition, recent studies have shown that intestinal flora can N-demethylate tricyclic antidepressants, suggesting that the human gut may be a possible site of extrahepatic drug metabolism . Therefore, we conducted a study to determine whether the concurrent use of erythromycin might influence the metabolism and steady-state plasma concentrations of tricyclic antidepressants . Six days of erythromycin administration caused no systematic change in either the parent tricyclic or its metabolite(s) . Thus, the short term concurrent use of erythromycin does not appear to alter hepatic or gut flora tricyclic metabolism to an appreciable extent . Nevertheless, prior reports of altered carbamazepine kinetics by erythromycin should increase the physician's awareness of a possible drug interaction when erythromycin is used concurrently with a tricyclic antidepressant.

Gastroenterol Clin North Am, 1991 Jun, 20(2), 335 - 49
New directions in the irritable bowel syndrome; Bailey LD Jr et al.; The irritable bowel syndrome (IBS) is an umbrella for the diagnosis of heterogeneous conditions that are awaiting better identification of specific manometric causes . This article focuses on the concept that future therapy for IBS will rely on identification of subgroups and in turn tailor the specific therapeutic approaches to an appreciation of the pathophysiology and symptom predominance of these subgroups . Future therapies will rely on the following principles: (1) prokinetic agents to coordinate upper gastrointestinal and colonic motility as well as improve the propulsive nature of colonic contractions; (2) gastrointestinal hormone agonists such as erythromycin and antagonists such as sandostatin and cholecystokinin antagonists; (3) spasmolytic therapy incorporating calcium channel blocking and anticholinergic agents; (4) inhibition of ovulatory cycle changes in circulating concentrations of gonadal hormones in women, who tend to dominate the IBS population; (5) incorporation of concepts relating to the role of subtypes of 5-hydroxytryptamine receptors in control of neural and myogenic function; (6) reassessment of food intolerance and sensitivity; and (7) incorporation of concepts relating to psychologic profiles and psychologic treatment approaches . IBS is a rich and fertile area for application of the exciting new pharmacologic advances relating to gastrointestinal smooth-muscle and neural innervation of the gut . Improvement in the understanding and treatment of IBS will be one of the major accomplishments of this decade.

J Pharmacol Exp Ther, 1991 Jun, 257(3), 1248 - 52
Erythromycin inhibits contractions of nerve-muscle preparations of the guinea pig small intestine; Minocha A et al.; The actions of the macrolide antibiotic, erythromycin lactobionate (EM), on nerve-mediated and drug-induced contractions of longitudinal and circular muscle of guinea pig small intestine were studied in vitro . Longitudinal muscle contractions, evoked by single transmural electrical stimuli, were inhibited by EM (10-300 microM) with half-maximal inhibition occurring at 161 microM (EC50) . EM-induced inhibition of longitudinal muscle contractions was not affected by the alpha-2 adrenergic antagonist, yohimbine (0.3 microM), by the adrenergic neuronal blocker, guanethidine (10 microM), or the opiate receptor antagonist, naloxone (1.0 microM) . Bethanechol-induced longitudinal muscle contractions were also reduced by EM . Noncholinergic longitudinal muscle contractions (1 microM scopolamine present), induced by trains of transmural stimuli, were reduced by EM (EC50, 142 microM); substance P (a mediator of noncholinergic contractions)-induced contractions were also reduced by EM . Circular muscle contractions, evoked by brief trains of transmural stimulation, were inhibited by EM but bethanechol- and substance P-induced contractions of the circular muscle were not altered by EM . Segments (2 cm) of small intestine were used to study reflex circular muscle contractions evoked by distention of the segment aboral to the recording point . Reflex contractions were inhibited by EM (EC50, 84 microM) . These data indicate that, in the guinea pig small intestine, EM inhibits nerve-mediated contractions by actions on enteric nerves and on longitudinal but not circular muscle.

J Allergy Clin Immunol, 1991 Jun, 87(6), 1050 - 5
Respiratory mucus hypersecretion (bronchorrhea): a case discussion--possible mechanisms(s) and treatment; Marom ZM et al.; The mechanism(s) underlying mucus hypersecretion (bronchorrhea) and the treatment of this condition are poorly understood . We have previously demonstrated that erythromycin inhibited mucus secretion from human airways and from secretory epithelial cells in vitro . We encountered a patient with airway obstruction marked by severe bronchorrhea, who previously had responded only to inhaled bronchodilators and high-dose prednisone . Many attempts to wean him from prednisone had failed . During the course of his disease, he had developed an IgG antibody to vasoactive intestinal peptide, had increased amounts of mucus secreted by his respiratory epithelial cells, and demonstrated hyperreactive airways as measured by methacholine challenge provocation test . Erythromycin was added to his therapy . The effect of erythromycin treatment was quite dramatic and included clinical and laboratory improvement . After a short trial of erythromycin, the patient tolerated low, every-other-day doses of prednisone . there was a significant reduction in the volume of his bronchorrhea, a major decrease in the epithelial mucins in his total expectorated mucus, complete inhibition of his airway hyperresponsiveness to inhaled methacholine, and significant reduction in the level of IgG antibody to vasoactive intestinal peptide . This response was specific for erythromycin since other antibiotics did not have any clinical, biochemical, or physiologic effects . We conclude that erythromycin may play a role in the treatment of patients with bronchorrhea and may have a steroid-sparing effect . Additional studies with larger numbers of patients are indicated.

Kansenshogaku Zasshi, 1991 Jun, 65(6), 692 - 7
{A study of bronchoalveolar lavage analysis in patients with diffuse panbronchiolitis--the results of low dose and long term erythromycin treatment}; Mukae H et al.; Cellular analysis including lymphocyte surface markers in BALF in 17 patients with DPB (14 male; 36 female) was performed . The total number of cells increased remarkably, especially the percentage of neutrophils (72.9 +/- 14.1%) . On the contrary the percentage of alveolar macrophage decreased (15.4 +/- 8.9%) . The CD4/CD8 ratio in DPB was also significantly decreased to 0.73 +/- 0.38% when compared with normal healthy nonsmokers . Five patients with low dose and long term EM treatment were analyzed . Total cell counts as well as the neutrophil percentage (7.3 +/- 4.0%) decreased significantly . On the other hand the percentage of alveolar macrophage increased to 76.6 +/- 0.6%, which was almost similar to those obtained from normal healthy volunteers . Therefore it is concluded that both clinical and BALF findings improved concordantly after EM treatment.

Kansenshogaku Zasshi, 1991 Jun, 65(6), 672 - 80
{Elastase activity in bronchoalveolar lavage fluid from patients with diffuse panbronchiolitis}; Ninomiya H et al.; The clinical and pathological features of diffuse panbronchiolitis (DPB) have been well reported to date though its pathogenesis remains unknown . This study was designed to evaluate the protease antiprotease imbalance in patients with DPB . For this purpose, we performed bronchoalveolar lavage (BAL) in sixteen patients with DPB, twelve patients with chronic bronchitis (CB) and control subjects (nine smokers and eleven non-smokers), and determined elastase activity and alpha 1 antitrypsin (alpha 1 AT) concentration in bronchoalveolar lavage fluid (BALF) . Elastase activity was measured using a synthetic substrate, succinyl-tri-L-alanine-p-nitroanilide . BALF from eleven of sixteen patients with DPB showed elastase activity . However, only two of twelve patients with CB showed elastase activity, and control subjects did not show any elastase activity in BALF . Although alpha 1 AT concentration is elevated in BALF from patients with DPB, it is assumed that elastase burden exceeded the elastase inhibitory capacity of alpha 1 AT in BALF . The percentage of neutrophils in BALF correlated significantly with elastase activity which was inhibited by DFP, but not by EDTA . These data revealed that the elastase in BALF was a serine protease of neutrophil origin . In five DPB-patients treated with low-dose long-term erythromycin chemotherapy, elastase activity in BALF decreased significantly . The above mentioned findings suggest that the neutrophil elastase plays an important role in the pathogenesis of DPB, and the mode of action of erythromycin on DPB is to decrease the elastase burden.

Monatsschr Kinderheilkd, 1991 Jun, 139(6), 344 - 8
{Ureaplasma urealyticum--a new problem pathogen in neonatology}; Satow K et al.; Some previous studies showed that Ureaplasma urealyticum is the most common germ that appears in the birthway of pregnant women and which is also frequently found in skin swabs and secretions of newborn and premature babies . The colonization of pregnant women by Ureaplasma urealyticum makes a premature birth more likely . Another factor of risk for a premature infant is a premature rupture of membranes for more than 24 hours which also makes an infection possible . There exists an association between pulmonary infection by Ureaplasma urealyticum and the development of a bronchopulmonary dysplasia especially for premature babies . According to our observations acute exacerbations of severe pneumonia can appear even after month . An attempt of therapy of pulmonary infection should be undertaken with erythromycin, if sensitive serotypes are present . In the case of erythromycin resistance chloramphenicol can be used but only under frequent controls of blood levels . We were able to observe rapid improvements with this effective therapy.

Ala Med, 1991 Jun, 60(12), 24 - 6, 28, 30
Current treatment of otitis media in children; Loftin LH; Otitis media is a common childhood disease with a spectrum of pathology ranging from acute, painful infection to persistent middle ear effusion to chronic negative middle ear pressure and development of cholesteatoma . Amoxicillin remains the initial empiric drug of choice with TMP-SMZ or erythromycin-sulfisoxazole used for penicillinallergic patients or for amoxicillin therapy failures . Amoxicillin-clavulante, cefuroxime axetil (no elixir form available) or cefixime may then be tried keeping in mind relative costs, side effects, dosing frequency and drug formulation . Prophylactic amoxicillin or sulfisoxazole at one-half the usual daily dose given once a day throughout the URI season is effective in reducing the number of episodes of AOME . Prolonged sulfonamide use should be carefully monitored . Tympanostomy tube insertion is indicated for frequently recurring otitis media and for persistent middle ear effusions . Adenoidectomy is an adjunctive procedure shown to be effective in children requiring a second set of tubes for recurrent infections or for children four years old or older with persistent middle ear fluid . Tympanoplasty may be necessary to prevent ossicular chain damage due to severe cases of MEVD or to repair non-healing perforations . Cholesteatomas must be surgically removed and may require elaborate reconstructive techniques.

Zhonghua Liu Xing Bing Xue Za Zhi, 1991 Jun, 12(3), 150 - 3
{Observation on clinical features and therapy in 4 elderly cases with legionellosis}; Wen B; Four elderly cases with Legionellosis were reported . All of them had pneumonitis and small amount of chest fluid . Erythromycin and rifadin were effective in all 4 patients . Three patients were positive for Legionella pneumophila serogroup 1 . The disease occurred in July or October . Diagnosis and therapy should be made as early as possible for those patients suspected of Legionellosis.

Clin Chest Med, 1991 Jun, 12(2), 257 - 68
Legionella infection; Nguyen ML et al.; As specialized laboratory tests became more widely available, Legionella species were found to be common causes of nosocomial and community-acquired pneumonia . Patients with chronic lung disease and organ transplants are at greatest risk . Clinical manifestations are non-specific, although fever greater than 39 degrees C and diarrhea are common . Erythromycin remains the antibiotic of choice, although many alternative agents are available . Once cases are discovered, a search for the organism in water distribution systems and respiratory equipment can be fruitful . Disinfection of water distribution systems by superheating and flushing or by hyperchlorination is feasible.

J Invest Dermatol, 1991 Jun, 96(6), 827 - 31
Cyclosporine A metabolism by cytochrome P-450III occurs in microsomes from rat liver but not from normal epidermis or psoriatic lesions; Duell E et al.; Cyclosporine A is efficacious in the treatment of psoriasis when taken orally or injected intralesionally but not topically . Lack of penetration to necessary locations or rapid metabolism during passage through the epidermis may account for the ineffectiveness . Cytochromes P-450III in the liver are known to be involved in cyclosporine metabolism and inactivation . This study was undertaken to determine if an epidermal cytochrome P-450III exists that can inactivate topical cyclosporine A . Rats were treated with the macrolide antibiotic erythromycin to induce the cytochrome P-450III family of enzymes . Microsomal fractions were prepared from liver and epidermis of rats and from lesional areas of psoriasis patients . NADPH cytochrome C reductase activity was determined as a positive control for microsomal enzymatic activity . Formation of metabolite 1, the predominant metabolite of cyclosporine A, by liver microsomes was increased 193% after 10 d erythromycin treatment . The cytochrome P-450 dependent activity in microsomes from the epidermis of control and erythromycin-treated rats and in microsomes from psoriatic tissue was at the detection limits of the assay system . Cytochrome P-450III gene family mRNA were detectable by polymerase chain reaction in liver but not in psoriatic or normal epidermis . The lack of detectable P-450III mRNA and the absence or minimal conversion of cyclosporine A to inactive metabolites by epidermal microsomes suggest that the ineffectiveness of topical cyclosporine A in psoriasis may not be due to inactivation of cyclosporine A by cytochrome P-450 in the skin.

Science, 1991 May 3, 252(5006), 675 - 9
Modular organization of genes required for complex polyketide biosynthesis; Donadio S et al.; In Saccharopolyspora erythraea, the genes that govern synthesis of the polyketide portion of the macrolide antibiotic erythromycin are organized in six repeated units that encode fatty acid synthase (FAS)-like activities . Each repeated unit is designated a module, and two modules are contained in a single open reading frame . A model for the synthesis of this complex polyketide is proposed, where each module encodes a functional synthase unit and each synthase unit participates specifically in one of the six FAS-like elongation steps required for formation of the polyketide . In addition, genetic organization and biochemical order of events appear to be colinear . Evidence for the model is provided by construction of a selected mutant and by isolation of a polyketide of predicted structure.

J Surg Res, 1991 May, 50(5), 494 - 8
Erythromycin acts through a cholinergic pathway to improve canine-delayed gastric emptying following vagotomy and Roux-Y antrectomy; Carlson RG et al.; We have demonstrated that erythromycin improves gastric emptying in dogs following truncal vagotomy and Roux-en-Y antrectomy (VRYA) . To explore its mechanism of action we studied gastric emptying and myoelectric activity in a canine Roux model and administered atropine simultaneously with erythromycin . Tachyphylaxis was evaluated following short-term administration . Four dogs with delayed gastric emptying following VRYA were studied . Radionuclide solid gastric emptying was measured, with simultaneous myoelectric recordings obtained from the duodenum and Roux limb . Study groups were: (1) saline control (VRYA dogs); (2) erythromycin 1 mg/kg iv over 1 hr; (3) erythromycin 3 mg/kg po tid for 1 week, with repeat studies using erythromycin 1 mg/kg iv over 1 hr; and (4) atropine 0.5 mg/kg iv bolus, followed by a 1-hr infusion of atropine 0.05 mg/kg and erythromycin 1 mg/kg . Control Roux animals had severe gastric retention (73 +/- 5% at 2 hr, compared to 27 +/- 6% following iv erythromycin (P less than 0.01) . Clustered spike bursts were observed in the Roux limb following erythromycin . Atropine abolished the gastrokinetic response and suppressed the myoelectric response to erythromycin (81 +/- 3% retention at 2 hr, P less than 0.01 compared to erythromycin alone) . The response to erythromycin was unchanged after 1 week of tid administration (40 +/- 14% retention at 2 hr postprandial, P = NS) . Erythromycin improves gastric emptying in VRYA dogs via a cholinergic pathway and does not exhibit tachyphylaxis following short-term administration.

Antibiot Khimioter, 1991 May, 36(5), 28 - 30
{Pharmacokinetics of protegentin, a combined preparation}; Gagaeva EV et al.; Protegentin is a combined preparation in the form of ointment containing 0.1 per cent of gentamicin, 0.25 per cent of erythromycin and 0.1 per cent of protease C . Pharmacokinetic studies on the preparation were conducted . Protegentin and gentamicin ointment, currently manufactured in this country, were applied to the surface of experimental pure cutaneous wounds in guinea pigs in a dose of 1 g . It was shown that inspite of the same contents of gentamicin in the ointments, the mean maximum concentration of the antibiotic in the underlying muscular tissue after the protegentin application was somewhat higher than that after the use of the gentamicin ointment . The differences in the drug concentration maintained during the whole observation period of 24 hours . However, they were not statistically significant . The gentamicin concentrations in serum after the use of protegentin were also somewhat higher than those after application of the gentamicin ointment (the differences were not statistically significant) . Still, in no case the concentrations reached the potentially toxic ones . The erythromycin concentrations in the muscular tissue were much higher than those in the blood.

Antimicrob Agents Chemother, 1991 May, 35(5), 903 - 9
Comparative activity of macrolides against Toxoplasma gondii demonstrating utility of an in vitro microassay; Chamberland S et al.; The utility of spiramycin for preventing transplacental transmission of toxoplasmosis and the efficacy of conventional macrolides against Toxoplasma gondii are subjects of active debate . An in vitro microassay was developed to determine the relative inhibitory activity against T . gondii of 24 conventional macrolides derived from erythromycin and tylosin (14- and 16-membered macrolides, respectively) . Macrolides and T . gondii RH tachyzoites were added to monolayers of BT cells grown in 96-well plates . Plates were incubated for 20 h at 37 degrees C, and the growth of T . gondii was then measured by the selective incorporation of {3H}uracil in trichloroacetic acid-precipitable material during an additional incubation of 20 h . Dose-response curves and 50 and 90% inhibitory concentrations (IC50 and IC90, respectively) were determined for each drug . Microscopic examination was performed on stained replicates of the infected monolayers, and the relative toxicities of the drugs for host cells were determined . Spiramycin and tylosin showed only limited activity against T . gondii (IC50 of 20.16 and 20.00 micrograms/ml, respectively) . Erythromycin and azithromycin had a better anti-Toxoplasma activity with IC50 of 14.38 and 8.61 micrograms/ml, respectively, whereas drugs like desmycosin, dirithromycin, and roxithromycin had no detectable activity . Although many macrolides inhibited intracellular proliferation of T . gondii, azithromycin was the only macrolide demonstrating prolonged inhibitory activity on the replication of intracellular tachyzoites . We conclude that conventional 14- and 16-membered macrolides often interfere with the growth of, but may not kill, T . gondii RH tachyzoites in vitro.

Drugs, 1991 May, 41(5), 780 - 98
Azelaic acid . A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders; Fitton A et al.; Azelaic acid is a naturally occurring saturated dicarboxylic acid which, on topical application (usually as a 20% cream), has been shown to be effective in the treatment of comedonal acne and inflammatory (papulopustular, nodular and nodulocystic) acne, as well as various cutaneous hyperpigmentary disorders characterised by hyperactive/abnormal melanocyte function, including melasma and, possibly, lentigo maligna . In addition, azelaic acid has an antiproliferative and cytotoxic effect on the human malignant melanocyte, and preliminary findings indicate that it may arrest the progression of cutaneous malignant melanoma . The mechanism of this selective cytotoxic action of azelaic acid is unclear, but may possibly be related to its inhibition of mitochondrial oxidoreductase activity and DNA synthesis . In controlled studies, topical azelaic acid demonstrated comparable anti-acne efficacy to topical tretinoin, benzoyl peroxide, erythromycin and oral tetracycline, while in patients with melasma azelaic acid proved at least as effective as topical hydroquinone . On topical application azelaic acid is well tolerated, with adverse effects apparently limited to a generally mild and transient local cutaneous irritation . Thus, topical azelaic acid, employed either as monotherapy or in combination with other treatments, is likely to prove of value in the management of acne and several hyperpigmentary disorders, most notably melasma.

Arzneimittelforschung, 1991 May, 41(5), 552 - 6
Effect of erythromycin on bronchial hyperresponsiveness in patients with bronchial asthma; Miyatake H et al.; The effects of erythromycin (erythromycin stearate, Erythromycin; CAS 643-22-1) on the bronchial hyperresponsiveness and the functions of lymphocytes and neutrophils were evaluated . Administration of erythromycin to asthmatic patients in a dosage of 600 mg/d for 10 weeks reduced the bronchial hyperresponsiveness measured by histamine inhalation test . Furthermore, incubation with erythromycin for 96 h inhibited the mixed lymphocyte reaction at the concentration of more than 10 mumol/l in a dose-dependent manner, and the value of IC50 was about 30 mumol/l . 2-h incubation with erythromycin showed a weak inhibition to n-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced superoxide production of polymorphonuclear neutrophils (PMNs) at the concentration of more than 30 mumol/l in a dose-dependent manner . 1-h incubation with 1 mumol/l and 100 mumol/l of erythromycin inhibited FMLP-induced chemotaxis of PMNs . The rates of inhibition at the concentration of 1 mumol/l and 100 mumol/l were 29.7% and 41.7%, respectively . Erythromycin thus showed a beneficial effect on bronchial hyperresponsiveness . This effect might be due to the regulation of the inflammatory cells.

J Chromatogr, 1991 Apr 19, 565(1-2), 265 - 75
Bioanalysis of erythromycin 2'-ethylsuccinate in plasma using phase-system switching continuous-flow fast atom bombardment liquid chromatography-mass spectrometry; Kokkonen PS et al.; A specific method for the determination of erythromycin 2'-ethylsuccinate (EM-ES) in plasma is described . The method involves a liquid-liquid extraction procedure followed by the analysis of extracts using phase-system switching (PSS) continuous-flow fast atom bombardment (CF-FAB) liquid chromatography-mass spectrometry (LC-MS) . In PSS EM-ES is enriched after analytical separation on a short trapping column, from which it is desorbed to the LC-MS interface . In this way, favourable mobile phases can be used for the LC separation and for the MS detection . Using the PSS approach a flow-rate reduction from 1.0 ml/min in the LC system to 15 microliters/min going into the mass spectrometer was achieved without splitting . The determination limit for EM-ES was 0.1 microgram/ml.

Acta Paediatr Scand, 1991 Apr, 80(4), 418 - 22
Acute otitis media in early infancy . Recurrence and prophylaxis; Fauskin G; During a four-year period, two groups of patients were observed for recurrences of bouts of acute otitis media (AOM) after initial episodes of AOM in early infancy . Of 19 infants with a first bout of AOM before 3 months of age, all had at least one recurrence within eight months, of them 15 (79%) within four months . All members of a second group of 37 infants with two bouts of AOM before 12 months of age had a third bout within 14 months, and 28 of them (76%) had a recurrence within four months . During the ensuing two years (phase two), a group of 6 infants with one bout of AOM before 3 months of age (group one) and a group of 25 infants with two bouts of AOM before 12 months of age (group two) were treated for four months with 25 mg/kg/day aminopenicillin as a single oral daily dose . There were no episodes of AOM in these infants during the prophylactic period . During a third phase lasting two years, patients were assigned to treatment or no treatment regimens for four-month periods . Patients in treatment regimens received aminopenicillin or erythromycin ethylsuccinate-sulfamethoxazole (EES-SMZ) once daily . In infants with one bout of AOM before 3 months (Group 1) there were seven bouts of AOM in 9 untreated vs . one bout in 13 treated patients . In the group of infants with two bouts of AOM before 12 months (Group 2), 13 untreated infants had six bouts of AOM vs . no bouts in 19 treated patients.

Ann Trop Med Parasitol, 1991 Apr, 85(2), 215 - 22
Plasmodium falciparum sensitivity to erythromycin and 4-aminoquinoline combinations in vitro; Khan B et al.; Although erythromycin has been reported to be active against Plasmodium falciparum in vitro and P . berghei in vivo and in vitro when given alone or with chloroquine, it has been difficult to demonstrate a beneficial effect for the combination of erythromycin and chloroquine when used for the treatment of P . falciparum infections in humans . We developed a seven-day test of parasite sensitivity to a 4-aminoquinoline and erythromycin combination in vitro . Eight isolates of P . falciparum from the Kenyan coast were culture-adapted and exposed to erythromycin with chloroquine or with amodiaquine . The interaction of the drugs was evaluated by plotting the concentration of each drug needed to inhibit parasite growth . In seven isolates the combination of chloroquine and erythromycin was antagonistic; one isolate showed slight synergy The combination of amodiaquine and erythromycin was synergistic in three isolates but antagonistic in five . An antagonistic interaction may explain why erythromycin does not enhance chloroquine treatment of malaria in vivo in Kenya.

J Microencapsul, 1991 Apr-Jun, 8(2), 171 - 83
Liposomes as carriers of macrolides: preferential association of erythromycin A and azithromycin with liposomes of phosphatidylglycerol containing unsaturated fatty acid(s); Stuhne-Sekalec L et al.; To assess the most favourable phospholipid composition of a liposomal carrier for antibiotics, small multilamellar liposomes were prepared from phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol of varying fatty acid composition in the presence of erythromycin A and azithromycin . Crude liposomes were subjected to Sepharose CL-4B column chromatography, and liposomes containing antibiotics were well separated from free antibiotics . These experiments established that the greatest association of antibiotics was achieved with liposomes prepared from phosphatidylglycerol rather than phosphatidylcholine or phosphatidylethanolamine . Furthermore, the composition of fatty acids in phosphatidylglycerol liposomes influenced the amount of antibiotics associated with liposomes; the highest amount was obtained with dioleoylphosphatidylglycerol followed by phosphatidylglycerol of fatty acid composition similar to that of egg yolk lecithin . It was established that purified liposomes, prepared from {3H}phosphatidylglycerol containing unsaturated fatty acid(s) bind about 25 per cent of originally present antibiotic . Both antibiotics, erythromycin A and azithromycin, were similar in respect to the amount of their association with liposomes . Determination of the size of phosphatidylglycerol/antibiotic liposomes established that the mean diameter of liposomes containing antibiotics was 200-350 nm, very close to that of liposomes without them.

Z Gastroenterol, 1991 Apr, 29 Suppl 3, 27 - 30
{Medicamentous modification of gastrointestinal motility and secretion}; Allescher HD; This article gives an overview on possible new pharmacological tools to modify gastrointestinal motility and/or secretion . The characterization of new subclasses of classical neurotransmitter receptors and of peptidergic receptors offer a new approach for the development of new therapeutic agents . Using molecular biology techniques a variety of receptor subclasses have been demonstrated for muscarinic and alpha 2-adrenergic receptors . Both receptor types are of major importance for the regulation of mucosal secretion in the submucosal plexus and specific ligands for these receptor subtypes could be of clinical interest . In the next paragraphs the possible therapeutic relevance of 5-HT3-receptor antagonists and of opiate agonist and -antagonists is discussed . 5-HT3-antagonists, which can be used as potent antiemetics, also demonstrate quite potent effects on upper gastrointestinal motility such as gastric emptying . Whereas the subclassification of opioids has so far no specific therapeutic consequences there is some evidence that casomorphin, a derivative of the casein of the milk, could be used as a possible antidiarhoic substance . The use of antagonist and agonists on peptidergic receptors with orally active ligands offer a further new therapeutic approach . This is discussed for CCK-antagonists and erythromycin-analogues which are agonists at the motilin receptor . Besides this experimental approach to modify defined receptor subclasses, there are new substances with so far not clearly defined mechanism of action, which, however, have potent therapeutic effects . Cisapride, a new potent prokinetic drug with little side effects, is now available for clinical use for a wide range of motility disorders.

Scand J Prim Health Care, 1991 Mar, 9(1), 35 - 9
Systemic or local treatment of erythrasma? A comparison between erythromycin tablets and Fucidin cream in general practice; Hamann K et al.; In a Danish multi-practice study the efficacy of erythromycin tablets (Abboticin 500 mg tablets), fusidic acid cream (Fucidin cream), and placebo was compared in 86 patients (71 men and 15 women) with erythrasma . The patients were treated 'double-blind' for 14 days with either active tablets + placebo cream, placebo tablets + active cream, or placebo tablets + placebo cream . The signs of erythrasma, i.e . colour intensity, demarcation, and scaling of the affected area, as well as degree of fluorescence under Wood's light, were recorded before treatment, after one and two weeks, and at follow-up four weeks later . Cure/improvement was obtained in 77% of the cases in the erythromycin group, 87% in the fusidic acid group, and 42% in the placebo group . There was no difference between the active preparations, whereas both were significantly better than placebo, P = 0.01.

Isr J Med Sci, 1991 Mar, 27(3), 145 - 9
Legionellosis at Hadassah University Hospital: a 1-year survey; Maayan S et al.; During 1985 in the Hadassah University Hospital we studied all hospitalized patients whose serum had been submitted for Legionella antibodies . Of 133 patients, 12 (9%) had legionellosis as diagnosed by serology, direct fluorescence, or culture . All Legionella cases appeared to be sporadic, nonseasonal, community-acquired pneumonia . There were no specific environmental co-factors or clustering . A significant predilection of the disease for immunosuppressed individuals was observed; the in-hospital mortality was high (5/12), especially if erythromycin therapy was delayed . L . pneumophila and L . bozemanii were the dominant etiological species . In Jerusalem, Legionella is not infrequently the etiological agent in community-acquired pneumonia in immunosuppressed patients.

Mol Pharmacol, 1991 Mar, 39(3), 275 - 80
Induction of cytochrome P450IIE1 in the obese overfed rat; Raucy JL et al.; Cytochrome P450IIE1 (IIE1) is a microsomal xenobiotic-activating enzyme that is inducible not only by various chemical agents but also by fasting and diabetes . Using a rat model that mimics human obesity, we have found that hepatic IIE1 levels are also increased by this common clinical disorder . Liver microsomes from rats made obese by feeding with an energy-dense diet displayed elevated aggregate P450 content (+28%) and enhanced catalytic activities associated with IIE1, including low-Km N-nitrosodimethylamine demethylation (+66%), aniline hydroxylation (+52%), p-nitrophenol hydroxylation (+170%), and acetaminophen-cysteine conjugate formation (+28%) . In contrast, obesity had no significant effect on cytochrome b5 content, P450 reductase activity, benzphetamine demethylation, or erythromycin demethylation, with the latter two reactions being linked with rat IIC11 and IIIA1, respectively . The enhancement of IIE1-dependent drug-metabolizing activities noted in liver microsomes from obese rats was paralleled by a similar increase (111%) in hepatic IIE1 protein content in these animals, as assessed on immunoblots developed with anti-hamster IIE1 IgG . Anti-IIE1-inhibitable rates of microsomal p-nitrophenol metabolism, a reaction highly correlated with IIE1 content (r = 0.88, p less than 0.01), were over 3-fold higher in obese rats than in nonobese controls, providing additional evidence for the obesity-related increase of hepatic IIE1 . The induction of IIE1 by the pathophysiological condition of obesity may provide a biochemical basis for the increased incidence of occult liver disease and certain cancers noted in obese individuals.

Chest, 1991 Mar, 99(3), 670 - 3
Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma; Miyatake H et al.; It has been demonstrated that bronchial hyperresponsiveness is a characteristic feature of bronchial asthma, and airway inflammation plays an important role in bronchial hyperresponsiveness . Erythromycin is an antibiotic extensively used worldwide which is also reported to have anti-inflammatory action . This study was designed to clarify whether erythromycin could favorably alter bronchial responsiveness in patients with bronchial asthma . To estimate bronchial responsiveness, histamine challenge was performed in 23 patients with bronchial asthma (atopic type, 11; nonatopic type, 12) . All patients were treated for ten weeks with erythromycin, 200 mg three times daily, orally . After ten weeks' treatment, PC20, an index of bronchial sensitivity, was increased significantly . There was no difference between atopic and nonatopic patients in the improvement of PC20 . It was concluded that erythromycin reduces the severity of bronchial responsiveness in patients with bronchial asthma.

Antimicrob Agents Chemother, 1991 Mar, 35(3), 587 - 9
Susceptibility of Mycoplasma pneumoniae to several new quinolones, tetracycline, and erythromycin; Kenny GE et al.; Mycoplasma pneumoniae (39 strains) was most susceptible to two quinolones, WIN 57273 and sparfloxacin, with MICs for 90% of the strains (MIC90S) of 0.125 and 0.25 micrograms/ml, respectively . It was susceptible to ofloxacin and ciprofloxacin at 2 micrograms/ml and to lomefloxacin and fleroxacin at 4 micrograms/ml . The MIC90 of erythromycin was 0.062 microgram/ml, and that of tetracycline was 1 microgram/ml.

J Clin Pharmacol, 1991 Mar, 31(3), 259 - 62
Evaluation of a potential interaction between erythromycin and glyburide in diabetic volunteers; Fleishaker JC et al.; The effects of erythromycin on the pharmacokinetics and pharmacodynamics of glyburide were evaluated in 12 patients with non-insulin-dependent diabetes mellitus (fasting blood glucose levels 140-280 mg/dL), who received 4 days of treatment with erythromycin base (333 mg administered orally every 8 hr) and a control treatment in a randomized crossover design; 5 mg glyburide was administered on day 4 of each study period . Serum glyburide concentrations were determined by high-performance liquid chromatography . Peak serum glyburide concentrations were increased by 18%, and mean time to peak glyburide concentrations (Tmax) decreased from 4.9 to 3.0 hours during erythromycin treatment; only the difference in Tmax was statistically significant . No significant effects on glyburide clearance were observed . No significant differences in glucose clearance after carbohydrate loads were observed between erythromycin + glyburide and glyburide treatments . These data show that oral erythromycin base treatment does not affect glyburide metabolism but does affect the rate of glyburide absorption . This effect may be mediated by the stimulation of gastric motility by erythromycin . The clinical significance of the effects of erythromycin on glyburide kinetics appears to be minimal, based on the determinations of serum glucose concentrations.

Antibiot Khimioter, 1991 Mar, 36(3), 17 - 20
{A system for screening natural immunosuppressors}; Bibikova MV et al.; Criteria for directed screening of antibiotics with immunosuppressive action were defined . The first stage included screening of cultures producing antiaspergillous antibiotics . At the second stage, the antibiotics whose antifungal activity decreases in the presence of insulin (at the background of calcium salts) and erythromycin and increases in the presence of verapamil were selected . The screening of antibiotic-producing cultures among 123 strains of mycelial fungi and 181 strains of actinomycetes resulted in isolation of 3 fungal cultures and 2 actinomycetes which produced antibiotics corresponding to cyclosporine A as evidenced by thin-layer and high performance liquid chromatographies.

J Antibiot (Tokyo), 1991 Mar, 44(3), 313 - 30
New ether oxime derivatives of erythromycin A . A structure-activity relationship study; Gasc JC et al.; The discovery of roxithromycin is the result of a rational and scientific process, based on the fact that at least one reason for erythromycin A's resorption variability after oral administration was its instability in the gastric juice . This instability is due to the reactivity of the ketone in position 9 in acidic medium and one chemical approach was to mask it by an oxime function . Both stereoisomers of this oxime were isolated . Direct O-alkylation of this oxime allowed access to various ether oxime derivatives and of the latter the E stereoisomers were more interesting than the Z ones . The choice of the nature of the oxime substitution was made according to the lipophilic or hydrophilic character of the aliphatic ether chain and these alterations were mainly carried out by introducing heteroatoms into this chain . These different derivatives were classified in 5 groups according to the chemical nature of the chain: Aliphatic, aromatic and nitrogen-, oxygen- and sulfur-containing chains . Two classes, those containing a nitrogen or an oxygen in the ether side chains, showed differential in vitro/in vivo antibiotic activities, with improved bioavailability . Some preliminary pharmacokinetic data confirmed this improvement and led to the selection of five candidates, from which roxithromycin emerged as the best compound.

Ann Allergy, 1991 Mar, 66(3), 216 - 8
Adverse cutaneous reactions due to macrolides; Igea JM et al.; Macrolides, which are widely prescribed and seldom produce hypersensitivity reactions, are considered to be safe drugs . We present five patients with generalized skin reactions due to erythromycin and/or spiramycin, proved by oral challenge tests . One patient showed reactions to both erythromycin and spiramycin . All skin prick and patch tests and histamine release tests with both macrolides were negative.

Naunyn Schmiedebergs Arch Pharmacol, 1991 Feb, 343(2), 202 - 8
Ca2+ dependence of motilide-induced contractions in rabbit duodenal muscle strips in vitro; Peeters TL et al.; Recent studies suggested that certain erythromycin A (EM-A) derivatives are motilin receptor agonists . As proposed by Itoh they may be called "motilides" . We have investigated the Ca2(+)-dependence of contractions induced by two potent motilides, ME-34 {de(N-methyl) 8,9-anhydroeryhtromycin A 6,9-hemiacetal} and EM-523 {de(N-methyl)-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal}, in duodenal tissues and compared the results with those previously obtained with motilin . Isometric and isotonic contractile responses of isolated longitudinal muscle sheets from the rabbit duodenum were tested under normal, Ca2(+)-free and depolarizing conditions . Prior to stimulation with motilides, the maximal response to acetylcholine was recorded and all responses were always expressed as a percentage of this response . Both motilides induced contractions in normally polarized tissue, with an EC50 of 26 +/- 5 nM for ME-34 (n = 7), and 27 +/- 5 nM for EM-523 (n = 16) and maximal responses of respectively 88 +/- 4% and 80 +/- 3% . Like motilin, both compounds induced an 'extra'-contraction in depolarized tissues . The EM-523 response in 140 mM K+ under isotonic conditions was 84 +/- 3% (n = 5) at 10(-5) M, with an EC50 that was shifted to 65 +/- 18 nM . Similar figures were obtained for ME-34 . When Ca2+ was added to Ca2(+)-depleted strips, half-maximal Ca2+ values (in mM) were 1.10 +/- 0.11 (n = 9) for EM-523 and 1.13 +/- 0.12 (n = 3) for ME-34, as compared with 1.12 +/- 0.13 (n = 7) for motilin and 2.8 +/- 1.1 (n = 9) for K+ . Both ME-34 and EM-523 also induced a transient contraction in Ca2(+)-free solutions under isometric conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Regul Pept, 1991 Feb 1, 32(2), 85 - 94
Effect of erythromycin and of octreotide on motilin receptor density in the rabbit; Depoortere I et al.; Recent studies have shown that erythromycin lactobionate (EMLB) acts as a motilin agonist and is able to accelerate gastric emptying in diabetic gastroparesis . Using the rabbit as a model, we have studied the changes in motilin receptor density induced by EMLB (a motilin agonist) and octreotide (a somatostatin analogue and an inhibitor of motilin secretion) . Binding studies were performed with antral smooth muscle tissue homogenates using iodinated nor-leucine13-porcine-motilin, and binding parameters were obtained from computerized fits to displacement curves . The contractile capacity towards motilin (10(-7) M) and EMLB (10(-5) M) was measured isotonically on duodenal segments and the response was expressed relative to the maximum obtained with ACh (10(-4) M) . The first hours after the last i.v . administrations of EMLB (50 mg/day given on 3 consecutive days), motilin binding was completely abolished to 0.02 +/- 0.006 fmol/mg protein, compared to the control group (0.64 +/- 0.12 fmol/mg protein) . The effect was dose-related: total doses of 17.5 mg, 87.5 mg, 175 mg EMLB reduced motilin binding and contractility towards motilin and EMLB to respectively 95 +/- 10, 82 +/- 5%; 36 +/- 9, 38 +/- 9%; 3 +/- 1, 24 +/- 2% of the control values . The effect was also long lasting: binding was still reduced to 60% of the control value 48 h after the highest dose . In contrast, octreotide induced a marked but short lasting upregulation . After 3 daily s.c . injections of 5 micrograms, Bmax rose to 13.6 +/- 1.9 fmol/mg protein (P less than 0.05) . It was already obtained 1 h after 3 x 2.5 micrograms/24 h . The changes in receptor-density were not related to changes in affinity . We conclude that motilin receptors can be regulated by EMLB and octreotide presumably because one compound mimicks hypermotilinemia, the other one induces hypomotilinemia.

Ann Hematol, 1991 Feb, 62(1), 32 - 4
Correction of neutropenia associated with chronic lymphocytic leukaemia following treatment with granulocyte-macrophage colony-stimulating factor; Hollander AA et al.; A patient with chronic lymphocytic leukaemia (CLL) and severe persisting neutropenia due to marrow infiltration of his leukaemia, developed bilateral Legionella pneumophila pneumonia for which he was treated with erythromycin, rifampin and ciprofloxacin . To increase the number of circulating polymorphonuclear neutrophils, the patient was treated with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) at a dose of 2 micrograms protein/kg bodyweight s.c./12 h . GM-CSF therapy resulted in a sustained rise of the neutrophil count from the fifth day of treatment onwards, without showing an effect on the number of circulating leukemic cells . The patient completely recovered from his pneumonia . It is suggested that the rise of the neutrophil count, due to GM-CSF, contributed to the improvement of the infection of this patient . Our observation illustrates that GM-CSF can be given safely to CLL-patients and that it can be used effectively in CLL patients with severe bacterial infections to restore neutropenia.

Antibiot Khimioter, 1991 Feb, 36(2), 36 - 9
{Erythromycin pharmacokinetics in children after rectal and oral administration}; Nazarov AD et al.; Pharmacokinetics of erythromycin base was studied clinically in children not older than 14 years treated with new children dosage forms of the antibiotic i . e . 0.1 and 0.25 g enteric coated tablets and 0.06 and 0.125 g suppositories . It was noted that the new dosage forms were characterized by higher availability which was 2.5-3 times higher than that after using the erythromycin base tablets without the coating . Systematic increasing of erythromycin availability after the use of the rectal suppositories was observed with increasing of the children age . Absolute absorption in newborns, sucklings and children over 1 year amounted to 28, 36 and 54 per cent respectively.

J Allergy Clin Immunol, 1991 Feb, 87(2), 490 - 8
Mucus secretagogue production by a human macrophage hybridoma; Sperber K et al.; A pulmonary macrophage-monocyte-derived mucus secretagogue (MMS) oligopeptide has been previously reported to induce mucus secretion in an in vitro model system with human airway explants and secretory epithelial cells . To understand the possible role of macrophages in the regulation of secretion of mucus, our laboratory has used a series of human macrophage hybridomas that were generated by fusing an hypoxanthine guanine phosphoribosyl transferase-deficient promonocytic line, U937, with macrophages obtaining by maturing monocytes in Teflon bags . The cell lines were proven to be true hybridomas by acquisition of donor class I antigens, additional chromosomes, as well as macrophage specific (maximum velocity) not present on the U937 parent line . One clone, clone 63, produced large amounts of an oligopeptide with an approximate molecular weight of 2000, which was identified from culture supernatants by ultrafiltration, chromatography, isoelectric focusing, and Western blot . Processed clone 63 supernatant had biologic activity causing increased secretion of radiolabeled glycoconjugate in both cultured airways and secretory epithelial cells . Immunoblot analysis with a polyclonal rabbit antisera generated against MMS was positive, and Western blot analysis produced a band at approximately 2000 daltons, consistent with the previously described MMS . MMS secretion could be stimulated by zymosan and lipopolysaccharide and inhibited by both cycloheximide and erythromycin . Dexamethasone had a different effect, appearing to stimulate MMS production intracellularly but inhibiting its release once it was synthesized . The availability of cloned hybridomas allows for study of the regulation of mucus secretagogue production as well as purification of molecular species and provides a valuable tool for the study of mucus secretion.

Arch Intern Med . 1991 Feb;151(2):380.
Ototoxic reaction to erythromycin; Agusti C et al.; We report a case of bilateral hearing loss in a patient treated with intravenous erythromycin lactobionate . The ototoxic reaction occurred despite the patient's having normal renal and hepatic function and the fact that serum erythromycin levels were within the predicted normal range . In addition to hearing loss, a marked labyrinthic hyporreflexia was also observed . Hearing loss improved after the treatment was discontinued, but labyrinthic abnormalities persisted suggesting that erythromycin had caused a permanent vestibular damage.

Chest, 1991 Feb, 99(2), 344 - 50
Comparative study of Legionella pneumophila and other nosocomial-acquired pneumonias; Roig J et al.; We studied, in a prospective way, the characteristics of definitively diagnosed nosocomially acquired pneumonias in our hospital over 36 months . Out of 55 cases, 27 were due to Legionella pneumophila and 28 to other, non-Legionella bacteria . The cases of legionellosis concentrated in July, August, and December . The only risk factors that showed significant differences (p less than 0.05) were general anesthesia and surgery and immunosuppressive disease, which were more frequent in the non-Legionella group, as were chronic liver disease and lowering of consciousness level . The absence of severe underlying disease, chronic or not, was uncommon in both groups, but more frequent in the Legionella group . We observed no differences in the clinical features of the two groups . Mean values of gamma-glutamyltranspeptidase and total bilirubin were higher (p less than 0.05) in the non-Legionella group . The only x-ray data that showed significant difference were pleural effusion, more frequent in the non-Legionella group (p less than 0.02) . The mortality rate of legionellosis was 14.6 percent compared to 35.7 percent for the non-Legionella group (p less than 0.05) . We conclude that a sure differential diagnosis based on clinical, roentgenographic and analytical features of both groups is not possible . The relatively low mortality rate of the Legionella group, when compared to other series of nosocomial legionellosis, could be due to the standard use of erythromycin in the therapeutic approach to nosocomial-acquired pneumonia in our hospital.

J Antimicrob Chemother, 1991 Feb, 27 Suppl A, 47 - 59
Efficacy of clarithromycin against Mycoplasma pneumoniae; Cassell GH et al.; The in-vitro susceptibility of Mycoplasma pneumoniae to clarithromycin, a new macrolide, was compared with that to erythromycin . A broth microdilution assay was used to evaluate 30 clinical isolates collected over a 15 year period from four countries (United States, Australia, Denmark and Japan) . Clarithromycin inhibited the growth of all M . pneumoniae strains at low concentrations (less than or equal to 0.008 mg/l) similarly to erythromycin (less than or equal to 0.008 mg/l) . In 120 outpatients with radiographically confirmed community acquired pneumonia (mean age 46.2 years), M . pneumoniae was detected culturally and/or serologically by ELISA and immunoblotting in 13% of patients, thus confirming the continued importance of this organism as a respiratory pathogen . M . pneumoniae isolates from these patients were shown to be equally susceptible to clarithromycin (less than or equal to 0.008 mg/l) and erythromycin (less than or equal to 0.008 mg/l) . Both clarithromycin and erythromycin were effective in the treatment of community-acquired pneumonia . There were no statistically significant or clinically important differences between the two treatment groups with respect to clinical or radiographic resolution of disease or improvement in signs and symptoms . While the number of clinically evaluable patients with M . pneumoniae infections was small, both macrolides seemed equally effective.

J Antimicrob Chemother, 1991 Feb, 27 Suppl A, 117 - 24
A comparative safety and efficacy study of clarithromycin and erythromycin stearate in community-acquired pneumonia; Anderson G et al.; The efficacy and tolerance of clarithromycin and erythromycin stearate in the treatment of community-acquired pneumonia were compared in a multicentre, double-blind randomized trial . Two hundred and eight adult patients were randomized to receive either clarithromycin 250 mg 12-hourly (96 patients) or erythromycin stearate 500 mg 6-hourly (112 patients), each for 14 days . One hundred and eight patients were evaluable for efficacy, 64 receiving clarithromycin and 44 erythromycin stearate . There was no significant difference between the two groups in terms of clinical cure (52% for clarithromycin, 40% for erythromycin) or clinical success (clinical cure and improvement; 89% for clarithromycin, 98% for erythromycin stearate), or radiological response (90% for both groups) . An intention-to-treat analysis, including all patients entering the study revealed significant differences in favour of clarithromycin . The clinical cure rate after two weeks of treatment was 45% in those who received clarithromycin compared with 25% in the erythromycin stearate group (P = 0.003), whilst improvement in cough was observed in 97% and 80% of patients receiving clarithromycin and erythromycin stearate, respectively (P = 0.07) . Adverse effects, mainly gastrointestinal, caused discontinuation of treatment in 4% (4/96) patients in the clarithromycin group in comparison with 19% (21/112) treated with erythromycin stearate (P less than 0.01) . These results demonstrate that clarithromycin twice daily is at least as effective as four times daily erythromycin stearate for the treatment of community-acquired pneumonia and is better tolerated.

J Antimicrob Chemother, 1991 Feb, 27(2), 233 - 42
Hepatic safety of erythromycin acistrate in 1549 patients with respiratory tract or skin infections; Lehtonen L et al.; Erythromycin acistrate is a new 2'-acetyl esther prodrug of erythromycin, whose structure resembles that of erythromycin estolate . However, in toxicological studies, it does not have the problems of hepatotoxicity . To assess its effects on hepatic functions in clinical practice, the liver parameters of patients with respiratory tract or skin infections were monitored during therapy . In total 1549 patients were treated for 7-14 days . In addition, 127 patients with suspected viral infections served as controls . There were no significant differences in serum aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyltransferase (gamma-GT) or alkaline phosphatase (APHOS) values between the erythromycin acistrate or control groups at the beginning or end of therapy . ASAT values increased moderately in 2.4% and clearly in 0.3% of patients treated, but also decreased in 2.0% . ALAT values were moderately increased in 9.9%, clearly increased in 0.6% and normalized in 3.5% of the patients . gamma-GT values increased moderately in 3.5% and and clearly in 0.3%, but decreased to normal in 3.3% of the patients . APHOS was moderately elevated in 1.0% of the patients and normalized in 1.3% . The correlation of changes between the different liver enzymes was poor . Only ten patients (0.6%) had two or more clearly elevated liver enzyme values by the end of the therapy, of whom five had increased liver enzyme activities before the treatment, two had underlying disease explaining the changes and in only three patients out of 1549 (0.2%) could hepatic changes be attributed to erythromycin acistrate therapy . These changes were reversible . The results demonstrate the hepatic safety of erythromycin acistrate in clinical practice . Concomitant food intake did not affect the safety profile.

Bol Asoc Med P R, 1991 Feb, 83(2), 65 - 8
Updates on AIDS cryptosporidiosis: a review; Garrido Davila JI et al.; Cryptosporidium is a protozoal coccidian parasite that produces among other diseases chronic watery diarrhea . The extent of the diseases is mostly dependent on the immune status of the individual . Mortality in immunosuppressed and AIDS individuals due to the diarrhea illness is nearly 80% . Although no effective treatment is available yet, promising results have been related to the use of Spiramycin, Erythromycin, Somatostatin and its analogues, and zidovudine.

J Biol Chem, 1991 Jan 25, 266(3), 1534 - 42
The conformation of nascent polylysine and polyphenylalanine peptides on ribosomes; Picking WD et al.; Polypeptide synthesis using either phenylalanine or lysine was initiated on Escherichia coli ribosomes; then the position and conformation of the nascent peptide were monitored by fluorescence techniques . To this end, fluorophores had been attached to the amino terminus of each nascent peptide, and major differences were observed as chain extension occurred . Polyphenylalanine appeared to build up as a hydrophobic mass adjacent to the peptidyl transferase center while polylysine apparently was extended directly from the ribosome into the surrounding solution . An explanation for these differences may be provided by the physical and chemical properties of each polypeptide . These properties may be responsible for the route by which each peptide exits the peptidyl transferase center as demonstrated by the different sensitivity of each to inhibition by erythromycin.

Peptides, 1991 Jan-Feb, 12(1), 89 - 94
Motilin receptors of the rabbit colon; Depoortere I et al.; Binding studies with iodinated motilin revealed that in the small intestine motilin receptor density decreased aborally, disappeared in the caecum but returned in the colon and rectum . The highest density was in the distal colon (112 +/-/11 fmol/mg protein) . The dissociation constant was the same in all regions (overall mean 1.10 +/- 0.22 nM) . The ability of erythromycin-A (EM-A) and of two derivatives, EM-A N-oxide and EM-523, to displace motilin showed no difference between the tissues studied . Their order of potency was: motilin greater than EM-523 greater than EM-A greater than EM-A N-oxide . Proximal circular colonic smooth muscle strips showed maximal contractile responses towards motilin, EM-523 and EM-A of, respectively, 80 +/- 3%, 78 +/- 4% and 84 +/- 2% relative to the maximum obtained with acetylcholine . In proximal longitudinal muscle only a response of +/- 20% was obtained . Similar responses were obtained in the distal colon . The order of potency to induce contractions as reflected in the pED50 values was: motilin (8.03 +/- 0.1) greater than EM-523 (7.55 +/- 0.03) greater than EM-A (5.84 +/- 0.04) in proximal circular colon . The responses were not blocked by TTX (10(-6) M) or atropine (10(-6) M), but were reduced by verapamil (10(-6)M) . The abundance of motilin receptors in colonic smooth muscle, if applicable to other species, opens new perspectives for the therapeutic applications of macrolides with motilin agonist properties.

Nihon Kyobu Shikkan Gakkai Zasshi, 1991 Jan, 29(1), 72 - 83
{Clinical and pathophysiological significance of neutrophil elastase in sputum and the effect of erythromycin in chronic respiratory diseases}; Mikami M; The concentration and activity of neutrophil elastase (NE) in sputa were measured in 24 patients with chronic respiratory diseases such as diffuse pan-bronchiolitis, bronchiectasis and and chronic bronchitis . The results were compared to the clinico-pathophysiological parameters such as clinical impairment score, concentration of albumin and ciliary transport velocity of the sputum . Furthermore, the relationship between the post-therapeutic change of NE in sputum and clinical effect of erythromycin (EM) was investigated in the same cases . Physico-chemical properties of the sputum, including rheological characteristics, mucus transport velocity, phospholipid composition, concentration of albumin and fucose were also analyzed before and after EM therapy . There was a significant positive correlation between NE in sputum and the clinical impairment score, which suggested that the concentration and activity of NE in sputum reflected the clinical severity in such diseases . The concentration and activity of NE also had significant positive and negative correlation to the concentration of albumin and ciliary transport velocity, respectively . Therefore, it was considered that NE in airway could bring the leakage of albumin from serum and interfere with mucociliary transport . The patients were divided into responders (n = 12) and non-responders (n = 12) after EM therapy based on the change of the clinical impairment score . The clinical effect of EM in chronic respiratory diseases was not associated with its bacteriostatic action, but with the quantitative and qualitative suppression of sputum NE . The decrease of the adhesive properties of the sputum, which was observed in responders after administration of EM, was considered to depend on the reduction of the concentration of albumin in sputum . Concerning the phospholipid composition of sputum, sphingomyelin and phosphatidyl-ethanolamine, which had been suggested to be components of serum and cellular membrane, had a tendency to decrease in responders . The proportion of phosphatidylcholine increased in responders . The improvement of ciliary transport velocity of the sputum, which was noted in responders, was probably due to the results mentioned above . In non-responders, these findings were not observed after EM therapy . EM had no influence on the production, release and activity of NE as a result of in vitro experiments using human peripheral neutrophils . Neutrophil chemotaxis was however suppressed after incubation with EM . These results suggest that the mechanisms of the effect of EM is not direct action on NE but through suppression of neutrophil chemotaxis.

Arch Fr Pediatr, 1991 Jan, 48(1), 39 - 41
{QT prolongation and circulatory arrest after an injection of erythromycin in a newborn infant}; Benoit A et al.; A 8 day-old full-term newborn showed severe cardiac disturbances after intravenous injection of erythromycin . The neonate, suspected of having Chlamydia pneumonitis because of tachypnea and rhinitis, had been given 5 injections of erythromycin without clinical effect . Pallor, vomiting and bradycardia developed a few minutes after the 6th injection, and ECG showed ventricular arrhythmia, prolonged QT interval and an atrioventricular block . The infant died in intensive care unit . This case and the analysis of other published cases of cardiac disturbances following the parenteral use of erythromycin, indicate the potential arrhythmogenic risk of this drug . It is suggested that newborns treated with erythromycin should be monitored by ECG.

J Acquir Immune Defic Syndr, 1991, 4(5), 532 - 7
Synergistic anti-Pneumocystis carinii effects of erythromycin and sulfisoxazole; Hughes WT et al.; Pneumocystis carinii pneumonitis was effectively prevented in 90% of immunosuppressed rats by the administration of 100 mg of erythromycin and 300 mg/kg/day of sulfisoxazole . All of the untreated control and erythromycin-treated animals developed the infection and 80% of rats given sulfisoxazole alone had the pneumonitis . A similar pattern of response occurred when the drugs were used therapeutically for rats with established P . carinii pneumonitis . The erythromycin and sulfisoxazole ratio of 1:3 was the most effective of several dose combinations tested . The established safety record from three decades of clinical use of this drug combination plus the broad spectrum of coverage for other causes of diffuse pneumonitis such as Chlamydia, Mycoplasma, and Legionella warrant further study of erythromycin-sulfisoxazole in AIDS patients.

Antimicrob Agents Chemother, 1991 Jan, 35(1), 5 - 9
Rifampin resistance of Legionella pneumophila is not increased during therapy for experimental Legionnaires disease: study of rifampin resistance using a guinea pig model of Legionnaires disease; Edelstein PH; Isolates of Legionella pneumophila serogroup 1, obtained from guinea pigs with experimentally induced Legionnaires disease, were tested for rifampin resistance . Thirteen isolates were from animals treated with rifampin alone, four isolates were from animals treated with saline, and three isolates each were from animals treated with erythromycin or erythromycin plus rifampin; all of these isolates were derived from the same parent strain, F889 . Most of the isolates were obtained from rifampin-treated animals that survived infection but had persistence of bacteria in their lungs at necropsy . No differences in rifampin agar dilution MICs were detected for the 23 isolates and parent strain that were tested . None of the 13 isolates from animals treated with rifampin alone had a high number of resistant organisms detected by using a rifampin gradient plate assay . Thirteen isolates plus the parent strain were tested by using a quantitative method of determining resistance frequency . Considerable heterogeneity among isolates was observed, but there was no evidence of increased resistance for any treatment group . The range of rifampin resistance frequencies was 10(-7) to 10(-8) . No evidence for rifampin-induced resistance of L . pneumophila was found in this study.

Curr Med Res Opin, 1991, 12(5), 296 - 303
Antipyretic effects of nimesulide in paediatric practice: a double-blind study; Lecomte J et al.; A double-blind, multi-centre study was carried out in 42 hospitalized children, aged 6 months to 8 years, suffering from acute respiratory tract infections with fever, to investigate the antipyretic activity of nimesulide . On entry, patients were allocated at random to receive either nimesulide oral suspension, 5 mg/kg/day divided into 3 daily doses, for 5 days or placebo . Both groups were treated simultaneously with antibiotics: children under 5 years of age received 100 mg amoxycillin/kg/day, those over 5 years received 40 to 50 mg erythromycin/kg/day . Measurements of rectal temperature before and during the 6 hours after the first dose of nimesulide showed a significant mean decrease from a baseline value of 38.89 +/- 0.74 degrees C to 37.28 +/- 0.76 degrees C at 6 hours . In the placebo group, no significant changes were observed between baseline (38.82 +/- 0.67 degrees C) and the 6-hour value (38.28 +/- 1 degree C) . Morning temperatures remained within the normal range on the following days . Nimesulide was well tolerated . The results indicate that nimesulide has a prompt antipyretic effect which may well be clinically helpful before the correct antibiotic therapy is effectively established.

Diabetes Care, 1991 Jan, 14(1), 65 - 8
Effect of motilin on gastric emptying in patients with diabetic gastroparesis; Schmid R et al.; OBJECTIVES: Because disturbances of gastric emptying are a serious complication in insulin-dependent diabetic subjects with regard to the maintenance of good metabolic control, we wanted to assess the effectiveness of motilin as a potential treatment for gastric emptying disturbances . RESEARCH DESIGN AND METHODS: The intestinal hormone motilin has been shown to accelerate gastric emptying in healthy subjects . Therefore, we examined the effect of intravenous motilin on gastric emptying of a 99mTc colloid-labeled semisolid test meal in 9 insulin-dependent diabetic patients with diabetic gastroparesis . All patients had a significantly delayed gastric emptying rate compared with a group of 11 healthy control subjects . RESULTS: During the infusion of motilin, gastric emptying was accelerated, and it was no longer significantly different from control values . CONCLUSIONS: These data demonstrate that motilin and related compounds such as erythromycin derivatives could be useful for the treatment of disturbed gastric emptying in diabetic subjects.

Am J Surg, 1991 Jan, 161(1), 31 - 4; discussion 34-5
Erythromycin enhances delayed gastric emptying in dogs after Roux-Y antrectomy; Carlson RG et al.; Delayed gastric emptying occurs in up to 50% of patients after truncal vagotomy and Roux-Y antrectomy and is often resistant to nonsurgical therapy . This study evaluates the effect of erythromycin, metoclopramide, and motilin on delayed gastric emptying in four dogs after Roux-Y antrectomy . Solid food gastric emptying was measured using a radionuclide technique . Study groups were: (1) saline control; (2) erythromycin 1 mg/kg intravenously over 1 hour; (3) erythromycin 3 mg/kg by mouth 45 minutes prior to feeding; (4) metoclopramide 0.6 mg/kg intravenously over 1 hour; and (5) motilin 500 ng/kg intravenously over 1 hour . After Roux-Y antrectomy, saline control dogs had 73% +/- 5% (SEM) gastric retention at 2 hours . After intravenous and oral erythromycin, gastric emptying improved at 2 hours to 27% +/- 6% and 39% +/- 5% (p less than 0.01 compared with control) . Erythromycin intravenously and by mouth improved gastric emptying compared with metoclopramide (64% +/- 8%, p less than 0.05) . Motilin enhanced gastric emptying to a similar degree as erythromycin, with a 2-hour gastric retention of 37% +/- 4% (NS) . Erythromycin improved gastric emptying in dogs with severe Roux-Y gastroparesis and may have clinical application.

Vet Hum Toxicol, 1991, 33 Suppl 1, 49 - 53
Oral and injectable applications of erythromycin in salmonid fish culture; Moffitt CM; Erythromycin is a macrolide antibiotic effective against Renibacterium salmoninarum, causative agent of bacterial kidney disease in salmonids . Although erythromycin is used on an experimental basis in private and conservation hatcheries, the drug is not registered with the US Food and Drug Administration for use in fish culture . Residues of erythromycin are retained in the tissues of juvenile and adult salmon for some time following administration of oral or injectable forms of the drug, a characteristic that may be important in the drug's efficacy against the slow growing R . salmoninarum pathogen . Before erythromycin can be registered, additional information must be collected about efficacy, toxicity, and environmental consequences of administration.

J Hyg Epidemiol Microbiol Immunol, 1991, 35(1), 27 - 34
On the clinical importance of Dientamoeba fragilis infections in childhood; Preiss U et al.; Clinical and laboratory findings among 123 paediatric patients infected by intestinal protozoa were analysed . Dientamoeba fragilis (D . f) was found in 102 cases . The other patients proved to be carriers of Giardia lamblia or of mixed infections with several protozoa . Acute and recurrent diarrhoea have been found to be the most common symptoms, whereas abdominal pain was most common in children with chronic infections . Peripheral blood eosinophilia was seen in a third of the children with dientamoebiasis . Metronidazole, oxytetracycline, doxycycline, and erythromycin were effective drugs in the treatment of D . f . infections . The therapy coincidentally led to the elimination of protozoal infections as well as the abdominal complaints . These results underline the pathogenic role of D . f . in children with gastrointestinal symptoms.

Scand J Infect Dis, 1991, 23(2), 159 - 62
Erythromycin for treatment of ornithosis; Hammers-Berggren S et al.; Patients with pneumonia not responding to treatment with betalactam drugs and patients where an "atypical" etiology is suspected from the beginning, are often given erythromycin to cover mycoplasma and legionella . Erythromycin has also been effective for Chlamydia pneumoniae . If, however, ornithosis is suspected the recommended drug has been tetracycline . Since we noted that several patients had a favourable course on erythromycin despite a final serological diagnosis of ornithosis, we retrospectively studied patients admitted with acute lower respiratory tract infection and a 4-fold titer rise to C . psittaci . We found 35 patients treated with a betalactam drug (n = 12), tetracycline (n = 2), or erythromycin (n = 5) alone, or with a betalactam, which because of non-responsiveness was followed by either tetracycline (n = 4) or erythromycin (n = 12) . The data were analysed with survival analysis by a Cox' regression model . There was a significant (p less than 0.001) effect of treatment on the time to defervescence, mainly due to a difference between the erythromycin treated group and the betalactam treated group . We found erythromycin to be at least as effective as tetracycline for treating C . psittaci pneumonia . Since erythromycin has to be used to cover legionella in patients with severe pneumonia when an atypical etiology cannot be excluded, it is an important conclusion that this drug seems to cover C . psittaci as well.

Australas J Dermatol, 1991, 32(1), 51 - 4
An open study of Triphasil and Diane 50 in the treatment of acne; Wishart JM; Levonorgestrel, as used in oral contraceptives, has antiovulatory activity at doses far lower than those producing androgenic effects . Triphasil, containing levonorgestrel was compared with Diane, containing cyproterone acetate in a trial of acne treatment . Twenty closely matched patients were alternatively allocated to 6 months of Triphasil or Diane treatment . Both groups had a 72% reduction in acne counts . Assays of total testosterone, androgen index, free testosterone, dehydroepiandrosterone sulphate and androstenedione showed significant reduction on treatment and sex hormone binding globulin was raised . All hormonal changes were more marked in the Diane group . Side effects caused only one withdrawal from the trialPIP: A comparison of the triphasic Triphasil and the combined oral contraceptive Diane 50 for treatment of acne for 6 cycles showed significant improvement in both groups . Triphasil (Wyeth-Ayerst) contains 50 mcg levonorgestrel and 30 mcg ethinyl estradiol, 75 mcg levonorgestrel and 40 mcg ethinyl estradiol for 5 days and 125 mcg levonorgestrel and 30 mcg ethinyl estradiol for 10 days . Diane 50 (Schering Ag) contains 2 mg cyproterone acetate and 50 mcg ethinyl estradiol for 21 days per cycle . 10 women in each group had physical, pelvic, ophthalmologic and neurologic exams, hematologic and biochemical screens, assays of free testosterone, sex hormone binding globulin (SHBG), androstenedione, dehydroepiandrosterone SO4 (DHEAS), progesterone, and computations of acne and hirsutism scores . Subjects had used tetracyclines, isotretinoin, erythromycin, topical clindamycin and benzoyl peroxide previously, but were withdrawn from medication in the cycle before the intervention . The mean acne scores, derived from grading and counting lesions and comedones, fell from 63.3 to 6 in the Diane 50 and from 64.2 to 4.5 in the Triphasil group . Subjective results were excellent for 6, good for 2 and unsatisfactory for 2 in the Diane 50 group, and excellent for 8 and good for 2 in the Triphasil group . In both groups mean free testosterone, androgen index, androstenedione and DHEAS, and an increase in SHBG were documented . 5 Triphasil and 5 Diane 50 subjects had increased cholesterol levels during the trial, the only abnormality detected . Side effects reported were recurrence of varicose veins and hemorrhoids in 1 women who withdrew, and complaints of mastalgia, nausea, dysmenorrhea, migraine, headache, backache and vaginal discharge .

Allergy, 1991 Jan, 46(1), 77 - 8
Fixed eruption due to erythromycin . A case report; Florido Lopez JF et al.; A case of fixed eruption due to erythromycin is reported . To our knowledge, there have been only two previous descriptions . Cross-sensitivity with other macrolides were not demonstrated.

Eur J Drug Metab Pharmacokinet, 1991, Spec No 3, 458 - 65
Use of human and animal liver microsomes in drug metabolic studies; Lacarelle B et al.; A bank of readily available well-characterized human and animal hepatic microsomal fractions has been established . By using these "in vitro" models, we evidenced large interspecies variabilities for various compounds including digoxin, minaprine and two vincaalkaloids (navelbine, vinblastine) . Therefore, extrapolation from animal to human appeared limited and we focused our interest on human liver microsomes . Enzymatic characteristics of human microsomes from 35 different livers were determined using specific monooxygenase (i.e . erythromycin, aniline, aminopyrin...) and UDP-glucuronosyltransferase substrates (i.e . p-nitrophenol, monodigitoxoside digitoxigenin...) . A wide variability was thus ascertained between individual for both phase I and phase II metabolic processes . Microsomal fractions were also shown to be of great interest for assessing the P450 cytochrome isoform(s) involved in the biotransformation of a given drug . For instance, using inhibitory experiments, we showed the implication of P450IID in minaprine metabolism . We also demonstrated that P450IIIA is probably involved in vindesine biotransformation . Drug metabolic interactions between cyclosporin A and macrolides were studied using the same model . These results demonstrating that erythromycin is a much more potent inhibitor of cyclosporin A biotransformation than spiramycin, agree closely with "in vivo" data . In conclusion, liver microsomes are powerful tools in studying: i) interspecies and interindividual variabilities, ii) metabolic drug interactions.

Eur J Drug Metab Pharmacokinet, 1991, Spec No 3, 321 - 3
Age dependence of erythromycin rectal bioavailability in children; Stratchunsky LS et al.; Erythromycin pharmacokinetics was studied in neonates (less than 1 month), infants (1-12 months) and other children (1-12 years) after the drug rectal and intravenous administration . The areas under the erythromycin serum concentration-time curves (AUC) were practically independent on children's age following the intravenous drug administration, but not its rectal administration . There was a distinct age dependency of the AUC parameter in the latter case . The increase of children's age was resulted in enhancement of the erythromycin total clearance, reduction of the steady-state volume of distribution and of the mean residence time . The extent of absolute bioavailability of rectally administered erythromycin was increased from 28 per cent in neonates to 36 per cent in infants and to 54 per cent in children greater than 1 year . Alteration of the mean absorption time parameter was reflected the delayed absorption of erythromycin in neonates.

J Pharm Biomed Anal, 1991, 9(7), 547 - 55
Quantitative analysis of erythromycin by reversed-phase liquid chromatography using column-switching; Cachet T et al.; A column-switching technique is described for LC of erythromycin . The method allows, in about 1 h, the separation of erythromycin A from all its known potential impurities, except erythromycin D, which is a minor impurity . The switching technique combines two columns (7.5 cm x 4.6 mm and 25.0 cm x 4.6 mm) both packed with RSil C 18 LL 10 microns . The mobile phase is acetonitrile-tetrabutylammonium sulphate (0.2 M, pH 6.0)-ammonium phosphate buffer (0.2 M, pH 6.0)-water (24:5:5:66, v/v/v/v) . Temperature was 35 degrees C, flow rate was 1.5 ml min-1, detection was by UV at 210 nm . Results for a number of commercial samples of various origin are reported.

Eur J Clin Pharmacol, 1991, 41(6), 573 - 8
In vitro forecasting of drugs which may interfere with the biotransformation of midazolam; Gascon MP et al.; The biotransformation of midazolam is mediated by a cytochrome P-450 isozyme (P-450 IIIA) whose activity is highly variable . The kinetics of the 1'- and 4-hydroxylation of midazolam, the major routes of midazolam oxidation, by human liver microsomes have been examined to characterize further the cytochrome isozyme(s) catalysing these reactions, and to screen for drugs that might interfere with them . In hepatic microsomal preparation from two kidney donors (extensive and poor metabolisers of debrisoquine) KM values for 1'-hydroxylation were 4.2 and 6.1 microM (extensive and poor metabolisers, respectively), and for the 4-hydroxylation they were 14.7 and 18.1 microM, respectively . The corresponding Vmax values were 25.8 and 29.8 and 17.0 and 18.1 nmol.mg P-1.h-1 . Both reactions appeared to be catalysed by the same or by coregulated isozymes . Midazolam hydroxylations in vitro are inhibited by many drugs, including nifedipine and other dihydropyridine-type calcium channel blockers, ergot alkaloids, cyclosporine, erythromycin and phenothiazine-type neuroleptics . A clinical case report illustrates the consequence of such a drug-drug interference with hepatic biotransformation; midazolam-induced sleep in a patient lasted for 6 days (t1/2 = 25 h).

Rev Pneumol Clin, 1991, 47(5), 214 - 6
{Pneumococcal pneumonia resistant to penicillin}; Garrait V et al.; The authors report a case of community-acquired pneumonia in a patient with chronic obstructive lung disease . The initial antibiotic therapy consisted of an amoxicillin-clavulanic acid combination and intravenous macrolides . Twenty-four hours after admission, blood cultures were positive for pneumococcus . Pending the results of disc sensitivity tests, the antibiotic therapy was modified and amoxicillin alone was prescribed . Clinical deterioration then developed rapidly, as the pathogen was amoxicillin-resistant . Subsequently, the patient recovered under erythromycin therapy . As illustrated by this case, the emergence of pneumococci resistant, or showing low sensitivity to penicillins raises the problem of the antibiotic therapy to be used against community-acquired lung diseases.

Rev Pneumol Clin, 1991, 47(2), 92 - 4
{Access of torsades de pointes in Legionnaires' disease: an uncommon adverse effect of erythromycin}; Staikowsky F et al.; We report the case of a 77-year-old man with legionnaires's disease who, immediately after an intravenous infusion of one gram of erythromycin presented with wave burst arrhythmia with widening of the QT space . The blood level of erythromycin at the time of this adverse reaction was the same as the peak observed in young subjects after intravenous administration of this drug . Fourteen similar cases were found in the literature . In vitro and in vivo studies have shown that erythromycin may exert on the cardiac muscle fibres an electrophysiological effect similar to that of class I antiarrhythmic agents.

Clin Pharmacokinet, 1991 Jan, 20(1), 66 - 80
Pharmacokinetic interactions between theophylline and other medication (Part I); Upton RA; Many drugs have been found to increase or decrease the clearance of theophylline, probably by interaction with one or more of the variants of the cytochrome P450 drug-metabolising system . Theophylline may be particularly susceptible to alteration of its clearance because of the particular form(s) of the P450 system involved, because its metabolism is saturable, and/or because 90% of its elimination is via metabolism . Its clearance has been found to be decreased (typically by around 25%, but often by far more) by erythromycin, troleandomycin (triacetyloleandomycin), roxithromycin, enoxacin, ciprofloxacin, pefloxacin, norfloxacin, ofloxacin, fluoroquinolone T-3262, pipemidic acid, cimetidine, etintidine, propranolol, verapamil, diltiazem, nifedipine, furosemide (frusemide), at least some anovulent agents, viloxazine, allopurinol, ticlopidine, idrocilamide, thiabendazole, disulfiram, influenza- and BCG-vaccination, interferon, and caffeine (half-life increase) . In contrast, theophylline clearance (clearance/bioavailability) was found to be increased by isoprenaline (isoproterenol), terbutaline, some corticosteroids, phenytoin, phenobarbital, activated charcoal, felodipine moricizine, benzodiazepines and sulfinpyrazone - typically by about 25%, but sometimes by as much as 80% or more . For several of these concomitant medications, however, only some of the published studies can substantiate an influence, which may highlight the sensitivity of some interactions to particular experimental and/or clinical conditions, e.g . with terbutaline, erythromycin, ciprofloxacin, norfloxacin, ofloxacin, phenobarbital, cimetidine, verapamil, diltiazem, nifedipine, anovulents, allopurinol and influenza vaccination . Moreover, reports both of inhibition and of induction of theophylline clearance by each of rifampicin and isoniazid have appeared . Nevertheless, under investigation many medications have not been found to perceptibly influence theophylline disposition kinetics, e.g . ephedrine, orciprenaline (metaproterenol), prednisone, prednisolone, temelastine, terfenadine, mequitazine, picumast, repirinast, josamycin, midecamycin, miocamycin, spiramycin, amoxicillin, ampicillin, cefalexin, cefaclor, ceftibuten, cotrimoxazole (trimethoprim plus sulfamethoxazole), tetracycline, doxycycline, lomefloxacin, fluoroquinolones NY-198 and AM-833, nalidixic acid, lincomycin, metronidazole, certain antacids, ranitidine, roxatidine, pirenzepine, rioprostil, metoclopramide, metoprolol, atenolol, nadolol, medroxyprogesterone, dextropropoxyphene (propoxyphene), piroxicam, ozagrel, mebendazole and ascorbic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

J Vet Pharmacol Ther, 1990 Dec, 13(4), 356 - 60
Pharmacokinetics and bioavailability of erythromycin in pigeons (Columba livia); Vanhaecke E et al.; Tissue and plasma concentrations were determined after intravenous and oral administration of erythromycin to pigeons to establish the pharmacokinetics and bioavailability of the drug . A short mean half-life of elimination of 0.9 h was found . The relative bioavailability after direct crop administration of erythromycin thiocyanate or erythromycin ethylsuccinate at a dosage rate of 100 mg/kg was less than 10% . At a drug concentration in drinking water of 1 g/l, erythromycin plasma levels were barely detectable, whilst lung and trachea concentrations reached a maximum of 1.6 micrograms/ml . Even after crop administration of 100-mg/kg erythromycin thiocyanate, low plasma levels were obtained, whilst lung and trachea concentrations were substantially higher . Prescribed drinking-water regimens seemed unable to yield therapeutic tissue concentrations . Only individual crop administration seemed an appropriate medication method . The use of erythromycin ethylsuccinate did not present any advantage in comparison with erythromycin thiocyanate.

J Vet Pharmacol Ther, 1990 Dec, 13(4), 340 - 9
The development of drug-metabolizing enzymes in female sheep livers; Kaddouri M et al.; The purpose of this investigation was to determine age-related changes of some hepatic drug-metabolizing activities in Lacaune ewes in the foetal, neonatal (1 and 4 weeks), growing (7 months), pregnant (11 months) and adult (6 years) stages . Although microsomal cytochrome P-450 was not detected in 3-month-old foetuses, it increased regularly from 1-week- to 11-month-old animals . Among mixed-function oxidases, the development of aminopyrine and ethylmorphine N-demethylases, benzo(alpha)pyrene hydroxylase and ethoxycoumarin O-deethylase were correlated to that of total cytochrome P-450 . Due to their presence in foetal liver or their more rapid evolution, cytochrome b5, NADPH cytochrome c reductase, aniline hydroxylase, benzphetamine N-demethylase and erythromycin N-demethylase did not parallel the ontogenesis of cytochrome P-450 . Hepatic transferases showed different developmental patterns from mono-oxygenases, so UDP glucuronyltransferase was detected in the foetus, reached maximum activity in all young ages up to the pregnant stage and subsequently fell in adult ewes . Concerning glutathione S-transferase accepting 1-chloro-2,4-dinitrobenzene as substrate, similar values were obtained in the foetus and all young animals, whereas five- to tenfold higher values were obtained in both pregnant and adult female sheep . N-acetyltransferase using sulphamethazine did not significantly change from foetuses to adults but there were large differences in the capacity of hepatic acetylation between animals belonging to the same group.

Hepatology, 1990 Dec, 12(6), 1371 - 8
Differential regulation of liver P-450III cytochromes in choline-deficient rats: implications for the erythromycin breath test as a parameter of liver function; Kolars JC et al.; Progressive liver fibrosis in rats develops when they are fed a diet deficient in choline . This diet also results in a pronounced and selective decrease in the liver microsomal content of a phase I drug-metabolizing enzyme belonging to the cytochrome P-450III gene family . Because P-450III cytochromes characteristically catalyze the N-demethylation of erythromycin, we believed that the production of breath CO2 from erythromycin would be dramatically reduced in choline-deficient rats . However, when 12 choline-deficient rats were compared with 9 control rats, the reduction in CO2 production from erythromycin (mean decrease 71%) was essentially identical to that from aminopyrine (mean decrease 69%), a substrate believed to be metabolized normally by the hepatocyte in fibrotic liver disease . Furthermore, we found that the relative erythromycin and aminopyrine demethylase activities were comparable when measured in vitro in liver microsomes prepared from the choline-deficient rats . To determine the molecular basis for the erythromycin demethylase activity in the choline-deficient rats, the liver microsomes were subjected to immunoblot analysis using a variety of polyclonal and monoclonal antibodies capable of distinguishing individual P-450III-related proteins . Our studies confirm that a major erythromycin demethylase belonging to the P-450III family, termed P-450p, was greatly reduced in the choline-deficient rat liver . However, the specific concentration of a second P-450p-related protein was essentially normal and that of a third P-450p-related protein was actually increased in the choline-deficient rat liver.(ABSTRACT TRUNCATED AT 250 WORDS)

J Infect Dis, 1990 Dec, 162(6), 1390 - 2
Transmission of Chlamydia pneumoniae in young children in a Japanese family; Yamazaki T et al.; Chlamydia pneumoniae strain TWAR was isolated from the respiratory tract of a 5-year-old girl suffering from pneumonia . The IgM and IgG antibody titers to TWAR were 1:32 and 1:128, respectively . Cultures and serology for other common bacterial and viral respiratory pathogens were negative . Although she was treated with 35 mg/kg/day rokitamycin, TWAR was repeatedly isolated after treatment . Her 3-year-old sister developed acute bronchitis, and TWAR was isolated from her nasopharynx . She was treated with 43 mg/kg/day erythromycin with prompt improvement, and TWAR was not isolated after treatment . Although her mother, grandmother, and 8-month-old sister suffered from respiratory illness during these periods, TWAR was not isolated from them . The repeated isolations from the index patient suggest that infection was transmitted from sister to sister . This case represents the first reported isolation of TWAR from young children in the same household and the first from Japan.

Zh Mikrobiol Epidemiol Immunobiol, 1990 Dec, (12), 26 - 30
{The clinical picture of legionnaires' disease}; Dukart VM et al.; The results of the clinico-laboratory study of 12 cases of acute pneumonia of Legionella etiology are presented . The laboratory diagnosis of Legionella infection was carried out by the study of paired sera in the passive hemagglutination test with the use of Legionella pneumophila (serotype 1) erythrocyte diagnosticum . The clinical picture of pneumonia was characterized by a severe and moderate course of the disease . Characteristic symptoms indicating the presence of indurations and infiltrations in the lung tissue were registered . Roentgenological examination revealed that the foci of pulmonary tissue infiltration appeared in the segments of the lower lobes of both lungs . In 6 patients neutrophil leukopenia, in 4 patients relative lymphocytopenia, in 5 patients monocytopenia, in 11 patients the increase of the erythrocyte sedimentation rate and in 4 patients normochromic anemia were registered . More seldom changes in the levels of residual nitrogen, urea, fibrinogen and transaminases were observed . In most cases the resolution of pneumonia was observed on weeks 2-3 of treatment . In this treatment erythromycin, rifampicin and oleandomycin, used in combination, used in combination with detoxication and infusion therapy, vitamins, vascular and other symptomatic remedies, proved to be most effective . The cases of Legionella infection under study were sporadic and epidemiologically unrelated . The severity of the course of the disease depended mainly on the general state of the patient prior to infection, age and concomitant diseases.

Antibiot Khimioter, 1990 Dec, 35(12), 3 - 7
{Cloning of clusters of erythromycin biosynthesis genes of Streptomyces erythraeus (Saccharopolyspora erythraea)}; Ukhabotina LS et al.; The erythromycin resistance gene (ermE) and part of erythromycin biosynthesis genes located in the same cluster with the ermE gene were cloned from S . erythraeus 3 subjected to improvement with respect to erythromycin production . For isolating the erythromycin biosynthesis genes, the plasmid vector pUC18 and the phage vector lambda EMBL3 were used . The ermE gene DNA was used as a labeled probe for analysis of the recombinant plasmids and phages . The recombinant phages lambda ermE1 and ermE4 containing fragments of the chromosomal DNA collinear to the genome DNA of S . erythraeus 3 were analyzed . The size of the cloned fragment of the chromosomal DNA of S . erythraeus 3 was about 20 kb . Subcloning with the vector pUS18 resulted in isolation of plasmids pSU235-pSU244 containing BamHI fragments of chromosomal DNA from S . erythraeus 3 . The restriction map of the chromosomal region of S . erythraeus 3 containing the ermE gene was constructed . The cloned genes of erythromycin biosynthesis are useful in the study of their structure and functions, construction of integrative vectors, improvement of cultures producing macrolide antibiotics and isolation of genes responsible for biosynthesis of other polyketide antibiotics.

Semin Respir Infect, 1990 Dec, 5(4), 295 - 302
Treatment of pneumonia in the elderly: pharmacological considerations; Gray J; Aging is associated with a number of physiological changes, including alterations in body mass, changes in organ blood flow, and reductions in renal function . The use of any drug in an older patient requires a knowledge of the effect of these physiological changes on the pharmacokinetics of that drug . Drugs with high renal clearance, such as penicillins and aminoglycosides, have a longer half-life in elderly patients . Erythromycin and ciprofloxacin, antibiotics that use both hepatic and renal clearance, require little or no dosage adjustment when used in older patients . Side effects and drug interactions occur much more commonly in older individuals and those antibiotics used in the management of pneumonia in the elderly are reviewed in detail.

Minerva Pediatr, 1990 Dec, 42(12), 515 - 30
{Childhood sinusitis . A description and comments based on a 10-year series of cases}; De Pra M et al.; Following a review of the embryology, evolution, anatomy and physiopathology of the paranasal naso-sinus apparatus, the paper briefly describes the history of pathological studies in this area . The main clinical symptoms connected to infantile sinusal pathologies are outlined and, on the basis of a series of 1982 affected subjects (16.45% of subjects studied), the frequency of these diseases is underlined together with the net prevalence of maxillary sinusal involvement in childhood, as is confirmed by data published in pediatric literature . After having described the pathogenesis, clinical symptoms and the possibilities of prophylaxis, the paper discusses a successful therapy using: a macrolide (erythromycin); a drug with a mixed action on the synthesis and composition of mucus and on the permeability of the mucosa (ambroxol); and a true mucolytic compound (acetylcysteine) . The cost/benefit ratio of this treatment is advantageous compared to other immunomodulating treatments . In conclusion, the paper suggests a careful search for this pathology among the recurrent respiratory infections, using the therapeutic protocol described in the event of sinusal infection, and reserving the use of immunomodulating drugs for those cases which do not form part of this group.

Can J Physiol Pharmacol, 1990 Dec, 68(12), 1510 - 3
Influence of sex and inducer treatment on the high- and low-affinity forms of hepatic microsomal erythromycin N-demethylase in rats; Chang T et al.; To study the regulation of the multiple forms of erythromycin N-demethylase, we determined the influence of sex and inducer treatment on this mixed-function oxidase activity in adult Wistar rats injected intraperitoneally once daily for 4 days with dexamethasone, pregnenolone-16 alpha-carbonitrile, phenobarbital, or 2% Tween 80 (control) . Based on the results from a computer curve-fitting procedure (ENZFITTER) as well as Eadie-Hofstee and Lineweaver-Burk plots, at least two forms of erythromycin N-demethylase were present in control, dexamethasone, pregnenolone-16 alpha-carbonitrile, and phenobarbital-treated male rats and in control and dexamethasone-treated female rats . Only a high-affinity form was apparent in pregnenolone-16 alpha-carbonitrile and phenobarbital-treated female rats . Therefore, more than one form of erythromycin N-demethylase exists in hepatic microsomes from adult rats, depending on sex and inducer treatment . As well, at a substrate concentration commonly used in the erythromycin N-demethylase assay, the relative contribution of the high- and low-affinity forms to the enzyme activity varies with sex and inducer treatment.

Klin Med (Mosk), 1990 Dec, 68(12), 35 - 6
{Sporadic cases of Legionella pneumonia}; Shchennikov EL et al.; Clinicoroentgenological presentation of Legionella-induced pneumonia diagnosed in a pulmonological department of the Khabarovsk regional hospital is illustrated on 5 cases confirmed serologically . Sporadic legionellosis is characterized by: an acute onset simulating croupous pneumonia, a severe lingering course, ++semi-segmental type of infiltration, pleural involvement, drastic alterations of peripheral blood (leukocytosis shift to the left, accelerated ESR), resistance to penicillin, cephalosporin and aminoglycoside antibiotics in contract to erythromycin exhibiting a pronounced therapeutic effect.

Acta Ophthalmol (Copenh), 1990 Dec, 68(6), 651 - 7
Chlamydial conjunctivitis in neonates and adults . History, clinical findings and follow-up; Stenberg K et al.; This study presents data from 73 neonatal and 60 adult patients with chlamydial conjunctivitis who were studied by culture, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) tests . All patients had visited three or more doctors before the diagnosis was established . Fourteen of the adults had consulted an ophthalmological emergency unit complaining of a foreign body sensation in the eye . The symptoms started monocularly in all 133 cases, however, the fellow eye was affected after 2-7 days in 54 of the neonates and in 5-30 days in 20 of the adult patients . The duration of symptoms before the etiological diagnosis was established was 5-198 days (mean 24 and median 15 days) in the neonates and 7-120 (mean 29 and median 22 days) in the adults . The conjunctivitis was mild, moderate and severe in 7, 72 and 48 of the neonatal eyes, when the etiological diagnosis was established . The corresponding figures for severity of conjunctivitis in the adult group were 9, 57 and 14 . Nasopharyngeal colonization occurred in 56 (77%) of the children and in 35 (58%) of the adults . In the adults, only two males complained of symptoms of genital infection . In 46 (77%) adults one or more of the chlamydial diagnostic tests performed on genital samples was positive for Chlamydia trachomatis . Forty-five of the neonates were treated with erythromycin 40-50 mg per kg body weight divided in four daily doses for 14 days, while 35 of the adults were given 250 mg x 4 x 14 of erythromycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibiot Khimioter, 1990 Dec, 35(12), 18 - 21
{Genetic instability of the feature of streptomycin resistance in Streptomyces erythraeus}; Zavorotnaia SA et al.; The feature of streptomycin resistance in S . erythraeus, a culture producing erythromycin, is genetically unstable . Mutants sensitive to 0.03 mg/ml of streptomycin are formed in the initial streptomycin resistant strains at a rate of 0.04 per cent . It was shown possible to perform step-by-step selection for increasing streptomycin resistance (from 0.2 to 15 mg/ml) in the mutants producing and not producing erythromycin . The increase in the streptomycin resistance did not lead to a higher resistance to other aminoglycosides . Restriction analysis of the total DNA with the use of various endonucleases demonstrated that the increase in the resistance was not associated with amplification of DNA nucleotide sequences.

Nihon Kyobu Shikkan Gakkai Zasshi, 1990 Dec, 28(12), 1574 - 80
{Analysis of peripheral lymphocyte subsets and changes due to erythromycin therapy in patients with diffuse panbronchiolitis}; Sugiyama Y et al.; It is well known that patients with diffuse panbronchiolitis (DPB) have various immunological abnormalities . The authors evaluated the peripheral lymphocyte subsets using two-color analysis by FACS . Convening percentages of activated CD3+, CD8+, and CD4+ cells in DPB patients, all, especially that of CD8+ cell, were greater in number before therapy compared to healthy controls . After erythromycin therapy, all three parameters decreased in all patients . Therapy with other antibiotics did not obtain any effects . These results suggested that patients with DPB had some immunological hyperreactivity and that erythromycin was effective in these patients by suppressing this activity . From these results, together with the fact that DPB is a type of sino-bronchial syndrome, the possible pathogenesis of DPB was thought to be related to some immunological defect and hyperreactivity in the respiratory system.

Med Clin North Am, 1990 Nov, 74(6), 1367 - 87
Chlamydial infections; Martin DH; Chlamydia trachomatis is a unique intracellular parasite that causes a number of common sexually transmitted disease syndromes, including nongonococcal urethritis in both men and women, epididymitis in men, and pelvic inflammatory disease in women . Infants exposed at delivery are at risk for the development of conjunctivitis and pneumonia . There is strong evidence that Chlamydia is a cause of obstructive infertility and ectopic pregnancy in women . It appears that these complications result from the chronic inflammatory response and secondary scarring that are elicited by long-term asymptomatic or nearly asymptomatic fallopian tube infections . Because treatment with tetracycline, doxycycline, or erythromycin is simple, effective, and inexpensive, major efforts should be put into identifying asymptomatic young women through screening of the subpopulations at highest risk . These include sexually active adolescent women and older women who are not monogamous . Blacks are at higher risk than other ethnic groups for infection . The cost of diagnosing chlamydial infection has decreased with the introduction of new nonculture diagnostic tests . This should increase the availability of testing for screening purposes . It is critical to remember that male sex partners of infected women must be treated; otherwise all efforts to prevent long-term complications by identifying and treating asymptomatic women are doomed to failure.

South Med J, 1990 Nov, 83(11), 1363 - 4
Pleuropulmonary tularemia: successful treatment with erythromycin; Harrell RE Jr et al.; A 64-year-old man had community-acquired pneumonia that was retrospectively diagnosed as pleuropulmonary tularemia . He was successfully treated with erythromycin . We review the case and briefly discuss the literature on this point.

Eur J Clin Microbiol Infect Dis, 1990 Nov, 9(11), 838 - 41
Comparative in vitro activity of azithromycin, clarithromycin, erythromycin and lomefloxacin against Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum; Renaudin H et al.; The in vitro activity of three macrolides, azithromycin, clarithromycin and erythromycin and a new fluoroquinolone, lomefloxacin, against pathogenic mycoplasma (16 to 18 strains of Mycoplasma pneumoniae, 41 to 77 strains of Mycoplasma hominis, 65 to 104 strains of Ureaplasma urealyticum) was compared . The three macrolides were highly active against Mycoplasma pneumoniae . Clarithromycin was the most active macrolide against Ureaplasma urealyticum whereas azithromycin was somewhat more active than erythromycin against Mycoplasma hominis . Lomefloxacin was moderately active against all three mycoplasma species.

Biochemistry, 1990 Oct 2, 29(39), 9203 - 11
Affinity labeling of the virginiamycin S binding site on bacterial ribosome; Di Giambattista M et al.; Virginiamycin S (VS, a type B synergimycin) inhibits peptide bond synthesis in vitro and in vivo . The attachment of virginiamycin S to the large ribosomal subunit (50S) is competitively inhibited by erythromycin (Ery, a macrolide) and enhanced by virginiamycin M (VM, a type A synergimycin) . We have previously shown, by fluorescence energy transfer measurements, that virginiamycin S binds at the base of the central protuberance of 50S, the putative location of peptidyltransferase domain {Di Giambattista et al . (1986) Biochemistry 25, 3540-3547} . In the present work, the ribosomal protein components at the virginiamycin S binding site were affinity labeled by the N-hydroxysuccinimide ester derivative (HSE) of this antibiotic . Evidence has been provided for (a) the association constant of HSE-ribosome complex formation being similar to that of native virginiamycin S, (b) HSE binding to ribosomes being antagonized by erythromycin and enhanced by virginiamycin M, and (c) a specific linkage of HSE with a single region of 50S, with virtually no fixation to 30S . After dissociation of covalent ribosome-HSE complexes, the resulting ribosomal proteins have been fractionated by electrophoresis and blotted to nitrocellulose, and the HSE-binding proteins have been detected by an immunoenzymometric procedure . More than 80% of label was present within a double spot corresponding to proteins L18 and L22, whose Rfs were modified by the affinity-labeling reagent . It is concluded that these proteins are components of the peptidyltransferase domain of bacterial ribosomes, for which a topographical model, including the available literature data, is proposed.

Antimicrob Agents Chemother, 1990 Oct, 34(10), 2024 - 6
Detection of erythromycin resistance by the polymerase chain reaction using primers in conserved regions of erm rRNA methylase genes; Arthur M et al.; Genes belonging to different erm DNA hybridization classes were selectively amplified by polymerase chain reaction with a pair of oligonucleotides that corresponded to conserved amino acid motifs in known ERM methylases . Identification of the resistance mechanism was possible despite substantial nucleotide sequence diversity among the erythromycin resistance genes.

J Antibiot (Tokyo), 1990 Oct, 43(10), 1271 - 7
Epimerization of erythromycin derivatives; Firl J et al.; Dirithromycin (3) isomerizes upon dissolution in different solvents . From X-ray analysis of V-T 108, an analogue of dirithromycin, and comparative 1H and 13C NMR, and MS data, the isomer of dirithromycin was confirmed to be the C-16-(S)-epimer . The ratio of the two epimers at equilibrium conditions was approximately 8:2 (R/S) in methanol at room temperature.

Ann Neurol, 1990 Oct, 28(4), 577 - 9
Aggravation of myasthenia gravis by erythromycin; May EF et al.; Erythromycin is not currently recognized as causing clinical aggravation of myasthenia gravis . We report the case of a patient who experienced exacerbations of myasthenia gravis subsequent to each of several doses of intravenous erythromycin . We suggest that erythromycin can cause clinical worsening in patients with disease of the neuromuscular junction.

Clin Pharmacokinet, 1990 Oct, 19(4), 319 - 32
Pharmacokinetic drug interactions with cyclosporin (Part I); Yee GC et al.; This article reviews the reported pharmacokinetic interactions between cyclosporin and other drugs . Both rifampicin and the majority of anticonvulsants can decrease cyclosporin concentrations to levels that are at or below the limit of detection for most assays . There have been no reports of any interaction between valproic acid and cyclosporin . Other drugs that have been reported to decrease cyclosporin concentration include sulfadimidine and trimethoprim, nafcillin and octreotide . Erythromycin, ketoconazole and some calcium channel blockers have been clearly shown to increase the concentration of cyclosporin . Other less well documented interactions have been reported with other macrolide antibiotics, other azole antifungal drugs, high dose methylprednisolone, metoclopramide, fluoroquinolones, imipenem/cilastatin, oral contraceptives/danazol, sulindac, methyltestosterone, colchicine, acetazolamide, alcohol and cimetidine . Although the most commonly reported mechanism is inhibition of cyclosporin metabolism, there is increasing evidence that erythromycin, metoclopramide and probably other drugs increase the bioavailability of oral cyclosporin . Two calcium channel blockers which have not been reported to interact with cyclosporin are nifedipine and nitrendipine . With increasing use of cyclosporin, the number of drugs reported to interact will rise . Prudent clinicians should monitor the concentration of this agent more frequently when another drug is added or discontinued and cyclosporin dosage should be adjusted when appropriate . Sustained changes in cyclosporin concentration can result in graft rejection (or graft-versus-host disease) or renal toxicity . Further studies are needed to determine the mechanism of most of these interactions.

Mol Gen Genet, 1990 Oct, 224(1), 65 - 71
Transposition of IS117 (the Streptomyces coelicolor A 3 (2) mini-circle) to and from a cloned target site and into secondary chromosomal sites; Henderson DJ et al.; IS117, previously known as the 2.6 kb mini-circle, is a transposable element found in Streptomyces coelicolor A 3(2) . It integrates predominantly into one preferred site when introduced into the closely related Streptomyces lividans 66, which lacks IS117 . This preferred integration site was deleted from the S . lividans chromosome by replacement with an erythromycin resistance gene delivered by a phi C31 phage vector . When IS117 was introduced into the resulting strain it integrated into many other sites, with some indication of site preference . By cloning a 200 bp fragment centred on the preferred integration site onto a low copy number, self-transmissible Streptomyces plasmid derived from SCP2* it was shown that this sequence is sufficient to define the preferred site: IS117 integrates efficiently into this sequence from its preferred site in the host chromosome and at a lower frequency from the plasmid into the preferred site on the S . lividans chromosome.

J Antimicrob Chemother, 1990 Oct, 26(4), 503 - 13
Uptake of clarithromycin by rat lung cells; Kohno Y et al.; To evaluate the affinity of clarithromycin (6-O-methylerythromycin A) for lung tissue, the in-vivo and in-vitro uptake of {14C}clarithromycin and {14C}erythromycin by rat lung cells was compared, and the characteristics of the uptake mechanism were investigated . After the administration into the external jugular vein of rats, clarithromycin was found in much higher concentrations in the lung tissue than erythromycin . In isolated lung cells, clarithromycin was also found in greater concentrations than erythromycin . The amount of clarithromycin was ten times that of erythromycin after 5 min incubation . This uptake profile was quite different from that observed in isolated liver cells . Uptake by lung cells for both antibiotics was shown to be an active process, as revealed by the need for cell viability, a suitable environmental temperature and ATP . Clarithromycin uptake proved to be dependent in part upon mitochondrial oxidative respiration . Kinetic analysis indicated that clarithromycin transport was saturable, with a relatively high binding affinity and velocity of uptake . Clarithromycin transport was significantly inhibited by 6-O-methylerythromycin analogues, but was not influenced by other analogues, including erythromycin . Competitive inhibition of clarithromycin uptake was demonstrated by 6,11,12.4"-tetra-O-methylerythromycin, one of the mutual inhibitors . These findings may suggest that clarithromycin utilizes a carrier-mediated transport system in the lung cells, which is common to 6-O-methylerythromycins . This difference of uptake mechanism between both antibiotics may account in part for the greater clarithromycin uptake by the lung cells.

Mol Pharmacol, 1990 Sep, 38(3), 319 - 26
Selective inactivation of mouse liver cytochrome P-450IIIA by cannabidiol; Bornheim LM et al.; Cannabidiol (CBD) inhibits hepatic drug metabolism in mice, particularly those activities known to be catalyzed by the cytochrome P-450IIIA (P-450IIIA) subfamily . CBD treatment (120 mg/kg) inhibited more than 75% of hepatic 6 beta-testosterone hydroxylase and erythromycin N-demethylase activities (functional markers of P-450IIIA) after 2 hr . An isozyme of the P-450IIIA subfamily (Mr 49,960) was purified to apparent homogeneity from hepatic microsomes of untreated mice and was found to catalyze testosterone hydroxylation at the 2 beta-, 6 beta-, and 15 beta-positions exclusively . Incubation of this isozyme with CBD in a reconstituted system resulted in a time- and concentration-dependent inactivation, with almost complete loss of P-450 chromophore and corresponding increase in P-420 content . NH2-terminal sequence analysis of the isozyme revealed an 86% similarity to the corresponding sequence of rat P-450IIIA2, a constitutive P-450 isozyme in the male rat liver . Pretreatment of mice with dexamethasone markedly (6-fold) increased the steroid-inducible P-450IIIA-dependent activities 6 beta-testosterone hydroxylation and erythromycin N-demethylation . CBD treatment of dexamethasone-pretreated animals failed to inhibit these activities, indicating that the steroid-inducible P-450IIIA was refractory to CBD-mediated inactivation . 3-Methylcholanthrene-inducible P-450IA and phenobarbital-inducible P-450IIB also appear to be refractory to CBD-mediated inactivation . On the other hand, erythromycin N-demethylase activity increased 4-fold after phenobarbital pretreatment and, as in untreated animals, was comparably inhibited by CBD, demonstrating its susceptibility to this drug . Thus, CBD appears to inactivate the P-450IIIA isozymes that are constitutively present in hepatic microsomes of untreated mice and/or inducible by phenobarbital pretreatment but not those that are steroid inducible.

Am J Physiol, 1990 Sep, 259(3 Pt 1), G355 - 63
Gastrointestinal motor effects of erythromycin; Otterson MF et al.; We studied the small intestinal motor effects of oral and intravenous (iv) erythromycin in 10 conscious dogs . After control recordings with placebo, oral or iv erythromycin was given at 40% of the migrating motor complex (MMC) cycle . Recordings were made after administration until normal contractile activity had returned or 12 h postdrug administration . Low doses initiated a premature MMC . High doses, however, prolonged the MMC cycle length . Erythromycin reduced the MMC propagation velocity at all doses . Both oral and iv erythromycin induced amyogenesia . During this pattern, electrical control activity was obliterated in the proximal and destabilized in the distal small intestine . Erythromycin also increased the incidence of retrograde giant contractions (RGCs) and vomiting . These effects occurred within the first 2 h after oral and within the first 30 min after iv administration . The incidence of giant migrating contractions (GMCs) increased significantly from 5 to 12 h but not from 0 to 5 h after administration . The distance of origination of GMCs from the ileocolonic junction was significantly increased from 5 to 12 h . The amplitude ratio, duration, and velocity of migration of GMCs induced after erythromycin were similar to control values . Clusters of coordinated antral and duodenal contractions also occurred early after administration . Our findings suggest that erythromycin has multiple motor effects on the stomach and small intestine . Diarrhea, abdominal cramping, and vomiting associated with erythromycin may be related to increased incidence of GMCs and RGCs . Erythromycin has a biphasic effect on MMC cycle length, initiating premature MMCs at low doses and prolonging their cycle length at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

J Pharmacol Exp Ther, 1990 Sep, 254(3), 940 - 4
EM-523, an erythromycin derivative, and motilin show similar contractile activity in isolated rabbit intestine; Satoh T et al.; The effect of EM-523 {de(N-methyl)-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal}, an erythromycin derivative, on preparations of isolated intestine of rabbits, rats and guinea pigs was investigated and compared to the effects of motilin and prostaglandin F2 alpha (PGF2 alpha) . EM-523 and motilin induced contractions in the rabbit intestinal preparations but not in the rat or guinea pig preparations . In contrast, PGF2 alpha induced contractions in all three intestinal preparations . The rabbit duodenum and jejunum were more sensitive than the ileum to EM-523 and motilin, but no selectivity was observed with PGF2 alpha . The contractile responses induced by EM-523 and by motilin were not influenced by pretreatment with tetrodotoxin, atropine, naloxone or mepyramine but were greatly suppressed by pretreatment with verapamil or removal of calcium ions from the medium, suggesting that both agents induce intestinal contractions by acting directly on smooth muscle and that their actions depend largely on extracellular calcium . The contractile response to EM-523 or motilin was reduced markedly after treatment of the preparation with a high concentration of either agent, and cross-tachyphylaxis between EM-523 and motilin was also observed . These findings indicate that the contractile activity of EM-523 is very similar to that of motilin and that EM-523 and motilin may share the same site of action.

J Pharmacol Exp Ther, 1990 Sep, 254(3), 1120 - 7
Inhibition of rat liver estrogen 2/4-hydroxylase activity by troleandomycin: comparison with erythromycin and roxithromycin; Fisher D et al.; Administration of troleandomycin (0.5 mmol.kg-1 p.o . daily for 5 days) decreased by 61% and 36%, respectively, the estradiol and ethinylestradiol 2/4-hydroxylase activities of hepatic microsomes from male Sprague-Dawley rats killed 2 hr after the last dose . This decrease did not appear to be due to the in vivo formation of the inactive cytochrome P-450 p Fe(II)-metabolite complex, since disruption of this complex with potassium ferricyanide did not increase estrogen hydroxylase activities . Troleandomycin administration, however, essentially suppressed cytochrome P-450 UT-A (one of the P-450 forms involved in the hydroxylation of estrogens) and resulted in the appearance of cytochrome P-450 forms whose estradiol hydroxylase activity was inhibitable by troleandomycin in vitro . Similarly, troleandomycin (2 mM) inhibited by 60% estradiol and ethinylestradiol 2/4-hydroxylase activities in microsomes from dexamethasone-treated rats, although it had no inhibitory effect in microsomes from control rats . In contrast, erythromycin and roxithromycin (2 mM) exerted no inhibitory effect, even in microsomes from dexamethasone-treated rats . In vivo, these macrolides (0.5 mmol.kg-1 p.o . daily for 5 days) decreased moderately cytochrome P-450 UT-A levels and estradiol 2/4-hydroxylase activity, and did not modify ethinylestradiol 2/4-hydroxylase activity . We conclude that the administration of troleandomycin, but not that of erythromycin or roxithromycin, decreases ethinylestradiol 2/4-hydroxylase activity in male rat liver microsomes, as a possible consequence of decreased cytochrome P-450 UT-A levels and of the induction of glucocorticoid-responsive P-450 forms whose ethinylestradiol hydroxylase activity is inhibitable by troleandomycin.

J Nucl Med, 1990 Sep, 31(9), 1490 - 3
Intravenous erythromycin dramatically accelerates gastric emptying in gastroparesis diabeticorum and normals and abolishes the emptying discrimination between solids and liquids; Urbain JL et al.; Erythromycin, a macrolide antibiotic, has recently been shown to have a motilin like effect on gastrointestinal muscle strips . In this study, we have evaluated the effect of erythromycin on patients with delayed gastric emptying and healthy subjects using the dual radionuclide technique . Twelve patients with gastroparesis diabeticorum and ten healthy age- and sex-matched controls were studied . Gastric emptying of solids and liquids was determined using 99mTc-SC scrambled egg and 111In-DTPA in water . Following a baseline study and on a separate day, each patient and control received a 15-min i.v . perfusion of erythromycin starting at meal ingestion . Eleven out of the 12 patients were restudied after a 3-wk oral administration . In patients and controls, i.v . erythromycin dramatically accelerated gastric emptying of both solids and liquids which were emptied at the same rate . After chronic oral administration, solid and liquid emptying remained significantly accelerated . Erythromycin appears to be a very powerful gastrokinetic drug . Derived compounds with the gastrokinetic effect and without the antibiotic activity could be useful in dyspeptic patients with delayed gastric emptying.

Gastroenterology, 1990 Sep, 99(3), 652 - 8
Development of motilin receptors and of motilin- and erythromycin-induced contractility in rabbits; Depoortere I et al.; The development of the motilin receptor was studied through contraction and binding studies of groups of three rabbits aged between 2 and 289 days . The contractility of small intestinal smooth muscle strips was measured isotonically . The aborally decreasing gradient in response to motilin, known to exist in adult rabbits, was already present at day 8 (maximum contractile responses expressed as a percent of the maximal response to acetylcholine were 77% +/- 9%, 34% +/- 10%, and 25% +/- 8% for duodenal, jejunal, and ileal strips, respectively) . Throughout the observation period, the doses of motilin and its agonist erythromycin that were required to induce 50% of the response remained constant and were not significantly different from doses required for adults (their negative logarithms were 8.55 +/- 0.35 and 5.70 +/- 0.25, respectively) . The correlation between the maximum contractile response toward motilin and erythromycin was almost perfect (r2 = 0.82) . Binding studies with iodinated norleucine13-porcine motilin were performed using antral smooth muscle tissue homogenates . The maximum number of binding sites increased rapidly after 8 days (3.3 +/- 0.4 fmol/mg protein) and reached a peak at 21 days (20.7 +/- 1.4 fmol/mg protein), but decreased at that point toward the adult value (40 days, 10.6 +/- 1.3; 289 days, 9.8 +/- 1.1 fmol/mg protein) . The dissociation constant, however, remained unchanged . The peak value of receptor density occurred at about the time that the rate of increase of the length of the intestine and of the weight of the antrum were at maximum levels (at 18 and 27 days, respectively) . Motilin receptors are expressed early postnatally, and the regional gradient in sensitivity towards motilin is also established soon after birth . If applicable to humans, an early response to erythromycin may have therapeutic value.

Yeast, 1990 Sep-Oct, 6(5), 367 - 82
The chromosomal constitution of wine strains of Saccharomyces cerevisiae; Bakalinsky AT et al.; A general procedure is described for determining the chromosomal constitution of industrial strains of Saccharomyces cerevisiae based on analysis of segregation frequencies for input markers among random spore progeny of industrial-laboratory strain hybrids . The multiply auxotrophic haploid testers used carried a dominant erythromycin-resistance marker, allowing hybrids to be selected in mass matings with spores produced by the wild-type industrial strains . Analysis of a number of independent crosses between the haploid testers and an unselected population of spores of each wine strain distinguished between disomic, trisomic and tetrasomic chromosomal complements in the parents . Possible explanations for a significant class of aberrant segregation frequencies are discussed . Results of the analysis indicate that UCD Enology 522 (Montrachet) is diploid and possibly trisomic for chromosome VII; 522X is diploid; UCD Enology 505 (California Champagne) is disomic for chromosome XVI, trisomic for chromosomes I, II, III, VI, VIII, IX, X, XII, XV, tetrasomic for chromosomes IV, XI, XIII, XIV and either trisomic or tetrasomic for chromosomes V and VII; and that UCD Enology 595 (Pasteur Champagne) is disomic for chromosomes I, II, III, IX, XVI, trisomic for chromosomes IV, VI, X, XII, XIV, XV, tetrasomic for chromosomes V, VIII, XI, XIII and either disomic or tetrasomic for chromosome VII.

J Fam Pract, 1990 Sep, 31(3), 265 - 70
Prospective comparison of patient tolerance to enteric-coated vs nonenteric-coated erythromycin; Ellsworth AJ et al.; Erythromycin base and its salts are frequently used in clinical practice . The most frequent side effects of oral erythromycin preparations are gastrointestinal . Various salts and enteric coatings have been developed without adequate comparison in regard to gastrointestinal side effects . The overall incidence of gastrointestinal side effects (abdominal pain and cramps, nausea, vomiting, diarrhea, and gas) of two common erythromycin base formulations, Erythromycin Base Filmtab (Abbott), a nonenteric-coated base tablet, and Eryc (Parke-Davis), a pelletized, encapsulated, enteric-coated base capsule, were compared in 368 adults at two dosage levels (1 g/d and 2 g/d) . Minimal differences were found when target symptoms were compared by preparation coating . In contrast, subjects receiving erythromycin at the 2-g/d dosage level reported higher incidence rates for each of the target symptoms, regardless of product coating, than did those patients treated at the 1-g/d dosage level . Enteric coating of erythromycin base offers little protection from the common dose-related gastrointestinal adverse effects of oral erythromycin.

Acta Gastroenterol Belg, 1990 Sep-Dec, 53(5-6), 523 - 31
{Pseudo-obstruction of the stomach and small intestines}; Vantrappen G et al.; The authors review the pathological classification of chronic pseudo-obstruction syndromes, the differential diagnosis of these syndromes in order to rule out an obstructive lesion, the differential diagnosis of idiopathic chronic pseudo-obstruction syndrome and systemic sclerosis, the diagnostic contribution of oesophageal manometry and of gastro-intestinal manometry and electromyography, and finally the treatment of these syndromes . The authors mention also their experience in the treatment of severe diabetic gastroparesis with erythromycin, agonist of the gastric and duodenal motilin receptors . In 10 patients compared to controls, delayed gastric emptying for solid and liquid foods was normalized after intravenous injection of 200 mg erythromycin versus placebo.

Drug Metab Dispos, 1990 Sep-Oct, 18(5), 711 - 9
Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem; Pichard L et al.; Oxidative metabolism of diltiazem (DTZ), a calcium channel blocker, was investigated in rabbit and human liver microsomes as well as in primary cultures of human hepatocytes . DTZ N-demethylation, the major metabolic pathway in man, was strongly increased by treatment of animals, patients, and hepatocyte cultures with rifampicin and other inducers of the P-450IIIA subfamily . In a reconstituted system with purified forms of P-450 and NADPH cytochrome P-450 reductase, P-450IIIA7 exhibited the highest DTZ N-demethylase activity . In both rabbit and human liver microsomes, this activity was highly correlated with erythromycin demethylase, a characteristic substrate of P-450IIIA, or with an immunoquantitated level of P-450IIIA, and was specifically inhibited by anti-P-450IIIA7 polyclonal and monoclonal antibodies . Cyclosporin A, another specific substrate of P-450IIIA in rabbit and human, competitively inhibited DTZ N-demethylase in both species . In primary cultures of human hepatocytes treated with various inducers, including rifampicin, dexamethasone, phenobarbital, phenylbutazone or beta-naphthoflavone, the rate of release of N-demethyl-DTZ in the extracellular medium was highly correlated with the intracellular level of P-450IIIA, which appeared to be strongly induced by rifampicin and phenobarbital and to a lesser extent by dexamethasone and phenylbutazone . In aggregate, these results are consistent with the view that in both rabbit and human, cytochromes P-450 from the P-450IIIA subfamily are the major enzymes involved in the N-demethylation of DTZ . Accordingly, drugs which may be specific substrates or inducers of this P-450 are likely to influence both the side effects and the efficacy of this molecule.

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