Erythromycin

Pediatr Med Chir, 1994 Mar-Apr, 16(2), 173 - 6
{Acute eosinophilic pneumonia: a case in an adolescent and a review of the literature}; Memmini G et al.; A previously healthy young girl presented with acute respiratory disease, high fever, increased number of eosinophils in peripheral white blood cells and diffuse bilateral infiltrates on chest radiograph . There was no evidence of an infectious etiology . The illness resolved rapidly after treatment with erythromycin and corticosteroids . Bronchoalveolar lavage was not performed . We believe that we are describing an acute form of eosinophilic pneumonia in adolescent.

Minerva Pediatr, 1994 Mar, 46(3), 89 - 97
{Pulmonary infections in children . I -- pneumonia due to Legionella pneumophila}; Della Santa L et al.; Pneumonia due to L . pneumophila occurs frequently in children even though "legionnaires' disease" in adults in usual . The authors show a literary scientific review of almost one hundred cases, sporadic generally, in childhood . In children legionnaires' disease remembers the adults infection, beginning with bronchiolitis . The extrarespiratory symptoms appears more frequently in adults . Chest roentgenograms obtained early reveal patchy infiltrates that become nodular areas of consolidation bilateral also, with pleural effusion . In children prognosis is poor (exitus in 15 about 97 described cases) . The infection responds to erythromycin; it is administered intravenously, but oral treatment may also be used.

J Pharmacol Exp Ther, 1994 Mar, 268(3), 1160 - 5
Cytochrome P450 3A-mediated human liver microsomal taxol 6 alpha-hydroxylation; Kumar GN et al.; The antitumor drug taxol was metabolized to one major (6 alpha-hydroxytaxol) and two minor metabolites by human liver microsomes . A 10-fold interindividual variability with a Vmax of 1.16 +/- 0.85 nmol/hr/mg of microsomal protein and a Km of 18.0 +/- 12.2 microM was observed for taxol 6 alpha-hydroxylation (mean +/- S.D.; n = 6) . The NADPH-dependency and the inhibitory effect of carbon monoxide and piperonyl butoxide on taxol metabolism indicated the involvement of cytochrome P450 (CYP) monooxygenases . Chemical inhibition studies pointed to the CYP 3A subfamily as being responsible for taxol 6 alpha-hydroxylation . However, although some CYP 3A substrates were inhibitory (midazolam, 17 alpha-ethinyl estradiol, quercetin, verapamil and testosterone), others were not (troleandomycin, erythromycin and cyclosporin A) . The inhibition was found to be competitive with low Ki values for midazolam (10.5 microM) and 17 alpha-ethinyl estradiol (4.5 microM) . Taxol 6 alpha-hydroxylation correlated well with the metabolism of 17 alpha-ethinyl estradiol (r = 0.874; P < .05) and midazolam (r = 0.954; P < .01) in the same livers . Rabbit anti-rat CYP 3A1 antibodies, which cross-react with human CYP 3A isoforms, were inhibitory of taxol 6 alpha-hydroxylation . Although the evidence from these experiments supported the CYP 3A mediation of taxol 6 alpha-hydroxylation, the lack of effect of some inhibitors combined with the inability of a human CYP 3A4 transfected cell line to metabolize taxol point to a CYP 3A isoform other than 3A4 . The findings in this study could prove clinically useful for the prediction of potential drug interactions, both inhibitory and inductive of taxol metabolism.

Dig Dis Sci, 1994 Feb, 39(2), 381 - 4
Motilin agonist erythromycin increases human lower esophageal sphincter pressure by stimulation of cholinergic nerves; Chaussade S et al.; During phases II and III of the migrating motor complex, there is an increase in plasma motilin level that is synchronous with phasic and tonic contractile activity of the lower esophageal sphincter and of the stomach . The action of motilin on human lower esophageal sphincter is proposed to be mediated by cholinergic mechanisms . Recently, it has been shown that erythromycin was a motilin agonist . This study evaluated the pharmacological effects and the mechanisms of action of intravenous erythromycin on esophageal motility in humans . Healthy volunteers were studied three times at seven-day intervals in a randomized, double-blind fashion . Subjects were first studied for 10 min before drug administration . Afterwards, they received blindly and randomly an intravenous injection of placebo or atropine (12 micrograms/kg) followed by a 20-min continuous intravenous administration of placebo or erythromycin (150 mg) . The difference (delta) between lower esophageal sphincter pressure and the duration, amplitude, and velocity of peristaltic contractions during the control period and after administration of drugs was compared . Erythromycin significantly increased (P < 0.05) the lower esophageal sphincter pressure (16.8 +/- 4.7 mm Hg) compared to placebo (-0.029 +/- 1.4 mm Hg) . Erythromycin significantly decreased peristaltic contraction velocity compared to placebo (P < 0.05) . The effects of erythromycin on lower esophageal sphincter pressure were completely blocked by previous administration of intravenous atropine . Erythromycin increased the number of fundic contractions compared to the placebo, but this effect was not blocked by the previous administration of atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Chest, 1994 Feb, 105(2), 520 - 3
Erythromycin does not directly affect neutrophil functions; Hojo M et al.; To determine whether erythromycin could affect neutrophil functions, we measured N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced chemotaxis and superoxide generation of neutrophils in the presence of erythromycin at various concentrations . Erythromycin had no effect on either of them . We further confirmed that intracellular free calcium concentration ({Ca2+}i) was not influenced by FMLP stimulation in the presence of erythromycin . Our results indicate that erythromycin has no direct effects on neutrophil functions in vitro, although it is reported that erythromycin inhibits the local migration of neutrophils in the small airways of subjects with asthma.

Chest, 1994 Feb, 105(2), 368 - 72
Torsades de pointes induced by erythromycin; Gitler B et al.; We describe two patients who develop torsades de pointes in a temporal relationship to the intravenous administration of erythromycin lactobionate in the absence of other drugs or metabolic abnormalities known to cause the arrhythmia . We also review the current literature regarding this topic, including other case histories and the evidence for erythromycin's effect on cardiac tissue . Due to the increasing use of erythromycin in clinical practice, we believe it is important that all physicians be made aware of this potential complication, which was not recognized at our institutions until these patients were seen by one of us (B.G.).

Antimicrob Agents Chemother, 1994 Feb, 38(2), 217 - 22
Azithromycin pharmacokinetics and intracellular concentrations in Legionella pneumophila-infected and uninfected guinea pigs and their alveolar macrophages; Stamler DA et al.; Azithromycin pharmacokinetics in Legionella pneumophila-infected and uninfected guinea pigs were assessed by measuring the drug concentration in whole lungs or the drug content in bronchoalveolar lavage (BAL) fluid in separate experiments . Azithromycin concentrations were measured by using a bioassay . The mean azithromycin content in the BAL fluid of infected guinea pigs was higher than that in controls at 10 h (0.87 versus 0.39 microgram; P = 0.05), 24 h (1.10 versus 0.37 microgram; P = 0.003), and 48 h (1.21 versus 0.28 microgram; P = 0.05) after a single intraperitoneal injection of drug (15 mg/kg) . The mean peak lung azithromycin concentration was higher in control animals than in infected animals (15.8 versus 13.4 micrograms/ml) . The mean lung azithromycin concentration in infected animals was significantly higher than that in controls 48 h after dosing (12.7 versus 10.4 micrograms/g; P = 0.04) . There were no significant differences between infected and uninfected animals in serum azithromycin levels . Complementary experiments assessed intracellular/extracellular concentration ratios of azithromycin and erythromycin in L . pneumophila-infected and control guinea pig alveolar macrophages . Azithromycin was highly concentrated in alveolar macrophages, and the intracellular/extracellular concentration ratios for infected cells were significantly higher (P < 0.0001) than those observed in controls after 4 h (127 versus 119), 24 h (481 versus 361), and 48 h (582 versus 520) of incubation . Erythromycin was also preferentially concentrated in infected cells (P < 0.0001) . AZ intracellular concentrations were at least fivefold higher than those measured for erythromycin, and this differential increased with incubation time . Thus, azithromycin recovery from BAL fluid, and from guinea pig lungs at the 48-h time point, was higher in the presence of experimental Legionnaires' disease . This likely results from recruitment of phagocytes, including macrophages, that have an enhanced capacity to highly concentrate the drug.

Gaoxiong Yi Xue Ke Xue Za Zhi, 1994 Feb, 10(2), 106 - 14
Intractable nontuberculous mycobacterial keratitis successfully treated by penetrating keratoplasty--3 cases report; Chang CH et al.; Since the first diagnosis of nontuberculous mycobacterial keratitis in Taiwan on 1983 by Chen et al., we have collected another 70 cases . Although most of the cases were difficult to treat medically, almost all cases healed before optical penetrating keratoplasties were performed . But, three of these cases responded poorly to medical treatment with sporadical relapse . Finally, penetrating keratoplasties (PKP) were performed on these three cases . These three cases were all males, aged 48, 27, and 35 respectively . The durations from the onset to receiving PK were 10, 4, and 6 months . All had histories of corneal trauma and all cases responded poorly or inconsistently to topical amikacin, erythromycin and antituberculous drugs . Histopathological examination of the diseased corneas in the first chronic case showed granuloma formation in the area of ulcer base . The second case presented lymphocyte clustering in the subepithelial region . The third case, which was operated in a relatively inflamed stage, had lymphocytes infiltrating the whole layer of the cornea . The results of PKP in the three eyes were therapeutically and optically successful, though the second case failed in the first penetrating keratoplasty due to acute tissue failure without recurrent infection . The best corrected visual acuities in the three eyes, postoperatively, were 20/25, 20/40, and 20/100 respectively . With the successful experience of these three cases, we suggest that performing PKP for intractable nontuberculous mycobacterial keratitis at an early stage may reduce the duration of the patients' suffering.

Nihon Kyobu Shikkan Gakkai Zasshi, 1994 Feb, 32(2), 138 - 45
{A clinical study of fulminant Legionnaires' disease}; Takada N et al.; Seven cases of fulminant Legionnaires' disease treated at Kitasato University Hospital between 1985 and 1992 were reviewed . These patients were male with a mean age of 55.9 years (range, 37-67 yrs), and five were heavy alcohol drinkers . All seven patients required mechanical ventilation . Four patients recovered (group 1) and three expired due to respiratory failure (group 2) . The mean interval from initial symptoms to the development of respiratory failure was 8.8 days in group 1 and 6.0 days in group 2, except in the one patient with lung cancer (case 6) . The progression of pneumonia was more rapid in group 2 . The mean intervals from admission to administration of erythromycin were 1.5 days and 3.5 days, respectively, in groups 1 and 2 . In group 1, pulmonary infiltrates and respiratory insufficiency worsened for the first few days after erythromycin administration but improved thereafter . The average duration of ventilatory care in group 1 was 13.3 days . The administration of rifampicin combined with erythromycin may be useful for the treatment of fulminant Legionnaires' disease . When fulminant pneumonia is encountered in a middle-aged or elderly male alcoholic, Legionnaires' disease should be suspected and erythromycin administration with rifampicin should be initiated as early as possible.

Kansenshogaku Zasshi, 1994 Feb, 68(2), 209 - 16
{Mechanism of efficacy of erythromycin on diffuse panbronchiolitis--effect of erythromycin on cytokine mRNA expression in human whole blood model}; Akiyoshi H et al.; Recently, "low-dose and long-term" erythromycin (EM) has been reported to be effective in treatment of diffuse panbronchiolitis (DPB), but its mechanism is still obscure . We studied the effect of EM on cytokine mRNA expression by using LPS-stimulated human whole blood as an experimental vivo model . IL-8 mRNA was expressed in biphasic fashion with peak expression at 6 hours and 20 hours from the start of LPS stimulation . When whole blood was pretreated with EM (2 micrograms/ml) for 1 hours . IL-8 mRNA expression was depressed at 20 hours (p < 0.025) from the start of LPS (1 microgram/ml) stimulation . However, when pretreated for 12 hours, it was not depressed . EM (2 micrograms/ml) also depressed IL-1 beta (p < 0.025) and TNF alpha (p < 0.05) mRNA expressions at 6 hours from the start of LPS stimulation . From the above results, it was suggested that the direct inhibition of IL-1 beta and TNF alpha production by EM resulted in subsequent depression of production of IL-8 that is a potent chemotactic factor for neutrophil, and consequently, EM acts to protect the bronchiole tissues of DPB patients from destruction by proteolytic enzymes released from neutrophils . This assumption seems to be supported by our previous observation that when patients with DPB were treated with EM a marked decrease in number of neutrophil in bronchoalveolar lavage fluid (BALF) was accompanied by clinical and radiographic improvement.

Arch Pediatr Adolesc Med, 1994 Feb, 148(2), 153 - 7
Outbreak of pertussis in a fully immunized adolescent and adult population; Mink CA et al.; OBJECTIVE: To evaluate the spread of pertussis in a fully immunized eighth-grade class and the household contacts of two coindex cases of pertussis . DESIGN: Survey of infected subjects and their contacts was performed using culture, direct fluorescent antibody assay, and serological assays to establish the diagnosis of Bordetella pertussis . SETTING: Middle-class parochial school . PARTICIPANTS: A volunteer sample of 15 eighth-grade students and 13 household contacts of two identified cases of B pertussis infection . INTERVENTIONS: All participants had medical histories (including immunization status) and laboratory evaluation for B pertussis infection (including nasopharyngeal specimens and serum samples) obtained initially and 30 days later . After initial evaluation, all subjects received erythromycin ethyl succinate therapy . MAIN OUTCOME MEASURES: Assessment of B pertussis infection as defined by positive nasopharyngeal culture, direct fluorescent antibody, or serological tests . RESULTS: Laboratory evidence of B pertussis infection was found in eight (47%) of 17 immunized eighth-grade classmates and in three (23%) of 13 household contacts, all of whom were 12 years of age or older . CONCLUSIONS: Vaccine-induced immunity wanes by early adolescence . These older age groups may be infected with B pertussis and may serve as reservoirs of infection for other susceptible individuals.

Mol Pharmacol, 1994 Feb, 45(2), 352 - 8
O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4; Relling MV et al.; We previously demonstrated that O-demethylation of the pendant dimethoxyphenol ring of epipodophyllotoxins to produce their respective catechol metabolites is catalyzed by cytochrome(s) P450 in human liver microsomes . Our objective was to identify the specific human cytochrome(s) P450 responsible for catechol formation . Using a panel of prototypical substrates and inhibitors for specific cytochromes P450, we identified substrates for CYP3A4 (midazolam, erythromycin, cyclosporin, and dexamethasone) as inhibitors of catechol formation from both etoposide and teniposide . Dexamethasone inhibition was competitive, with Ki values of 60 and 45 microM for etoposide and teniposide, respectively . In 58 human livers, the correlation coefficients for teniposide catechol formation versus 1'- and 4-hydroxymidazolam formation were 80% and 85%, respectively; for etoposide catechol formation versus 1'- and 4-hydroxymidazolam formation r2 was 83% and 79%, respectively . Teniposide and etoposide catechol formation rates were also significantly correlated with immunodetectable CYP3A (r2 = 49% and 51%, respectively) and not with immunodetectable CYP1A2, 2E1, or 2C8 . Finally, cDNAs for human CYP3A4, 3A5, 2A6, 2B6, 2C8, and 2C9 were functionally expressed in HepG2 cells, using a vaccinia viral vector . Teniposide and etoposide catechol formation was catalyzed primarily by 3A4 (15.4 and 40.9 pmol/pmol/hr, respectively) and to a lesser degree by 3A5 (1.94 and 11.3 pmol/pmol/hr, respectively), whereas there was no detectable O-demethylation of epipodophyllotoxins by 2A6, 2B6, 2C8, 2C9, or the control virus alone . Moreover, the relative activities of midazolam hydroxylation, compared with O-demethylation of epipodophyllotoxins, were similar for heterologously expressed 3A4 and for human liver microsomes . We conclude that catechol formation from teniposide and etoposide is primarily mediated by human CYP3A4, making these reactions susceptible to inhibition by prototypical 3A substrates and inhibitors.

Xenobiotica, 1994 Feb, 24(2), 169 - 82
Modification of hepatic drug-metabolizing enzymes in rat fed naturally occurring allyl sulphides; Haber D et al.; 1 . The effects of feeding allyl sulphides to rat (2000 ppm of the diet for 15 days) were investigated on various microsomal hepatic drug-metabolizing enzymes by their immunochemical detection and catalytic activity . 2 . Allyl sulphides provoked a temporary dietary restriction, which enhanced the microsomal level of P450 and the activities of NADH-cytochrome c reductase and p-hydroxybiphenyl UDP-glucuronyltransferase (UDPGT 2), and lowered the activities of p-nitrophenol hydroxylase (PNPH), N-nitrosodimethylamine demethylase (NDMAD), laurate omega-hydroxylase (LAH) and glutathione S-transferase (GST) . Therefore, pair-fed animals were used as a more relevant control for the dietary effects of allyl sulphides . 3 . Diallyl sulphide (DAS) as well as diallyl disulphide (DADS) produced an enhancement of the microsomal level of P4501A2, 2B1/2 and 3A1/2, and epoxide hydrolase (EH) proteins, with an increase in the enzymatic activities they catalyse: ethoxyresorufin O-deethylase (EROD), aryl hydrocarbon hydroxylase (AHH), methoxyresorufin O-demethylase (MROD), ethoxycoumarin O-deethylase (ECOD), pentoxyresorufin O-depentylase (PROD), benzoxyresorufin O-debenzylase (BROD) and EH . Although P4502E1 proteins were lowered on treatment, NDMAD activity was not modified, and PNPH activity was even enhanced by allyl sulphides . Only DAS treatment raised erythromycin N-demethylase (ERDM) activity . 4 . Both DAS and DADS increased the activity of GST and p-nitrophenol UDP-glucuronyltransferase (UDPGT 1), whereas UDPGT 2 activity was enhanced only by DAS.

Biochem Biophys Res Commun, 1994 Jan 28, 198(2), 411 - 6
The motilin antagonist ANQ-11125 blocks motilide-induced contractions in vitro in the rabbit; Peeters TL et al.; Studies on the physiological role of motilin, and more recently, on the relationship between motilin and erythromycin A, have been hampered by the lack of antagonists . We now have discovered such a compound . ANQ-11125 displaces motilin bound to an homogenate of rabbit antral smooth muscle tissue . The dissociation constant (pKd) was 8.16 +/- 0.10 . However, ANQ-11125 did not induce contractions of segments of rabbit duodenum, except at high concentrations . In the presence of 1 microM ANQ-11125 the dose response curves of erythromycin-A, De(N-methyl)-N-ethyl-8,9 anhydroerythromycin A 6,9-hemiacetal and motilin were shifted about one log unit to the right, but the responses to ACh and Substance P were unaffected . Schild-analysis showed the competitive nature of the interaction and allowed the calculation of the pA2: 7.03 +/- 0.05 (motilin curves) and 7.55 +/- 0.06 (EM-523 curves) . This is the first report of a motilin antagonist . Its properties definitively prove that motilides are motilin agonists.

Science, 1994 Jan 21, 263(5145), 378 - 80
Stereospecific acyl transfers on the erythromycin-producing polyketide synthase; Marsden AF et al.; During assembly of complex polyketide antibiotics like erythromycin A, molecular recognition by the multienzyme polyketide synthase controls the stereochemical outcome as each successive methylmalonyl-coenzyme A (CoA) extender unit is added . Acylation of the purified erythromycin-producing polyketide synthase has shown that all six acyltransferase domains have identical stereospecificity for their normal substrate, (2S)-methylmalonyl-CoA . In contrast, the configuration of the methyl-branched centers in the product, that are derived from (2S)-methylmalonyl-CoA, is different . Stereoselection during the chain building process must, therefore, involve additional epimerization steps.

Am J Ophthalmol, 1994 Jan 15, 117(1), 50 - 7
Comparative diagnosis of neonatal chlamydial conjunctivitis by polymerase chain reaction and McCoy cell culture; Talley AR et al.; Cervical and ocular swabs from 100 mother/newborn pairs delivering on the clinic service were assayed for Chlamydia trachomatis with standard McCoy cell culture and with standard and biotinylated polymerase chain reaction techniques, using primers directed against the major outer membrane protein gene and C . trachomatis-specific cryptic plasmid, respectively . Using the polymerase chain reaction, 20 (20%) mothers and seven (7%) neonates were positive for Chlamydia . All neonates positive by polymerase chain reaction were from mothers positive by polymerase chain reaction, yielding a 35% transmission rate . Only five of 20 (25%) mothers and two of seven (28%) neonates positive by polymerase chain reaction were positive by cell culture . All cell culture samples were positive by polymerase chain reaction testing . Culture and polymerase chain reaction analysis two weeks after treatment with oral erythromycin were negative . The polymerase chain reaction assay appears to be equally specific and more sensitive than McCoy cell culture for the detection of C . trachomatis from ocular specimens.

Cancer Res, 1994 Jan 15, 54(2), 386 - 92
Taxol metabolism by human liver microsomes: identification of cytochrome P450 isozymes involved in its biotransformation; Cresteil T et al.; The biotransformation of taxol by human liver was investigated in vitro with microsomes isolated from adult and developing human tissues . In vitro, no metabolism was detected with kidney microsomes, whereas two metabolites were generated by liver microsomes . The most prominent metabolite, termed M5, corresponded to an hydroxylation at the C6 position on the taxane ring, while the other metabolite, termed M4, corresponded to an hydroxylation at the para-position on the phenyl ring at the C3'-position of the C13 side chain . These two taxol derivatives have been shown to be the major metabolites recovered in bile from a patient infused with taxol . Several approaches have been used to identify the cytochrome P450 (CYP) isozymes involved in these reactions . No positive correlation was observed between the in vitro synthesis of these two metabolites, suggesting that two cytochrome P450 isozymes could be involved, although they could not be distinguished by their apparent affinities (Km approximately 15 microM) . The formation of metabolite M4 was substantially reduced both by antibody directed against CYP3A and by the addition of CYP3A substrates such as orphenadrine, erythromycin, troleandomycin, and testosterone . Conversely, the formation of metabolite M5 remained unaffected by antibodies against CYP3A and by CYP3A substrates but was sensitive to diazepam inhibition, a preferential substrate of CYP2C . Correlation between CYP2C content or diazepam demethylation and the synthesis of metabolite M5 was highly positive . The formation of metabolite M4 developed during the early postnatal period . In contrast, the synthesis of metabolite M5 rose only after 3 months of age . These data clearly implicate CYP3A in the formation of metabolite M4 and CYP2C in the synthesis of metabolite M5 . Microsomes from patients treated with barbiturates and benzodiazepines increased the formation of metabolite M4 to the level of metabolite M5, demonstrating that drug interactions could modify the human metabolism of taxol.

Arch Biochem Biophys, 1994 Jan, 308(1), 175 - 81
Purification of a thymidine-diphospho-4-keto-6-deoxy-D-glucose epimerase from an erythromycin-producing strain of Saccharopolyspora erythraea; Jarvis BW et al.; A thymidine-diphospho-4-keto-6-deoxy-D-glucose epimerase was purified from Saccharopolyspora erythraea, the producer of the macrolide antibiotic erythromycin, by a high resolution chromatographic method that exploited the difference in behavior of the protein on ion exchange columns at pH 7.5 and 5.5 . By this procedure and by hydrophobic interaction chromatography, the enzyme was purified more than 400-fold to apparent homogeneity . The epimerase is a monomer of M(r) 55,000, as determined by reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration . The apparent Michaelis-Menten kinetic constants were determined to be K'm of 120 microM and V'max of 0.38 mumol mg-1 min-1 . Southern analysis indicates that this epimerase is encoded by a gene that is not located within the known confines of the erythromycin biosynthetic gene cluster.

Am J Surg, 1994 Jan, 167(1), 169 - 72; discussion 172-3
Erythromycin strengthens the defective lower esophageal sphincter in patients with gastroesophageal reflux disease; Pennathur A et al.; Motilin induces phase III activity of the gastrointestinal tract . Erythromycin has a motilin-like effect on the stomach and significantly increases the lower esophageal sphincter (LES) pressure in normal volunteers . This investigation was performed to evaluate the effects of erythromycin on esophageal function in patients with gastroesophageal reflux disease (GERD) . Esophageal manometry was performed in 10 GERD patients before and after intravenous infusion of 500 mg of erythromycin . Values are expressed as mean +/- SEM . LES pressure increased from 13.9 +/- 2.9 mm Hg at baseline to 28.9 +/- 3.6 mm Hg after infusion of erythromycin (p < 0.01) . The duration of contractions in the proximal, middle, and distal esophagus was significantly prolonged from 3.5 +/- 0.4 seconds, 3.8 +/- 0.4 seconds, and 4.1 +/- 0.5 seconds to 4.2 +/- 0.2 seconds, 4.6 +/- 0.5 seconds, and 5.6 +/- 0.6 seconds, respectively, after infusion of erythromycin (p < 0.05 for each comparison) . Erythromycin did not effect esophageal body contraction amplitude or velocity, or the upper esophageal sphincter . Serum motilin decreased slightly after the administration of erythromycin . We concluded the following: (1) Erythromycin profoundly stimulates the defective LES in patients with GERD . This appears to be a direct motilin agonist-like effect rather than being mediated by release of endogenous motilin . (2) Erythromycin has less effect on the esophageal body, although it does prolong the duration of esophageal contractions.

J Pharmacol Exp Ther, 1994 Jan, 268(1), 515 - 21
Administration of high doses of human recombinant interleukin-2 decreases the expression of several cytochromes P-450 in the rat; Thal C et al.; Human recombinant interleukin-2 (IL-2) administration is being tested in patients with advanced cancer . Its effects on the expression of cytochromes P-450 were determined in rats . IL-2 administration (1-25 x 10(6) U/kg i.v . twice daily for 1 to 4 days) resulted in a time- and dose-dependent decrease in cytochrome P-450 measured by the absorbance of its Fe(++)-CO complex . After 25 x 10(6) U/kg twice daily for 4 days, cytochrome P-450 decreased 44%; immunoreactive cytochrome P-450 1A1 decreased nonsignificantly (22%); but cytochrome P-450 1A2 decreased 68%; 2B1/2, 50%; 2C11, 75%; 2D1, 36%; and 3A, 70% . Aminopyrine N-demethylase activity decreased 53%, ethoxycoumarin O-deethylase 64%, benzo(a)pyrene hydroxylase 71%, ethoxyresorufin O-deethylase 42%, pentoxyresorufin O-dealkylase 81% and erythromycin N-demethylase 56% . In rats treated with 3-methylcholanthrene for 4 days, IL-2 coadministration (25 x 10(6) U/kg i.v . twice daily for 4 days) did not decrease significantly immunoreactive cytochrome P-450 1A1 and 1A2, whereas cytochromes P-450 2B1/2, 2C11 and 3A decreased 39, 54 and 67%, respectively . In rats treated with phenobarbital for 4 days, IL-2 coadministration decreased immunoreactive cytochromes P-450 2B1/2 29%, whereas cytochromes P-450 1A2, 2C11 and 3A decreased 38, 63 and 67%, respectively . We conclude that administration of high doses of IL-2 decreases the expression of several cytochromes P-450 in rats . Microsomal enzyme inducers appear to limit the effects of IL-2 on the induced forms of cytochromes P-450 . Because much lower doses are used in humans, their potential effects on drug metabolism cannot be assessed from present results.

Dig Dis Sci, 1994 Jan, 39(1), 129 - 37
Effects of oral erythromycin on esophageal pH and pressure profiles in patients with gastroesophageal reflux disease; Champion G et al.; Erythromycin, a possible motilin agonist, is a potent gastrokinetic agent that may increase the lower esophageal sphincter pressure . Therefore, we assessed the effects of erythromycin in two dosages (250 and 500 mg per os four times a day) on esophageal pH and pressure profiles in reflux patients using prolonged ambulatory monitoring systems . Studies were blinded, placebo-controlled with randomized crossover design . Patients took each drug for three days prior to studies, with erythromycin serum levels obtained the day of esophageal studies . Erythromycin 250 mg four times a day had no effect on esophageal contraction pressures or peristalsis during the day or meal periods . In the supine position, however, erythromycin significantly (P = 0.012) decreased esophageal contraction velocity and showed a strong trend (P = 0.059) towards increasing the percentage of peristaltic waves . Despite these potentially beneficial effects on esophageal clearance, no significant difference in acid exposure times during 24-hr pH studies were observed between placebo and low-dose erythromycin . High-dose erythromycin (500 mg four times a day) was associated with drug levels in the typical antibiotic efficacy range (normal 1-3 micrograms/ml; patients 1.7-7.0 micrograms/ml), but, here again, there was no significant difference in all acid reflux parameters between placebo and erythromycin phases . Therefore, "standard" doses of erythromycin have no important clinical effects on esophageal pressures or acid reflux parameters.

Dig Dis Sci, 1994 Jan, 39(1), 124 - 8
Erythromycin accelerates solid emptying at the expense of gastric sieving; Lin HC et al.; Erythromycin accelerates gastric emptying by inducing antral contractions similar to phase III of interdigestive MMC . These powerful contractions are capable of forcing coin-sized indigestibles out of the stomach . In contrast, fed motility is associated with submaximal contractions that fragment (trituration) and propel solids while retaining large (> 0.5 mm) pieces for further size reduction (gastric sieving) . In this study, using dogs with duodenal fistulas, we tested the hypothesis that erythromycin-induced acceleration of gastric emptying resulted in the passage of inadequately triturated (> 0.05 mm) chunks of solids into the duodenum . We found that gastric emptying was accelerated by erythromycin (vs 0.15 M NaCl control, P < 0.05) . However, the percentage of chyme collected in the > 0.5-mm fraction was much greater (P < 0.01) in the erythromycin-treated experiments (63 +/- 9%) than the controls (7 +/- 1%) . Correspondingly, while a fine gruel was passed during controls, under erythromycin infusion, most of the solids were emptied as large chunks virtually unchanged from the swallowed pieces . We conclude that erythromycin accelerates gastric emptying at the expense of gastric sieving.

Rev Esp Enferm Dig, 1994 Jan, 85(1), 38 - 40
{Usefulness of erythromycin in severe postoperative gastroparesis}; Charco Torra R et al.; Erythromycin has recently been shown to exert a great effect on gastroduodenal motor activity . This prokinetic action may be clinically useful in patients with gastrointestinal hypomotility such as diabetic or postsurgical gastroparesis . The case of a diabetic patient who underwent antrectomy Billroth II for gastric cancer is presented . Severe gastroparesis appeared after surgery and nasogastric aspiration could not be removed, although the patient was treated with metoclopramide, and glucose levels, hydroelectrolytic balance and nutritional status were corrected . Forty-one days after the first operation, a second gastrectomy with Bilroth II reconstruction was performed because of supposed anastomotic narrowing, which was not confirmed at surgery . Fourteen days later, i.v . erythromycin (200 mg/4h) was started owing to gastroparesis persistence . Six days after treatment the patient tolerated oral ingestion . Prokinetic drugs constitute the specific therapy for gastroparesis . Metoclopramide is the most used, although its efficacy is limited . In the last few years, erythromycin has proved to have a powerful effect on gastroduodenal motility . This effect is mediated, at least in part, by its motilin stimulating activity accelerating gastric emptying . Our patient completely recovered from gastroparesis after erythromycin treatment . Recent results of erythromycin therapy in these patients have been promising, despite the difficult management involved.

J Dermatol, 1994 Jan, 21(1), 46 - 9
Febrile ulceronecrotic Mucha-Habermann's disease; Maekawa Y et al.; Febrile ulceronecrotic Mucha-Habermann's disease (FUMH) was first described by Degos in 1966 . In the literature, nine cases of FUMH have been reported in both children and adults . We report a 16-year-old boy with the febrile ulceronecrotic type . A review of the nine cases in the literature showed acute necrotic lesions, as well as rare complications such as fever, superinfected lesions and viral infection which are not as common in pityriasis lichenoides et varioliformis acuta . There is no definitive treatment, but systemic corticosteroid, methotrexate, antibiotics (tetracycline, erythromycin), aciclovir, and 4,4-diaminodiphenyl sulfone (DDS) have been frequently used . The most common histologic feature is mononuclear perivascular infiltrates consisting of T lymphocytes . The etiology is not known, but a hypersensitivity reaction, possibly to an infectious agent, is suggested.

Epilepsia, 1994, 35 Suppl 3, S14 - 9
Oxcarbazepine: pharmacokinetic interactions and their clinical relevance; Baruzzi A et al.; Antiepileptic drug (AED) interactions are a common problem during epilepsy treatment . Oxcarbazepine (OCBZ) is a keto homologue of carbamazepine (CBZ) with a completely different metabolic profile . In humans, the keto group is rapidly and quantitatively reduced to form a monohydroxy derivative (MHD), which is the main active agent during OCBZ therapy . MHD is eliminated by renal excretion, glucuronidation and, marginally, by hydroxylation to a diol derivative . This metabolic profile, and in particular the limited involvement of oxidative microsomal enzymes, suggests that OCBZ may have fewer drug interactions compared with traditional AEDs . This possibility has been investigated in experimental studies and, retrospectively, in data obtained from clinical trials . The capacity of OCBZ to induce microsomal enzymes of the P-450 family has mostly been examined by use of antipyrine and CBZ kinetics as markers . The results suggest that OCBZ has little enzyme inducing capacity . In clinical trials in which OCBZ was substituted for CBZ, plasma concentrations of concomitant AEDs were increased, possibly as a consequence of total or partial de-induction . OCBZ interference with other drugs has been evaluated for warfarin, felodipine, and oral contraceptives, three medications strongly influenced by enzyme-inducing AEDs . OCBZ does not modify the anticoagulant effect of warfarin, whereas some reduction in felodipine concentration and a clinically significant reduction of contraceptive drug levels and efficacy were observed . Polytherapy with established AEDs does not significantly modify OCBZ disposition (MHD kinetics); however, available information is not extensive . Finally, the action on OCBZ kinetics of a group of drugs (verapamil, cimetidine, erythromycin, dextropropoxyphene, and viloxazine) known to inhibit the metabolism of some AEDs has been studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Arch Dermatol Res, 1994, 286(2), 104 - 6
Influence of oral isotretinoin on hepatic and cutaneous P-450-dependent isozyme activities; Goerz G et al.; Oral administration of isotretinoin (13-cis-retinoic acid) (6 mg/kg per day), 0.05% hexachlorobenzene (HCB) or both drugs simultaneously for 10 days to female Wistar rats caused a statistically significant induction of aminopyrine-N-demethylase (ADM), 7-ethoxyresorufin-O-deethylase (7-ERO-D) and erythromycin-N-demethylase (EMDM) in the liver microsomes . Oral administration of isotretinoin alone or together with HCB induced a marked induction of 7-ERO-D and EMDM in the skin . Administration of isotretinoin alone for 60 days resulted in the induction of EMDM in the liver microsomes, and in combination with HCB caused a statistically significant induction of all hepatic isozymes . HCB alone caused a marked induction of only 7-ERO-D in the skin . These results clearly show that oral isotretinoin is capable of inducing hepatic and cutaneous microsomal P-450-dependent catalytic activities . It remains to be elucidated whether the induction of these enzymes is of importance for the therapeutic action of isotretinoin.

Drug Metab Dispos, 1994 Jan-Feb, 22(1), 65 - 73
Induction of cytochromes P-450 2B and 3A in mice following the dietary administration of the novel cognitive enhancer linopirdine; Diamond S et al.; The effects of the novel cognitive enhancer linopirdine {3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one} on hepatic cytochromes P-450 (CYP) and linopirdine metabolism were determined in female mice fed 0, 10, 50, and 250 mg/kg/day of linopirdine in the diet for 4, 7, 14, and 28 days . Linopirdine induced CYP maximally by day 4 only at the highest dose, as demonstrated by significant (p < 0.05) increases in total spectral CYP and liver weight . SDS-PAGE revealed induced 52 kDa microsomal protein(s), identified as CYP2B and 3A by immunoblotting . Linopirdine also increased the rates of reactions selectively catalyzed by CYP2B and 3A (pentoxyresorufin O-dealkylation, benzphetamine N-demethylation, erythromycin N-demethylation, and testosterone 2 beta-, 6 beta-, 16 beta-hydroxylation), 1.7- to 3.0-fold vs . control, similar to increases produced by the prototypical CYP2B and 3A inducers phenobarbital and dexamethasone . No increase in microsomal CYP1A or 2E levels was demonstrated by immunoblotting or selective substrate assays . CYP induction increased the metabolism of linopirdine . The area under the plasma concentration-time curve of linopirdine after a 250 mg/kg/day dose decreased 11-fold from day 1-28, and microsomes from a parallel 250 mg/kg/day group metabolized linopirdine 1.9-fold faster than control (p < 0.05) . This autoinduction was due primarily to the induced CYP3A, because antibodies recognizing CYP3A inhibited the microsomal metabolism of linopirdine by 85%, whereas antibodies to CYP2B were not inhibitory . In summary, the dietary consumption of 250 mg/kg/day of linopirdine by female mice coinduced CYP2B and 3A maximally by day 4, and resulted in an increased rate of metabolism of linopirdine, predominantly due to CYP3A.

Adv Surg, 1994, 27, 233 - 55
Diagnosis and management of gastric emptying disorders; Behrns KE et al.; In summary, although gastric emptying disorders are relatively uncommon, they are potentially devastating conditions resulting from pathophysiologic motor disturbances . Rapid gastric emptying of liquids is the hallmark of the dumping syndrome and occurs after operations, including vagotomy . Vagal denervation abolishes receptive relaxation and accommodation in the proximal stomach (the storage site for ingested liquids) resulting in increased intragastric pressure which forces liquids through an ablated or bypassed pylorus . Dumping symptoms may occur in up to 50% of postgastrectomy patients, but most patients are treated satisfactorily by dietary manipulation or, in the rare incapacitated patient, by the long-acting somatostatin analogue octreotide . Reconstructive gastric surgery may rarely be indicated to slow gastric emptying and alleviate the dumping syndrome . Reoperative procedures include pyloric reconstruction after pyloroplasty, small intestinal pouches, interposed isoperistaltic and antiperistaltic jejunal segments, and a Roux-en-Y gastrojejunostomy . Interposed jejunal loops and the Roux-en-Y gastrojejunostomy provide the most satisfactory results . Delayed gastric emptying may occur in the acute postoperative period or be a late complication of gastric surgery . Loss of vagal input to the gastric antrum and resection of the antrum with vagotomy may produce an atonic stomach or atonic gastric remnant, respectively, which fails to grind and propel solids into the small intestine . Scintigraphic imaging of both the liquid and solid components of the meal is a valuable diagnostic adjunct . Gastric ileus occurring in the early postoperative period generally resolves within 6 weeks of operation, and the temptation to reoperate on a nonobstructed stomach should be avoided . Pharmacologic therapy of chronic gastric stasis with the benzamide prokinetic agents (metoclopramide, cisapride, renzapride), domperidone, and the motilin agonist erythromycin, may be effective initially, but long-term results are still undefined, and postvagotomy and postgastrectomy patients have not been studied adequately . Persistent postoperative gastric atony and the Roux stasis syndrome should be managed surgically by near-total gastrectomy which should result in symptomatic improvement in two thirds of patients.

Acta Anaesthesiol Scand, 1994 Jan, 38(1), 15 - 29
Drug interactions with intravenous and local anaesthetics; Quist Christensen L et al.; Relatively few clinically significant drug interactions with anaesthetics have been documented in the literature . The following should be stressed since these interactions are not readily predictable or are potentially fatal . Pethidine should never be administered to patients who have received monamine oxidase inhibiting drugs within the last fortnight, since a fatal hyperpyrexia and/or hypertension may result . Thiopentone induction seems to make the heart more susceptible to arrhythmias caused by adrenergic drugs, and may cause severe arterial hypotension in patients treated with diazoxide . Midazolam orally should possibly be avoided as premedication in patients treated with erythromycin since anaesthetic concentrations of midazolam may result . Patients for whom bupivacaine analgesia is planned could preferentially be premedicated with other drugs than diazepam, which causes the serum level of bupivacaine to increase . Bradycardia and hypotension not attributable to sympathetic blockade have been reported following bupivacaine extradurally in verapamil-treated patients . Sulfonamides and the ester group of local anaesthetics, such as prilocaine in combination, may result in severe methaemoglobinaemia in infants . Epinephrine added to local anaesthetics may cause local vasodilation if administered to patients concurrently being treated with cyclic antidepressants, and the combination imposes the risk of severe hypertension and arrhythmias.

J Antibiot (Tokyo), 1994 Jan, 47(1), 80 - 9
Erythromycin promotes monocyte to macrophage differentiation; Keicho N et al.; Recent reports have suggested that long-term administration of erythromycin (EM) appears to ameliorate some of chronic inflammatory processes where macrophages and lymphocytes play important roles . Our study was initiated to examine the effect of EM on monocyte-macrophage lineage in vitro . EM (1 approximately 100 micrograms/ml) significantly increased the number of adherent monocyte-derived macrophages after 7 days of culture . The combination of EM and macrophage colony stimulating factor (M-CSF) synergistically increased the number of monocyte-derived macrophages, while the combination of EM and granulocyte-macrophage colony stimulating factor exerted an additive effect . Culture with EM induced the expression of a surface antigen CD71, one of the activation markers of macrophages as compared with control cultures . The combination of EM plus M-CSF significantly enhanced H2O2-producing capacity of those cells as compared with M-CSF alone . A differentiation process of monocytoid THP-1 cells was also augmented by EM . These results indicate that EM promotes differentiation of human monocyte-macrophage lineage, altering their functions.

Transpl Int, 1994, 7(1), 62 - 4
Erythromycin ototoxicity in liver transplant patients; Moral A et al.; We report on three liver transplant patients who developed erythromycin-related ototoxicity . This complication has been described in renal transplant patients and in patients with liver dysfunction, but to our knowledge it has not yet been reported in liver transplant patients . The influence of hepatic dysfunction, common renal failure, and the interaction between cyclosporin and erythromycin in the development of erythromycin ototoxicity are discussed.

Arch Pediatr, 1994 Jan, 1(1), 46 - 8
{Percutaneous embolization of a pulmonary arteriovenous fistula in a child}; Callebaut B et al.; BACKGROUND--Pulmonary arteriovenous fistula is a rare vascular abnormality in children that is usually treated by lobectomy . This report describes a case that was improved by coil embolization . CASE REPORT--A thoracic X-ray was routinely taken before amygdalectomy in a 6 year-old girl . It showed a consolidation area in the left superior lobe that persisted despite treatment with erythromycin for 3 weeks . Bronchoscopy was normal, but study of blood gases showed a refractory hypoxemia with moderate cyanosis and hemoglobin at 16.2 g/dl . Right-heart catheterization and angiography showed a pulmonary arteriovenous fistula that was treated by coil embolization . A control investigation 3 months later showed normal arterial oxygen saturation, hemoglobin at 14.5 g/dl and reduced pulmonary condensation . CONCLUSION--Pulmonary arteriovenous fistula may show few symptoms . Coil embolization appears to be a useful initial non-aggressive treatment.

Gen Pharmacol, 1994 Jan, 25(1), 93 - 6
Effect of erythromycin on different parts of the rabbit intestine: comparison with motilin; Koutsoviti-Papadopoulou M et al.; 1 . The effect of erythromycin on the rabbit intestinal smooth muscle was investigated and was compared to that of motilin . 2 . Whole isolated segments from the duodenum, jejunum, ileum and ascending colon, as well as strips from the circular and longitudinal smooth muscle of the ascending colon were used . 3 . Erythromycin was found to possess a concentration-dependent contractile effect on the above intestinal parts but in different degree of intensity . 4 . The order of the sensitivity of the intestinal parts to erythromycin was duodenum = jejunum > ascending colon > ileum . 5 . The circular smooth muscle of the ascending colon was found to be more sensitive than the longitudinal smooth muscle . 6 . A similar contractile effect, but at lower concentrations, and the same regional specificity were observed with motilin.

Eye, 1994, 8 ( Pt 1), 134 - 42
Mycobacterium chelonei keratitis: a case report and review of previously reported cases; Broadway DC et al.; A 56-year-old woman who wore hard contact lenses developed a keratitis due to Mycobacterium chelonei . The organism was only sensitive to imipenem and partially to ciprofloxacin and erythromycin . After an initial response to topical therapy with these antibiotics the infection relapsed and a penetrating keratoplasty was performed, with resulting cure . M . chelonei has not previously been reported as a cause of keratitis associated with hard contact lens wear; neither has its treatment with imipenem and/or ciprofloxacin . A detailed photographic record showing the natural history of the keratitis is presented . Previously reported cases of M . chelonei keratitis are reviewed.

Eur J Clin Pharmacol, 1994, 46(6), 551 - 5
A pharmacokinetic interaction between roxithromycin and midazolam; Backman JT et al.; The interaction between roxithromycin and midazolam was investigated in a double-blind, randomised crossover study of two phases . Ten healthy volunteers were given roxithromycin (300 mg) or placebo once daily for 6 days . On the sixth day they ingested 15 mg midazolam . Plasma samples were collected and psychomotor performance measured for 17 h . Roxithromycin administration significantly increased the area under the plasma midazolam concentration-time curve from 8.3 to 12.2 micrograms.ml-1.min and the elimination half-lives from 1.7 to 2.2 h . In psychomotor performance only minor differences were seen between the treatments in one of the measured psychomotor parameters . Thus, in contrast to the strong interaction between erythromycin and midazolam, the interaction between roxithromycin and midazolam appears less likely to be clinically significant.

Peptides, 1994, 15(6), 1067 - 77
Migrating motor complex recorded spontaneously and induced by motilin and erythromycin in an ex vivo rabbit intestinal preparation; Marzio L et al.; We investigated basal motility and the motor effects of motilin, erythromycin, and prostigmine on segments of rabbit gastrointestinal tract removed from extrinsic neural and vascular pathway and immersed in an oxygenated organ bath . Motility was recorded by means of four strain gauges sutured on the serosal surface of the segment . During basal recording, clusters of duodenal contractions that propagated distally, resembling phase III activity of migrating motor complex, were seen . Motilin (10(-6) M) and erythromycin (10(-6) M) induced a propagated cluster of contractions similar to the phase III recorded during the basal period . Prostigmine (10(-6) M) induced a simultaneous increase in gastric and small intestinal motility . Atropine (10(-5) M) prevented the motor effect of motilin, erythromycin, and prostigmine . Thus, MMCs do not appear to require central input for initiation and propagation . Motilin and erythromycin stimulate MMCs through an enteric cholinergic mechanism; therefore, the previously reported smooth muscle receptors for both substances were not apparent in the ex vivo preparation.

Eur J Clin Pharmacol, 1994, 47(1), 49 - 52
Azithromycin does not alter the effects of oral midazolam on human performance; Mattila MJ et al.; Since macrolide antibiotics inhibit the oxidative hepatic metabolism of various drugs, including midazolam, the present double blind studies were conducted to find out if azithromycin, a new macrolide of the azalide type, would inhibit the metabolism of midazolam and enhance the effects of midazolam on human performance . In Study I, 64 healthy medical students, divided in four parallel groups received placebo, midazolam (10 mg or 15 mg), and midazolam 10 mg combined with azithromycin (500 mg + 250 mg) . In Study II, three males received oral midazolam 10 mg in combination with placebo, azithromycin or erythromycin 750 mg (as a positive control) in a cross-over trial . Objective and subjective tests were done before the intake of midazolam and 30 and 90 min after it, and venous blood was sampled for the assay of midazolam . In the placebo group in Study I, the mean numbers of letters cancelled (LC) at baseline, 30 min and 90 min were 21, 20 and 20, respectively, and the corresponding mean numbers of correct digit symbol substitutions (DSS) were 126, 137 and 140, indicating a practice effect . Midazolam 10 mg impaired these performances (21, 13 and 12 for LC, and 127, 113 and 111 for DSS) . Either dose of midazolam produced clumsiness, mental slowness and poor subjective performance, midazolam 15 mg being slightly more active . The corresponding, scores in the azithromycin+midazolam group were 21, 16, 16 for LC, and 132, 121 and 119 for DSS, the only significant difference from placebo being the impairment of DSS at 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Scand J Infect Dis, 1994, 26(4), 453 - 7
Effect of erythromycin treatment on antibody responses in pertussis; Granstrom G et al.; The effect of erythromycin treatment on antibody responses to Bordetella pertussis filamentous haemagglutinin (FHA) and pertussis toxin (PT) was investigated in convalescent blood samples from 105 children with pertussis . Erythromycin had been given to 59 children, median age 3.2 years (range 0.3-9.9) on median day 7 (range 11-14) after onset of disease while the remaining 46 children, age 3.45 (0.6-8.1) were untreated . No significant differences in IgG antibody concentration were noted to FHA by ELISA and to PT, neither by NT nor by ELISA, but a tendency towards lower median titers was seen to both antigens and by both type of assays in the erythromycin-treated group . Similarly, early erythromycin treatment i.e . within 7 days of onset of symptoms, did not influence significantly of the development of the antibody responses but tended to lead to lower titer levels . A significant response to PT and FHA was found in about 90% of blood samples, irrespective of treatment . All 56 children with culture-confirmed B . pertussis infection had a significant response to PT . The study has thus shown a slight but not significant effect of erythromycin treatment on antibody responses in pertussis.

Bull Soc Pathol Exot, 1994, 87(4), 253 - 60
{Malaria in children at the Sihanoukville Hospital (Cambodia)}; Imbert P et al.; The authors have studied 68 children admitted with malaria in Sihanoukville Hospital (Cambodia) from December 1992 to April 1993 . Sihanoukville is located on coast of the country, in a hypoendemic area with seasonal transmission occurring during this study . The patients lived in urban (1/3) or in rural areas (2/3) . Plasmodium (P.) vivax alone was found in 15 cases . Among them, two patients presented with severe malaria, but chloroquine was efficient in all cases . P . falciparum with or without P . vivax, was predominant (53 cases) . Most of these cases were severe, according to WHO criteria (n = 43), from which 11 deaths occurred (25%) . There were 26 cases of cerebral malaria, with a death rate of 34.6% . A severe course was observed with the following criteria: prostration or coma (p = 0.029), severe anaemia (p = 0.037) and hyperparasitaemia (p = 0.00078) . A significant longer delay for treatment and admission was noted among rural patients (p = 0.023 and p = 0.011 respectively) . In those children, hyperparasitaemia, poor clinical status on admission and lethality were more frequent . The clinical course was not clearly improved with the addition of erythromycin in the quinine regimen . No quinine resistance was observed in this data.

Eur Arch Otorhinolaryngol, 1994, 251(7), 375 - 92
Experimental, clinical and preventive aspects of ototoxicity; Chiodo AA et al.; Ototoxicity is an important clinical problem and accounts for a significant proportion of sensorineural hearing loss in some parts of the world . Ototoxicity is predominantly an iatrogenic condition . However, with proper dosing, prudent monitoring of serum levels of ototoxic medications and serial audiometry, ototoxicity can be prevented . A number of the more common ototoxic medications, including aminoglycosides, erythromycin, loop diuretics, salicylates, cisplatin, deferoxamine and ototopical agents, are outlined in this review . Their pharmacology, mechanisms of action and methods of preventing complications are discussed together with animal and clinical studies.

Proc Natl Acad Sci U S A, 1993 Dec 15, 90(24), 11748 - 52
Human cytochrome P450 3A4: enzymatic properties of a purified recombinant fusion protein containing NADPH-P450 reductase; Shet MS et al.; Human cytochrome P450 3A4 is recognized as the catalyst for the oxygen-dependent metabolism of a diverse group of medically important chemicals, including the immunosuppressive agent cyclosporin; macrolide antibiotics, such as erythromycin; drugs such as benzphetamine, nifedipine, and cocaine; and steroids; such as cortisol and testosterone to name but a few . We have engineered the cDNA for human cytochrome P450 3A4 by linkage to the cDNA for the rat or human flavoprotein, NADPH-P450 reductase (NADPH:ferrihemoprotein oxidoreductase, EC 1.6.2.4) . An enzymatically active fusion protein (rF450{mHum3A4/mRatOR}L1) has been expressed at high levels in Escherichia coli and purified to homogeneity . Enzymatic studies show a requirement for lipid, detergent, and cytochrome b5 for the 6 beta-hydroxylation of steroids and the N-oxidation of nifedipine . In contrast, these additions are not required for the N-demethylation of erythromycin or benzphetamine . A spectrophotometrically detectable metabolite complex of P450 3A4 is formed during the metabolism of triacetyloleandomycin, and this has a pronounced inhibitory effect on the metabolism of both testosterone and erythromycin . These results relate to the interpretation of current methods used to assess the in vivo activity of P450 3A4.

Plant Cell, 1993 Dec, 5(12), 1853 - 63
Synechocystis sp PCC 6803 strains lacking photosystem I and phycobilisome function; Shen G et al.; To design an in vivo system allowing detailed analysis of photosystem II (PSII) complexes without significant interference from other pigment complexes, part of the psaAB operon coding for the core proteins of photosystem I (PSI) and part of the apcE gene coding for the anchor protein linking the phycobilisome to the thylakoid membrane were deleted from the genome of the cyanobacterium Synechocystis sp strain PCC 6803 . Upon transformation and segregation at low light intensity (5 microE m-2 sec-1), a PSI deletion strain was obtained that is light tolerant and grows reasonably well under photoheterotrophic conditions at 5 microE m-2 sec-1 (doubling time approximately 28 hr) . Subsequent inactivation of apcE by an erythromycin resistance marker led to reduction of the phycobilin-to-chlorophyll ratio and to a further decrease in light sensitivity . The resulting PSI-less/apcE- strain grew photoheterotrophically at normal light intensity (50 microE m-2 sec-1) with a doubling time of 18 hr . Deletion of apcE in the wild type resulted in slow photoautotrophic growth . The remaining phycobilins in apcE- strains were inactive in transferring light energy to PSII . Cells of both the PSI-less and PSI-less/apcE- strains had an approximately sixfold enrichment of PSII on a chlorophyll basis and were as active in oxygen evolution (on a per PSII basis) as the wild type at saturating light intensity . Both PSI-less strains described here are highly appropriate both for detailed PSII studies and as background strains to analyze site- and region-directed PSII mutants in vivo.

Epidemiol Infect, 1993 Dec, 111(3), 483 - 90
The coccoid forms of Helicobacter pylori . Criteria for their viability; Bode G et al.; The fact that Helicobacter pylori can revert to a coccoid form has stimulated speculation about its role in transmission and as a possible cause of reinfection in duodenal ulcer disease . Bismuth subcitrate (32 micrograms/ml), bismuth subsalicylate (64 micrograms/ml), amoxicillin (0.05 micrograms/ml) and erythromycin (4 micrograms/ml) inhibited the growth of H . pylori and stimulated the formation of basically respiring but non-culturable coccoid structures . The presence of polyphosphates as energy and phosphorus source permits a certain level of endogenous metabolism to preserve RNA and DNA, as well as structural components like cell wall, cell membrane and cytoplasma for at least 3 months . However, the applied standard laboratory methods were insufficient for regrowth of H . pylori out of the coccoid form.

Dig Dis Sci, 1993 Dec, 38(12), 2236 - 40
5-hydroxytryptamine 3-receptor antagonist modulates gallbladder emptying and motilin release induced by erythromycin; Fiorucci S et al.; In the present study we evaluated the effect of ondansetron (formerly indicated as GR38032F), a potent and selective type-3 5-hydroxytryptamine receptor antagonist, on erythromycin-induced gallbladder emptying and motilin release, as well as gallbladder emptying induced by a regular meal in healthy volunteers . Gallbladder emptying was evaluated by sonography . Ondansetron, at the dose of 0.05 mg/kg, significantly reduced (P < 0.001 by ANOVA) the gallbladder emptying induced by 2 mg/kg/hr erythromycin, but did not increase basal gallbladder volume or inhibit gallbladder emptying induced by a regular meal . Ondansetron also inhibited the motilin release induced by erythromycin (P < 0.001, by ANOVA) . These results suggest that serotoninergic mechanisms modulate the effects of erythromycin on the gastrointestinal tract . The exact site of action of ondansetron remains to be identified.

J Chemother, 1993 Dec, 5(6), 556 - 61
Respiratory infections in children: when is brodimoprim indicated?
Herz G.
Respiratory infections are the most common infection in children . They differ remarkably according to age, bacteria and viruses . Therefore a careful history of outbreak, age, former infections, involvement of surroundings, symptoms, etc are essential . The present study included 50 children, aged between 0.3 and 12 yrs, all treated ambulatorily . 21 received brodimoprim (B) and 29 erythromycin (E) . Indications were: tonsillitis, bronchitis, otitis media, sinusitis and scarlet fever . Dosages were: B was given 10 mg/kg body weight (b.w.) initially followed by 5 mg/kg b.w., once-a-day . The duration of treatment varied between 4 and 14 days (mean 8.3 days) . E was given 30.50 mg/kg b.w . 3 times per day; duration 4 to 14 days (mean 8.6 days) . Overall results were: in group B:12 cures, 5 improvements, 3 failures; 1 not assessable . In group E: 20 cures, 8 improvements, 1 failure . Side effects: in group B: vomiting (1), skin reaction (2), discontinuation (2); in group E: skin reaction (1), diarrhea (5), diarrhea+vomiting (1); discontinuation (2) . The differences in efficacy and tolerability in the two groups are not statistically significant . The improved compliance with a single versus t.i.d . dosages has to be taken into account.

J Chemother, 1993 Dec, 5(6), 546 - 7
A randomized, open, comparative study of brodimoprim versus erythromycin in patients with acute tonsillitis or bronchitis; Salzberg R; The objective of the study was the comparison of the efficacy and tolerability of brodimoprim to those of erythromycin in children with acute tonsillitis or bronchitis . 50 children aged 0.5 to 9.3 years were included in the study, 25 treated either with brodimoprim or with erythromycin . The evaluation of the therapeutic response was based exclusively on clinical criteria . In the brodimoprim group the therapy was successful in 24 patients (one failure), in the erythromycin group the therapy was also successful in 24 children (one failure) . Side effects: three patients treated with brodimoprim reported adverse reactions (stomatitis, vomiting, skin rash), whereas only one patient in the erythromycin group developed a skin rash . Conclusion: both therapeutic regimens were equally effective against bronchitis and tonsillitis in children . The tolerability was good in both groups.

Acta Derm Venereol, 1993 Dec, 73(6), 452 - 5
Systemic corticosteroid and isotretinoin treatment in cystic acne; Karvonen SL et al.; Prednisolone combined with erythromycin was given to 6 patients with cystic acne . The treatment responses were compared to those in 6 patients with cystic acne receiving isotretinoin and erythromycin and also to those in 3 patients with acne fulminans treated with prednisolone and erythromycin . During the first 4 weeks cystic acne showed a clear improvement in 5 out of 6 patients in both treatment groups . A similar improvement occurred in all 3 patients with acne fulminans . When corticosteroid was stopped, 2 out of 5 patients with cystic acne had a relapse and needed isotretinoin for complete control . In the isotretinoin-treated group, one patient with cystic acne needed prednisolone because the acne worsened to an ulcerative form . Slightly elevated liver enzymes, possibly due to erythromycin treatment, were observed in 2 patients with cystic acne and in one patient with acne fulminans . The present results show that prednisolone combined with erythromycin is an effective treatment during the early stages of cystic and febrile acne, but isotretinoin is needed for long-term control.

Gastroenterology, 1993 Dec, 105(6), 1746 - 53
Nitric oxide mediates nonadrenergic, noncholinergic neural relaxation in the Australian possum; Baker RA et al.; BACKGROUND: Nitric oxide has been shown to play an important role in neurally mediated relaxations of gastrointestinal smooth muscle . The aim of this study was to determine whether NO may be the inhibitory transmitter to circular smooth muscle from the sphincter of Oddi of the Australian brush-tailed possum (Trichosurus vulpecula) . METHODS: The effects of drugs on relaxations evoked by electrical-field stimulation of circular muscle strips precontracted with either erythromycin or carbachol were studied . Preparations were also processed histochemically to determine the presence of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase reactivity in the tissue . RESULTS: NG-nitro-L-arginine methyl ester reduced the amplitude of relaxations; this effect could be partially reversed by millimolar concentrations of L-arginine but not by D-arginine . Oxyhemoglobin also reduced the amplitude of the relaxations, and sodium nitroprusside mimicked the relaxations in precontracted strips . Histochemical processing revealed the presence of nerve cell bodies and nerve fibers associated with the circular muscle layer, which are reactive for NADPH-diaphorase and are thus likely to contain NO synthase . CONCLUSIONS: These results are all consistent with NO released from nerve cells mediating a significant part of the nonadrenergic, noncholinergic relaxation of the circular muscle layer of the sphincter of Oddi.

Diabetes Care, 1993 Nov, 16(11), 1511 - 4
Comparison of metoclopramide and erythromycin in the treatment of diabetic gastroparesis; Erbas T et al.; OBJECTIVE--To compare the effects of erythromycin and metoclopramide on gastric emptying and symptoms of gastroparesis in diabetic patients with delayed gastric emptying . RESEARCH DESIGN AND METHODS--The study group consisted of 13 patients with symptoms of severe gastroparesis and delayed gastric emptying . Gastric emptying was evaluated using a radionuclide method, and gastrointestinal symptoms were scored . The patients were given either erythromycin (250 mg 3 times/day) or metoclopramide (10 mg 3 times/day) in random order for 3 wk, and after a washout period of 3 wk they were crossed-over to the other medication for another 3 wk . Parameters of gastric emptying were assessed before treatment and after both erythromycin and metoclopramide administration . RESULTS--The half-time of gastric emptying in diabetic subjects was 110 (77-120) min before treatment . At 60 and 90 min, the median value of residual isotope activity was 66.5 (55-83.5) and 55% (43-74.3), respectively . The half-time decreased to 55 min (28.6-115) after 3 wk of treatment with erythromycin and percentages of meal retention in the stomach at 60 and 90 min were 49.9 (38.4-70) and 40.5% (29.7-60), respectively . After taking metoclopramide, the median value of half-time was 67 min (15-115) and percentages of meal retention at 60 and 90 min were 51 (34.5-93.9) and 42% (24-71.2), respectively . When compared with baseline values a significant difference in gastric emptying parameters was found after both erythromycin and metoclopramide . A significant improvement of the total score for gastrointestinal symptoms was observed with both drugs, but this improvement was more pronounced with erythromycin . CONCLUSIONS--Erythromycin, a macrolide antibiotic and a motilin receptor agonist, appears to stimulate intestinal motility and seems to be an alternative agent for the treatment of gastroparesis caused by diabetic autonomic neuropathy.

Nihon Kyobu Shikkan Gakkai Zasshi, 1993 Nov, 31(11), 1449 - 55
{A case of primary amyloidosis with diffuse alveolar hemorrhage}; Yanase K et al.; A 58-year-old man was admitted complaining of hemoptysis and dyspnea . Chest roentgenogram demonstrated bilateral alveolar infiltrates in the middle and lower lung fields . Diffuse alveolar filling shadows were seen on standard chest CT images . His symptoms and pulmonary infiltrates gradually resolved after administration of high-dose corticosteroids and erythromycin . Immunoelectrophoresis showed increased IgM of lambda type . Transbronchial lung biopsy specimens revealed amyloid deposits in the alveolar septa and blood vessel walls . Cervical lymph node biopsy specimen also showed amyloid deposits . The amyloid in this case stained positively with anti-A lambda type amyloid antibody . A diagnosis of primary systemic amyloidosis was made.

Nihon Kyobu Shikkan Gakkai Zasshi, 1993 Nov, 31(11), 1367 - 76
{Effect of erythromycin on mucociliary transport and clinical symptoms in patients with sinobronchial syndrome}; Nishi K et al.; The effect of erythromycin (EM) on mucociliary transport function assessed by saccharin test and clinical symptoms were studied in 19 patients with sinobronchial syndrome (SBS) . Before treatment with EM, the mean nasal clearance time (NCT) of SBS patients was 51.9 +/- 40.5 (SD) min, which was significantly (p < 0.01) longer than that of control subjects (12.4 +/- 5.3 min) . After 4-week treatment with oral EM (600 mg/day), NCT of SBS patients significantly (p < 0.01) improved (29.2 +/- 34.2 min) . In 11 of 19 SBS patients, bacteria from sputum culture disappeared after EM therapy . Frequency of cough and volume of sputum were significantly (p < 0.05) decreased by EM therapy . Nasal symptoms (such as nasal obstruction and rhinorrhea) were also significantly (p < 0.05) improved by EM therapy . These findings suggested that disorder of mucociliary transport function was present in patients with SBS, and EM therapy improved this function . EM clinically improved not only the lower airway symptoms, but also the nasal symptoms.

Nat Immun, 1993 Nov-Dec, 12(6), 326 - 38
Proliferation of erythromycin-stimulated mouse peritoneal macrophages in the absence of exogenous growth factors; Kita E et al.; Erythromycin (0.2-20 micrograms/ml) induced the proliferation of macrophages of mouse peritoneal exudate cells (PEC) in a liquid medium without exogenous growth factors . The proliferating macrophages formed giant colonies between days 22 and 26 of culture; these colonies continued to proliferate even after subculture . The erythromycin-induced cell proliferation was independent of fibroblasts, T cells, B cells, or endotoxins . This activity seemed to be specific to erythromycin since other antibiotics such as tetracycline, streptomycin, gentamicin, penicillin G, and josamycin did not induce the proliferation of macrophages . Any known cytokines, including IL-2, IL-3, IL-4, IL-6, and GM-CSF, were not detectable by ELISA tests in any of the culture supernatants sampled from day 7 through day 28 . The culture supernatants, however, had the capability of inducing the growth of macrophages, only in the presence of bioactive erythromycin at concentrations higher than 1.6 micrograms/l . Moreover, the culture supernatants, sampled after giant colonies had been formed, were capable of inducing giant colonies in the culture of adherent PEC . Thus, the erythromycin-induced macrophage proliferation might be due to the direct effect of this antibiotic, whereas the formation of giant colonies might be due to the production of some unidentified soluble factor produced by the proliferating macrophages . These data indicate that mouse PEC contain a subset of peritoneal macrophages capable of responding to erythromycin by forming proliferating colonies without exogenous growth factors.

Epidemiology, 1993 Nov, 4(6), 496 - 501
The increased risk of hospitalizations for acute liver injury in a population with exposure to multiple drugs; Perez Gutthann S et al.; We conducted a nested case-control study to estimate and compare the relative risks for hospitalizations for newly diagnosed acute liver injury associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) and other hepatotoxic drugs and their interaction . The source population comprised 228,392 members of the Saskatchewan Health Plan from 1982 to 1986 . We used hospital records and the databases of the Department of Health . Thirty-four cases with confirmed liver injury were hospitalized . We randomly selected 500 controls from the source population . Crude risks ranged from 1 case per 100,000 prescriptions in current users of methyldopa, ampicillin, or NSAIDs to 14 cases per 100,000 prescriptions in current users of erythromycin estolate . The age-adjusted odds ratios for current users of NSAIDs was 1.8 {95% confidence interval (CI) = 0.8-3.7} and for other hepatotoxic drugs 5.9 (95% CI = 2.8-12.4) . The adjusted relative excess risk due to the interaction between current exposure to both categories of drugs was 3.6, accounting for 31% of the cases of acute liver injury among those with exposure to both types of drugs . We conclude that the risk of hospitalization for acute noninfectious liver injury is different among users of various individual potentially hepatotoxic drugs . Concomitant current exposure to two or more drugs increases this risk above what would merely be expected from the sum of the individual risks.

Br J Dermatol, 1993 Nov, 129(5), 563 - 70
The effect of zinc in the form of erythromycin-zinc complex (Zineryt lotion) and zinc acetate on metallothionein expression and distribution in hamster skin; Morgan AJ et al.; The occurrence of zinc-induced synthesis of metallothionein in skin after topical application of the anti-acne drug Zineryt lotion was investigated in hamster ears . The dinitrophenyl hapten-sandwich immunohistochemical method involving a monoclonal anti-metallothionein (MT) antibody (E9) was used to detect and localize zinc-binding MT in the 'treated' and untreated hamster skin . Atomic absorption spectrophotometry and dithizone histochemistry indicated that zinc penetrated the skin more readily, and accumulated more efficiently within the sebaceous glands, when applied to the skin surface as the organo-zinc complex, rather than as the inorganic zinc salt . MT and zinc had similar distributions in hamster skin exposed to the metal . Thus, MT immunoreactivity was especially intense in the sebaceous glands of Zineryt lotion-treated skin, with evidence of nuclear distribution in some cells . Zinc delivered to the sebaceous glands, and released from the organo-complex under the prevailing aqueous conditions, certainly induced MT synthesis; the cysteine-rich protein may protect the pilosebaceous units during the inflammatory phase of acne by scavenging generated oxyradical species.

Cancer Res, 1993 Nov 1, 53(21), 5121 - 6
Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions; Zhou-Pan XR et al.; Vinblastine biotransformation was investigated by using a human liver microsomes library . The drug was converted into one major metabolite (M) upon incubation with the microsomes . A large interindividual variation in vinblastine metabolism was observed among the samples tested, with a 4.4 ratio between the lowest and the highest metabolic rates . The biotransformation of vinblastine followed Michaelis-Menten kinetics (Km = 6.82 +/- 0.27 microM and Vmax = 0.64 +/- 0.06 nmol/min/mg protein) . The involvement of the cytochrome P450 3A subfamily in vinblastine metabolism was demonstrated by the following body of evidence: (a) the competitive inhibition of vinblastine biotransformation by cytochrome P450 3A specific probes with Ki values of 0.17, 22.5, 14.8, and 35.3 microM for ketoconazole, erythromycin, troleandomycin, and vindesine, respectively; (b) the immunoinhibition of vinblastine metabolism by polyclonal anti-cytochrome P450 3A antibodies; (c) the highly significant correlation between the level of cytochrome P450 3A determined by Western blots and vinblastine metabolism (r = 0.759, P < 0.001); (d) the highly significant correlation between erythromycin N-demethylase activity (mediated by cytochrome P450 3A) and vinblastine metabolism (r = 0.83, P < 0.001); (e) the significant correlation between the CYP3A4 mRNA level and vinblastine metabolism (r = 0.60, P < 0.1) . Although vincristine and navelbine (members of the Vinca alkaloid family) also inhibit the metabolism of vinblastine, suggesting the involvement of the cytochrome subfamily in their respective metabolisms, other anticancer drugs currently associated with vinblastine in chemotherapy (etoposide, Adriamycin, lomustine, and teniposide) also interfere with vinblastine biotransformation . These metabolic drug interactions may alter the antitumor activity and/or toxicity of the drug during anticancer chemotherapy.

Radiology, 1993 Nov, 189(2), 559 - 62
Diffuse panbronchiolitis: follow-up CT examination; Akira M et al.; PURPOSE: The authors reviewed serial computed tomographic (CT) scans obtained in 19 patients with diffuse panbronchiolitis (DPB) to evaluate changes in disease pattern over time . MATERIALS AND METHODS: Nineteen patients with DPB were entered into the study . After initial CT examination, 12 patients were randomly assigned to receive long-term low-dose (200 mg three times daily) erythromycin therapy; seven patients received no treatment . RESULTS: Follow-up CT scans revealed that centrilobular areas of high attenuation observed initially had progressed to dilatation of the proximal airway in some patients in the untreated group . In the treated group, the centrilobular and branched linear areas of high attenuation were decreased in number and size, although the airway dilatation and decreased lung attenuation in the peripheral areas remained unchanged or were slightly increased . CONCLUSION: CT scans are valuable in the study of the disease process and response to therapy in DPB.

J Hepatol, 1993 Nov, 19(3), 367 - 76
Effect of tauroursodeoxycholate on actin filament alteration induced by cholestatic agents . A study in isolated rat hepatocyte couplets; Thibault N et al.; The mechanism of the protective effect of ursodeoxycholic acid in cholestatic liver diseases remains unclear . Since there is evidence that alterations in the pericanalicular actin microfilament network play a major role in cholestasis, the aims of this study were (a) to determine the effect of the cholestatic agents, taurolithocholate (TLC) and erythromycin estolate (ERY), on F-actin distribution in isolated rat hepatocyte couplets and (b) to assess the effect of tauroursodeoxycholate (TUDC) and taurocholate on the modifications induced by these two compounds . F-actin was stained with fluorescein-isothiocyanate phalloidin and fluorimetric measurements were performed using a scanning laser cytometer ACAS 570 . F-actin distribution was assessed in the couplets by the ratio of the pericanalicular area fluorescence/total couplet fluorescence (CF/TF) . At non-cytotoxic concentrations, TLC (50, 100 microM) and ERY (10, 50, 100 microM) induced a significant accumulation of F-actin around the bile canaliculus as indicated by increased fluorescence in the pericanalicular area and by the increased CF/TF ratio compared with the controls . Electron microscopy studies showed significant alterations in bile canaliculi microvilli in couplets treated with 100 microM TLC . Only a few canaliculi showed an increase in pericanalicular microfilaments after treatment with 100 microM ERY . As assessed by scanning laser cytometry, TUDC prevented changes in F-actin distribution when it was added to the medium with taurolithocholate or erythromycin estolate at equimolar concentrations . However, the morphological changes observed by electron microscopy after treatment with TLC were not modified by co-treatment with TUDC . Taurocholate was ineffective . We conclude that (a) abnormalities of pericanalicular F-actin microfilaments occur in two different models of cholestasis, (b) tauroursodeoxycholate prevents the accumulation of pericanalicular F-actin detected by scanning laser cytometry but not the morphological changes of the canaliculus observed by electronic microscopy . Therefore, in these experimental conditions, the protective effect of TUDC appears to be partial.

J Pediatr Gastroenterol Nutr, 1993 Nov, 17(4), 387 - 91
Treatment of cyclic vomiting in childhood with erythromycin; Vanderhoof JA et al.; Cyclic vomiting syndrome is an unusual cause of episodic emesis in children . It manifests as intermittent episodes of severe vomiting, similar in time of onset and duration, with no symptoms during the intervening period . Dehydration necessitating intravenous fluid therapy may occur . Most therapeutic maneuvers have proven unsuccessful . We report the use of erythromycin as a prokinetic agent in the treatment of cyclic vomiting in 20 children (9 boys, 11 girls) . Many patients had mild associated abdominal pain with their vomiting . Thirteen patients had previously been given metoclopramide, but none responded . Two patients were mildly developmentally delayed . Twenty patients were given oral erythromycin ethylsuccinate, approximately 20 mg/kg/day, in 2-4 divided doses for 7 days . This dosage was repeated as needed when symptoms reappeared . Thirteen of 20 patients reported total resolution of symptoms when reevaluated at 2 and 6 months . All males responded, 4 of 13 responders were female, and all seven with partial or no response to therapy were female . This uncontrolled trial suggests that erythromycin may be a useful prokinetic agent in the treatment of cyclic vomiting syndrome in childhood . As the study was uncontrolled, placebo effect cannot be excluded . Case-controlled, double-blinded prospective trials should be considered to evaluate the effectiveness of erythromycin in cyclic vomiting syndrome.

Peptides, 1993 Nov-Dec, 14(6), 1153 - 7
Distribution and characterization of motilin receptors in the cat; Depoortere I et al.; We demonstrate binding of {125I}{Nle13-po}motilin to homogenates of cat gastric and small intestinal, but not to colonic smooth muscle tissue . The density was (Bmax in fmol/mg protein): 0 (fundus); 12 +/- 2 (corpus); 22 +/- 3 (antrum); 55 +/- 12 (duodenum); 44 +/- 10 (jejunum); 17 +/- 1 (ileum); 0 (colon) . A significant (p < 0.05) difference was found between the dissociation constant for motilin in the stomach (pKd = 8.84 +/- 0.06) and in the small intestine (pKd = 8.58 +/- 0.08) . The motilides erythromycin-A (EM-A), EM-523, and EM-A N-oxide displaced labeled {Nle13-po}motilin bound to cat duodenal receptor with potencies (pKd) of 5.47 +/- 0.23, 7.60 +/- 0.24, and < 4.3, respectively . Studies with {Leu13-po}motilin fragments showed that the N-terminus of motilin interacts with the receptor . In the tissue bath, duodenal strips mounted in the longitudinal direction responded to motilin, EM-523, and EM-A (pEC50: 8.29 +/- 0.08; 7.12 +/- 0.12; 5.99 +/- 0.15) . The compounds had a comparable intrinsic activity (83 +/- 3%; 80 +/- 5%; 82 +/- 5% of the response to ACh), which was unaffected by atropine, TTX, hexamethonium, and zacopride but reduced by verapamil and calcium-free medium . Cat stomach and small intestine possess smooth muscle motilin receptors, which have comparable properties as those found in man and in rabbit.

Md Med J, 1993 Nov, 42(11), 1119 - 22
Desquamative interstitial pneumonia: a case presentation; Patel MB; A 25-year-old African-American woman presented in the emergency room of a community hospital complaining of shortness of breath . The patient was admitted with a diagnosis of atypical pneumonia . Her respiration worsened despite intravenous erythromycin, nebulized albuterol, 40% oxygen via ventimask, and guaifenesin . An open lung biopsy revealed pulmonary tissue showing interstitial fibrosis with lymphocytes and histiocytes scattered within the fibrous tissue . Numerous alveoli contained mononuclear cells as seen in desquamative interstitial pneumonia . The patient did not respond to methylprednisolone and died on the eighteenth hospital day.

An Med Interna, 1993 Nov, 10(11), 547 - 8
{Pulmonary abscess and pleural empyema caused by Legionella pneumophila in kidney transplant recipient}; Zamarron Sanz C et al.; A kidney transplanted patient developed a nosocomial pneumonia and pleural empyema due to Legionella pneumophila . Despite erythromycin and rifampin treatment the patient died . The diagnosis was made by direct fluorescent antibody staining of pleural fluid.

S Afr Med J, 1993 Nov, 83(11), 855 - 6
Bacillary angiomatosis . The first case reported in South Africa; Levy GR et al.; A 28-year-old white man, positive for HIV, who was admitted to hospital for pneumonia, had for 2 months had several fluctuating cutaneous purple nodules on his legs and abdomen . Cultures of two lesions were negative, but light and electron microscopy showed organisms characteristic of bacillary angiomatosis . The patient responded well to therapy with erythromycin . This is the first reported case of bacillary angiomatosis in South Africa.

Allergol Immunopathol (Madr), 1993 Nov-Dec, 21(6), 225 - 6
Urticaria from erythromycin; Lopez Serrano C et al.; We report an adverse cutaneous reaction (urticaria) due to erythromycin . A positive skin prick and leukocyte histamine release tests, as well as a positive single-blind, placebo controlled oral challenge to erythromycin, strongly suggest an IgE mediated hypersensitivity mechanism.

Res Commun Chem Pathol Pharmacol, 1993 Nov, 82(2), 209 - 16
Effects of twenty-three drugs on the metabolism of FK506 by human liver microsomes; Iwasaki K et al.; We investigated the effects of 23 drugs on the metabolism of FK506 by human liver microsomes . Acyclovir, amphotericin B, cefixime, cefotaxime, ciprofloxacin, cyclosporin A, diltiazem, enoxacin, erythromycin, ethinyl estradiol, fluconazole, fosfomycin, kanamycin, lincomycin, loxoprofen, minocyclin, nifedipine, nilvadipine, norethindrone, ofloxacin, phenobarbital, prednisolone, or rifampicin was added to the reaction media at equimolar or at ten times an excess molar ratio of the substrate concentration; their effects on FK506 metabolism were examined . Drugs known to be the substrate of cytochrome P-450 3A inhibited the metabolism of FK506, and among the drugs tested, the inhibition by cyclosporin A and nifedipine was the strongest.

Pharm World Sci, 1993 Oct 15, 15(5), 212 - 8
Public health problems and the rapid estimation of the size of the population at risk . Torsades de pointes and the use of terfenadine and astemizole in The Netherlands; Herings RM et al.; Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern . Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia . The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine . To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied . Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals . The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low . Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.

Aten Primaria, 1993 Oct 15, 12(6), 359 - 62
{Acquired pneumonias in the community of Andoain}; Aguirre I et al.; OBJECTIVE . To discover the clinical-epidemiological characteristics of pneumonias in our community . DESIGN . Descriptive study . SETTING . Andoain Health Centre . PATIENTS AND OTHERS PARTICIPANTS . There were 8,862 people in the reference population . All the cases of acquired pneumonia in the community were recorded . This register included those diagnosed in the Health Centre and in Casualty Departments and hospitals where patients were referred, between June 1 1991 and September 30 1992 . The inclusion criteria were: acute fever chart and/or acute respiratory infection accompanied by a radiological image of pneumonic condensation . INTERVENTIONS . The model treatment was 500 mg of Erythromycin at six-hourly intervals for 14 days . 500 mg of Cefuroxim every twelve hours was added in cases considered at risk . MEASUREMENTS AND MAIN RESULTS . A total of 97 pneumonias were recorded, which represented an incidence of 8.82 pneumonias per thousand inhabitants per year . 63% were male . The average age was 42 (SD 19.25) . 83% were diagnosed at the Health Centre . One-third presented a recent viral infection . Half had some risk factor: tobacco use was the most common . Response to treatment was satisfactory . Five percent had some complication . No death was recorded . CONCLUSIONS . Pneumonia is a frequent cause of attendance at Primary Care centres . There are several clear clinical symptoms, a good response to treatment with Erythromycin and virtual absence of complications {corrected}.

Biochem Pharmacol, 1993 Oct 5, 46(7), 1151 - 7
Metabolism of cyclosporine after orthotopic liver transplantation; Fabre JM et al.; The aim of this work was to determine whether the extensive metabolism of cyclosporine, acquired in a donor by treatment with an inducer of cytochrome P450 3A (P450 3A) (cyclosporine oxidase), was transmissible to the recipient by orthotopic liver transplantation . For this purpose, male Wistar rats were divided into five groups including: control animals (group C), animals treated with dexamethasone (an inducer of P450 3A, 50 or 300 mg/kg/day, for 4 days, group D), animals transplanted with the livers of control rats (group G) or with the livers of dexamethasone-induced rats (group GD), and animals treated with beta-naphthoflavone (an inducer of P450 1A, group B) . All animals received a single i.v . dose of 10 mg/kg cyclosporine 24 hr after either the last dose of inducer or the transplantation . For each group of animals, the area under the curve (AUC) of cyclosporine was calculated from the curves of blood cyclosporine levels (by radioimmunoassay) against time; liver microsomes were assayed for cyclosporine oxidase activity by HPLC, erythromycin demethylase and P450 3A level by western blot with specific anti-P450 3A antibodies . The decrease in the AUC in groups D and GD with respect to C and G was correlated with increased level of P450 3A (4-5-fold with respect to control) as well as of microsomal cyclosporine oxidase . In addition, cyclosporine oxidase activity of liver microsomes was specifically inhibited by anti-P450 3A antibodies and troleandomycin . The animals in group B did not exhibit increased metabolism of cyclosporine either in vivo or in vitro . We conclude that: (1) cyclosporine is predominantly oxidized in the rat liver by a form of P450 from the 3A subfamily; (2) the extensive metabolism of cyclosporine acquired by donor rats after treatment with dexamethasone is transmissible to the recipients through orthotopic liver transplantation.

Infect Immun, 1993 Oct, 61(10), 4139 - 46
Characterization of the tpr gene product and isolation of a specific protease-deficient mutant of Porphyromonas gingivalis W83; Park Y et al.; The previously described protease gene (tpr) of Porphyromonas gingivalis W83 was shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the recombinant protein and in vitro translation to encode a 50-kDa protein whose active form migrates with an apparent molecular mass of 90 kDa . The 50-kDa protein was expressed at high levels by using a T7 RNA polymerase/promoter system . The NH2-terminal sequence of the protein was identical to the amino acid sequence deduced from the DNA sequence of the protease gene . Affinity-purified antibody to the 90-kDa recombinant protease reacted with an 80-kDa P . gingivalis protein . A specific protease (Tpr)-deficient isogenic mutant of P . gingivalis was generated by homologous recombination between P . gingivalis chromosomal DNA and a suicide plasmid carrying the cloned gene disrupted by insertion of an erythromycin resistance gene . Gelatin substrate zymography showed that cell extracts of the mutant lacked a protease band that migrated with an apparent molecular mass of 80 kDa . Western immunoblots of the cell extracts indicated the loss of an antigen with a similar mass.

Chest, 1993 Oct, 104(4), 1191 - 3
Anti-inflammatory action of erythromycin . Its inhibitory effect on neutrophil NADPH oxidase activity; Umeki S; The effects of erythromycin on the NADPH oxidase activity in the neutrophils of normal subjects and patients with bronchiolitis were investigated . In the patients receiving erythromycin, NADPH oxidase activity was significantly lower in a whole-cell system than that before therapy . Erythromycin was also found to inhibit the superoxide generation of neutrophils exposed to phorbol myristate acetate in a whole-cell system and the activation of superoxide-generating NADPH oxidase by sodium lauryl sulfate (sodium dodecyl sulfate) in a cell-free system . The concentration of the drug required for 50 percent inhibition of the oxidase was 0.7 mM in the whole-cell system and 0.2 mM in the cell-free system . These results suggest that erythromycin, an antibiotic which penetrates well into human neutrophils, may exhibit an anti-inflammatory action due to inhibiting of neutrophil NADPH oxidase activation.

Circulation, 1993 Oct, 88(4 Pt 1), 1832 - 44
Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome; Rubart M et al.; BACKGROUND . Erythromycin is known to prolong ventricular repolarization and has been associated with the occurrence of torsades de pointes . In this study, we have investigated potential mechanisms in vivo and in vitro for induction of an acquired long QT syndrome by erythromycin . METHODS AND RESULTS . Ventricular electrograms and endocardial monophasic action potentials were recorded in anesthetized open-chest dogs before and after administration of 40 to 120 mg/kg of erythromycin lactobionate . Conventional microelectrode techniques were used to record transmembrane action potentials in isolated dog Purkinje fibers and papillary muscles . Erythromycin at concentrations > 20 mg/L prolonged action potential duration . At higher concentrations (100 to 200 mg/L), erythromycin induced phase 2 and phase 3 early afterdepolarizations (EADs) both in vivo and in vitro . The effects of erythromycin on repolarization were more marked in Purkinje fibers than in papillary muscle . Pretreatment of Purkinje fibers with erythromycin antagonized the effects of dofetilide, a selective delayed-rectifier potassium channel (IK) blocker . Pretreatment with prazosin or tetrodotoxin had no effect on erythromycin-induced changes in action potential duration . CONCLUSIONS . These pharmacological studies suggest that erythromycin prolongs repolarization to a large extent by block of IK . In turn, prolongation of action potential duration resulting from erythromycin's actions on IK may promote the development of EADs . The induction of ventricular arrhythmias observed clinically after exposure to erythromycin may be related to the development of EADs . The rarity of occurrence of ventricular arrhythmias suggests that other predisposing factors contribute to the acquired long QT syndrome associated with erythromycin.

Ann Intern Med, 1993 Oct 1, 119(7 Pt 1), 576 - 83
Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines; Carson JL et al.; OBJECTIVE: To determine whether erythromycins, sulfonamides, and tetracyclines are associated with an increased risk for acute hepatitis . DESIGN: Case-control study . SETTING: Medicaid billing data from Michigan and Florida between 1980 and 1987 . PATIENTS: The 107 cases included patients hospitalized with acute symptomatic hepatitis without an identifiable cause of liver disease noted in the medical record . Four controls per case were randomly selected and were matched for age, sex, and state . RESULTS: Five cases (4.7%) and four controls (0.9%) were exposed to erythromycins, yielding an odds ratio of 5.2 (95% Cl, 1.1 to 26.6) . No case or control was exposed to erythromycin estolate . Eight cases (7.5%) and three controls (0.7%) were exposed to oral sulfonamides, yielding an odds ratio of 11.4 (Cl, 2.7 to 67.8) . All (except one control) had received trimethoprimsulfamethoxazole . Five cases (4.7%) and four controls (0.9%) were exposed to tetracyclines, yielding an odds ratio of 5.2 (Cl, 1.4 to 19.7) . The results did not change substantively for erythromycin or sulfonamides after adjustment using multiple logistic regression for age, sex, state, and use of other hepatotoxic drugs . With tetracyclines, however, the odds ratio decreased to 3.6 (Cl, 0.9 to 14.3) . Associations were also seen with isoniazid (P = 0.008) and rifampicin (P = 0.04) . The number of patients developing acute symptomatic liver disease resulting in hospitalization for each million patients treated with a 10-day course of erythromycin was 2.28 cases; for sulfonamides, this figure was 4.8 cases; and for tetracycline, the figure was 1.56 cases . CONCLUSION: Erythromycin, sulfonamides, and tetracyclines are associated with acute symptomatic hepatitis resulting in hospitalization . Given the widespread use of these drugs, they will be among the more common drugs associated with hepatitis.

Jpn J Pharmacol, 1993 Oct, 63(2), 209 - 17
Comparison of the motor-stimulating action of EM523, an erythromycin derivative, and prostaglandin F2 alpha in conscious dogs; Inatomi N et al.; The effect of EM523 {de(N-methyl)-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal}, an erythromycin derivative, on gastrointestinal motility was investigated using conscious dogs in the fasting state, and it was compared with those of motilin and prostaglandin F2 alpha (PGF2 alpha) . EM523 and motilin given as i.v . infusions induced strong contractions in the stomach that migrated along the intestine . On the other hand, PGF2 alpha stimulated intestinal contractions, but its effect on gastric motility was weak . EM523 had 1/50 the potency of motilin and 6 times the potency of PGF2 alpha for stimulation of intestinal motility . Atropine at 0.1 mg/kg, i.v . strongly inhibited gastrointestinal contractions induced by EM52 EM523 or motilin and partly inhibited PGF2 alpha-induced intestinal motility . ICS-205-930, a 5HT3-receptor antagonist, at a dose of 1 mg/kg, i.v . strongly inhibited EM523 or motilin-induced gastric contractions but did not affect the action of PGF2 alpha . Infusion of EM523 at 100 micrograms/kg/hr induced strong migrating contractions even when motility was depressed by dopamine infusion or laparotomy . Infusion of PGF2 alpha at 300 micrograms/kg/hr stimulated intestinal but not gastric motility under these conditions . The results of this study indicate that the cholinergic pathway and 5HT3 receptors are involved in EM523 and motilin-induced migrating gastrointestinal contractions, whereas the cholinergic pathway seems to be only partly involved in PGF2 alpha-induced intestinal contractions.

Nihon Kyobu Shikkan Gakkai Zasshi, 1993 Oct, 31(10), 1251 - 6
{Clinical effects of low-dose and long-term erythromycin in diffuse panbronchiolitis with chronic respiratory failure}; Ohno S et al.; We studied the effects of erythromycin (EM) in diffuse panbronchiolitis (DPB) with chronic respiratory failure . Seventeen patients with DPB or sinobronchial syndrome receiving home oxygen therapy (HOT) were treated with EM of 400-600 mg/day for twelve months . Five patients discontinued HOT, and hypoxemia was improved in five other patients . Clinical effects were evident at one month after the start of EM administration, and a stable state was achieved after six months of EM therapy . FEV1 was significantly increased in pulmonary function tests . Factors which influenced the effects of EM included the period between onset of clinical symptoms and commencement of HOT and/or between commencement of HOT and administration of EM . EM was effective for patients with obstructive, but not constrictive impairment in pulmonary function tests . These findings indicate that EM is effective for DPB even in patients with chronic respiratory failure.

Biopharm Drug Dispos, 1993 Oct, 14(7), 615 - 25
Cyclosporin A and erythromycin: a study of a drug interaction in the in situ perfused rat liver model; Hughes CM et al.; Using the in situ perfused rat liver model, the effect of erythromycin (Ery) on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1, was investigated . Prior to perfusion experiments, oral dosing was carried out for three days on three groups of male Sprague-Dawley rats (300-350 g), involving pretreatment with water (control and H2O/Ery groups) or erythromycin (Ery oral group) . On the fourth day, perfusion experiments took place using standard techniques, with the addition of 20 mg Ery to the H2O/Ery and Ery oral groups, and 2.5 mg CyA to all groups . Perfusate and bile samples were collected and assayed for CyA and AM1 by HPLC . Results indicated that inhibition of CyA metabolism had occurred as the CyA concentration in perfusate was significantly higher in both Ery groups at all times compared to the control group, and the levels of AM1 in both perfusate and bile were significantly lower than in the control group . There was also a marked reduction in the apparent metabolic clearance of CyA in the Ery groups . It was concluded that AM1 production had been inhibited by Ery, the most likely mechanism being inhibition of the isoenzyme CYP3A with which Ery forms a stable complex.

Otolaryngol Clin North Am, 1993 Oct, 26(5), 811 - 9
Ototoxic liability of erythromycin and analogues; Brummett RE; This article details clinical reports and studies of ototoxicity associated with the administration of erythromycin and its analogues . Suspected mechanisms of ototoxicity also are discussed . Ototoxicity due to erythromycin appears to be clearly dose related.

Practitioner, 1993 Oct, 237(1531), 789 - 91
Serious drug interactions; Aronson J; PIP: Of the many varieties of drug interactions, which occur when the disposition or actions of one drug are changed by another, only a few are serious or potentially fatal . A representative outline of some of these illustrates the problem . Precipitant drugs are those which produce the interaction, and object drugs are those whose effects are changed . The interactions which are usually significant are those which alter the metabolism, involve renal excretion, or change the effects of the object drug, especially when the object drug has a low therapeutic index (cardiovascular drugs, anticoagulants, drugs acting on the brain, hypoglycemic drugs, hormones, and cytotoxic drugs) . Warfarin toxicity, for example, is produced by aspirin, phenylbutazone, and azapropazone . The dosage requirements of warfarin are reduced by chloramphenicol, ciprofloxacin and other quinolones, erythromycin and some of the other macrolides, metronidazole and other imidazoles, tetracyclines, amiodarone, cimetidine (but not ranitidine), and fibrates . Potassium-depleting drugs can potentiate the action of digoxin, and the elimination of digoxin can be reduced by amiodarone, propafenone, quinidine, and verapamil . Combined oral contraceptives can lose effectiveness through the interaction of carbamazepine, griseofulvin, phenytoin, or rifampicin, which increase estrogen metabolism . In addition, broad-spectrum antibiotics such as ampicillin or tetracyclines also reduce contraceptive effectiveness by altering gut absorption . Even a single drink of an alcoholic beverage may be dangerous to people taking antidepressants, antihistamines, antipsychotic drugs, benzodiazepines, or lithium . Antihistamines suffer inhibited metabolism in the liver if taken in conjunction with the antifungal imidazoles and some of the macrolide antibiotics . Cardiotoxicity of antihistamines is also enhanced by drugs with similar cardiotoxic effects . Lithium potentiation is enhanced by the new serotonin-reuptake inhibitors, and lithium excretion can be reduced by diuretics or fluoxetine . When drugs such as antifungal imidazoles, azapropazone, or phenylbutazone are permitted to inhibit the metabolism of sulphonylureas, hypoglycemic effects are enhanced and, if unnoticed, may cause brain damage . Fibrates should not be combined with HMG-CoA reductase inhibitors because of the increased risk of myopathy . Patients taking non-selective monoamine oxidase inhibitors should avoid amine-containing foods and drugs such as matured cheeses, meat, yeast extracts, some wines, unfresh protein, and cold-curing medications . The metabolism of azathioprine is inhibited by allopurinol, and this combination requires a reduced dosage of azathioprine . Mercaptopurine, used in the treatment of leukemia, is also a metabolite of azathioprine . Sources of comprehensive information on drug interactions are 1) the "British National Formulary," appendix 1; 2) Chapter 10 of "The Oxford Textbook of Clinical Pharmacology and Drug Therapy"; and 3) a monograph by Stockley entitled "Drug Interactions."

FEBS Lett, 1993 Sep 27, 331(1-2), 145 - 9
Similarity between serine hydroxymethyltransferase and other pyridoxal phosphate-dependent enzymes; Pascarella S et al.; A structural homology of the pyridoxal-5'-phosphate (PLP)-dependent enzyme serine hydroxymethyltransferase (SHMT) with aspartate aminotransferase (AAT) is proposed . Although the two sequences are very dissimilar, a reasonable alignment was obtained using the profile analysis method . Sequences of AAT and dialkylglycine decarboxylase (DGD), for which crystal structure data are available, have been aligned on the basis of their structure superposition . A profile was then calculated and SHMT sequence aligned to it . Three of the four residues conserved in all aminotransferases (including the PLP-binding lysine) are matched . A profile search with DGD-AAT-SHMT profile is more selective and sensitive than individual sequence profiles for PLP-dependent enzyme detection . Potential homologies with the eryC1 gene product involved in erythromycin biosynthesis and with amino acid decarboxylases were observed . Homology with AAT will be used as a guideline for planning site-directed mutagenesis experiments on SHMT.

Tidsskr Nor Laegeforen, 1993 Sep 20, 113(22), 2810 - 1
{Hearing loss after erythromycin therapy}; Lind O et al.; We describe the case of a patient who developed bilateral loss of hearing during intravenous treatment with erythromycin . Predisposing factors may have been reduced renal and hepatic function and treatment with diuretics and aminoglycosides . Recovery was late, but hearing was probably restored to almost pre-treatment level . Patients receiving high doses of erythromycin should, as a routine, be questioned about hearing loss and tinnitus.

J Chromatogr, 1993 Sep 8, 619(1), 63 - 9
Determination of erythromycin A by liquid chromatography and electrochemical detection, with application to salmon tissue; Janecek M et al.; The chromatographic performance of erythromycin A (EA) is improved significantly over that achieved on polymeric columns by using a sterically shielded octyldiisopropylsilica (Zorbax Rx-C8) column and a neutral mobile phase consisting of 5 mM aqueous sodium perchlorate-acetonitrile (50:50) . This mobile phase facilitates electrochemical detection of EA at the 3-pmol level . Temperature control of both column and detection cell is important for minimizing detector noise and drift . A clean-up procedure, based on aminopropylsilica solid-phase extraction, allows the detection of EA in salmon flesh down to the 0.2-ppm level . Some of the metabolites of EA that retain the tertiary amine may also be detected by this method.

Monatsschr Kinderheilkd, 1993 Sep, 141(9), 711 - 3
{Legionellosis in a newborn infant}; Ahrens F et al.; We describe a case of successful therapy of a neonatal Legionellosis with Erythromycin . On his 6th day of life a full term newborn with normal body weight was affected by a severe pneumonia . This was at first resistant to therapy and required mechanical ventilation . Diagnosis of Legionella pneumophila serotype 1 was made by culture from bronchial lavage . Only few cases of neonatal Legionellosis have been reported until now . In three cases diagnosis was made post mortem.

Ophthalmology, 1993 Sep, 100(9), 1358 - 66
Effective treatment of phlyctenular keratoconjunctivitis with oral tetracycline; Culbertson WW et al.; PURPOSE: To determine the clinical characteristics, possible etiologic agents, and response to oral antibiotic therapy in patients with phlyctenular keratoconjunctivitis . METHODS: The authors reviewed the medical records of the 17 patients with phlyctenular keratoconjunctivitis who were seen and treated at the Bascom Palmer Eye Institute between 1981 and 1991 . RESULTS: All 17 patients were younger than 18 years of age at the onset of their disease . Girls (n = 14) outnumbered boys (n = 3) 4:1 . Significant incapacitating symptoms and ocular morbidity occurred frequently, including three perforated corneas . Five of ten patients who were tested for Chlamydia infection had positive test results and five patients possibly had early rosacea dermatitis . All patients experienced long-term remission of their ocular disease after a course of oral tetracycline or erythromycin . Two patients demonstrated unique linear (fascicular) corneal phlyctenules . CONCLUSION: Oral tetracycline or erythromycin treatment produces long-lasting remission of phlyctenular keratoconjunctivitis in affected children.

Surgery, 1993 Sep, 114(3), 543 - 8
The effect of erythromycin on motility of the duodenum, sphincter of Oddi, and gallbladder in the prairie dog; Kaufman HS et al.; BACKGROUND . Interdigestive motility of the stomach, duodenum, sphincter of Oddi, and gallbladder is mediated through the migrating myoelectric complex and the action of motilin . Erythromycin, a motilin agonist, has recently been studied as a gastrointestinal and biliary prokinetic agent . We hypothesized that erythromycin would increase interdigestive duodenal and sphincter of Oddi motility in a dose-dependent manner . METHODS . In 10 anesthetized prairie dogs we determined the motility responses of the duodenum, sphincter of Oddi, and gallbladder to erythromycin infusion during a three-log dosing regimen and correlated activity with serum concentrations of the drug . RESULTS . Erythromycin administered at 0.01 and 0.1 mg/kg had no effect on duodenal or sphincter motility . At 1.0 and 10 mg/kg, duodenal motility index increased by 451% +/- 114% and 1070% +/- 480%, respectively, when compared with baseline values, (p < 0.05) . Sphincter of Oddi motility index increased by 122% +/- 38% and 323% +/- 99%, respectively, at these same doses of erythromycin (p < 0.05) . Gallbladder pressure did not change significantly during erythromycin infusion . Erythromycin serum concentration at 1.0 mg/kg was 1.0 +/- 0.7 micrograms/ml . CONCLUSIONS . These data suggest that erythromycin stimulates interdigestive motility of the duodenum and sphincter of Oddi in a dose-dependent manner at otherwise subtherapeutic concentrations of the drug.

Surgery, 1993 Sep, 114(3), 538 - 42
Postoperative gastroparesis and tachygastria--response to electric stimulation and erythromycin; Hocking MP; BACKGROUND . The purpose of this study was to correlate clinical course, gastric emptying, and gastric myoelectric activity in a patient after gastric operation and to determine the effect of electric stimulation and the administration of erythromycin on the patient's gastric rhythm . METHODS . Daily myoelectric recordings were obtained through implanted gastric electrodes after truncal vagotomy and gastroenterostomy for an obstructing duodenal ulcer . RESULTS . The patient had acute postoperative delayed gastric emptying, accompanied initially by stomal edema but subsequently associated with persistent tachygastria . The gastric rhythm was only transiently slowed by multiple attempts at electroversion but appeared to respond dramatically to intravenous erythromycin therapy . Although delayed gastric emptying persisted on radionuclide gastric emptying studies, the patient slowly improved clinically with continued erythromycin therapy . CONCLUSIONS . Disturbances in gastric rhythm may accompany postoperative gastroparesis, although in our patient the dysrhythmias appeared to occur secondary to gastric outlet obstruction . Although his stomach could be paced, pacing was not effective in restoring a normal gastric rhythm . In contrast, intravenous erythromycin therapy was associated with rapid restoration of a normal gastric rhythm and slow improvement in gastric function.

Gastroenterology, 1993 Sep, 105(3), 773 - 80
5-hydroxytryptamine-3 receptors are involved in the initiation of gastric phase-3 motor activity in humans; Wilmer A et al.; BACKGROUND: 5-hydroxytryptamine-3 (5-HT3) receptor antagonists inhibit gastric phase-3 motor activity in the dog . This study examined the role of 5-HT3 receptors in the generation of gastric phase 3 of the migrating motor complex in humans . METHODS: Interdigestive motor activity was recorded manometrically in 16 subjects before and after administration of ondansetron, a selective 5-HT3 receptor antagonist . Plasma motilin values were also assayed in 7 individuals . The incidence of gastric activity fronts before and after ondansetron was compared with a control group that had not received ondansetron . The ability of erythromycin to induce a gastric activity front in the presence of ondansetron was also evaluated in 7 subjects . RESULTS: The incidence of gastric activity fronts was 69% before ondansetron vs . 19% after ondansetron . In contrast, in the control group there was no significant change in the incidence of gastric activity fronts over time . Activity fronts preceding ondansetron were associated with motilin peaks while activity fronts after ondansetron were not . Despite the previous administration of ondansetron, erythromycin induced gastric activity fronts in 89% of cases . CONCLUSIONS: Selective antagonism of 5-HT3 receptors suppresses the gastric component of phase-3 motor activity and simultaneously suppresses plasma motilin peaks . The results suggest that the suppression of gastric activity fronts is achieved via the suppression of plasma motilin peaks because in the presence of ondansetron a motilin agonist like erythromycin restores the gastric phase 3.

Zentralbl Bakteriol, 1993 Sep, 280(1-2), 259 - 72
Coccoid like forms (CLF) of Helicobacter pylori . Enzyme activity and antigenicity; Nilius M et al.; In this study we attempted to transform "helical" forms of Helicobacter pylori to "coccoid like forms" (CLF) by induction with the following substances in vitro: bismuth subcitrate, bismuth subsalicylate, ampicillin, amoxicillin, erythromycin, ursodeoxycholic acid and glycochenodeoxycholic acid . Some liquid cultures were incubated for 24 days to induce CLF by aging . Changes in the protein pattern, urease enzyme activity and in the serological response against specific antigens were investigated . In all strains a significant but strain-variable rate of CLF was detected by induction of the tested substances . Beta-lactams and erythromycin generated a population of nearly 100% CLF, including many "spheroblasts" . Relative induction rates by these substances were in the following order: beta-lactams and erythromycin > bismuth subcitrate > bismuth subsalicylate > bile acids . Strain variable reaction also was true for both inhibition of urease activity and influence on immunological response . Urease activity was lost in CLF induced by aging and was inhibited by bismuth salts . CLF induced by aging showed a loss of reactivity bands in the immunoblot . They always lost a 160 kD band and depending on the strain, 115 kD, 108 kD, 100 kD and 95 kD bands . Immunological response to the 120 kD band was reduced . Ultrastructural studies showed great degenerative changes of the cell wall in CLF induced by antibiotics but only few in CLF induced by bismuth salts and bile acids.

Minerva Anestesiol, 1993 Sep, 59(9), 455 - 8
{ARDS in a severe case of primary pulmonary infection caused by Legionella pneumophila}; Da Broi U et al.; The authors report a case of ARDS following pneumonia caused by Legionella pneumophila, in a thirty year old young man . Mechanical ventilation was maintained for twenty days . The gravity of ARDS and pneumonia, perhaps was caused because infective agent and the efficacious antibiotic were identified too late: twelve days after the comparison of symptoms . In fact, early laboratory diagnosis of Legionella pneumonia, is currently very difficult . A primitive extranocosomial pneumonia with rapid development to ARDS, in a good health young man, is an uncommon event . The exclusion of particular causes of ARDS, such as narcotic over-dose, AIDS, lung cancer, lymphatic carcinomatosis, and the clinical suspicion of Legionella pneumonia presence, can be useful: waiting for the right diagnosis from the laboratory, it will be possible to begin antibiotic therapy with Erythromycin (often used for slight respiratory infections), and to prevent the evolution of illness.

Pharmacol Toxicol, 1993 Sep, 73(3), 180 - 5
Oral single doses of erythromycin and roxithromycin may increase the effects of midazolam on human performance; Mattila MJ et al.; Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolam in vitro and in vivo . To find out if significant interactions take place after single oral doses of these agents to man, 0.25 mg triazolam and 5, 10 and 15 mg of midazolam in capsule from were given with and without 750 mg erythromycin or 300 mg roxithromycin to parallel groups of healthy subjects in four placebo-controlled double-blind studies . Objective tests and subjective assessments were made before the intake of hypnotics and 30 and 90 min after it . In Study I, triazolam impaired letter cancellation, the combination triazolam+erythromycin impaired digit symbol substitution and letter cancellation, and triazolam+roxithromycin impaired digit symbol substitution, all at 90 min . In Study II, midazolam 5 mg and midazolam 10 mg proved quite inert but the combination midazolam 5 mg+erythromycin impaired digit symbol substitution . In Study III, both midazolam 10 mg and midazolam 15 mg impaired digit substitution and letter cancellation, the effects of 15 mg being more prominent . The strongest drug effects were found with midazolam 10 mg+erythromycin which differed from placebo and midazolam (10 mg and 15 mg) in several objective and subjective test variables . In Study IV, the combination midazolam 10 mg+roxithromycin impaired several objective and subjective variables but it was not stronger than midazolam 15 mg . These results were supported by the direct measurements of plasma midazolam in three subjects: erythromycin increased plasma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Clin Exp Dermatol, 1993 Sep, 18(5), 410 - 3
Effect of a topical erythromycin-zinc formulation on sebum delivery . Evaluation by combined photometric-multi-step samplings with Sebutape; Pierard GE et al.; Zinc displays 'in vitro' some antiandrogen activity through an inhibition of the 5 alpha-reductase activity . The clinical relevance of this effect is unknown, particularly during zinc therapy of acne . As sebum production could be a pharmacological target, a sensitive method was used for measuring the rate of sebum delivery to the skin surface during treatment with a topical 4% erythromycin-1.2% zinc acetate formulation . A series of four successive 1-h samplings with Sebutape was taken to derive the rate of sebum output from the slope of the regression line given by cumulative data . As a control the classical photometric method was used . Such combined evaluation revealed a sebosuppressive effect for the topical zinc formulation tested.

Arzneimittelforschung, 1993 Sep, 43(9), 1014 - 7
Twice daily dosing of erythromycin acistrate in the treatment of acute bronchitis and pneumonia; Wiesner B et al.; Erythromycin acistrate (Erasis, CAS 96128-89-1) is a 2'-acetyl ester prodrug of erythromycin . Due to prolonged half-life it is more suitable for twice daily dosing than the conventional erythromycin preparations . In the present double-blind trial, totally 297 ambulatory patients with respiratory tract infections were treated either with erythromycin acistrate 800 mg daily or doxycycline 100 mg daily . 243 of the included patients had bronchitis, 15 patients bronchitis and other respiratory tract symptoms, 25 patients pneumonia and 14 other respiratory tract infections . The duration of treatment varied from 7 to 14 days depending on the severity of infection . The efficacy of both treatments was very good . 96.6% of the patients treated with erythromycin acistrate and 97.2% of the patients treated with doxycycline improved . The efficacy of erythromycin acistrate in the treatment of bronchitis and pneumonia was 96.7 and 100%, respectively . Only 5 of the totally 148 patients failed . Side effects (mainly gastrointestinal symptoms) were seen in 12.1% of the patients (20 patients in the erythromycin acistrate group and 16 patients in the doxycycline group) . The results show that erythromycin acistrate dosed twice daily is as effective as doxycycline and well tolerated in the treatment of lower respiratory tract infections.

Ann Surg, 1993 Sep, 218(3), 229 - 37; discussion 237-8
Erythromycin accelerates gastric emptying after pancreaticoduodenectomy . A prospective, randomized, placebo-controlled trial; Yeo CJ et al.; OBJECTIVE: This study tested the hypothesis that erythromycin, a motilin agonist, reduces the incidence of early DGE after pancreaticoduodenectomy . SUMMARY BACKGROUND DATA: Delayed gastric emptying (DGE) is a leading cause of morbidity after pancreaticoduodenectomy, occurring in up to 40% of patients . The pathogenesis of DGE has been speculated to involve factors such as peritonitis from anastomotic leaks, ischemia to the antropyloric muscles, and gastric atony in response to resection of the duodenal pacemaker or reduction in circulating motilin levels . METHODS: Between November 1990 and January 1993, 118 patients undergoing pancreaticoduodenectomy completed this prospective, randomized, placebo-controlled trial . The patients received either 200 mg of intravenous erythromycin lactobionate every 6 hours (n = 58), or an identical volume of 0.9% saline (n = 60) from the third to tenth postoperative days . On the tenth postoperative day, a dual phase radionuclide gastric emptying study was performed . RESULTS: The erythromycin and control groups were comparable regarding multiple preoperative, intraoperative, and postoperative factors . The erythromycin group had a 37% reduction in the incidence of DGE (19% vs . 30%), a significantly reduced (p < 0.05) need to reinsert a nasogastric tube for DGE (6 vs . 15 patients), and a significantly reduced (p < 0.01) per cent retention of liquids at 30 minutes and solids at 30, 60, 90, and 120 minutes . No major adverse reactions to erythromycin were observed . CONCLUSIONS: Erythromycin is a safe, inexpensive drug that significantly accelerates gastric emptying after pancreaticoduodenectomy and reduces the incidence of DGE by 37% . These data support the use of erythromycin to decrease early DGE after pancreaticoduodenectomy.

Am Rev Respir Dis, 1993 Sep, 148(3), 744 - 51
Elevation of tumor-associated carbohydrate antigens in patients with diffuse panbronchiolitis; Mukae H et al.; We investigated the serum levels of the tumor-associated carbohydrate antigens sialyl SSEA-1 (SLX) and sialyl Lewis(a) (CA19-9) in patients with diffuse panbronchiolitis (DPB) and other nonmalignant lung diseases . Both antigens were high in the serum and bronchoalveolar lavage fluid (BALF) of patients with DPB, bronchiectasis (BE), idiopathic pulmonary fibrosis (IPF), and interstitial pneumonia associated with collagen vascular disease (CVD) . Markedly high levels of the antigens were demonstrated in the serum and BALF from patients with DPB . An immunohistochemical study of open-lung biopsy specimens from patients with DPB indicated that these antigens were selectively expressed on the bronchiolar epithelial cells and mucinous exudates in airspaces . Low-dose, long-term erythromycin (EM) treatment was recently reported to be effective for DPB, and we investigated its influence on serum and BALF antigen levels in DPB patients . Antigen levels in both serum and BALF decreased after EM treatment, with improvement of symptoms and laboratory data, and there was a significant correlation between the reduction in the SLX level in serum and neutrophil percentage in BALF pre- and post-EM treatment . Our result suggests that secreted carbohydrate antigens from the bronchiolar epithelium in DPB may appear in the serum as a result of airway damage in the lower respiratory tract, and serum levels of the antigens may be decreased by a reduction in neutrophils in BALF after EM treatment.

Drug Metab Dispos, 1993 Sep-Oct, 21(5), 753 - 60
Comparison of human and rhesus monkey in vitro phase I and phase II hepatic drug metabolism activities; Stevens JC et al.; Twelve human and six rhesus monkey liver samples were analyzed in vitro for phase I metabolism and phase II conjugation activity . Of the eight P-450-dependent activities measured, only N-nitrosodimethylamine N-demethylase activity was not significantly different between the two species . Coumarin 7-hydroxylase activity was greater in the human as compared with the rhesus monkey samples, whereas erythromycin N-demethylase, benzphetamine N-demethylase, pentoxyresorufin O-dealkylase, ethoxycoumarin O-deethylase, and ethoxyresorufin O-deethylase activities were significantly greater in rhesus monkey microsome samples (p < or = 0.01) . Cimetidine S-oxygenation and chlorpromazine N-oxygenation were 2.1- and 2.6-fold higher in rhesus monkey samples . Of the seven microsomal and cytosolic phase II activities measured, only 17 alpha-ethynylestradiol glucuronidation was significantly higher in the human samples . The genetic polymorphism for isoniazid acetylation was evident only in the human samples, with activities varying 200-fold . This study shows that, although the rhesus monkey is often used by the pharmaceutical industry as a representative mammalian species for drug testing, the in vitro metabolic capabilities of the human and rhesus monkey drug metabolizing enzymes are different.

Clin Cardiol, 1993 Sep, 16(9), 683 - 6
Torsade de pointes; Roden DM; The polymorphic ventricular tachycardia torsade de pointes can occur in the congenital long QT syndromes or as a consequence of therapy with QT-prolonging drugs . The latter can include not only antiarrhythmic drugs such as quinidine, but also a number of drugs which are not usually considered to have major cardiovascular effects: these include nonsedating antihistamines, such as terfenadine; antibiotics such as erythromycin; and neuroleptics such as thioridazine . The electrocardiographic hallmark of both the congenital and acquired forms of the long QT syndrome is marked QT(U) lability, particularly as a function of heart rate . The underlying mechanism is thought to be triggered activity arising as a consequence of early afterdepolarizations . An understanding of the basic mechanism has led to an understanding of the effective forms of therapy, which include maneuvers to include the heart rate (pacing, isoproterenol) as well as maneuvers which may not necessarily alter the QT interval but may prevent the arrhythmia (magnesium, beta blockers) . Intensive study of the clinical features and basic mechanisms underlying torsade de pointes has led to the definition of a new mechanism for cardiac arrhythmias; understanding such mechanisms may ultimately lead to the development of safer antiarrhythmic therapy.

Drug Metab Dispos, 1993 Sep-Oct, 21(5), 850 - 4
Isolation and identification of a novel isomerized epoxide metabolite of FK-506 from erythromycin-induced rabbit liver microsomes; Lhoest G et al.; A novel metabolite of FK-506-a C13, C15, C31 O-demethyl C19 hydroxymethyl C36 isomerized epoxide of FK-506 obtained from erythromycin-induced rabbit liver microsomes--was isolated by HPLC and identified by FAB/MS and NMR . The existence of ring-chain tautomers for this metabolite is demonstrated by NMR spectroscopy . FAB/MS, and HPLC.

Am J Cardiol, 1993 Aug 26, 72(6), 26B - 31B
Variability of the QTc interval: impact on defining drug effect and low-frequency cardiac event; Morganroth J et al.; Prolongation of the QT interval corrected for heart rate (QTc) can lead to the development of torsades de pointes, a life-threatening form of polymorphic ventricular tachycardia . However, the QTc interval duration exhibits a high degree of spontaneous variability and is not necessarily a direct predictor of the risk of torsades . This observation holds implications for the assessment of the potential proarrhythmic effects of noncardiac pharmacologic agents . To date, the antihistamine terfenadine is the only noncardiac drug that has undergone a comprehensive and systematic evaluation related to the consequences of its causing QTc prolongation . The results suggest that QTc prolongation resulting solely from terfenadine at clinical doses does not have an important impact on clinically relevant endpoints . The risk of serious ventricular arrhythmias with terfenadine using epidemiologic data is the same or less than that associated with traditional first-generation antihistamines . The risk of a clinical cardiac event (QTc prolongation, ventricular arrhythmias, syncope, or sudden death) with terfenadine is similar to that of other antihistamines . Factors associated with increased risk in patients taking terfenadine include significant liver disease, hypokalemia, overdose, and concomitant administration of ketoconazole-like agents or erythromycin; use of terfenadine is relatively contraindicated in these settings . No increased risk of serious arrhythmias has been confirmed in conjunction with the use of terfenadine in patients with cardiac disease.

Lancet, 1993 Aug 21, 342(8869), 453 - 6
Randomised controlled trial of single-dose azithromycin in treatment of trachoma; Bailey RL et al.; Blindness due to trachoma is a serious public health issue world wide . The currently recommended treatment of active trachoma with repeated doses of tetracycline eye ointment has many disadvantages . The new azalide antibiotic azithromycin is effective as a single oral dose in the chemotherapy of genital Chlamydia trachomatis infections, and we have assessed its efficacy for trachoma treatment . We carried out a randomised single-blind comparison of azithromycin (a single oral dose of 20 mg/kg) with conventional treatment (6 weeks of topical tetracycline plus erythromycin for severe cases) in two villages with endemic trachoma in The Gambia . The patients were followed up for 26 weeks from the start of treatment by an observer unaware of treatment allocation . By 6 months' follow-up, trachoma had resolved in 76 (78%) of 97 subjects who received azithromycin compared with 70 (72%) of 97 who were treated conventionally (95% CI for difference -6% to 18%) . Compliance with both treatments was good, but that for conventional treatment could probably not be achieved outside the research setting . There were no significant differences in treatment effect, baseline characteristics, or re-emergent disease between the treatment groups . Azithromycin was well tolerated . As a systemic treatment effective in a single dose it has important potential for trachoma controlPIP: Azithromycin is effective against Chlamydia trachomatis in vitro and as a single dose for the treatment of chlamydia infection of the genital tract . A randomized single-blind study was conducted in 2 Gambian villages (Jali with a population of 900 and Berending with 500) in order to assess the effectiveness and safety of a single oral dose of 20 mg/kg azithromycin compared with conventional treatment in ocular C . trachomatis infection . In May 1992 an ocular survey was done in both villages, and 199 subjects with active trachoma were identified (128 in Jali and 71 in Berending) . Of these, 194 patients were randomly assigned to conventional or azithromycin treatment . Azithromycin was administered in a single dose of 20 mg/kg . Subjects receiving conventional treatment were given 1% tetracycline eye ointment to each eye twice daily for 6 weeks . Severe cases were given oral erythromycin stearate based on an adult dose of 250 mg 4 times daily for 2 weeks . Subjects were examined 4, 8, 16, and 26 weeks after treatment . In 20% of the subjects diarrhea, vomiting, and abdominal pain occurred . Clinical signs had resolved by 6 months' follow-up in 146 patients: 70 (72%) in the conventional treatment group, and 76 (78%) in the azithromycin group . At 6 months the symptoms of 9 subjects with severe disease, and 21 with moderate disease had resolved . However, during follow-up, 11 of those with severe disease, 30 of those with moderate disease, and 129 of those with mild disease had resolution at some point, which reflects the scale of re-emergent disease . To allow for the effect of recrudescent disease on point prevalences at follow-up, a survival analysis of time to loss of clinical signs as outcome was done . There was no difference between treatments (p 0.9) . 21 of the 194 subjects were antigen positive in their nasal secretions at baseline . Of these, 18 still had clinical signs at 4 weeks compared with 87 of the 173 with antigen-negative nasal secretions ( p = 0.004; odds ratio 5.93) .

Biochem Pharmacol, 1993 Aug 17, 46(4), 683 - 9
Induction of rat liver drug-metabolizing enzymes by heterocycle-containing mono-, di-, tri- and tetra-arylmethanes; Franklin MR; The effect of a nitrogen heterocycle constituent on the ability of arylmethanes to induce phase I and phase II drug-metabolizing enzymes has been examined . Rats were treated with tetra-, tri-, di- or monoarylmethane compounds daily for 3 days at a dose of 75 mg/kg . Induction of UDP-glucuronosyltransferase (morphine) activity was seen with twelve of the eighteen compounds investigated, and for three compounds it occurred independent of any induction of cytochrome P450 . Induction of glutathione S-transferase activity was seen with ten of the compounds and was generally paralleled by changes in overall cytochrome P450 concentration and in both pentoxyresorufin and erythromycin dealkylase activities . Major induction of ethoxyresorufin deethylase activity was only apparent with two diarylmethanes that contained a 1-substituted imidazole moiety . UDP-glucuronosyltransferase (1-naphthol) activity was coinduced by these two compounds . A third compound, diphenyl-4-pyridylmethane, induced UDP-glucuronosyltransferase (1-naphthol) activity without increasing ethoxyresorufin deethylase activity . Cytosolic sulfotransferase activity was not induced by the administration of any compound in this study . Among arylmethane derivatives, the presence of two aryl groups appeared to be a minimum requirement for induction of drug-metabolizing enzymes . If one of the aryl groups was not a heterocycle, or if the nitrogen atom of the heterocycle was sterically hindered, major induction of cytochrome P450 did not occur . With triarylmethanes, induction was independent of whether the heterocycle was imidazole, pyridine or pyrimidine.

Dtsch Med Wochenschr, 1993 Aug 13, 118(32), 1150 - 4
{Thoracic actinomycosis masquerading as a central bronchial carcinoma}; Kremer H et al.; A 41-year-old cachectic woman (weight 42.7 kg, height 1.65 m) was admitted to hospital because a chest radiogram had suggested a left central bronchial carcinoma . Four days previously she had noted for the first time a firm elastic swelling parasternally in the fourth intercostal space . This swelling was directly aspirated by needle after bronchoscopic results had been nonspecific . Surprisingly, pus containing actinomyces filaments was aspirated . Computed tomography confirmed a paramediastinal abscess, 8 x 5 x 6 cm, which had infiltrated into the left thoracic wall . The abscess was incised and drained . After treatment for two weeks, initially with three times daily 10 mega penicillin G intravenously, followed by erythromycin, 500 mg twice daily for 12 weeks, the thoracic actinomycosis was no longer demonstrable radiologically and by ultrasound . It is suggested that in any unclear pulmonary infiltrate without evidence of tuberculosis or carcinoma actinomycosis should be included in the differential diagnosis.

J Mol Biol, 1993 Aug 5, 232(3), 725 - 31
Erythromycin binding is reduced in ribosomes with conformational alterations in the 23 S rRNA peptidyl transferase loop; Douthwaite S et al.; The antibiotic erythromycin inhibits protein synthesis by binding to the 50 S ribosomal subunit, where the drug interacts with the unpaired bases 2058A and 2059A in the peptidyl transferase loop of 23 S rRNA . We used a chemical modification approach to analyse conformational changes that are induced by mutations in the peptidyl transferase loop, and to determine how these changes affect drug interaction . Mutations at positions 2057 (G-->A) and 2058 (A-->G, or -->U), all of which confer drug resistance, induce a more open conformation in the peptidyl transferase loop . Erythromycin still protects against chemical modification in the mutant peptidyl transferase loops, but the affinity of the drug interaction is reduced 20-fold in the 2057A mutant, 10(3)-fold in the 2058U mutant and 10(4)-fold in the 2058G mutant . Single mutations at position 2032 in the adjacent hairpin loop, which have previously been shown to alter drug tolerances, gave no detectable effects on the structure of the peptidyl transferase loop or on erythromycin binding . Dual mutations at positions 2032 and 2058, however, induce a marked change in the rRNA conformation with opening of the phylogenetically conserved base-pair 2063C.2447G, and confer a slow growth, drug-sensitive phenotype . The data suggest that the target site of erythromycin lies within the peptidyl transferase loop, and that limited disruption of the conformation of this site reduces drug binding, and consequently confers resistance . In addition, there is structurally and functionally important interaction between the drug target site in the peptidyl transferase loop and position 2032.

Biochem Pharmacol, 1993 Aug 3, 46(3), 493 - 501
Interaction of caffeine with acetaminophen . 1 . Correlation of the effect of caffeine on acetaminophen hepatotoxicity and acetaminophen bioactivation following treatment of mice with various cytochrome P450 inducing agents; Jaw S et al.; The combination of caffeine with acetaminophen (APAP) is used widely in the treatment of headache . The effects of caffeine on APAP-induced hepatotoxicity and APAP bioactivation by liver microsomes from uninduced mice and from mice pretreated with various agents that induce cytochrome P450 were studied . When 1 mM caffeine was included, the rate of glutathione-APAP conjugate (GS-APAP) formation was increased significantly by 33 and 39% in microsomes from phenobarbital (PB)- and dexamethasone (DEX)-treated mice, respectively, whereas this parameter was decreased 39 and 12% by caffeine in microsomes from beta-naphthoflavone (beta NF)- and acetone-treated mice, respectively . A 5 mM concentration of caffeine increased GS-APAP formation by 47, 107 and 117% in microsomes from control, PB-, and DEX-treated mice, respectively, and decreased it 39 and 25% in microsomes from beta NF- and acetone-treated mice, respectively . Caffeine was a competitive inhibitor of APAP bioactivation in microsomes from beta NF- and acetone-treated mice . While caffeine increased APAP bioactivation in microsomes from uninduced, PB-, and DEX-treated mice, the apparent Km values for APAP were increased by caffeine, indicating that this enhancement was not due to a direct effect of caffeine on APAP binding to cytochrome P450 but may be due to an effect of caffeine on the substrate-enzyme complex . The variable effect of caffeine on APAP hepatotoxicity correlated with the effect of caffeine on APAP bioactivation by liver microsomes, regardless of pretreatment . Lack of correlation of aminopyrine N-demethylase, but good correlation of erythromycin N-demethylase activity with the extent of caffeine enhancement of APAP bioactivation following PB or DEX treatment suggests that a murine P450 subfamily similar to the rat P450 3A subfamily may be the candidate in mediating the stimulatory effect of caffeine on APAP bioactivation and APAP-induced hepatotoxicity.

Pharmazie, 1993 Aug, 48(8), 599 - 602
Erythromycin-antacid interaction; Arayne MS et al.; The in vitro release of erythromycin stearate in the presence of aluminium hydroxide, aluminium trisilicate, magnesium oxide, magnesium trisilicate, sodium hydrogen carbonate and a combination of aluminium hydroxide gel, magnesium hydroxide and dimethyl polysiloxane has been studied by the USP XX dissolution method . The dissolution of erythromycin was found to be markedly retarded in the presence of all the antacids studied except sodium hydrogen carbonate . An attempt was made to elucidate the mechanism of this effect.

Enferm Infecc Microbiol Clin, 1993 Aug-Sep, 11(7), 382 - 4
{Persistent cough caused by Bordetella pertussis . Study of 6 cases}; Ibanez Perez R et al.; BACKGROUND: Pertussis is currently an infrequent illness in Spain, since DTP vaccine was introduced . Immunity acquired after immunization is, nevertheless, lower than immunity acquired after the clinical disease, and decreases steadily . After the adolescence, serum levels of antibodies against B . pertussis may not be enough, leading to atypical infections in other wise immunized patients . METHODS: We inoculated, during 6 months, nasal swabs of patients with symptoms of pertussis and of patients with persistent cough on blood agar, MacConkey agar, chocolate agar, charcoal agar and Bordet Gengou agar . RESULTS: We isolated B . pertussis from 6 patients . Five of them were children between 8 and 14 years old, correctly immunized, whose only symptomatology was persistent cough . The only patient incorrectly immunized showed a clinical picture of pertussis . All the patient evolved favorably with erythromycin . CONCLUSIONS: Immunization with DTP drastically reduces the incidence of serious illness but, after some years, do not protect enough against the appearance of milder, atypical pertussis . These data obligate to take into account the possibility of pertussis infection when persistent cough is observed, in absence of any other factors that can justify it.

Acta Obstet Gynecol Scand, 1993 Aug, 72(6), 470 - 4
Erythromycin versus metronidazole in the treatment of bacterial vaginosis; Wathne B et al.; Of 101 women, 15-50 years of age, presenting with vaginal discharge, 34 had bacterial vaginosis and were randomly assigned to a seven-day course of oral treatment with either erythromycin (0.5 g b.i.d.) or metronidazole (0.4 g b.i.d.) in a single-blind, cross-over study . Treatment failure (> or = three clinical signs of bacterial vaginosis) occurred in 13 (81%) of 16 patients given erythromycin, as compared with three (17%) of 18 women treated with metronidazole (p < 0.001) . Persistence of Gardnerella vaginalis, Mobiluncus species and/or Mycoplasma hominis was found in 14 of 16 patients treated with erythromycin, and in four of 16 patients treated with metronidazole . Treatment with metronidazole was successful (< or = two clinical signs of bacterial vaginosis) in eight of 10 cases of erythromycin treatment failure . Neither of two cases of metronidazole treatment failure was cured with erythromycin . At three-month follow-up of 31 women, persistence or recurrence of bacterial vaginosis was diagnosed in 11 cases (36%).

Acta Paediatr, 1993 Aug, 82(8), 690 - 3
Ureaplasma urealyticum in the cerebrospinal fluid of a premature infant; Hentschel J et al.; A premature infant, born at 28 weeks' gestation, was found to be colonized with Ureaplasma urealyticum and developed intraventricular hemorrhage and progressive hydrocephalus during the first weeks of life . The organism was isolated from the infant's cerebrospinal fluid in the absence of marked cerebrospinal fluid pleocytosis, but meningitis was suspected on the basis of low glucose and high protein content . Since this organism was resistant to erythromycin by clinical criteria, the infant was treated with chloramphenicol for 20 days . Cerebrospinal fluid sterilization was demonstrated; hydrocephalus, however, was persistent and made intraventricular shunt placement necessary.

W V Med J, 1993 Aug, 89(8), 331 - 4
Chlamydia trachomatis genital infections; Fisher MA; Chlamydia trachomatis genital infections are among the most common sexually transmitted diseases in the United States today . Although these organisms are obligate intracellular pathogens, they more closely resemble bacteria than viruses . C . trachomatis is responsible for considerable morbidity in women, causing urethritis, cervicitis, endometritis, and pelvic inflammatory disease . The latter complication is associated with a high incidence of infertility and ectopic pregnancy, even when the infection is asymptomatic . In young men, C . trachomatis is a common cause of urethritis and epididymitis . Diagnostic tests include tissue culture which has the greatest sensitivity and specificity but is difficult and costly, and various antigen assays which are useful in high-risk, high-prevalence populations . Treatment is effective with doxycycline or erythromycin, but success also depends on appropriate follow-up and empiric treatment of sexual partners . Control of C . trachomatis genital infections is crucial to the control of all sexually transmitted diseases including HIV infection.

J Pharmacol Exp Ther, 1993 Aug, 266(2), 852 - 6
Down-regulation of motilin receptors on rabbit colon myocytes by chronic oral erythromycin; Bologna SD et al.; Acutely, erythromycin stimulates colonic smooth muscle contraction via action on motilin receptors, but the effects of chronic erythromycin exposure are unknown . Thus contraction and motilin binding studies were performed on rabbit colonic smooth muscle after 2 weeks of oral erythromycin ethyl succinate (25 mg/kg, twice a day) . Isolated colon myocytes from untreated rabbits contracted to erythromycin with an EC50 of 30 +/- 17 pM and peak shortening of 24.1 +/- 0.8% at 10 nM . Motilin evoked similar contractions with an EC50 of 63 +/- 13 pM and peak shortening of 26.8 +/- 0.9% at 10 nM . Myocytes from treated rabbits exhibited reduced contractile responses to erythromycin with an EC50 of 203 +/- 27 pM (P < .002) and decreased peak shortening to 20.1 +/- 2.9% at 100 nM (P < .05) . Motilin responses were also blunted {EC50 of 326 +/- 16 pM, peak shortening of 16.2 +/- 1.2% at 1 microM (P < .002)} . {125I}motilin binding to untreated colon smooth muscle homogenates was saturable and specific with a Kd of 0.53 +/- 0.10 nM and a Bmax of 48 +/- 6 fmol/mg protein . Muscle from treated rabbits exhibited no change in motilin receptor affinity (Kd = 0.50 +/- 0.08 nM) but showed a 63% reduction in receptor density (Bmax = 18 +/- 4 fmol/mg protein; P < .03) . In conclusion, chronic erythromycin administration results in decreased contractile potency and efficacy of motilin and erythromycin on colonic myocytes, associated with decreased motilin receptor density but no change in receptor affinity . Thus chronic erythromycin exposure leads to tolerance to its colonic smooth muscle motor effects via motilin receptor down-regulation.

Proc Natl Acad Sci U S A, 1993 Aug 1, 90(15), 7119 - 23
An erythromycin analog produced by reprogramming of polyketide synthesis; Donadio S et al.; The polyketide-derived macrolactone of the antibiotic erythromycin is made through successive condensation and processing of seven three-carbon units . The fourth cycle involves complete processing of the newly formed beta-keto group (beta-keto reduction, dehydration, and enoyl reduction) to yield the methylene that will appear at C-7 of the lactone ring . Synthesis of this molecule in Saccharopolyspora erythraea is determined by the three large eryA genes, organized in six modules, each governing one condensation cycle . Two amino acid substitutions were introduced in the putative NAD(P)H binding motif in the proposed enoyl reductase domain encoded by eryAII . The metabolite produced by the resulting strain was identified as delta 6,7-anhydroerythromycin C resulting from failure of enoyl reduction during the fourth cycle of synthesis of the macrolactone . This result demonstrates the involvement of at least the enoyl reductase from the fourth module in the fourth cycle and indicates that a virtually complete macrolide can be produced through reprogramming of polyketide synthesis.

Surgery, 1993 Aug, 114(2), 295 - 8; discussion 298-9
Erythromycin, motilin, and the esophagus; Pennathur A et al.; BACKGROUND . Motilin induces phase III activity of the gastroesophageal tract . Erythromycin has a motilin-like effect on the stomach, but possible esophageal effects have not been evaluated and are the focus of our investigation . METHODS . Esophageal manometry was performed in 11 healthy volunteers before and after intravenous infusion of 500 mg erythromycin . Values are expressed as means +/- SEM . RESULTS . Lower esophageal sphincter (LES) pressure increased from 21.1 +/- 2.6 mm Hg at baseline to 37.5 +/- 3.8 mm Hg after erythromycin infusion (p < 0.0001) . Erythromycin did not affect LES length, esophageal body contraction amplitude, duration or velocity, or the upper esophageal sphincter . Serum motilin levels decreased from 96.4 +/- 10.9 pmol/L to 81.8 +/- 10.9 pmol/L (p < 0.01) after erythromycin administration . CONCLUSIONS . Erythromycin profoundly stimulates the normal human LES . This is a direct motilin agonist-like effect and is not mediated by release of endogenous motilin . Erythromycin has no important effect on the esophageal body or the upper esophageal sphincter.

Singapore Med J, 1993 Aug, 34(4), 352 - 3
Atypical pneumonia due to Chlamydia pneumoniae: a case report; Cheong YM et al.; A first case of Chlamydia pneumoniae pneumonia in Malaysia is reported . The diagnosis was made by a significant change in C . pneumoniae antibody titre . The infection responded well to a course of erythromycin.

Antimicrob Agents Chemother, 1993 Aug, 37(8), 1704 - 6
Comparative in vitro activities of clarithromycin, azithromycin, and erythromycin against Borrelia burgdorferi; Dever LL et al.; The in vitro activities of the macrolide antibiotics clarithromycin, 14-hydroxy-clarithromycin, azithromycin, and erythromycin against 19 isolates of Borrelia burgdorferi were investigated . MICs ranged from 0.003 to 0.03 microgram of clarithromycin per ml, 0.007 to 0.03 microgram of 14-hydroxyclarithromycin per ml, 0.003 to 0.03 microgram of azithromycin per ml, and 0.007 to 0.06 microgram of erythromycin per ml . Time-kill studies using the B31 strain of B . burgdorferi demonstrated a > or = 3-log10-unit killing after 72 h with each of the macrolide antibiotics tested in concentrations representing twice the respective MICs.

Gut, 1993 Aug, 34(8), 1123 - 7
Erythromycin induces supranormal gall bladder contraction in diabetic autonomic neuropathy; Catnach SM et al.; Gall bladder motor function is impaired in some patients with diabetes . It has been suggested that the abnormalities of gall bladder motility are confined to those patients with autonomic neuropathy . Erythromycin, a motilin receptor agonist, causes gall bladder contraction in both normal subjects and patients with gall stones with impaired gall bladder emptying . The effect of erythromycin on gall bladder motility in seven patients with diabetes with an autonomic neuropathy, six patients with diabetes without autonomic neuropathy, and 17 normal subjects was studied using ultrasound . There was no significant difference in gall bladder fasting volume between the three groups, but the patients with diabetes with autonomic neuropathy had impaired postprandial gall bladder emptying compared with normal subjects (percentage emptied (SEM) 40 (10.3)% v 64 (2.8)%, p < 0.01) and those with autonomic neuropathy (48 (7.7)%, NS) . Erythromycin produced a dramatic reduction in gall bladder fasting volume in patients with diabetes with an autonomic neuropathy, compared with either normal subjects or patients with diabetes without autonomic neuropathy (percentage reduction 62 (4.6)% in patients with autonomic neuropathy, v 37 (17.6)% in those without autonomic neuropathy, and 26 (7.3)% in the normal subjects, (p < 0.02) and returned gall bladder emptying to normal in all patients with impaired emptying . The pronounced effect of erythromycin in diabetic autonomic neuropathy suggests denervation supersensitivity and that the action of erythromycin on the gall bladder is neurally modulated.

Enzyme Microb Technol, 1993 Aug, 15(8), 657 - 63
Estimation of the kinetic constants and elucidation of trends in growth and erythromycin production in batch and continuous cultures of Saccharopolyspora erythraea using curve-fitting techniques; McDermott JF et al.; The kinetics of erythromycin production were dependent on the identity of the growth rate-limiting nutrient during batch cultures of Saccharopolyspora erythraea . Semilogarithmic linear regression provided a single estimate of growth rate during the exponential phase, but partial cubic spline curve fit derivatives provided time-dependent specific growth and production rate profile . Non-growth-linked product formation was observed when the medium was glucose- or phosphate-limited . However, growth-linked product formation was observed in a nitrate-limited medium . The kinetics observed in nitrate-limited chemostat culture provided evidence that Saccharopolyspora erythraea may be subject to noncompetitive inhibition by a growth-linked product under these conditions . A mathematical model was used to test this theory . The model simulation fitted the observed data very closely and was used to calculate estimates of the kinetic parameters involved: {formula; see text}

Am J Trop Med Hyg, 1993 Jul, 49(1), 101 - 5
Antimalarial activity of azithromycin and erythromycin against Plasmodium berghei; Gingras BA et al.; Several antibiotics that inhibit protein synthesis on 70S ribosomes, including the macrolide erythromycin, and the azalides azithromycin (ZITHROMAX) and CP-63,956, demonstrated antimalarial activity against two strains of Plasmodium berghei . In a four-day in vivo test, the azalides were 25-fold more potent than erythromycin against the chloroquine-sensitive P . berghei N strain, and displayed additive effects with chloroquine . This effect was not observed with the erythromycin-chloroquine combination . Against the chloroquine-resistant P . berghei MSU/RC strain, the azalides were 60-fold more potent than erythromycin . Additive effects were observed with azalide-chloroquine combinations against this strain, but these results were not significantly different from the erythromycin-chloroquine combination.

Br J Surg, 1993 Jul, 80(7), 879 - 81
Erythromycin improves emptying of the denervated stomach after oesophagectomy; Hill AD et al.; Oesophagectomy, necessitating vagotomy, is associated with delayed gastric emptying . Cisapride and erythromycin have prokinetic effects and improve emptying of the innervated stomach . Their effect on the denervated stomach following oesophagectomy is unknown . The effect of pyloroplasty, cisapride and erythromycin on the rate of gastric emptying after oesophagectomy was studied using a radiolabelled meal . Oesophagectomy was associated with a marked delay in gastric emptying (56 per cent of the test meal remaining after 4 h) compared with age- and sex-matched normal controls (16 per cent; P < 0.001) . Erythromycin improved the rate of gastric emptying to preoperative control values (18 per cent) . Cisapride had no significant effect on gastric emptying . After pyloroplasty, 32 per cent of the label remained at 4 h (P = 0.065) . The mean(s.e.m.) half-emptying time in patients receiving erythromycin was 94(29) min, which was similar to control values, 55(3) min (P = 0.26) . Erythromycin may have a role in the treatment of gastric stasis following oesophagectomy or truncal vagotomy.

Ann Pharmacother, 1993 Jul-Aug, 27(7-8), 950 - 5
Erythromycin-induced hypoacusis: 11 new cases and literature review; Sacristan JA et al.; OBJECTIVE: To report 11 cases of possible erythromycin-induced hearing loss and to review all cases reported in the literature . CASE SUMMARY: In the 11 cases reported, the following are reviewed: age, gender, time to onset of and recovery from hypoacusis in relation to erythromycin administration, presence or absence of renal or hepatic disease, underlying disorders, and concurrent administration of other drugs . Hypoacusis appeared with dosages equal to or higher than 4 g/d in patients with a mean age of 52.5 +/- 19 years, a high percentage of whom (45 percent) presented with renal impairment . The hearing loss was reversible in all cases, and subsided a few days (median = 3) after dosage reduction or drug discontinuation . DISCUSSION: Our patients' characteristics are similar to those of patients reported in the literature . Most data indicate that erythromycin-induced hypoacusis is a dose-dependent effect; however, its occurrence in patients otherwise free from disposing factors suggests that it is idiosyncratic . CONCLUSIONS: Erythromycin administered for appropriate indications and dosage adjustments in patients with impaired renal and/or liver function may prevent or reduce the incidence of erythromycin-induced hypoacusis.

Eur J Pediatr, 1993 Jul, 152(7), 599 - 600
Ureaplasma urealyticum infection in newborns: three case reports; Gjuric G et al.; We report three newborns with different manifestations of Ureaplasma urealyticum infection; a term newborn with acute neonatal pneumonia and two very low birth weight infants with bronchopulmonary dysplasia and osteomyelitis of the femur, respectively . The association of U . urealyticum with acute and chronic respiratory disease in term and preterm newborns has recently been reported . Our two cases are similar to other case reports from the literature, but we were unable to find any previous reports of osteomyelitis due to U . urealyticum in the premature babies . Isolation of U . urealyticum in pure culture from the blood was considered to be related to local infection in all three patients . All patients were cured by erythromycin.

Dis Colon Rectum, 1993 Jul, 36(7), 696 - 708
Prokinetic agents for lower gastrointestinal motility disorders; Longo WE et al.; Prokinetic agents are currently being investigated as potential therapies for motility disorders of the lower gastrointestinal tract . Cholinergic agonists such as bethanechol are known to improve postoperative ileus but are limited because of side effects . Dopamine antagonists such as domperidone appear to have maximal prokinetic effect in the proximal gastrointestinal tract and are effective for such conditions as gastroparesis and gastroesophageal reflux, but they appear to have little physiologic effect in the colon or in colonic motility disorders . Naloxone, an opioid antagonist, appears to hold promise in patients with irritable bowel syndrome, small intestinal pseudo-obstruction, and constipation . Erythromycin exerts its prokinetic effect by acting as a motilin agonist; it has been used in the treatment of diabetic gastroparesis and appears to improve symptoms of colonic pseudo-obstruction and postoperative ileus . Metoclopramide, a combined cholinergic agonist and dopamine antagonist, is currently used exclusively for proximal motility dysfunction . Cisapride appears to hold the most promise for patients with colonic motility disorders . In patients with postoperative ileus, cisapride is associated with an increased return of bowel function compared with placebo . In patients with chronic constipation, cisapride increases stool frequency and decreases laxative abuse in both adults and children . Hopefully, as an understanding of gastrointestinal motility increases, effective prokinetic agents will be developed that will improve symptoms of patients with large bowel motility disorders and may also help to predict those patients who benefit from surgical management for constipation.

Int J Dermatol, 1993 Jul, 32(7), 528 - 32
Clarithromycin in the treatment of skin and skin structure infections: two multicenter clinical studies . Clarithromycin Study Group; Parish LC; BACKGROUND . Clarithromycin is a new macrolide analog of erythromycin with activity against a number of dermatologic pathogens . METHODS . The efficacy and safety of clarithromycin, 250 mg bid, were compared with those of reference drugs, cefadroxil and erythromycin, in two multicenter studies: (1) a randomized, double-blind 45-center study, in which clarithromycin or cefadroxil 500 mg bid was given for 5-14 days; and (2) a single-blind 31-center study, in which clarithromycin or erythromycin, 250 mg qid, was given for < or = 14 days . RESULTS . In the first study, efficacy and safety were evaluated in 299 and 538 patients, respectively . In the second study, the numbers were 141 and 261 patients, respectively . Overall, clarithromycin was as effective and safe as cefadroxil and erythromycin . CONCLUSIONS . Clarithromycin provides an alternative therapy to cefadroxil and erythromycin for skin and skin structure infections, especially in beta-lactam allergic patients.

J Pharmacol Exp Ther, 1993 Jul, 266(1), 1 - 7
Involvement of cytochrome P-450IIIA in metabolism of potassium canrenoate to an epoxide: mechanism of inhibition of the epoxide formation by spironolactone and its sulfur-containing metabolite; Cook CS et al.; In vitro metabolism studies of potassium canrenoate (PC) were conducted to examine whether spironolactone (SP) and/or its sulfur-containing metabolites inhibit the PC metabolic pathways to mutagenic metabolites and to elucidate the mechanism for any observed inhibitory effect . The mechanistic study was conducted using liver microsomes prepared from male and female rats with and without pretreatment of a cytochrome (Cyt) P-450IIIA inducer {pregnenolone-16 alpha-carbonitrile (PCN) or dexamethasone (DEX)} and with and without a Cyt P-450IIIA inhibitor, triacetyloleandomycin (TAO) . The present study demonstrates that SP and its sulfur-containing metabolite 7 alpha-thio-spirolactone substantially inhibited the formation of promutagen 6 beta, 7 beta-epoxycanrenone (6 beta, 7 beta-epoxy-CAN) from PC . The sulfur-containing metabolite of SP that inhibit promutagen formation were not formed from PC, although a glutathione conjugate of PC was formed . The formation rate of 6 beta, 7 beta-epoxy-CAN was greater in liver microsomes prepared from rats pretreated with a Cyt P-450IIIA inducer (PCN or DEX) than in liver microsomes prepared from the untreated rats . The formation rate of the epoxide metabolite was lower after in vitro addition of TAO . Pretreatment of animals with TAO 4 hr before sacrifice produced similar results . Erythromycin, which is N-demethylated by Cyt P-450IIIA, also reduced the formation rate of 6 beta, 7 beta-epoxy-CAN . Inhibition of PC metabolism to 6 beta, 7 beta-epoxy-CAN by TAO and erythromycin, and its induction by DEX and PCN, suggest involvement of Cyt P-450IIIA, which is in turn inhibited by SP and 7 alpha-thio-spirolactone.

Drug Metab Dispos, 1993 Jul-Aug, 21(4), 645 - 56
Metabolism of the antimammary cancer antiestrogenic agent tamoxifen . I . Cytochrome P-450-catalyzed N-demethylation and 4-hydroxylation; Mani C et al.; Previous studies suggested that the therapeutic effect of the antimammary cancer agent tamoxifen might be related to its metabolism . This study examined the cytochrome P-450 enzymes in rat and human liver catalyzing the metabolism of tamoxifen . Incubations of tamoxifen with rat liver microsomes yielded three major polar metabolites identified as the N-oxide, N-desmethyl, and 4-hydroxy derivatives . N-Oxide formation was catalyzed by the flavin-containing monooxygenase (see part II) . Carbon monoxide, SKF-525A, metyrapone, and benzylimidazole strongly inhibited N-demethylation and 4-hydroxylation, indicating the participation of P-450 monooxygenase in these reactions . Antibodies to NADPH-P450 reductase inhibited N-demethylation and 4-hydroxylation . Comparison of the metabolism of tamoxifen in untreated male and female rats demonstrated some sexual dimorphism . N-Demethylation was higher in the male rat and 4-hydroxylation was higher in the female . Treatment of rats with phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN), and methylcholanthrene (MC) enhanced N-demethylation, demonstrating the potential participation of multiple P-450s in N-demethylation . Evidence strongly indicates that CYP3A enzyme(s) catalyzes N-demethylation in liver microsomes of PB- and PCN-treated rats (PB and PCN microsomes, respectively): i) N-demethylation was inhibited by cortisol and erythromycin (alternate substrates) and a time-dependent inhibition was observed with troleandomycin (TAO) in vitro; ii) treatment of female rats with TAO, followed by dissociation of the microsomal TAO-P-450 complex, elevated N-demethylation; iii) treatment of PCN-induced female rats with chloramphenicol inhibited N-demethylation; and iv) polyclonal antibodies (PAbs) to CYP3A1 inhibited N-demethylation in PCN- and PB-treated female rats . Although we were unable to reconstitute the N-demethylation activity with purified CYP3A1, which is difficult to reconstitute, collectively the evidence demonstrated that CYP3A enzymes catalyze N-demethylation in PB and PCN microsomes . By contrast, antibodies against CYP2B1/B2 did not inhibit N-demethylation and reconstituted 2B1 did not catalyze N-demethylation of tamoxifen, indicating that 2B1 was not involved . The increase in N-demethylation by MC treatment appears to be due to elevation of CYP1A1/1A2 (P-450c/d) . Alternate substrates of CYP1A1/1A2 inhibited N-demethylation and reconstituted rat CYP 1A1-catalyzed N-demethylation . Surprisingly, monoclonal antibodies (MAbs) against CYP1A1/1A2 only partially inhibited, and PAbs against CYP1A1 did not inhibit N-demethylation in MC microsomes, indicating that in MC microsomes, 1A1 does not contribute significantly to that reaction . Mab anti-CYP2C11/2C6 (P-450h/k) inhibited N-demethylation in PB, PCN, and control male rat liver microsomes, suggesting that CYP2C11 and/or CYP2C6 catalyze this reaction to some extent.(ABSTRACT TRUNCATED AT 400 WORDS)

Clin Pharmacol Ther, 1993 Jun, 53(6), 630 - 6
The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans; Honig PK et al.; Terfenadine is rapidly and nearly completely biotransformed during a first pass to an active acid metabolite . Accumulation of unmetabolized terfenadine has been associated with altered cardiac repolarization . Drug-drug interactions resulting in the accumulation of terfenadine have been reported for ketoconazole and erythromycin . Six subjects were given the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral fluconazole (200 mg once daily) . The mean metabolite area under the concentration-time curve increased by 34% and the time to maximum concentration of the metabolite was delayed from 2.3 to 4 hours by concurrent fluconazole . Unmetabolized terfenadine was not present in any subject, and cardiac repolarization was not significantly changed from baseline during any phase of the study . We conclude that a pharmacokinetic interaction between terfenadine and fluconazole exists; however, the absence of accumulation of parent terfenadine in plasma suggests that a clinically significant interaction is unlikely.

Dig Dis Sci, 1993 Jun, 38(6), 1026 - 31
Effect of erythromycin derivative EM523L on human interdigestive gastrointestinal tract; Kawamura O et al.; We investigated the effect of an erythromycin derivative, EM523L, on interdigestive gastrointestinal motor activity and plasma motilin concentrations in three healthy volunteers using an infused catheter system . We administered doses of 500, 1000, and 2000 micrograms of EM523L to each subject as well as physiological saline . EM523L induced interdigestive migrating contractions (IMCs) that originated in the stomach and migrated to the duodenum . This response was noted in all three subjects after each dose of EM523L, while no IMCs were induced by saline . There were no significant differences in the characteristics of the EM523L-induced IMC and the spontaneous IMC . The initiation time, ie, the interval between the start of EM523L infusion and the onset of the IMC became shorter in a dose-dependent manner . Plasma motilin concentrations increased significantly after EM523L administration, suggesting that motilin is involved in the mechanism of IMC induction by this drug.

Carcinogenesis, 1993 Jun, 14(6), 1167 - 73
Structure-activity relationships of arylalkyl isothiocyanates for the inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism and the modulation of xenobiotic-metabolizing enzymes in rats and mice; Guo Z et al.; Many arylalkyl isothiocyanates are potent inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in rats and mice . In the mouse, 4-phenylbutyl isothiocyanate (PBITC) and 6-phenylhexyl isothiocyanate (PHITC) exhibited greater inhibition than benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) . The present study was conducted to investigate the structure-activity relationships of these four arylalkyl isothiocyanates for their inhibition of NNK oxidation and effects on xenobiotic-metabolizing enzymes in rats and mice . A single dose (0.25 or 1.00 mmol/kg) of each isothiocyanate was given to F344 rats 6 or 24 h before death . The rates of NNK oxidation were decreased in microsomes from the liver, lung and nasal mucosa of rats . Generally, PEITC was more potent than BITC but less potent than PBITC and PHITC . The rates in rat liver microsomes were decreased at 6 h but recovered or increased at 24 h; the rates in rat lung microsomes were markedly decreased at both 6 and 24 h; and the rates in rat nasal mucosa microsomes were also significantly decreased . The same treatment decreased the rat liver N-nitrosodimethylamine demethylase activity dramatically and ethoxyresorufin O-dealkylase and erythromycin N-demethylase activities moderately . However, the rat liver microsomal pentoxy-resorufin O-dealkylase activity was decreased at 6 h but increased at 24 h, with PEITC showing the most marked induction . The rat liver NAD(P)H:quinone oxidoreductase activity was increased 1.4- to 3.3-fold, with PEITC being most effective; and the glutathione S-transferase activity was increased slightly . Similarly, at a single dose of 0.25 mmol/kg (5 mumol/mouse) 24 h before death, PEITC, PBITC, PHITC but not BITC, decreased NNK oxidation in mouse lung microsomes by 40-85%, with PBITC and PHITC showing greater inhibition . Furthermore, all four isothiocyanates extensively inhibited NNK oxidation in rat lung and nasal mucosa microsomes as well as mouse lung microsomes in vitro, with PEITC (IC50 of 120-300 nM) being more potent than BITC (IC50 of 500-1400 nM) but less potent than PBITC and PHITC (IC50 of 15-180 nM) . PHITC was a very potent competitive inhibitor of NNK oxidation in mouse lung microsomes with apparent K(i) values of 11-16 nM . These results indicate that PBITC and PHITC are more potent inhibitors of NNK bioactivation in rats and mice than PEITC . In addition, these arylalkyl isothiocyanates could be effective in protecting against the actions of a broad spectrum of carcinogenic or toxic compounds.

Arch Otolaryngol Head Neck Surg, 1993 Jun, 119(6), 648 - 51
Erythromycin therapy for otitis media with effusion in sinobronchial syndrome; Iino Y et al.; Chronic sinusitis is frequently associated with chronic lower respiratory tract diseases, and the association is referred to as sinobronchial syndrome (SBS) . This study was carried out to determine the incidence of otitis media with effusion in the patients with sinobronchial syndrome and to investigate the efficacy of low-dose and long-term erythromycin therapy for otitis media with effusion associated with sinobronchial syndrome . We have found a high incidence of otitis media with effusion in patients with sinobronchial syndrome, the morbidity rate being 54% in 50 cases studied . This ear disease seems to be the major cause of hearing disturbance in patients with sinobronchial syndrome . Sixteen patients with both sinobronchial syndrome and otitis media with effusion were given low-dose and long-term erythromycin therapy (erythromycin base, 600 mg/d for more than 4 months); of these, 13 became effusion-free and most subjects showed improvement in the symptoms of sinobronchial syndrome . The erythromycin therapy thus seems to be exceedingly effective for the treatment of sinobronchial syndrome and associated otitis media with effusion.

Clin Pharm, 1993 Jun, 12(6), 440 - 8
Drug-induced pancreatitis; Underwood TW et al.; Recent information about drugs implicated in causing pancreatitis is summarized . Although the frequency of drug-induced acute pancreatitis is generally low, the disease is associated with substantial morbidity and mortality, which makes timely identification of the offending agent important . Mechanisms suggested for drug-induced pancreatitis include pancreatic duct constriction; immunosuppression; cytotoxic, osmotic, pressure, or metabolic effects; arteriolar thrombosis; direct cellular toxicity; and hepatic involvement . Agents reported to have a definite association with pancreatitis are asparaginase, azathioprine, didanosine, estrogens, furosemide, mercaptopurine, pentamidine, sulfonamides, sulindac, tetracyclines, thiazides, and valproic acid . Agents reported to have a probable association with pancreatitis include cimetidine, clozapine, corticosteroids, endoscopic retrograde cholangiopancreatography contrast media, methyldopa, metronidazole, salicylates, and zalcitabine . Agents reported to have a questionable association with pancreatitis include acetaminophen, cyclosporine, cytarabine, erythromycin and roxithromycin, ketoprofen, metolazone, and octreotide . When ethanol abuse and biliary disease are ruled out as etiologies for pancreatitis, the possibility of drug-induced disease should be investigated.

J Antimicrob Chemother, 1993 Jun, 31 Suppl E, 111 - 7
Clinical safety and tolerance of azithromycin in children; Hopkins S; An analysis of the safety data emanating from several clinical trials of the use of azithromycin in children has been undertaken . The studies compared azithromycin with standard regimens of various comparator agents: co-amoxiclav, amoxycillin, penicillin V, erythromycin, dicloxacillin and flucloxacillin, in the treatment of otitis media, pharyngitis and skin infections . Side-effects, based on the investigators' assessments of the severity and possible relationship to the study drugs, were measured within 35 days of the start of therapy . The total number of side-effects reported was significantly lower in the azithromycin-treated patients (46/606; 7.6%) than in the comparator-treated patients (72/523; 13.8%; P = 0.001) . Two (0.3%) and five (1.0%) patients, respectively, withdrew from treatment in each group . The most frequently reported side-effects were gastrointestinal with an incidence of 5.6% (34 patients) in the azithromycin group and 11.7% (61 patients) in the comparator group (P < 0.001) . The only other organ system with more than 0.5% of subjects reporting side-effects was the skin, with nine (1.5%) patients in the azithromycin and 11 (2.1%) patients in the comparator group complaining of dermatological reactions . Azithromycin was equally well tolerated in children of all ages . Inspection of individual studies showed no significant differences in laboratory test abnormalities between treatment groups . Overall, the most frequently (> or = 1% incidence) reported treatment-related laboratory test abnormalities were changes in neutrophil count (3.2%), lactate dehydrogenase (1.5%), blood urea (1.3%) and potassium (1.2%) in the azithromycin group; and in neutrophil (3.2%) and eosinophil count (2.1%) in the comparator group.(ABSTRACT TRUNCATED AT 250 WORDS)

Pediatr Infect Dis J, 1993 Jun, 12(6), 504 - 9
Clinical and laboratory diagnosis of pertussis in the regions of a large vaccine efficacy trial in Germany; Heininger U et al.; As a support service for a pertussis vaccine efficacy trial, a central diagnostic laboratory was established . Physicians in the geographic areas of the planned study were encouraged to send nasopharyngeal specimens from children and household contacts with cough illnesses whether or not the illnesses were typical of pertussis . From April, 1991, to February, 1992, 3629 specimens were received and in 601 instances (16.6%) Bordetella pertussis was isolated . Only 3.3% of patients with positive cultures had received pertussis vaccine whereas 16.1% of culture-negative patients had received vaccine (P < 0.0001) . Fever was more common (12.2%) in patients with negative cultures compared with those with positive cultures (5.4%) (P < 0.0001) . B . pertussis isolation rates fell markedly after 21 days of cough . Significantly more patients with negative cultures compared with those with positive cultures had been treated with erythromycin (8.5 vs . 2.9%; P < 0.0001) . Patients with cough for greater than 4 weeks and specimen collection within 2 weeks of cough onset had a B . pertussis isolation rate of 59% . Similarly if whoop occurred under the same circumstances the isolation rate was 80% . In this study 25.5% of patients with culture confirmed pertussis had illnesses with cough of less than 21 days duration . This finding suggests to us that a pertussis case definition in efficacy trials that requires cough of 21 days is excessively restrictive.

Int J Dermatol, 1993 Jun, 32(6), 428 - 31
Stevens-Johnson syndrome and toxic epidermal necrolysis in Thailand; Leenutaphong V et al.; BACKGROUND . Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening illnesses that have often been linked to drug exposure . METHODS . We looked retrospectively for all cases of SJS and TEN that were admitted to Siriraj Hospital between 1981 and 1990 to determine the drug etiology . RESULTS . Fifty-eight cases of SJS and 20 cases of TEN were identified . Eight patients initially had an SJS-like aspect, which subsequently evolved into TEN . A culpable drug was determined in 60 patients (77%) . The mean time from first drug administration to onset of SJS or TEN was 6.8 +/- 6.5 days (range, 1 to 28 days) . A longer incubation period was observed with thiacetazone (10.5 +/- 5.6 days), phenytoin (12 +/- 8.5 days), and carbamazepine (11.3 +/- 3.4 days) . CONCLUSIONS . The culprit drugs included the following: antibiotics, 32 cases (penicillin, sulfonamides, tetracycline, erythromycin); anticonvulsants, nine (phenytoin, carbamazepine, barbiturates); antitubercular drugs, eight (thiacetazone); analgesics, four (acetylsalicylic acid, fenbufen); sulfonylurea, two; allopurinol, one; and others, four . The most frequent underlying diseases justifying the ingestion of one or more drugs in our patients were infections (52.7%), followed by pulmonary tuberculosis (10.8%), and by seizures (8.1%) . The total mortality rate was 14%; 5% for SJS, and 40% for TEN . Mortality was not affected by the type of drug responsible.

Mol Cell Biochem, 1993 May 26, 122(2), 101 - 12
Generation of oxygen free radicals during the metabolism of cyclosporine A: a cause-effect relationship with metabolism inhibition; Serino F et al.; A better understanding of the mechanism of lipid peroxidation during the metabolism of cyclosporine A (CsA) might help explain the toxicities of this immunosuppressive drug on various organs . Our in vitro work used microsomes prepared from livers of phenobarbital-induced male rats . The incubations (total volume 1ml) also contained a NADPH regenerating system and substrate (i.e., CsA, carbon tetrachloride, or aminopyrine) dissolved in ethanol . Lipid peroxidation was inferred from the presence of malondialdehyde (MDA) which was detected by the thiobarbituric acid assay . The formation of CsA hydroxylated metabolites (AM9 and AM1) was monitored by liquid chromatography . The activity of the microsomal incubation was confirmed by measurements of MDA and formaldehyde production caused by increasing concentrations of CsA, carbon tetrachloride, and aminopyrine . The occurrence of hydroxylated metabolites was not coupled to the production of MDA . Aminopyrine could inhibit MDA production by CsA, but CsA could not reduce the formation of formaldehyde by aminopyrine . Erythromycin, a competitor for the binding site of CsA on cytochrome P450, reduced MDA production by CsA, and CsA inhibited formaldehyde production by erythromycin . Interaction studies with SKF 525A, ketoconazole, superoxide dismutase, catalase, alpha-tocopherol, and reduced glutathione confirmed the role of cytochrome P450 and the presence of activated oxygen species as a source of microsomal peroxidation which in return may explain the inhibitory effect of CsA on cytochrome P450 itself.

Eur J Biochem, 1993 May 15, 214(1), 305 - 11
Heterologous expression in Escherichia coli of an intact multienzyme component of the erythromycin-producing polyketide synthase; Roberts GA et al.; 6-Deoxyerythronolide B synthase 3 (DEBS 3) is proposed to catalyse the fifth and sixth condensation cycles in the assembly of the polyketide 6-deoxyerythronolide B, the first isolatable intermediate in the biosynthesis of erythromycin A by Saccharopolyspora erythraea . The gene encoding DEBS 3 has previously been cloned and sequenced, and the deduced product is predicted to house nine fatty acid synthase-like activities on a 330-kDa polypeptide chain . The gene has been engineered into a pT-7-based expression system for over-expression in Escherichia coli . Recombinant DEBS 3 was found to constitute, after induction, 1-2% of soluble intracellular protein . DEBS 3 was purified from extracts of the recombinant E . coli to apparent homogeneity, and was found not to be modified by covalent attachment of the prosthetic group 4'-phosphopantetheine . Incubation with (R,S)-methylmalonyl-CoA, the presumed source of extension units for polyketide chain assembly, led to hydrolysis of the thioester, implying that the methylmalonyl-CoA:ACP acyltransferase domains in DEBS 3 are correctly folded and able to catalyse this side-reaction . During this reaction, DEBS 3 became transiently radiolabelled, consistent with the intermediacy of an acylenzyme . The native molecular mass of the protein by gel filtration chromatography was 668 kDa which corresponds either to a dimer or to a highly asymmetric monomer.

Postgrad Med, 1993 May 15, 93(7), 69 - 72, 75-6, 79-82
Atypical pneumonias . Clinical and extrapulmonary features of Chlamydia, Mycoplasma, and Legionella infections; Johnson DH et al.; Pneumonias caused by atypical organisms usually have extra-pulmonary features . Chlamydial pneumonia often starts with hoarseness and fever, and respiratory tract symptoms may not appear for days . Mycoplasmal pneumonia may manifest with ear pain and a nonproductive cough . Legionnaires' disease presents with high fevers and central nervous system and gastrointestinal abnormalities . Diagnosis of chlamydial infection is accomplished with serologic testing . Patients are unresponsive to erythromycin treatment and should be started on empirical doxycycline (Doryx, Vibramycin) therapy . The presence of cold agglutinins in the appropriate clinical setting permits a presumptive diagnosis of mycoplasmal infection . Clinical diagnosis of Legionella pneumonia may be made in patients with pneumonia who also have relative bradycardia with elevated serum transaminases or hypophosphatemia with gastrointestinal or central nervous system symptoms . Erythromycin is the mainstay of treatment of legionnaires' disease, but treatment failures have been reported . Doxycycline is less expensive, has a better safety profile, and is better tolerated than erythromycin.

Med J Aust, 1993 May 3, 158(9), 600 - 2
Erythromycin-associated cholestatic hepatitis; Derby LE et al.; OBJECTIVE: To estimate the risk of cholestatic hepatitis of uncertain origin in patients who had recently received erythromycin, a drug which is known to cause this disorder . DESIGN: A retrospective cohort study using data automatically recorded on general practitioners' office computers . SETTING: Some 600 general practices in the United Kingdom . SUBJECTS: 366,064 people who received erythromycin . MAIN OUTCOME MEASURE: Clinically documented cholestatic hepatitis of uncertain origin diagnosed 1-45 days after a prescription for erythromycin . RESULTS: There were 13 cases of cholestatic hepatitis of uncertain origin diagnosed within 45 days of receiving erythromycin which were either characteristic of or consistent with a syndrome previously described as being associated with this drug . CONCLUSION: The risk of cholestatic jaundice associated with erythromycin is estimated to be in the range of 3.6 per 100,000 users (95% confidence interval, 1.9-6.1).

Can J Anaesth, 1993 May, 40(5 Pt 1), 444 - 7
Interactions of pre-operative erythromycin administration with general anaesthesia; Narchi P et al.; Previous reports have demonstrated a gastric emptying effect of erythromycin due to a motilin-like mechanism . We studied 50 patients, scheduled for daycase laparoscopy, randomly assigned to one of two groups: Group P patients received 30 min before induction of anaesthesia, in a double-blind manner an infusion of 250 ml dextrose 5% while patients in Group E (n = 25) received 500 mg of erythromycin diluted in 250 ml dextrose 5% . An orogastric tube was inserted to measure both gastric pH using a pHmeter and residual gastric volume (RGV) using the phenol red dilutional technique . Six patients were excluded for surgical reasons . More patients in Group P (6/22) than in Group E (0/22) had RGV > 25 ml and more patients in Group P (17/22) presented with a gastric pH < 2.5 than in Group E (5/22), P < 0.05 . Since coma and respiratory depression have been reported recently after midazolam and alfentanil administration in patients having received erythromycin, recovery conditions were assessed and were found to be comparable between groups . In conclusion, the administration of iv erythromycin before outpatient laparoscopy decreased residual gastric volume and increased gastric pH without affecting recovery from general anaesthesia.

J Infect, 1993 May, 26(3), 315 - 9
Mycoplasma hominis sternal wound infection and bacteraemia; Smyth EG et al.; Mycoplasma hominis is a rare cause of bacteraemia in adult males . We believe this report to be the first of Mycoplasma hominis bacteraemia and wound infection complicating cardiac surgery . Because of difficulties in isolating the organism, cases may be missed . Review of the literature on M . hominis bacteraemia in adult males reveals that infection is often mild and most often associated with urethral catheterisation . M . hominis is resistant to many antibiotics including erythromycin . If treatment is indicated, tetracycline or clindamycin is the drug of choice.

Am J Physiol, 1993 May, 264(5 Pt 1), G928 - 34
Gastric axial forces in experimentally delayed and accelerated gastric emptying; Prather CM et al.; The aim of this study was to assess the relationship between altered axial forces and gastric emptying of solids by experimentally inhibiting or stimulating gastric axial forces by intraduodenal lipid or intravenous erythromycin, respectively . In 15 healthy volunteers, we simultaneously measured gastric emptying of solids by scintigraphy, gastroduodenal motility by manometry, and forces along the longitudinal axis of the distal stomach by an axial force transducer . When 25% of the radiolabel had emptied from the stomach, subjects (n = 5 in each group) received normal saline (controls), intraduodenal lipid, or intravenous erythromycin . The test period consisted of the infusion period (10 min) and the subsequent 30 min . Lipid significantly reduced and erythromycin increased axial forces compared with control (lipid: median 0.6 N {0-1.4 interquartile range (IQR)}; erythromycin: median 18.2 N (16.5-20.5 IQR); control: median 4.7 N (3.9-5.2 IQR); P < 0.01) . Similarly, antral phasic pressure activities were different relative to control . Gastric axial forces correlated significantly with gastric emptying (Spearman rank correlation = 0.86; P < 0.01) . These data are consistent with the hypothesis that axial forces affect gastric emptying of solids and suggest that measurement of axial forces provides an assessment of overall gastric propulsion during the emptying of solids.

Gastroenterology, 1993 May, 104(5), 1320 - 7
Mechanism of gastroprokinetic effect of EM523, an erythromycin derivative, in dogs; Ohtawa M et al.; BACKGROUND: The pharmacological properties of EM523, a nonpeptide motilin agonist, have not been well characterized . METHODS: The prokinetic effect of EM523 on motor-stimulating activity in the stomach, duodenum, and jejunum in seventeen conscious dogs was studied using force transducers implanted long term . EM523 (0.3-10.0 micrograms/kg) and receptor antagonists were injected intravenously during the interdigestive state . RESULTS: EM523 induced phase III-like contractions in a dose-dependent manner, and the contractions were inhibited dose dependently by pretreatment with cholinergic and 5-HT3 receptor antagonists and dopamine but not by adrenoceptor and opiate antagonists or methysergide . The plasma immunoreactive motilin level was increased after EM523 to 60% of the mean maximum value during the spontaneous phase III contractions . Pretreatment with anti-canine motilin serum inhibited EM523-induced contractions by 19.2% in the motor index, but the contractile pattern was not affected . CONCLUSIONS: EM-523-induced phase III-like contractions are brought about through the cholinergic neural pathway and 5-HT3 receptors, and endogenous motilin release is partially involved.

Dig Dis Sci, 1993 May, 38(5), 870 - 6
Effect of erythromycin on interdigestive gastrointestinal contractile activity and plasma motilin concentration in humans; Kawamura O et al.; The effects of erythromycin (EM) on gastrointestinal contractile activity during the interdigestive period were investigated in seven healthy subjects using an infused catheter system, and the changes in the plasma motilin concentration were also determined . Graded EM doses (0.1-1.5 mg/kg) were administered intravenously over 5 min, usually during gastric phase I . EM induced interdigestive migrating contractions (IMCs) . Their induction rate was low after low doses of EM, but gradually increased as the dose increased to reach 71.4% at an EM dose of 0.375 mg/kg . Strong contractions, which were quite similar to phase III activity of the stomach but did not migrate or migrated incompletely to the duodenum, were observed at EM doses above 0.375 mg/kg . Therefore, the optimum dose of EM for inducing an IMC was established to be 0.375 mg/kg . In comparison with spontaneous IMCs, EM-induced IMCs had a significantly longer duration in the stomach and a significantly lower amplitude in the duodenum . These observations indicate that EM induced phase III activity more intensively in the stomach than in the duodenum . The plasma motilin concentration increased significantly during EM-induced IMCs, and this suggested a close relationship between this hormone and induction of the IMC . The increase in motilin levels was also observed of the strong gastric contractions which did not migrate or migrated incompletely to the duodenum . Therefore, it seems reasonable to suggest that motilin is involved in phase III activity of the stomach rather than in that of the duodenum.

Obstet Gynecol, 1993 May, 81(5 ( Pt 1)), 745 - 9
Double-blind randomized study comparing amoxicillin and erythromycin for the treatment of Chlamydia trachomatis in pregnancy; Magat AH et al.; OBJECTIVE: To compare the efficacy and patient tolerance of amoxicillin to that of erythromycin in the treatment of lower genital tract chlamydia infections during pregnancy . METHODS: A double-blind, randomized study was conducted comparing oral amoxicillin 500 mg three times daily versus oral erythromycin 500 mg four times daily for 7 days . One hundred forty-three women with positive cervical cultures for chlamydia at less than 36 weeks' gestation were enrolled . A test-of-cure culture was obtained 4 weeks after entry into the study and side effects were assessed . Success of the regimen was defined as completing the course of medication and having a negative test-of-cure culture . RESULTS: Thirty of the 65 women in the erythromycin group (46.1%) developed symptoms while taking the medication and 15 of them were unable to continue treatment (23.1%) . In contrast, five of the 65 women (7.7%) in the amoxicillin group became symptomatic, with only one of these patients intolerant of the side effects (1.5%) (P < .001) . Of the 50 patients in the erythromycin group who were able to complete their course of medication, only three had a positive test of cure (6.0%) . In comparison, nine of the 64 patients (14.1%) taking amoxicillin who completed their course had positive cultures at test of cure . This difference was not statistically significant (P = .14) . Forty-seven of the 65 patients (72.3%) in the erythromycin group successfully completed their regimen, compared to 55 of the 65 women (84.6%) in the amoxicillin group . This difference was not statistically significant . CONCLUSIONS: These findings suggest that amoxicillin is a reasonable alternative for the treatment of chlamydia in pregnant patients intolerant to erythromycin . The incidence of side effects and intolerance to therapy for amoxicillin are less than those for erythromycin.

Analyst, 1993 May, 118(5), 567 - 71
Extraction-spectrofluorimetric method for the determination of erythromycin and its esters in pharmaceutical formulations using manual and flow-injection procedures; Sanz A et al.; A sensitive and rapid extraction-spectrofluorimetric method for the determination of erythromycin, based on the formation of an ion pair with Erythrosine B, is described . The calibration graph resulting from the measurement of the fluorescence of the chloroform extract (10 cm3) at 560 nm with excitation at 544 nm is linear over the range 10-600 micrograms of erythromycin per 20 cm3 of total volume of aqueous phase, with a relative standard deviation (RSD) of 1.5% for 3.7 micrograms cm-3 erythromycin . The method can be successfully adapted to an unsegmented flow system, the peak height being proportional to erythromycin concentration over the range 0.65-5.88 micrograms of erythromycin per 400 mm3 of sample solution injected . Up to 45 samples h-1 can be processed with an RSD of 2.9-3.8% . Manual and flow-injection methods were satisfactorily applied to the determination of erythromycin in pharmaceutical preparations.

Ann Vasc Surg, 1993 May, 7(3), 291 - 6
Erythromycin-associated ergotamine intoxication: arteriographic and electrophysiologic analysis of a rare cause of severe ischemia of the lower extremities and associated ischemic neuropathy; Ghali R et al.; Vasospasm associated with ergotamine is a well-known phenomenon . In this case report we present a rare drug interaction between erythromycin and ergotamine at normal doses causing lower extremity ischemia in a 36-year-old woman . Nitroprusside proved to be the treatment of choice . The response was dramatic and took place in a matter of hours in this patient . Ischemic monomelic neuropathy is a recently described entity in which axonal necrosis is caused by a loss of distal extremity blood flow . The association between erythromycin and ergotamine may be a dangerous pharmacologic combination; drugs that have a hepatic cycle with ergotamine derivatives must be used with caution.

Neurosurgery, 1993 May, 32(5), 716 - 20; discussion 720
Long-term survival in patients with glioblastoma multiforme; Chandler KL et al.; Few patients with glioblastoma multiforme survive more than 5 years . To identify the factors associated with long-term survival, patients with primary supratentorial glioblastoma multiforme diagnosed between 1969 and 1985 were identified from our computer data base . Twenty-two (5%) of the 449 patients identified survived at least 5 years after surgical diagnosis . There were 12 female and 10 male patients, with a mean age of 39.2 years (range, 15 to 63 yr) . Twenty patients had a subtotal resection, and 2 had a gross total resection . The median duration of survival was 9.4 years . As of August 1, 1992, 10 patients were alive 5.2 to 13.6 years after diagnosis, and 1 patient was lost to follow-up after 9.4 years . Ten patients died from their tumors; 2 patients with stable tumors died, 1 from a ruptured intracranial aneurysm and 1 from erythromycin-induced hepatitis . Unusual sequelae were noted in irradiated areas in several cases . One patient had a scalp sarcoma and a basal cell carcinoma, and three patients had strokes; each of these events occurred more than 5 years after diagnosis . We conclude that among patients with glioblastoma multiforme, long-term survival is most likely for those who have a long disease-free interval after the initial diagnosis and receive multimodal therapy, including aggressive tumor removal . Other factors associated with long-term survival were younger age and high Karnofsky scores.

Q J Med, 1993 May, 86(5), 327 - 32
Severe community-acquired legionella pneumonia: treatment, complications and outcome; Hubbard RB et al.; Legionella pneumophila is the second most common cause of severe community-acquired pneumonia requiring treatment with intermittent positive pressure ventilation . The prognosis of this condition and its complications have not been well documented . Erythromycin is the first-line antibiotic of choice based on clinical experience . Rifampicin has been recommended as an additional agent, though clinical experience has not been reported . We have retrospectively examined 30 cases of severe community-acquired legionella pneumonia . The mean age of the patients was 53 years, 24 were male and eight died (27%, mean age 57 years) . During admission 26 patients received erythromycin (eight died) and 15 received rifampicin in addition (five died); four received neither drug and survived . Mean duration of intermittent positive pressure ventilation was 15.9 days for survivors and 14.1 days for fatal cases . Acute renal failure requiring dialysis developed in 13 (43%), of whom five died (38%) . Positive inotropic drugs were used in 10 patients and of these six died . Jaundice occurred in 11 patients and was significantly more common (p = 0.028) in patients who received rifampicin (60%) than in those who did not (17%) . Excess bilirubin was largely conjugated when measured and there was no consistent hepatitic or obstructive change in the liver enzymes . Severe community-acquired legionella pneumonia has a relatively good outcome with a mortality of 27%, though prolonged intermittent positive pressure ventilation may be required . Acute renal failure is common but reversible in survivors, and jaundice is more common in those who receive rifampicin.

Arch Mal Coeur Vaiss, 1993 May, 86(5 Suppl), 757 - 67
{Drug-induced ventricular tachycardia}; Fauchier JP et al.; Certain drugs can induce ventricular tachycardia (VT) by creating reentry, ventricular after potentials or exaggerating the slope of phase 4 . These may or may not be symptomatic, sustained or non-sustained and have variable ECG appearances: monomorphic or polymorphic, bidirectional, torsades de pointes . They risk degenerating into ventricular flutter of fibrillation and have been held responsible for the increased mortality observed unexpectedly in some long-term treatments . The drugs responsible are mainly those used in cardiology, probably due to predisposing circumstances (cardiomegaly, cardiac failure, previous severe ventricular arrhythmias, therapeutic associations, metabolic abnormalities) . These include primarily the antiarrhythmic drugs (IA, IC, sotalol and bepridil), digitalis, sympathomimetics and phosphodiesterase inhibitors . These complications may be toxic or idiosyncratic, in patients with or without cardiac disease, and may also occur with other drugs: vasodilators and anti-anginal drugs (lidoflazine, vincamine, fenoxedil), psychotropic agents (phenothiazine and imipramine), antimitotics, antimalarials (chloroquine) or antibiotics (erythromycin, pentamidine) . The prognosis is severe and the treatment is often difficult which makes prevention, helped by repeated surface ECG (or Holter monitoring), very important with careful assessment of patients at risk.

Drug Metab Dispos, 1993 May-Jun, 21(3), 520 - 3
Modulation of rat hepatic CYP3A1 induction by the interferon inducer polyinosinic acid-polycytidylic acid (polyic); Delaporte E et al.; Interferon and interferon inducers are well known to depress hepatic cytochrome P-450 (P-450) . Previous reports have suggested that all constitutive members of the P-450 family of proteins are affected in this manner, whereas inducible P-450s--including cytochrome P-4503A1 (CYP3A1)--are resistant to the effects of interferons . We examined the effect of interferon {produced in response to polyinosinic acid-polycytidylic acid (polyIC; 10 mg/kg) administration} on the induction of CYP3A1 in the female rat by the macrolide antibiotic troleandomycin (TAO; 200 mg/kg), and the antiglucocorticoid pregnenolone-16 alpha-carbonitrile (PCN; 300 mg/kg) . The induction of CYP3A1 was characterized by erythromycin N-demethylation, Western blotting, and mRNA quantitation with a specific oligonucleotide cDNA probe . PCN-mediated induction of erythromycin metabolism was depressed by 85% following polyIC administration . PolyIC depressed the induction of CYP3A1 apoprotein by TAO (84%) and PCN (73%) . The depression of enzyme activity and protein were accompanied by a corresponding decrease in hepatic CYP3A1 mRNA . It is concluded that CYP3A1 is sensitive to the depressant effects of interferon, and that interferon appears to act at a pretranslation step that is independent of the induction process per se.

Gene, 1993 Apr 15, 126(1), 147 - 51
IS1136, an insertion element in the erythromycin gene cluster of Saccharopolyspora erythraea; Donadio S et al.; The Saccharopolyspora erythraea eryAI and eryAII genes, which, together with eryAIII, are responsible for the formation of the macrolactone portion of the antibiotic erythromycin, are separated by a 1.46-kb segment, designated IS1136, with the characteristics of an insertion sequence . It contains an open reading frame of 425 codons similar to that of the Anabaena IS891 and is present in four nonidentical copies in the Sac . erythraea genome . Inverted repeats were found near the ends of IS1136, and in the copy in eryA, one of the ends was found to overlap the 5' end of eryAII . Hybridization analysis suggests that IS1136 is confined to Saccharopolyspora species containing eryA-homologous DNA.

Arch Intern Med, 1993 Apr 12, 153(7), 879 - 82
Clinically significant hearing loss in renal allograft recipients treated with intravenous erythromycin; Vasquez EM et al.; BACKGROUND: Hearing loss is generally regarded as a rare side effect of erythromycin therapy . However, our own clinical experiences in erythromycin-treated patients led us to suspect that this complication may be more common among renal allograft recipients . The purpose of this study was to evaluate the incidence, predisposing factors, clinical characteristics, and outcomes of erythromycin-induced hearing loss among renal allograft recipients . METHODS: We reviewed medical records of renal transplant patients treated for pneumonia with intravenous erythromycin lactobionate . Patients were evaluated for the occurrence of clinically significant hearing loss (including onset, duration, and reversibility), other signs and symptoms of ototoxicity (vertigo and tinnitus), daily erythromycin dose and duration of treatment, concurrent ototoxic drug therapy, renal and hepatic function, and history of previous otic disease . RESULTS: Eleven (32%) of 34 courses of intravenous erythromycin therapy resulted in hearing loss . The incidence of hearing loss was 53% (eight of 15 courses) in patients treated with 4 g of erythromycin daily compared with 16% (three of 19 courses) among those receiving 2 g/d (P = .05) . In addition, courses of erythromycin were longer in those suffering auditory toxicity (9.6 +/- 4.7 days) than in nontoxic patients (5.7 +/- 3.6 days) (P < .05) . Hepatic and renal function did not differ between toxic and nontoxic patients . All episodes of erythromycin-induced hearing loss were reversible . CONCLUSIONS: We conclude that clinically significant hearing loss occurs in more than 30% of renal allograft recipients treated for pneumonia with intravenous erythromycin lactobionate . Patients who require prolonged courses of erythromycin and those treated with 4 g/d are at particular risk for the development of auditory toxicity . With prompt recognition and modification of therapy, erythromycin-induced hearing loss appears to be completely reversible.

Genitourin Med, 1993 Apr, 69(2), 108 - 11
Clinico-epidemiological study of donovanosis in Durban, South Africa; O'Farrell N; OBJECTIVE: To describe the epidemiological and clinical features of donovanosis and their relevance to the possible coincident risk of HIV-1 transmission in patients attending an STD clinic . DESIGN: Assessment of patients with donovanosis diagnosed by the detection of Donovan bodies on tissue smears stained by the RapiDiff technique . SETTING: City Health STD Clinic, King Edward VIII Hospital, Durban, South Africa . PARTICIPANTS: One hundred and seventy one patients with donovanosis . RESULTS: Donovan bodies were detected in 171 (130 men, 41 women) . Ulcers were present for longer than 28 days in 72 (55.4%) men and 19 (46.3%) women . Ninety five (55.6%) came from rural areas . Lesions were ulcero-granulomatous in 162, hypertrophic in eight and necrotic in one . Anal lesions were detected in one woman . Only one of 21 regular sexual partners examined was infected with donovanosis . Complete healing was observed in 41 (24%) who attended for follow up . Extensive lesions were sometimes observed in pregnant women . Serological tests for syphilis were positive in 40 (23.4%) . HIV-1 antibodies were detected in 4/48 men and 0/15 women who underwent HIV testing . Donovanosis ulcers in three HIV-1 seropositive men were cured by standard antibiotic therapy . CONCLUSIONS: Delay in presentation, extensive areas of genital ulceration and lack of co-existent infection with donovanosis among sexual partners were notable features . Primary health care facilities in rural areas do not appear to be providing an adequate service for patients with donovanosis . HIV control programmes should consider specific measures aimed at eradicating donovanosis in areas where the condition is prevalentPIP: In 1988, in South Africa, staff at the City Health STD Clinic at King Edward VIII Hospital in Durban took tissue smears from 130 men and 41 women to study the epidemiological and clinical features of donovanosis as it relates to a possible risk of HIV-1 transmission . Laboratory personnel used the RapiDiff staining method and histological examinations to detect Donovan bodies in 169 and 2 of the patients, respectively . 96% of patients were 16-39 years old . 55.6% came from rural areas . Lesions were mainly limited to the genital area (96.2% for men and 78% for women) . Women were more likely to also have lesions in the inguinal area (17.1% vs . 1.5%) . Most donovanosis lesions were ulcero-granulomatous (96.2% for men and 90.2% for women) . 3 of the 6 pregnant female patients had hypertrophic lesions . The only case of anal donovanosis was a woman . Even though the patients had ulcers, many continued to have sexual intercourse . 55.4% of the men and 46.3% of the women had ulcers for more than 28 days before coming to the clinic . 40 patients with donovanosis (23%) also had syphilis . Donovanosis was diagnosed in just 1 of 21 regular sexual partners examined . 2 tablets of co-trimoxazole 2 times daily for, mostly, 14 days cured 41 (24%) patients who returned to the clinic for follow-up . Pregnant women took 500 mg of erythromycin 2 times a day . A few cases had to take 100 mg minocycline twice a day . 4 men tested positive for HIV-1 antibodies while none of the women did . 3 of the HIV-1 positive men who returned to the clinic were completely cured of donovanosis . None of these men had HIV-related symptoms . They were treated with co-trimoxazole . These findings suggest that rural health facilities are not adequately serving patients with donovanosis . Since genital ulcer disease, such as donovanosis, facilitates transmission of HIV-1, strategies to curb the spread of HIV should consider specific measures aimed at eradicating donovanosis in areas where it is prevalent .

Mikrobiyol Bul, 1993 Apr, 27(2), 137 - 42
{Legionnaires' disease following kidney transplantation}; Ogunc G et al.; Legionella pneumonia was diagnosed in two patients receiving triple immunosuppressive drug therapy after renal transplantation . High fever was the predominant symptom of these patients . Hyponatremia, leucopenia and anemia were also observed . The disease was diagnosed by immunofluorescence antigen technique and easily controlled with erythromycin therapy.

J Antibiot (Tokyo), 1993 Apr, 46(4), 647 - 60
Chemical modification of erythromycins . IX . Selective methylation at the C-6 hydroxyl group of erythromycin A oxime derivatives and preparation of clarithromycin; Watanabe Y et al.; Although erythromycin A contains five hydroxyl groups, regioselective methylation at the C-6 hydroxyl group was achieved to the extent of 90% when a 9-O-substituted erythromycin A 9-oxime was employed as substrate . The methylation and its selectivity are dependent on an O-protecting group at the 9-oxime, solvent, base, and methylating reagent . In particular, the use of a polar aprotic solvent is indispensable for the methylation . Among the 9-oxime derivatives, 2'-O,3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A 9-{O-(2-chlorobenzyl)oxime} was the most important intermediate for the synthesis of clarithromycin (6-O-methylerythromycin A).

Neonatal Netw, 1993 Apr, 12(3), 13 - 8
Ureaplasma urealyticum and its role in neonatal lung disease; Gannon H; Ureaplasma urealyticum, a species of mycoplasma organisms, is a sexually transmitted organism which can cause a pneumonia in premature neonates . Ureaplasma urealyticum infection in the neonate occurs secondary to maternal transmission of the organism to the neonate . Recent studies show very low birth weight neonates with Ureaplasma urealyticum pneumonia are approximately two times more likely to develop chronic lung disease . Clinically Ureaplasma urealyticum pneumonia presents in a premature neonate and is often coexistent with hyaline membrane disease, leukopenia, thrombocytopenia, and continued respiratory distress without identification of a causative organism . Diagnosis is generally by tracheal aspirate or spinal fluid culture . Ureaplasma urealyticum requires specific culture media to grow, and recovery of the organism can take several weeks . Clinical management of the infant includes administration of erythromycin and meticulous pulmonary toilet . A case study which represents the typical presentation of Ureaplasma urealyticum pneumonia is included.

Am J Gastroenterol, 1993 Apr, 88(4), 485 - 90
Erythromycin: a motilin agonist and gastrointestinal prokinetic agent; Weber FH Jr et al.; Erythromycin, a commonly used antibiotic, has recently emerged as a potential gastrointestinal prokinetic agent . This follows a decade of research into the mechanism of well-recognized gastrointestinal side effects of erythromycin . Early investigations demonstrated that erythromycin increased gastrointestinal motility, and more recent studies suggest that it fortuitously binds to and stimulates the receptor for the gastrointestinal peptide motilin . From this work it appears that a new and powerful class of gastrointestinal prokinetic agents will evolve from erythromycin and its derivatives . The role of motilin in the genesis of the fasting and fed patterns of gastrointestinal motility is emerging through the study of these motilin agonists.

Gastroenterology, 1993 Apr, 104(4), 1030 - 6
Motilin and erythromycin stimulate pepsinogen secretion by chief cells isolated from guinea pig stomach; Fiorucci S et al.; BACKGROUND: Motilin and erythromycin bind the same receptor in the gastrointestinal muscle cells . Motilin stimulates pepsinogen secretion in humans and dogs . However, it is unclear whether it acts directly on gastric chief cells or via other neurotransmitters . METHODS: Isolated gastric chief cells were obtained from guinea pig stomach by collagenase digestion and calcium chelation with ethylene glycol-bis(B-amynomethyl ether)-N,N,N',N'-tetraacetic acid . RESULTS: Significant stimulation of pespinogen secretion induced by motilin occurred at 1 pmol/L, half maximum at 10 pmol/L, and maximum at 100 pmol/L . Erythromycin caused significant stimulation at 1 pmol/L, half maximum at 100 pmol/L, and maximum at 1 nmol/L . Atropine (1 mumol/L) had no effect on either motilin- or erythromycin-induced pepsinogen secretion . Motilin and erythromycin determined a threefold increase in the intracellular calcium concentrations . Pretreatment of isolated chief cells with motilin and erythromycin induced a reversible, dose- and time-dependent desensitization of the pepsinogen secretion stimulated by carbachol and cholecystokinin but not that stimulated by secretin, vasoactive intestinal peptide, or prostaglandin E2 . CONCLUSIONS: Motilin and erythromycin directly stimulate pepsinogen secretion in isolated chief cells.

Arch Surg, 1993 Apr, 128(4), 441 - 4
Experience with ambulatory preoperative bowel preparation at the Johns Hopkins Hospital; Handelsman JC et al.; A transition to ambulatory preoperative antibiotic bowel preparation was carried out . The protocol included a liquid diet for 40 hours preceding surgery and coordination of purging with buffered oral saline laxative, 45 mL containing 8 g sodium phosphate and 22 g sodium biphosphate (Fleet Phospho-Soda, C.B . Fleet Co, Lynchburg, Va) and bisacodyl preparation with an oral erythromycin base-neomycin routine . Enemas were omitted . Personnel in the preoperative evaluation center had the responsibility of instructing patients, distributing directions and drugs, and reviewing for compliance and possible problems during the preoperative period . All patients scheduled for any of a variety of gastrointestinal procedures, as well as some other complex operations, were included in this study . Follow-up data were obtained . Surgeons' comments regarding efficacy were highly favorable . In only five cases was there comment regarding liquid stool, and this was no impediment to surgery . This incidence was comparable with that of the inpatient experience, as was the spectrum of postoperative complications . Transfer of responsibility to the department proceeded with ease . Results were entirely comparable with those of the former inpatient experience.

J Nucl Med, 1993 Apr, 34(4), 582 - 8
Effects of erythromycin on gastric emptying, alcohol absorption and small intestinal transit in normal subjects; Edelbroek MA et al.; The effects of erythromycin on gastric emptying and intragastric distribution of a mixed solid/liquid meal, alcohol absorption and small intestinal transit were examined in eight male volunteers . Each subject received, in double-blind randomized order, either erythromycin as the lactobionate (3 mg.kg-1 i.v . over 20 min) or saline immediately before the consumption of a radioisotopically labeled test meal, which consisted of 330 g minced beef and 400 ml of orange juice containing ethanol (0.5 g.kg-1 body weight) and 10 g lactulose . Erythromycin increased the rate of total stomach emptying and proximal stomach emptying of both the solid and liquid components of the meal (p < 0.001), but slowed small intestinal transit (p < 0.01) . Peak blood alcohol concentrations (p < 0.01) were higher after erythromycin, with a mean increase of 40% . There was a significant inverse relationship between peak blood alcohol concentrations and the 50% emptying time for the liquid component of the meal after saline (r = -0.70, p < 0.05), but not after erythromycin (r = -0.57, p < 0.1) . The total area under the venous blood alcohol concentration time curve (i.e., total absorption) was greater (p < 0.01) after erythromycin . These results suggest that: faster emptying from the proximal stomach contributes to more rapid gastric emptying induced by erythromycin, erythromycin retards small intestinal transit and that erythromycin increases the total amount of alcohol absorbed as well as the rate of alcohol absorption . These latter effects are likely to reflect more rapid delivery of alcohol to the small intestine and reduced metabolism of alcohol by the gastric mucosa.

Biochem Pharmacol, 1993 Mar 9, 45(5), 1097 - 105
Effect of rociverine on P450-dependent monooxygenases and its N-deethylation metabolism in rat liver microsomes; Menicagli S et al.; Rociverine {2-(diethylamino)-1-methylethyl cis-1-hydroxy {bicyclohexyl}-2-carboxylate} citrate (ROC) is an antispasmodic agent therapeutically active in humans at doses of 0.5-1 mg/kg . This study investigated the effect of acute administration of the drug on hepatic microsomal cytochrome P450 (P450)-catalysed drug metabolism . Only high doses (> or = 100 mg/kg) of ROC were able to induce in rats the hepatic microsomal pentoxyresorufin O-depenthylase (PROD) and 16 beta-testosterone hydroxylase activities both associated with P4502B1/2 and the erythromycin N-dimethylase (ErD) and 2 beta-testosterone hydroxylase activities both dependent on P4503A1/2 . However, at 100 and 200 mg/kg of ROC, the 16 beta-testosterone hydroxylase and PROD were the most induced activities, suggesting that P4502B1/2 are the isoforms most sensitive to ROC induction . Accordingly, ROC treatment enhanced, in a dose-dependent manner, the amount of P4502B1/2 and 3A1/2 in microsomes as assayed by western blotting . The northern blot analysis of ROC-treated rat liver showed that the P4502B1/2 induction appears to be regulated at the mRNA level as in the induction by phenobarbital (PB) . The oxidative metabolism of ROC with hepatic microsomes from control or PB- and ROC-induced rats resulted in a N-deethyl ROC derivative (major metabolite) and an unknown minor ROC derivative . The kinetic parameters for the N-deethylation of ROC were studied with purified P4502B1 and with microsomes from control or rats treated with various inducers (phenobarbital, ethanol, beta-naphthoflavone, dexamethasone and rociverine) . It was found that phenobarbital-, dexamethasone- and rociverine-induced microsomes deethylated ROC with a Vmax about five times higher than that (0.9 nmol/min/mg protein) of control microsomes, although with a similar affinity (Km approximately 0.3 mM) . In a reconstituted system, the purified P4502B1 metabolized ROC with a high deethylation rate (22 nmol/min/nmol P450) . Moreover, the ROC deethylation was inhibited by compounds such as hexobarbital, metyrapone and triacetyloleandomicin, selective inhibitors for P4502B and/or P4503A enzymes . On the other hand ROC, when added in vitro, inhibited the 16 beta- and 2 beta-testosterone hydroxylases and the PROD and ErD activities . Taken together, these results indicate that the ROC-inducible P4502B and P4503A are involved in ROC deethylation . In conclusion, it has been demonstrated that ROC is a weak phenobarbital-like inducer of P450, probably able at high and reiterated doses to alter its own metabolism, at least in the rat liver.

Biochem Pharmacol, 1993 Mar 9, 45(5), 1065 - 77
Initial characterization of the major mouse cytochrome P450 enzymes involved in the reductive metabolism of the hypoxic cytotoxin 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide (tirapazamine, SR 4233, WIN 59075); Riley RJ et al.; The benzotriazine di-N-oxide SR 4233 (tirapazamine, WIN 59075) is currently in phase I clinical trials as the lead compound in a series of novel and highly selective antitumour hypoxic cytotoxins . Reductive bioactivation is thought to proceed via a one-electron reduced, oxidizing nitroxide radical and also forms the inactive single N-oxide SR 4317 via radical disproportionation or a second one-electron reduction . In mouse liver microsomes reductive metabolism is catalysed predominantly by cytochrome P450 (70%) and cytochrome P450 reductase (30%) . The aim of the present study was to examine which cytochrome P450 isozymes may be involved . Reduction of SR 4233 to SR 4317 was monitored by HPLC analysis . Metabolism by microsomes from both control and dexamethasone-induced BALB/c male mice was 70% inhibited by carbon monoxide . The cytochrome P450 inhibitor SKF 525A, following aerobic preincubation, also inhibited SR 4233 reduction by 58% . Reduction was induced 2-3-fold by dexamethasone and was not accountable by increases in cytochrome P450 reductase or DT-diaphorase . The induction data and the greater degree of inhibition of SR 4233 reduction by metyrapone compared to alpha-naphthoflavone suggested a possible involvement of Cyp2b, Cyp2c and Cyp3a cytochrome P450 subfamilies . Both Cyp3a (7.4-fold) and Cyp2b (1.8-fold) type enzymes were shown by western immunoblot analysis to be induced by dexamethasone, the latter correlating more closely with increased SR 4233 reductase activity and also with the 2-fold induction of benzphetamine N-demethylase, a Cyp2b-type enzyme . No inhibition of SR 4233 reduction was seen with erythromycin or cyclosporin A which act as substrates/inhibitors for Cyp3a-type enzymes, but inhibition was seen with p-nitrophenol and tolbutamide which are substrates for Cyp2el- and Cyp2c-type enzymes, respectively (11% and 25% inhibition in induced microsomes) . SR 4233 itself inhibited benzphetamine N-demethylase, which is catalysed by Cyp2b-type enzymes but not erythromycin N-demethylase which is catalysed by Cyp3a-type isoforms . Immunoinhibition studies with epitope specific monoclonal antibodies were consistent with the major involvement of phenobarbitone- and steroid-inducible products of the Cyp2b and Cyp2c subfamilies . These forms contributed at least 53% and 26%, respectively, of the cytochrome P450-associated SR 4233 reductase activity in the induced microsomes . The findings support our earlier conclusion that cytochrome P450 is the major SR 4233 reductase in mouse liver and provides leads as to the possible involvement of specific isoforms in human tumours and normal tissues.

Biochemistry, 1993 Mar 2, 32(8), 1905 - 13
Substrate specificity of 6-deoxyerythronolide B hydroxylase, a bacterial cytochrome P450 of erythromycin A biosynthesis; Andersen JF et al.; The 6-deoxyerythronolide B hydroxylase (EryF) is a soluble cytochrome P450 responsible for the stereospecific C-6 hydroxylation of the erythromycin precursor, 6-deoxyerythronolide B . Using the expression of the eryF gene in Escherichia coli {Andersen, J . F., & Hutchinson, C . R . (1992) J . Bacteriol . 174, 725-735} as the enzyme source, we examined the catalytic activity of the EryF protein toward several macrolide substrates related to 6-deoxyerythronolide B . The results of these studies were compared with measurements of the apparent dissociation constants for various substrates and with information from molecular modeling studies of the substrates and the enzyme-substrate complex . Only minor changes in the structure of 6-deoxyerythronolide B resulted in substrates with catalytic rates less than 1% of those seen with the natural substrate . Although the 9S epimer of 9-deoxo-9-hydroxy-6-deoxyerythronolide B was hydroxylated at a rate approximately equal to the natural substrate, the 9R epimer was hydroxylated at a 2-fold lower rate . Examination of molecular models revealed that the position of the 9-hydroxyl oxygen in the 9S epimer resembles that of the 9-oxo oxygen in the natural substrate more closely than in the 9R epimer . 8,8a-Deoxyoleandolide, which is identical to 6-deoxyerythronolide B except for the presence of a C-13 methyl group, and its (9S)-9-deoxo-9-hydroxy derivative were C-6 hydroxylated at a 4-fold lower rate than the natural substrate, and the 9-oxo form showed a substantially larger apparent dissociation constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Baillieres Clin Obstet Gynaecol, 1993 Mar, 7(1), 237 - 55
Infection due to Chlamydia trachomatis in pregnancy and the newborn; Smith JR et al.; Bacteria in the genus Chlamydia comprise three species, C . trachomatis, C . psittaci and C . pneumoniae . C . trachomatis infection is common, varying in prevalence in women from 0% to 37% . In the United States, the prevalence rate is estimated currently to be about 5% . Pregnancy may predispose to an increased chance of infection with C . trachomatis, through physiological immunosuppression and/or cervical ectopy . Maternal antibodies to C . trachomatis provide limited, if any, protection for the newborn . C . trachomatis causes pelvic inflammatory disease--which can result in tubal infertility or ectopic pregnancy and postabortal or late postpartum endometritis . It may also cause chorioamnionitis and premature delivery of the fetus . The incidence of vertical transmission of chlamydiae from mother to baby varies; if the mother is untreated, 20-50% of the newborns will develop conjunctivitis and 10-20% will develop pneumonia . C . psittaci infection in pregnancy is rare, but can cause spontaneous abortion . Whether C . pneumoniae infection in pregnancy has any influence on the outcome has not been ascertained . C . trachomatis can be detected by one or more of several methods; enzyme immunoassays are the least sensitive, but the most widely used . Screening for C . trachomatis in pregnancy may be of benefit in areas of high prevalence, and is generally regarded as being cost-effective if the prevalence rate is more than 5% . Pregnant women are best treated with erythromycin, 250 mg four times daily for 7 days . This will prevent infection of the newborn in more than 90% of cases . The infected neonate should be treated with erythromycin, given systemically and also with topical tetracycline if conjunctivitis is present.

Am J Otol, 1993 Mar, 14(2), 186 - 8
Ototoxicity of erythromycin in man: electrophysiologic approach; Sacristan JA et al.; Ototoxicity is probably the least acknowledged adverse reaction of erythromycin . The mechanism of erythromycin ototoxicity is still unknown . Here we report on two new cases of erythromycin-induced hearing loss . In both of them, serial evoked auditory brainstem potentials (EABPs) were obtained . The recorded EABPs showed absence of waves I to III during treatment with erythromycin, and normalization of all EABP waves after the administration of erythromycin had been stopped . Our findings support the hypothesis that erythromycin-induced hearing loss is attributable to a functional disorder in the peripheral parts of the auditory system.

Peptides, 1993 Mar-Apr, 14(2), 207 - 13
Cholinergic regulation of motilin release from isolated canine intestinal cells; Poitras P et al.; An in vitro model was developed to study the regulation of motilin release from its endocrine-producing cell . Enzymatically dispersed cells from canine duodenojejunal mucosa were separated by centrifugal counterflow elutriation to enrich motilin content . From the motilin-enriched cell preparation, the release of motilin was determined under stimulation with various agents . Carbachol dose-dependently stimulated the release of motilin from its producing cell . Bombesin, morphine, and erythromycin, recognized stimulants for motilin release in vivo, failed to influence the secretion of motilin in vitro . Serotonin, GIP, CCK, pentagastrin, cisapride, neosynephrine, isoproterenol, or muscimol were also ineffective in the in vitro model . The response to carbachol was abolished by atropine but was not affected by somatostatin, serotonin, secretin, CCK, or GIP . These results suggest that muscarinic receptors are present on the motilin cell membrane and that acetylcholine is a major regulator of motilin release.

J Antimicrob Chemother, 1993 Mar, 31 Suppl C, 175 - 85
Safety profile of dirithromycin; Sides GD et al.; Dirithromycin is a recently developed oral antibiotic, and has been shown to be effective in the treatment of respiratory tract, skin and soft tissue infections . Dirithromycin is administered once daily which may contribute to patient compliance . In this paper we review the data from studies conducted in Europe, USA, Israel and South Africa over a six-year period to assess the safety and efficacy of dirithromycin in the treatment of a variety of acute infectious illnesses, and to compare it with structurally related antibiotics (erythromycin base, roxithromycin, and miocamycin) given orally . A total of 7437 patients have been enrolled from a total of 66 studies and trials, 4263 (57.3%) treated with dirithromycin and 3174 (42.7%) treated with a comparator antibiotic . Patients received either 500 mg dirithromycin (two tablets once daily), 1000 mg erythromycin base (250 mg qid), 300 mg roxithromycin (150 mg bid), or 1200 miocamycin (600 mg bid); the length of therapy ranged from 7 to 14 days . These studies have shown that dirithromycin has a safety profile similar to the comparator agents . The most frequently reported adverse events for both dirithromycin and comparator treatment groups were gastrointestinal in nature . The majority (99%) of adverse events reported from patients treated with dirithromycin were considered mild or moderate in severity . Early discontinuation of antibiotic therapy was infrequent (3-4%) in both treatment groups, and considered to be possibly drug-related in 2-3% of the population . The safety profile of dirithromycin in elderly patients was comparable to that recorded in the overall patient population . The incidence and nature of abnormal clinical laboratory evaluation were similar in dirithromycin and comparator groups . Notable alterations in laboratory tests of haematological or hepatic function were infrequent and were not associated with clinical manifestations . Routine monitoring of standard clinical laboratory tests in patients prescribed dirithromycin does not appear to be necessary.

Int J STD AIDS, 1993 Mar-Apr, 4(2), 70 - 82
A review and update on adult syphilis, with particular reference to its treatment; Goldmeier D et al.; Syphilis has become less common in Europe in the last decade, but has once again become a major problem in the USA, and remains so in many developing countries . Several treponemal genes have now been cloned and expressed in Escherichia coli, allowing study of treponemal proteins . The importance of cell mediated immunity in syphilis has been demonstrated in animal models . A diagnosis of syphilis is usually confirmed by dark-field microscopy or serological tests . Seroconversion may be delayed in HIV infected individuals . A positive reaginic test in cerebrospinal fluid (CSF) has a high specificity but low sensitivity in the diagnosis of neurosyphilis . Indeed, virulent treponemes can be identified in CSF samples which have negative reaginic tests, normal cell counts and protein levels . In the CSF, the FTA-Abs test has a high sensitivity but low specificity for neurosyphilis . Penicillin remains the treatment of choice for all stages of syphilis, although it penetrates the blood brain barrier poorly . Treatment with intramuscular benzathine penicillin 2.4 million units stat, or 600,000 units procaine penicillin daily does not produce treponemicidal levels within the CSF . However, the incidence of neurosyphilis is low in immunocompetent patients treated with such regimens during early syphilis . Acceptable alternatives in penicillin-allergic patients include ceftriaxone and doxycycline . Erythromycin is not recommended as it has produced unacceptably high rates of treatment failure . Recently, a strain of macrolide-resistant Treponema pallidum was isolated from a patient with secondary syphilis . For the treatment of neurosyphilis, treponemicidal levels of penicillin can be achieved in the CSF using 2.4 million units procaine penicillin daily with concurrent probenecid 500 mg 4 times a day, or an intravenous infusion of benzyl penicillin 12-24 million units daily . Early syphilis can be treated adequately over 10 days, but 21 to 28 days is appropriate for late syphilis . In HIV-infected patients syphilis may present atypically with initially negative serological tests . Treatment of early syphilis in HIV-positive patients has been associated with the early development of neurosyphilis . It is advisable to treat all patients co-infected with HIV with an antibiotic regimen that achieves adequate levels within the CSF.

Clin Pharmacol Ther, 1993 Mar, 53(3), 298 - 305
A potentially hazardous interaction between erythromycin and midazolam; Olkkola KT et al.; Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies . In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week . On the sixth day, the subjects ingested 15 mg midazolam . In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments . Plasma samples were collected, and psychomotor performance was measured . Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p < 0.001) and reduced clearance of intravenously administered midazolam by 54% (p < 0.05) . In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p < 0.05) from 15 minutes to 6 hours . Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction . Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Can J Physiol Pharmacol, 1993 Mar-Apr, 71(3-4), 191 - 4
Effect of erythromycin on D-galactose absorption and sucrase activity in rabbit jejunum; Navarro H et al.; Erythromycin, an antibiotic used in the treatment of infectious diseases, produces gastrointestinal side effects such as diarrhea . The mechanisms by which erythromycin produces these effects are not known . However, erythromycin has been shown to increase gastrointestinal motor activity and to inhibit intestinal neutral amino acid absorption . Both effects could contribute to the gastrointestinal side effects observed . Because the intestinal systems of amino acid and sugar transport present similar characteristics, the aim of the present work was to determine whether erythromycin also alters D-galactose absorption and sucrase activity in rabbit jejunum . The results show that erythromycin diminishes intestinal D-galactose absorption . This effect seems to be due to an action mainly located on the Na(+)-dependent sugar transport of the mucosal border of the intestinal epithelium . Erythromycin also inhibits the Na(+)-K+ ATPase activity of the enterocyte, which might explain the inhibition of the D-galactose Na(+)-dependent transport . However, a direct action of the erythromycin molecule on the Na(+)-dependent carrier cannot be excluded . Erythromycin did not alter sucrase activity.

Comp Biochem Physiol C, 1993 Mar, 104(3), 433 - 7
Effects of dexamethasone on the hepatic cytochrome P450IIIA subfamily in two hamster strains Mesocricetus auratus and Cricetus griseus; Antignac E et al.; 1 . Administration of dexamethasone significantly reduced the amount of hepatic cytochrome P450 in Syrian golden and Chinese hamsters, while it increased the amount in rats . 2 . In contrast to rats, the induction rate of the activities of erythromycin and troleandomycin N-demethylases by dexamethasone was relatively low, while that of the testosterone 6 beta-hydroxylase was high in the two hamster strains . 3 . Western blot analysis revealed that dexamethasone did not modify markedly the pattern of the P450IIIA subfamily proteins in the two hamster strains.

Biochem Pharmacol, 1993 Feb 24, 45(4), 853 - 61
Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation . Metabolic drug interactions; Zhou XJ et al.; Vindesine biotransformation was investigated using a bank of human liver microsomes . The drug was converted into one major metabolite (M) upon incubation with the microsomes . Large interindividual variations were observed: vindesine biotransformation rates ranged from 1.2 to 12.9 pmol/min/mg protein . Vindesine metabolic processes followed Michaelis-Menten kinetics: Km = 24.7 +/- 9.4 microM, Vmax = 1.5 +/- 0.8 nmol/min/mg protein . The involvement of human cytochrome P450 3A isozymes in vindesine metabolism was demonstrated by: (1) competitive inhibition of vindesine biotransformation by compounds known to be specifically metabolized by human cytochrome P450 3A . Apparent Ki values were 3.6, 17.9 and 19.8 microM for quinidine, troleandomycin and erythromycin, respectively; (2) immunoinhibition of vindesine metabolism by polyclonal anti-P450 3A antibody; (3) significant correlation between immunoquantified P450 3A and vindesine biotransformation (r = 0.800, P < 0.001); and (4) significant correlation between erythromycin N-demethylase activity, which was supported by P450 3A in humans, and vindesine biotransformation (r = 0.853, P < 0.001) . Other vinca alkaloids also exerted an inhibitory effect on vindesine biotransformation with apparent Ki values of 3.8, 10.6 and 19.2 microM for vinblastine, vincristine and navelbine, respectively, suggesting a possible involvement of the same cytochrome subfamily in their hepatic metabolism . Moreover, a number of anticancer drugs currently associated with the vinca alkaloids, such as teniposide, etoposide, doxorubicin, lomustine, folinic acid and mitoxantrone, significantly inhibited vindesine biotransformation.

Nucleic Acids Res, 1993 Feb 11, 21(3), 635 - 9
Erythromycin and 5S rRNA binding properties of the spinach chloroplast ribosomal protein CL22; Carol P et al.; The spinach chloroplast ribosomal protein (r-protein) CL22 contains a central region homologous to the Escherichia coli r-protein L22 plus long N- and C-terminal extensions . We show in this study that the CL22 combines two properties which in E . coli ribosome are split between two separate proteins . The CL22 which binds to the 5S rRNA can also be linked to an erythromycin derivative added to the 50S ribosomal subunit . This latter property is similar to that of the E . coli L22 and suggests a similar localization in the 50S subunit . We have overproduced the r-protein CL22 and deleted forms of this protein in E . coli . We show that the overproduced CL22 binds to the chloroplast 5S rRNA and that the deleted protein containing the N- and C-terminal extensions only has lost the 5S rRNA binding property . We suggest that the central homologous regions of the CL22 contains the RNA binding domain.

Tijdschr Kindergeneeskd, 1993 Feb, 61(1), 20 - 4
{Ureaplasma urealyticum in tracheal aspirate of ventilated premature infants: report of 6 cases}; Groenendaal F et al.; In the Netherlands, up till now no reports have appeared describing neonatal colonisation of mechanically ventilated preterm neonates with Ureaplasma urealyticum . The present, prospective study was designed to assess the incidence of U . ureaplasma infections in a group of preterm newborns with prolonged ventilatory support because of respiratory failure . In 1989 110 preterm newborns with hyaline membrane disease (HMD) were mechanically ventilated; 23 for more than 7 days because of pulmonary abnormalities . Six of them (26%) had positive cultures of endotracheal aspirate for U . urealyticum . Gestational age at birth ranged from 26 to 33 5/7 weeks, birth weight from 790 to 2545 gram . Other bacteria or viruses were not present . Although all patients with positive cultures for U . urealyticum were treated with erythromycin and U . urealyticum was eradicated, no clinical effect was seen . Five of the 6 patients (83%) with U . urealyticum developed bronchopulmonary dysplasia (BPD), 2 of them (33%) died . Of the 17 neonates without U . urealyticum 9 (53%) developed BPD, whereas one (6%) died . Differences were not significant (Chi 2 test/Fisher exact test) . Also in the Netherlands U . urealyticum can be demonstrated in endotracheal aspirate of ventilated preterm newborns . The hypothesis, that early diagnosis and treatment of U . urealyticum in this group of patients might decrease the morbidity and mortality caused by HMD and BPD, needs further study.

Kansenshogaku Zasshi, 1993 Feb, 67(2), 163 - 6
{A case of Legionnaires' disease due to aspiration of hot spring water and isolation of Legionella pneumophila from hot spring water}; Mashiba K et al.; We report a case of fulminant pneumonia that was due to aspiration of contaminated hot spring water and was not affected by beta-lactam antibiotics . We suspected that the patient had Legionnaires' disease and treated the clinical symptoms with erythromycin . Legionellaceae could not be isolated from sputum or lung biopsy material, but an elevated titer to Legionella pneumophila serogroup 4 was found by indirect immunofluorescence test . We diagnosed the patent as having Legionnaires' disease with improved clinical symptoms . Furthermore, we went to the hot spring that he visited and tried to isolate Legionellaceae . Hot spring water was collected from the bathroom and water, hot water, and shower water from the guest-room . After using a low-pH method, samples were cultured on BCYE alpha medium . Serogroups are classified by agglutination method with immune rabbit serum . As a result, we successfully isolated Legionella pneumophila serogroup 4 from hot spring water (42 degrees C) from the bath . No bacteria could be isolated from the other samples . Therefore, we believe that this case of Legionnaires' disease was caused by aspiration of contaminated hot spring water . The infection route of Legionnaires' disease is unclear . There are no previous reports of isolation of Legionellaceae from Japanese hot springs . This case would provide important information when considering the infection route of Legionnaires' disease in Japan.

Semin Vet Med Surg (Small Anim), 1993 Feb, 8(1), 42 - 9
Ototoxicity in dogs and cats; Pickrell JA et al.; Ears are special sense organs whose principal functions are hearing and maintaining equilibrium . Aminoglycoside antibiotics, erythromycin, polymyxin B, and cisplatin can affect either or both of these functions by binding with, injuring, and/or destroying special receptor cells associated with these functions . Severe hearing loss manifests itself as deafness, whereas loss of equilibrium will present as abnormal righting reflexes, nausea, and vomiting . Damage is proportional to levels of these ototoxins in the endolymphatic fluids . Evidence suggests that toxicity may be influenced by endolymphatic calcium concentrations, and levels of cAMP and cGMP are altered in specialized cochlear cells during ototoxicity, suggesting an additional mechanism for ototoxicity . The administration of salicylates and loop diuretics may potentiate the action of ototoxins, especially aminoglycoside antibiotics, probably by increasing the levels of these toxins in the endolymphatic fluid . Although many of these assessments have been made in laboratory animals, applicability may also be expected in small domestic animals, and extreme care should be taken in prescribing potentially ototoxic drugs to small animals . Cochlear damage from ototoxic compounds occurs initially in the cells detecting high-frequency sounds located at the lower basal region . In aging dogs and humans, this sensitivity of receptors in the lower basal region is enhanced . Early auditory damage is detectable by BAER and cochlear microphonic potentials . Vestibular responses can also be detected early as vestibular ocular reflexes and visual-vestibulo-ocular reflexes . Early detection is especially important because early changes can sometimes be reversible . Cavinton (apovincaminic acid) and fosfomycin represent examples of experimental agents being evaluated in laboratory animals for application as potential treatments to limit the ototoxicity associated with various drugs.

Antimicrob Agents Chemother, 1993 Feb, 37(2), 265 - 9
Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers; Lindstrom TD et al.; Some macrolide antibiotics cause clinical drug interactions, resulting in altered metabolism of concomitantly administered drugs, via formation of an inactive cytochrome P-450 complex . In the present study, the formation of a cytochrome P-450 type I binding spectrum and a metabolic intermediate complex by troleandomycin and dirithromycin was assessed in liver microsomes obtained from untreated rats and phenobarbital- or dexamethasone-pretreated rats . Troleandomycin produced a type I binding spectrum and metabolic intermediate complex in microsomes from dexamethasone- and phenobarbital-pretreated rats . Dirithromycin did not produce a detectable type I binding spectrum but formed a small cytochrome P-450 metabolic intermediate complex (6% of that formed by troleandomycin) in microsomes from dexamethasone-pretreated rats only . The formation of a cytochrome P-450 type I binding spectrum and a metabolic intermediate complex by troleandomycin, erythromycin, dirithromycin, and erythromycylamine was also assessed in microsomes prepared from human livers . Troleandomycin and erythromycin formed a type I binding spectrum and a metabolic intermediate complex which were larger in microsomes from subjects on barbiturate therapy than in microsomes from subjects with no recent barbiturate exposure . Erythromycylamine did not form a detectable type I binding spectrum with any of the human microsomal samples, but a small metabolic intermediate complex was formed with microsomes from a subject on phenobarbital, phenytoin, and propranolol therapy . Dirithromycin did not form a detectable type I binding spectrum or a metabolic intermediate complex in any human liver sample . Preclinical quantitation of the human metabolic intermediate complex may be helpful in predicting the possibility of clinical drug interactions of new drug candidates.

Aliment Pharmacol Ther, 1993 Feb, 7(1), 55 - 9
Dose-dependent stimulation of gallbladder contraction by intravenous erythromycin in man; Catnach SM et al.; We have previously shown that a single oral dose of 500 mg erythromycin causes gallbladder contraction . The effect of intravenous erythromycin on antroduodenal motility is dose-dependent; < 3 mg/kg body weight stimulates propagated contractions in a fashion similar to motilin while doses > 7 mg/kg cause giant non-propagated antral contractions not seen with motilin . Using ultrasound, we have examined the effect of differing doses of intravenous erythromycin on gallbladder motility in man . Erythromycin (1 mg/kg) caused fasting gallbladder contraction to 52% of basal gallbladder volume (P < 0.001), and increased gallbladder emptying following a liquid meal (maximal percentage emptied 75 +/- 6.8% vs . 58 +/- 9.0% following saline, P < 0.05) . Erythromycin (7 mg/kg) however, had no effect on gallbladder fasting or post-prandial motor activity . We conclude that the effect of erythromycin on gallbladder motility is dose-dependent, with higher doses having no effect . It is possible that at higher doses erythromycin stimulates other receptors in addition to the motilin receptor, and that the combined effect is different to the stimulation of the motilin receptor alone.

Anesthesiology, 1993 Feb, 78(2), 260 - 5
Sufentanil disposition . Is it affected by erythromycin administration?
Bartkowski RR, Goldberg ME, Huffnagle S, Epstein RH.
BACKGROUND: Because oral erythromycin administration has been associated with reduced elimination of alfentanil, suspicion has been raised about related opioids with similar metabolic pathways . A controlled crossover study of sufentanil pharmacokinetics was undertaken to resolve this issue . METHODS: Six subjects had measurements of plasma concentrations for 9 h after intravenous administration of sufentanil (3 micrograms/kg) . Each subject was studied following no erythromycin (control) and after 1- and 7-day courses of erythromycin base . RESULTS: Plasma concentrations during the 9 h of measurement were similar before and after erythromycin . Terminal half-life and clearance and distribution volume did not change significantly among treatment groups . Values measured after 7 days of erythromycin were similar to controls . CONCLUSIONS: Prior administration of erythromycin does not alter pharmacokinetics of sufentanil in the 9 h following sufentanil administration . Thus, there are no apparent clinical consequences of prior or concomitant erythromycin administration in patients receiving sufentanil for procedures of 9 h or less.

Gut, 1993 Feb, 34(2), 166 - 72
Erythromycin effects on gastric emptying, antral motility and plasma motilin and pancreatic polypeptide concentrations in anorexia nervosa; Stacher G et al.; In primary anorexia nervosa, gastric motility is often impaired and ensuing symptoms further discourage eating . Prokinetic agents have been shown to accelerate gastric emptying in affected patients . This study investigated whether emptying of a radiolabelled semisolid 1168 kJ meal and antral contractility were enhanced by intravenous erythromycin . Eight women and two men with anorexia nervosa (21-46 years, 50-75% of ideal body weight) received 200 mg erythromycin or placebo under crossover double blind conditions . Gastric emptying and antral contractility were recorded scintigraphically for 90 minutes . In addition, plasma motilin and pancreatic polypeptide concentrations were determined . With placebo, antral contractions were of regular 3 cycles/minute frequency . With erythromycin, less frequent and partly arrhythmic long duration contractions set in and emptying was accelerated: after 90 minutes, the activity remaining in the stomach was markedly less than with placebo in all patients (Sign test, p < 0.002) . Basal motilin and pancreatic polypeptide concentrations were normal and showed a normal response to the meal in all patients . Motilin concentrations decreased slightly more and pancreatic polypeptide concentrations increased markedly more with erythromycin than with placebo, possibly because the meal reached the intestine earlier . In conclusion, erythromycin accelerated emptying markedly and in most patients induced an antral motor activity characterised by long duration contractions occurring at often irregular intervals.

Ann Emerg Med, 1993 Feb, 22(2), 212 - 5
Dexamethasone as adjuvant therapy for severe acute pharyngitis; O'Brien JF et al.; STUDY OBJECTIVE: To determine the efficacy of dexamethasone as adjuvant therapy to improve pain relief in patients with severe, acute exudative pharyngitis . DESIGN: Prospective, randomized, double-blinded, placebo-controlled clinical trial . SETTING: Large, urban community hospital emergency department with an emergency medicine residency program . TYPE OF PARTICIPANTS: Patients aged 12 to 65 years old with exudative pharyngitis and severe dysphagia/odynophagia . Patients with cancer, AIDS, diabetes mellitus, recent steroid use, pregnancy, or suspicion of peritonsillar abscess were excluded . INTERVENTIONS: All patients received oral penicillin (500 mg Pen VK) or erythromycin (333 mg base) three times daily for ten days in addition to either 10 mg single-dose dexamethasone or saline placebo IM injection . MEASUREMENTS AND RESULTS: Fifty-eight patients graded their initial degree of throat pain on a visual-analog scale that was 15 cm long and scored from 0 to 3.0 in 0.5-cm increments . Follow-up was obtained on 51 patients to determine their condition at 24 hours . At entry, there was no difference in age, weight, antibiotic assignment, or initial pain score between groups . Improvement in pain score (initial versus 24 hours) was 1.8 +/- 0.8 in the 26 patients of the dexamethasone group and 1.2 +/- 0.9 in the 25 patients of the placebo group (P < .05) . Time to onset of pain relief was also faster in steroid-treated patients who demonstrated relief beginning at 6.3 +/- 5.3 hours, compared with 12.4 +/- 8.5 hours in the placebo group (P < .01) . Of the 26 patients evaluated at seven days (13 in each group), time to complete lack of pain averaged 15.0 +/- 11.4 hours in the dexamethasone group and 35.4 +/- 17.9 hours in the placebo group (P < .02) . Complications attributable to dexamethasone were not observed . CONCLUSION: In patients with severe, acute exudative pharyngitis, single-injection dexamethasone adjuvant compared with placebo resulted in statistically and clinically significant improvement, as evidenced by more rapid onset and greater degree of pain relief.

Am J Gastroenterol, 1993 Feb, 88(2), 208 - 11
Effect of intravenous erythromycin on postoperative ileus; Bonacini M et al.; We attempted to determine whether the administration of erythromycin shortens the period of postoperative ileus by a prospective, double-blind, placebo-controlled study . Seventy-seven patients were randomized and included in the statistical calculations . The patients were stratified according to the operation performed (cholecystectomy, celiotomy, or other major abdominal operations) . Forty-one patients (group 1) received 250 mg erythromycin intravenously every 8 h for nine doses upon admission to the recovery room . Thirty-six patients (group 2) received placebo . The time (in hours) to first passage of flatus, first liquid meal, first bowel movement, and total length of hospital stay was recorded . There was no significant difference between group 1 and group 2 in time to first flatus (54.9 +/- 29 vs . 53.9 +/- 27 h, respectively), first meal (70.4 +/- 44 vs . 71.7 +/- 65), first bowel movement (81.8 +/- 32 vs . 80.1 +/- 28), or length of hospital stay (185.2 +/- 183 vs . 182.1 +/- 163) . Erythromycin, in the dosage tested in this study, does not seem to alter clinical parameters of gastrointestinal motility after an abdominal operation . New prokinetic agents may deserve further studies.

Am J Gastroenterol, 1993 Feb, 88(2), 203 - 7
The treatment of idiopathic and diabetic gastroparesis with acute intravenous and chronic oral erythromycin; Richards RD et al.; The objective of this study was to investigate the effects of intravenous erythromycin and chronic oral dosing of erythromycin on gastric emptying in patients with idiopathic or diabetic gastroparesis . Symptoms were assessed on oral dosing and during long-term follow-up in an ambulatory setting at a University referral center . Fourteen patients (10 idiopathic and four diabetic gastroparesis) were studied . Four patients left during the 4-wk study; two due to rash, one with cramps and vomiting on erythromycin, and one due to other medical problems . Ten patients completed the 4-wk study and commenced long-term therapy . Five of these patients experienced enough symptomatic relief to continue oral erythromycin long-term, being followed for an average period of 8.4 months . After initial documentation of delayed gastric emptying, patients received 6 mg/kg intravenous erythromycin lactobionate before a second gastric emptying study . Erythromycin base was then given orally at a dose of 500 mg tid-ac and qhs, with a final gastric emptying study performed after 4 wk . During long-term follow-up, erythromycin dosage was adjusted to minimize symptoms . Radionuclide-labeled gastric emptying of a solid meal was studied at baseline, following intravenous erythromycin, and after 4 wk of oral treatment with erythromycin . Symptom scores were assessed at baseline, at 4 wk, and then at 8-wk intervals . The percentage of the solid meal retained in the stomach at 2 h decreased from 85% +/- 11% (SD) at baseline to 20% +/- 29% following intravenous erythromycin (p < 0.001), and to 48% +/- 21% after 4 wk of oral therapy (p < 0.01 vs . baseline) . There was a reduction in total symptom scores and a significant reduction in global assessment scores (p = 0.03) . We conclude that erythromycin has a strong gastric prokinetic effect in both idiopathic and diabetic gastroparesis, and may represent a useful new therapeutic approach to this problem.

Am J Gastroenterol, 1993 Feb, 88(2), 198 - 202
The effect of erythromycin in gastric emptying of solids and hypertonic liquids in healthy subjects; Mantides A et al.; We report our study of the effect of erythromycin on gastric emptying of solid and liquid meals in 10 healthy subjects . On different occasions, subjects consumed either a radiolabeled 50% glucose solution, or a radiolabeled standard solid meal after placebo, and after receiving 200 mg of erythromycin intravenously . Erythromycin accelerated the gastric emptying of the hypertonic liquid meal by significantly decreasing the duration of lag phase (p < 0.0001), by significantly increasing the emptying rate at the postlag period (p < 0.001), and by significantly decreasing the duration of the postlag period (p < 0.0001) and the meal remaining in the stomach at 15 (p < 0.05), 30 (p < 0.001), and 60 (p < 0.01) min postprandially . In addition, erythromycin administration induced a significant plasma fall at 15 (p < 0.05) and 30 (p < 0.01) min and a significant increase in pulse rate at 15 and 30 min (p < 0.01) after consumption of the hypertonic glucose solution, whereas three subjects experienced symptoms suggesting dumping syndrome . Furthermore, erythromycin administration enhanced the gastric emptying of solids by almost abolishing the duration of lag phase (p < 0.0001) and by reducing the overall t1/2 of emptying (p < 0.0001), whereas less food was retained in the stomach at 60 (p < 0.001) and 120 (p < 0.0001) min postprandially . Conversely, the postlag t1/2 of the solid meal emptying was not affected by erythromycin, as compared to placebo . We conclude that erythromycin has gastrokinetic properties, affecting the gastric emptying of both liquids and solids.

Am J Gastroenterol, 1993 Feb, 88(2), 193 - 7
Erythromycin accelerates gastric emptying of indigestible solids and transpyloric migration of the tip of an enteral feeding tube in fasting and fed states; Keshavarzian A et al.; Erythromycin has been shown to initiate gastric interdigestive migrating motor complexes, which are the motor events responsible for gastric emptying of indigestible solids . Hence, erythromycin should also accelerate gastric emptying of indigestible particles and facilitate transpyloric migration of the tip of an enteral feeding tube . Accordingly, we assessed the effect of erythromycin on these events, using a single-blind crossover study . Healthy subjects were nasally intubated with an enteral feeding tube . For fasting studies, the subjects remained fasted; in the fed studies, the subjects were fed a cheeseburger and fries after placement of the feeding tube . Then, ten 1-cm radiopaque plastic segments were swallowed by each subject, followed by an iv infusion of either erythromycin (200 mg over 20 min) or saline . Abdominal x-rays were then taken at regular intervals to document the location of the tube tip and the plastic segments . Erythromycin significantly shortened gastric emptying time of the indigestible particles during both fasting and fed states . Erythromycin also accelerated transpyloric migration of the tip of the feeding tube in both fasting and fed states . Hence, erythromycin can be beneficial when placement of a feeding tube in the small intestine is clinically desired.

Hepatology, 1993 Feb, 17(2), 230 - 5
Interferon suppresses erythromycin metabolism in rats and human subjects; Craig PI et al.; Interferon down-regulates expression of cytochrome P-450 3A in male rats . This study explored the hypothesis that interferon therefore decreases the metabolism of drugs catalyzed by cytochrome P-450 3A . Initial experiments in male rats used microsomal erythromycin N-demethylase activity as a probe for cytochrome P-450 3A catalytic activity . After administration of rat interferon-gamma, erythromycin metabolism was impaired (53% of control; p < 0.01) . This change correlated with the decline in cytochrome P-450 3A-dependent androstenedione 6 beta-hydroxylase activity, indicating that the decrease in erythromycin N-demethylase activity could be attributed to interferon-mediated suppression of cytochrome P-450 3A . We then used the {14C}N-methyl erythromycin breath test to assess the activity of hepatic cytochrome P-450 3A in rats and human subjects before and after a single dose of interferon . In rats, rat interferon-gamma decreased erythromycin metabolism to 57% of control (p < 0.005) . In the human study, six patients with chronic active hepatitis C and four healthy controls were examined 20 to 26 hr after receiving a subcutaneous injection of human interferon-alpha 2b . Interferon produced a small decrease (median = 15%; range = 3% to 35%) in erythromycin metabolism (p < 0.05), as determined by 2-hr excretion of 14CO2 in the breath . Thus interferon-mediated suppression of cytochrome P-450 3A is less strong in human subjects than in male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Biotherapy, 1993, 6(1), 19 - 23
Clinical usefulness of continuous administration of Nocardia rubra cell wall skeleton (N-CWS) in diffuse panbronchiolitis (DPB); Ishioka S et al.; Eight patients with diffuse panbronchiolitis (DPB) who had repeated intractable airway infections were continuously treated with Nocardia rubra cell wall skeleton (N-CWS), a biological response modifier . As a result, subjective symptoms were reduced in 6 patients . Antibiotics therapy could be discontinued completely in two patients and the dose of antibiotics could be reduced considerably in two other patients . No adverse reactions in relation to N-CWS were observed . These results suggest that N-CWS is effective in treating erythromycin-resistant DPB.

Fundam Clin Pharmacol, 1993, 7(2), 69 - 75
Identification of the human and animal hepatic cytochromes P450 involved in clonazepam metabolism; Seree EJ et al.; This report characterizes the cytochrome P450 isozyme involved in clonazepam metabolism . This study was undertaken using a library of liver microsomal fractions prepared from untreated rabbits or those treated with drugs known to specifically induce various cytochrome P450 isozymes (ie P450 2B4 by phenobarbital, P450 1A1 and P450 1A2 by 3-methylcholanthrene and beta-naphthoflavone, P450 2E1 by acetone and ethyl alcohol, and P450 3A6 by erythromycin) . Only microsomes obtained from phenobarbital-treated rabbits exhibited a type II binding spectrum upon addition of clonazepam (Ks(app) = 31.4 +/- 3.8 microM) and significantly metabolized clonazepam to 7-aminoclonazepam . Benzphetamine, which is a known substrate for P450 2B1 was also extensively metabolized by microsomes prepared from phenobarbital treated rabbits . This indicates that the same isozyme (P450 2B subfamily) was involved in the biotransformation of both substrates . Experiments performed on 14 human liver microsomal preparations showed a wide interindividual variability (from 1-4) and a good correlation (r = 0.70) between benzphetamine and clonazepam metabolism . Since P450 3A4 (nf25) was involved in benzphetamine metabolism, clonazepam was probably nitroreduced by the same isozyme . An oligonucleotide specific for the P450 3A4 gene subfamily was synthetized and used for hybridization on total RNA from human liver samples . Two transcripts of 2.2 and 3.0 kb were detected and the level of the 2.2 kb mRNA expression was significantly correlated (r = 0.61) with the intensity of clonazepam nitroreduction by the corresponding microsome batches.

An Otorrinolaringol Ibero Am, 1993, 20(2), 173 - 8
{Evaluation of the possible ototoxicity of josamycin by high frequency audiometry}; Domenech J et al.; Josamycin is an antibiotic macrolide similar to erythromycin, with some differences in its biologic behaviour . There have been no reports of ototoxic effects caused by this drug, but its similitudes with erythromycin have prompted us to undertake a study about its possible cochleo-toxicity . Most trials of this kind have been carried out using conventional audiometry (up to 8,000 Hz), thus not being able to detect threshold shifts above this frequency . Ototoxic lesions usually begin in the upper frequency limit . Twenty-eight patients without previous auditory impairment were studied with conventional (up to 8,000 Hz) and high-frequency audiometry (up to 20,000 Hz) before and after oral treatment with josamycin during eight days . No significant differences were found in auditory thresholds registered before and after treatment in any of the patients . These results suggest that josamycin is devoid of any cochleo-toxic effect in all the frequencies that a normal subject can hear.

Eur J Epidemiol, 1993 Jan, 9(1), 97 - 9
Diagnosis of Mycoplasma pneumoniae infection by specific IgM antibodies using a new capture-enzyme-immunoassay; Samra Z et al.; A total of 1226 sera from 1055 patients with respiratory tract infections were tested . IgM antibodies were detected by an antibody-capture enzyme-immunoassay (Mp TEST, Diatech Diagnostica Ltd, Israel) . Acute infection with IgM antibodies to Mycoplasma pneumoniae was detected in 211 patients . Presence of IgM was closely associated to some or all pneumonia-related symptoms . Eighty-one of IgM-positive patients treated with tetracycline or erythromycin responded positively . Of the 211 patients, 63 (30%) had low levels and 23 (11%) had moderate levels of IgM antibodies already in the first serum sample . In these 86 patients (41%) the complement fixation (CF) test was negative or very low positive . Thus in these cases, the CF test would have missed the early diagnosis in the first serum samples.

Drug Saf, 1993 Jan, 8(1), 30 - 48
Drug interactions of clinical significance with opioid analgesics; Maurer PM et al.; Opioid analgesics and other drugs interact through multiple mechanisms, resulting in pharmacological effects that depend upon the pharmacodynamic action studied, the interacting agents and the route of administration . Many interactions result from induction or inhibition of the hepatic cytochrome P450 mono-oxygenase system . The elimination of opioids is largely dependent on hepatic metabolism, and drug interactions involving this mechanism can therefore be clinically significant . Antibiotics are often used concomitantly with opioids in patients undergoing medical or surgical procedures; the best documented metabolic interactions are with erythromycin and rifampicin (rifampin) . Erythromycin increases and rifampicin decreases the effects of opioids . Cimetidine may increase the effects of opioids by increasing their duration of action; there have been no documented cases of interactions with ranitidine . Carbamazepine, phenytoin and the barbiturates can enhance the metabolism of opioids that rely on hepatic metabolism . Other pharmacokinetic interactions include those with benzodiazepines, tricyclic antidepressants, phenothiazines and metoclopramide . Interactions involving pharmacodynamic mechanisms are more common than pharmacokinetic ones . Such interactions are manifested clinically as as a summation (additive or synergistic) of similar or opposing pharmacological effects on the same body system . Idiosyncratic interactions also occur, the mechanisms of which have not been proven to be solely modulated by either pharmacokinetic or pharmacodynamic means . The knowledge of particular opioid-drug interactions, and the causative pharmacokinetic, pharmacodynamic, and idiosyncratic mechanisms, allows for the safer administration of opioid analgesics.

Kansenshogaku Zasshi, 1993 Jan, 67(1), 7 - 11
{Effect of erythromycin on neutrophil adhesion molecules}; Kusano S et al.; The mechanisms of erythromycin (EM) in chronic lower respiratory tract diseases including diffuse panbronchiolitis (DPB) has been reported . In this study we investigated the effect of EM on peripheral neutrophil adhesion molecules such as LFA-1 and Mac-1 obtained from six healthy subjects . Pretreatment of neutrophils with each concentration (10 ng/ml approximately 100 micrograms/ml) of EM resulted in no significant reduction in the expression of LFA-1 alpha, beta and Mac-1 . Moreover, EM had no capability of reducing these expressions even when neutrophils were pretreated with 1 microgram/ml of EM at time from 0 to 60 min . These findings indicate that EM does not directly reduce the expression of LFA-1 alpha, beta and Mac-1 on peripheral neutrophil obtained from healthy subjects.

Arzneimittelforschung, 1993 Jan, 43(1), 53 - 6
Erythromycin and 2'-acetyl erythromycin concentrations in plasma and pelvic tissues after repeated doses of erythromycin acistrate; Lehtonen L et al.; The concentrations of erythromycin (E) and 2'-acetyl erythromycin (2'-AE) in female pelvic organs, i.e . endometrium, myometrium, ovary and Fallopian tube, as well as in plasma, were determined after oral dosing of erythromycin acistrate (EA, CAS 96128-89-1), a erythromycin prodrug . Ten patients undergoing selective gynecological operation were given three doses of EA (400 mg) at 8-h intervals immediately before the operation . Tissue samples were taken 75-205 min after the intake of the last dose . Blood samples were collected immediately prior to and up to 8 h after the intake of the last dose . High total antibiotic (erythromycin + 2'-acetyl erythromycin) concentration in plasma were measured throughout the dose interval after the last dose . The concentrations of E in plasma were over the MICs for most of the erythromycin-sensitive bacteria (0.5 micrograms/ml) in 7 out of 10 patients (mean 0.66 micrograms/ml) at the end of the third dose interval . The drug concentrations in tissues were lower than in plasma (due to short treatment time of totally 24 h) . The mean percentage of penetration (tissue/plasma ratios) for erythromycin ranged from 63 to 95% in various pelvic tissues . However, rather extensive interindividual variation was observed . The degree of hydrolysis of 2'-acetyl erythromycin to erythromycin was 29-39% in plasma and 42-73% in tissue samples . There were negligible amounts of inactive anhydro forms in plasma after EA and their concentrations in tissue samples were low, as well.

Chem Biol Interact, 1993 Jan, 86(1), 51 - 68
Effects of acute sodium arsenite administration on the pulmonary chemical metabolizing enzymes, cytochrome P-450 monooxygenase, NAD(P)H:quinone acceptor oxidoreductase and glutathione S-transferase in guinea pig: comparison with effects in liver and kidney; Falkner KC et al.; Tissue specific changes in the cytochrome P-450 (P-450) monooxygenase system were observed following a single subcutaneous dose of sodium arsenite (75 mumol/kg), a known inducer of stress proteins . P-450 monooxygenase activities were assayed with several isozyme selective substrates; 7-ethoxyresorufin, 7-pentoxyresorufin, 4-aminobiphenyl and erythromycin . Both tissue selective and isozyme selective changes in monooxygenase activity were noted . For example, the rate of 4-aminobiphenyl N-hydroxylation (ABH) was increased by arsenite administration in lung but not in liver . Arsenite inhibited 7-ethoxyresorufin O-deethylation (ERF) in all tissues of control animals, but to a lesser extent in lung . However, increases of ERF activity occurred after arsenite treatment in lung of beta-naphthoflavone (beta NF)-treated guinea pigs whereas arsenite decreased ERF activities in the kidney and liver of these animals . These complex effects on ERF activity may in part be modulated by induction of heme oxygenase, whose activity was increased 2.5-3.5-fold in these organs by arsenite . The highest heme oxygenase activity was found in kidney with lower activities being present in liver and lung, respectively . These data are consistent with the decreased P-450 content observed in kidney and liver microsomes of arsenite treated guinea pigs . On the other hand there was either no change or a slight increase (about 2-fold) in the pulmonary microsomal P-450 content of these animals . A complex pattern of induction for the non-heme, Ah locus associated enzyme, NAD(P)H:quinone acceptor oxidoreductase (QOR) was also observed . With menadione as substrate arsenite treatment increased QOR activity in all tissues studied . However, with dichlorophenolindophenol (DCPIP) as substrate a significant arsenite effect was observed only in the kidney . Significant differences between the QOR substrates were also observed in beta NF-treated guinea pigs and control animals . Our results are consistent with the presence of more than one form of QOR in the guinea pig . Arsenite treatment also caused an increase in glutathione S-transferase activity, with 2,4-dinitro-1-chlorobenzene (DNCB) as substrate, of guinea pig kidney but not liver or lung.

Int J STD AIDS, 1993 Jan-Feb, 4(1), 5 - 7
The value of tests of cure following cervical chlamydial infection; White DJ et al.; Test of cure (TOC) was performed 2, 4 and 6 weeks after treatment for cervical chlamydia infection with 10-14 days of Deteclo one tablet twice daily, erythromycin 500 mg twice daily or doxycycline 100 mg twice daily . Testing was by chlamydia culture and IDEIA (DAKO diagnostics Ltd) . Discrepant results were subsequently checked by immunofluorescence (Syva MicroTrak) of both sets of left over transport media . Two hundred and three patients attended on at least one occasion; 189, 146 and 107 at 2, 4 and 6 weeks respectively . Of these 127, 70 and 34, respectively, denied sexual intercourse or had consistently used condoms . Fourteen were positive over the study period by either or both methods of detection . Of 8 culture positive results 3 were negative by IDEIA . Two of these had elementary bodies (EBs) on immunofluorescence of both sets of saved transport media . One had EBs on immunofluorescence of the saved culture transport medium only . None of the 6 IDEIA positive, culture negative patients had immunofluorescent EBs in the IDEIA transport media although one had EBs in the saved culture transport medium . One IDEIA suspicious, culture negative patient had EBs in both sets of saved transport media . There was no significant difference in the rate of chlamydia detection from patients admitting to or denying unprotected intercourse . TOC has a low yield in cases of cervical chlamydial infection when there has been careful contact tracing and treatment has been completed . If TOC is performed culture should be used if available and where antigen detection methods are used confirmation should be sought for any positive results.

Eur Respir J, 1993 Jan, 6(1), 19 - 22
Chlamydia pneumoniae infection in acute exacerbations of COPD; Blasi F et al.; Chlamydia pneumoniae, strain TWAR, is a frequent causative agent of acute respiratory disease . We assessed the incidence and prevalence of Chlamydia pneumoniae infections in COPD . We studied, from January 1990 to May 1991, 142 out-patients with acute purulent exacerbations of chronic obstructive pulmonary disease (COPD) and 114 healthy control subjects . Oropharyngeal swab specimens were collected at each exacerbation and analysed using a high definition monoclonal indirect fluorescent antibody test for Chlamydia pneumoniae identification . Immunoglobulins G and M (IgG and IgM) fractions of antibodies to Chlamydia pneumoniae were studied by microimmunofluorescence test . Prevalence of specific IgG was 63% in COPD, and 46% in controls (Chi-squared test p = 0.007) . Moreover, mean titre of IgG was significantly higher in COPD than in controls . Five patients were positive for specific IgM (> or = = 1:16), and one had a fourfold increase of IgG titre; four of these patients had been treated with ciprofloxacin 1 g.day-1 for 10 days, and two with erythromycin, 3 g.day-1 for 14 days, with remission of signs and symptoms of exacerbation . Chlamydia pneumoniae identification was always negative . Our data suggest that Chlamydia pneumoniae infection is a rather frequent event in COPD, since at least 4% of exacerbations may be associated with it.

Am Rev Respir Dis, 1993 Jan, 147(1), 153 - 9
A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis; Kadota J et al.; Recently, "low-dose and long-term" erythromycin treatment has been reported as effective on diffuse panbronchiolitis (DPB), but its mechanism is still obscure . Patients with DPB were found to have significantly higher percentages of neutrophils in the pre-erythromycin treatment bronchoalveolar lavage fluid (BALF) than healthy nonsmoking volunteers (p < 0.001) . They showed a significant reduction in BALF neutrophil percentages after erythromycin treatment (p < 0.01) . The neutrophil chemotactic activity (NCA) was significantly elevated in BALF obtained from 19 patients with DPB compared with that from healthy volunteers (p < 0.001) . A significant reduction in the NCA was observed in post-erythromycin treatment BALF of 11 patients with DPB (p < 0.001) . Additionally, there was a significant correlation between the reduction of NCA and neutrophil percentage in pre- and post-erythromycin treatment BALF (r = 0.726, p < 0.05) . Finally, we investigated the effect of erythromycin on the intrapulmonary influx of neutrophils by intratracheal injection of lipopolysaccharide (LPS) and interleukin-8 (IL-8) in mice . The intrapulmonary influx of neutrophils was significantly suppressed (p < 0.001) in mice intraperitoneally injected with erythromycin at 5 mg per animal 2 h before intratracheal injection of LPS (control group: 6.5 +/- 1.6 x 10(5) versus erythromycin-treated group: 1.7 +/- 0.5 x 10(5)), but not 10 h before lung challenge . This inhibition was observed at 6 h after lung challenge and became maximal with 84% suppression at 24 h . Week-long administration of erythromycin did not alter the intrapulmonary influx of neutrophils . The number of neutrophils in the peripheral blood was not affected by erythromycin, indicating that the drug was not toxic.(ABSTRACT TRUNCATED AT 250 WORDS)

J Bacteriol, 1993 Jan, 175(1), 182 - 9
Identification of a Saccharopolyspora erythraea gene required for the final hydroxylation step in erythromycin biosynthesis; Stassi D et al.; In analyzing the region of the Saccharopolyspora erythraea chromosome responsible for the biosynthesis of the macrolide antibiotic erythromycin, we identified a gene, designated eryK, located about 50 kb downstream of the erythromycin resistance gene, ermE . eryK encodes a 44-kDa protein which, on the basis of comparative analysis, belongs to the P450 monooxygenase family . An S . erythraea strain disrupted in eryK no longer produced erythromycin A but accumulated the B and D forms of the antibiotic, indicating that eryK is responsible for the C-12 hydroxylation of the macrolactone ring, one of the last steps in erythromycin biosynthesis.

Eur J Clin Pharmacol, 1993, 45(1), 41 - 6
Effect of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and electrocardiographic effects of terfenadine; Honig PK et al.; Terfenadine is a widely prescribed non-sedating antihistamine which undergoes rapid and almost complete first pass biotransformation to an active carboxylic acid metabolite . It is unusual to find unmetabolised terfenadine in the plasma of patients taking the drug . Terfenadine in vitro is a potent blocker of the myocardial potassium channel . Overdose, hepatic compromise and the coadministration of ketoconazole and erythromycin result in the accumulation of terfenadine, which is thought to be responsible of QT prolongation and Torsades de Pointes ventricular arrhythmia in susceptible individuals . Cimetidine and ranitidine are two popular H2 antagonists which are often taken with terfenadine . The effects of cimetidine and ranitidine on terfenadine metabolism were studied in two cohorts of 6 normal volunteers given the recommended dose of terfenadine (60 mg every 12 h) for 1 week prior to initiation of cimetidine 600 mg every 12 h or ranitidine 150 mg every 12 h . Pharmacokinetic profiles and morning pre-dose electrocardiograms were obtained whilst the patients were on terfenadine alone and after the addition of cimetidine or rantidine . One of the subjects in each cohort had a detectable plasma level of parent compound after 1 week of terfenadine therapy alone; it did not accumulate further after addition of the H2 antagonist . The pharmacokinetics of the carboxylic acid metabolite of terfenadine (Cmax, tmax, AUC) were not significantly changed after co-administration of either H2 antagonist . None of the remaining 5 subjects in either cohort demonstrated accumulation of unmetabolised terfenadine after addition of the respective H2 antagonist and electrocardiographic QT intervals and T-U morphology in them was not changed during the course of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Perit Dial Int, 1993, 13 Suppl 2, S183 - 6
Gastroparesis: an important cause of hospitalization in continuous ambulatory peritoneal dialysis patients and the role of erythromycin; Gallar P et al.; Gastroparesis is a disabling complication in diabetic patients . It has been reported as the second most frequent cause of hospitalization in diabetic patients on continuous ambulatory peritoneal dialysis (CAPD) . We analyzed infectious and noninfectious complications in our CAPD patients . We included 31 patients (12 diabetics and 19 nondiabetics) with an average time on CAPD of 14 +/- 7 months . The incidence of peritonitis was 1.68 episodes/patient/year in diabetics and 0.84 in nondiabetics . Nine (75%) diabetic patients had peritonitis, 5 (42%) had vomiting, and 4 (33%) had ischemic heart disease . The hospitalization index (days/year) was greater in diabetics: 11.83 +/- 11.36 versus 4.16 +/- 8.84 in nondiabetics (p < 0.05) . Vomiting was the first cause of admission in diabetics . We were unable to control severe gastroparesis with cisapride and metoclopramide in 4 patients . Erythromycin, 100 mg/2-L bag of dialysate, improved symptoms in all of them . We concluded that gastroparesis is an important cause of morbidity in CAPD patients . Intraperitoneal erythromycin can improve symptoms if other prokinetic drugs fail.

Biol Neonate, 1993, 63(6), 349 - 52
Erythromycin increases gastric antral motility in human premature infants; Tomomasa T et al.; The aim of this study was to determine if erythromycin (EM), which is a potent motilin agonist, alters gastrointestinal motility in premature infants . Six infants who were born after 23-30 weeks gestation and weighed 825-1,408 g at birth were studied when 6-31 days old . Intraluminal pressure changes within the gastric antrum and proximal duodenum were recorded . We infused EM 0.75 mg/kg intravenously for 15 min and we compared gastric and duodenal contractions for 30 min between before and after the initiation of EM infusion . In these preterm infants the migrating complex was not present, and was not induced by EM . However, in all 6 infants EM increased nonpropagating antral clusters of contractions (p < 0.05) . The antral motility index increased 4-fold (p < 0.05) . We concluded that human premature infants have functioning motilin receptors.

Australas J Dermatol, 1993, 34(2), 41 - 4
Bullous pemphigoid in an Aborigine; Lo S et al.; OBJECTIVE: To present the first case of bullous pemphigoid in an Australian Aborigine . CLINICAL FEATURES: A 47 year old female aborigine presented with a three week history of a generalised skin eruption consistent with bullous pemphigoid . Immunohistological examination confirmed the diagnosis . Therapy required high dose oral steroids, azathioprine and erythromycin as well as topical agents . Treatment was complicated by isolation and poor compliance but was ultimately successful in inducing and retaining remission . CONCLUSION: This is the first description of bullous pemphigoid in an Australian Aborigine . We recommend early biopsy to confirm diagnosis and plan therapy, and careful attention to patient education to encourage compliance.

Gastroenterol Clin Biol, 1993, 17(10), 710 - 7
{Antro-pyloro-bulbar contractibility in diabetics studied by cineradiography . Effect of erythromycin}; Boiron M et al.; We studied antropyloroduodenal contractility in diabetics and the effect of erythromycin IV (100-500 mg) using the non invasive Boiron cineradiographic method analysis . Fourteen diabetics and 22 controls were examined . Four hours after a standard liquid-solid meal, patients drank 250 mL baryum solution . Fluorographic plates (10 x 10 cm) were taken every 2 s during 30 s . Semi-automatic data processing analysis allowed to measure motility parameters including antral (CA) and bulbar (CB) contractility indexes; pyloric opening index (OP), gastric (FG) and bulbar (FB) frequencies . Three types of pylorus behaviour patterns were define: A and B related to antropyloric and antropyloroduodenal coordination respectively and N without coordination . In diabetics, CA, OP and FG were decreased vs controls (P < 0.01) (CA: 65.5 +/- 6.8 vs 83.1 +/- 2.4%; OP: 60.9 +/- 8.7 vs 84.8 +/- 1.9%; FG: 2.42 +/- 0.14 vs 3.08 +/- 0.04 c/min) and antropylorbulbar coordination altered (N was predominant; no bulbar cycles at 3/min) . Antral hypocontractility was correlated with autonomic neuropathy . After erythromycin, radiological parameters returned to normal values (CA = 83.0 +/- 2.4%; OP = 86.0 +/- 4.7%; FG = 3.0 +/- 0.16 c/min) and coordination improved type N disappeared and FB = 3 c/min (58%) . Cineradiographic analysis is simple, able to show antropylorobulbar contractile abnormalities, to study pharmacological effects, and in diabetics is capable of studying improvement of motility parameters with erythromycin.

Scand J Infect Dis, 1993, 25(4), 533 - 6
Imported relapsing fever in European tourists; Colebunders R et al.; Two 'imported' cases of relapsing fever after a trip through Senegal are described . Two women developed a tick-borne relapsing fever after having slept outdoors on a terrace in Zinguichor, Senegal . The first patient was rapidly cured after a course of doxycycline . The second patient initially received erythromycin, but despite this treatment she developed neurological symptoms and Borrelia persisted in the thick-smear examination . After treatment with doxycycline she developed a Jarish-Herxheimer reaction . Treatment with doxycycline was continued and finally all symptoms disappeared within 36 hours after starting this treatment . A diagnosis of relapsing fever should be considered in all patients returning from the tropics with recurrent fever, especially if no malaria parasites are found.

Kurume Med J, 1993, 40(2), 65 - 7
Low-dose/long-term erythromycin for treatment of bronchiolitis obliterans organizing pneumonia (BOOP); Ichikawa Y et al.; Bronchiolitis obliterans organizing pneumonia (BOOP) is a pathologic entity characterized by intraluminal fibrosis of distal air spaces . Corticosteroids have been widely used for the treatment of this condition, and most patients showed a dramatic response to it . However, long-term treatment with corticosteroids, which often increases the risk of several undesirable side-effects, is usually required because a relapse tends to occur soon after termination of treatment . We administered erythromycin (EM) at low-dose (600 mg daily) for 3-4 months to 6 patients with BOOP, and obtained a good clinical, radiological, and physiological improvement . This suggests that EM can be successfully used, instead of corticosteroids, in the treatment of BOOP.

AIDS Clin Rev . 1993-94;:43-60.
Bacillary angiomatosis; Berger TG et al.; The manifestations of bacillary angiomatosis include diverse cutaneous lesions, visceral parenchymal bacillary peliosis of the spleen and liver, and involvement of single or multiple organ systems . The organisms causing BA are R . henselae and R . quintana, and these organisms have now been cultured from the spleen and cutaneous lesions of BA as well as the blood of patients with visceral and cutaneous BA . The antibiotic regimen of choice for HIV-infected patients is erythromycin 500 mg 4 x a day for 2-4 months, but relapse may necessitate lifelong suppressive therapy . We are maintaining a registry of patients with bacillary angiomatosis and request that we be contacted (415-206-8680, UCSF) if you diagnose a case, preferably before therapy is instituted.

Acta Diabetol, 1993, 30(3), 128 - 31
Insulin-mimetic effects of vanadate in preventing the increase of P450IIIA and P450IA subfamily proteins in streptozotocin-diabetic rats; Verrecchia A et al.; The insulin-mimetic effects of vanadate in preventing the increase in the level and activity of several P450 proteins in streptozotocin-diabetic rats were examined, in order to extend knowledge of the insulin-like actions of vanadate from glucose metabolism to P450-dependent metabolism . The diabetic state caused by the pancreatic beta cell toxin streptozotocin results, like the diabetes of genetic origin, in major alterations in the expression of P450 isozymes . We focused our attention on the P450III and P450I isoforms, known to be altered during the onset of diabetes . We found an increase in P450IIIA1-linked erythromycin demethylase activity (to about double the control level) and in the relative levels of P450III and P450I isozymes after 2 weeks of uncontrolled diabetes . These parameters were not different from control values in rats given vanadate in drinking water for 2 weeks after streptozotocin administration or in insulin-treated rats . In summary, vanadate appears to exert insulin-mimetic actions on the P450III and P450I family proteins that have a key role in cytochrome P450-dependent metabolism.

Br J Pharmacol, 1993 Jan, 108(1), 44 - 9
Effects of cholinoceptor and 5-hydroxytryptamine3 receptor antagonism on erythromycin-induced canine intestinal motility disruption and emesis; Qin XY et al.; 1 . Erythromycin administration is associated with gastrointestinal problems, disturbed gastrointestinal motility and emesis . This study in the dog investigates the underlying mechanisms . 2 . Intestinal myoelectrical activity and the occurrence and latency of emesis were recorded in eight conscious dogs . All drugs were administered intravenously . 3 . Erythromycin (7 mg kg-1) increased contractions of the proximal small intestine, and caused emesis in all fasted dogs and in 5 dogs after food . Atropine (50 mg kg-1 min-1) and hexamethonium (10 mg kg-1 h-1) partially inhibited the GI motility effects but did not significantly reduce emesis . 4 . Metoclopramide at a high dose (2 mg kg-1 h-1) reduced the incidence of emesis in the presence of increased intestinal motility, but a low dose (150 micrograms kg-1 h-1) was ineffective . 5 . A 5-hydroxytryptamine3 (5-HT3) receptor antagonist, MDL 72222 (1 mg kg-1), reduced emesis when given alone and combined with metoclopramide (low dose) . The 5-HT4 receptor agonist BRL24924 (Renzapride, 1 mg kg-1) had no effect on emesis either alone in combination with metoclopramide . 6 . In conclusion, erythromycin-induced GI motility disturbances and emesis are not causally related . Whereas the increase in intestinal smooth muscle activity is possibly cholinergically mediated, emesis occurs at least in part via a 5-hydroxytryptaminergic mechanism, but does not involve the dopamine system.

Antonie Van Leeuwenhoek, 1993-94, 64(2), 165 - 76
Genetic control of polyketide biosynthesis in the genus Streptomyces; Hutchinson CR et al.; The genetic control of polyketide metabolite biosynthesis in Streptomyces sp . producing actinorhodin, daunorubicin, erythromycin, spiramycin, tetracenomycin and tylosin is reviewed . Several examples of positively-acting transcriptional regulators of polyketide metabolism are known, including some two-component sensor kinase-response regulator systems . Translational and posttranslational control mechanisms are only briefly mentioned since very little is known about either of these processes . Examples of how enzyme levels and substrate supply affect polyketide metabolism also are discussed.

Antibiot Khimioter, 1993 Jan, 38(1), 24 - 8
{Isolation and characterization of genetic recombinants in protoplast fusion in Saccharopolyspora erythraea.}; Kirichenko NV et al.; Formation of genetic recombinants after conjugation and protoplast fusion in Saccharopolyspora erythraea, an organism producing erythromycin, was studied comparatively . After the protoplast fusion the frequency of all the classes of the haploid recombinants increased 10 to 460 times by comparison with the conjugation . The protoplast fusion was characterized by higher diversity of the recombinant classes, up to 45.5 per cent of the recombinants being formed at the account of multiple crossing overs . It was shown that unlike conjugation of the S . erythraea strains the protoplast fusion had no gradient of inheritance of the parent genetic markers by the recombinants . The results indicated that in S . erythraea protoplast fusion the recombination involved more genes of the parent strains . This makes promising the procedure for genetic analysis and design of erythromycin-producing strains.

Ter Arkh, 1993, 65(11), 28 - 9
{An unusual variant of secondary recurrent syphilis in an HIV-infected patient}; Potekaev NS et al.; Asymptomatic syphilis eventually manifesting with symptoms of the secondary disease was observed in a male with HIV-infection . Large focuses of alopecia reported in this male are suggested as a clinical marker of HIV-infection . A defective antibody response to T . pallidum in HIV-infection has been confirmed . Levomycetin (0.5 g 4 times a day in 5-20-day courses at two-week intervals) proved highly effective as compared to penicillin, erythromycin and tetracycline administration due to poor tolerance of the above antibiotics.

Pharm Acta Helv, 1993, 68(1), 35 - 41
Isolation and identification by FAB mass spectrometry and NMR spectroscopy of a demethylated metabolite of FK506 from erythromycin-induced rabbit liver microsomes; Lhoest G et al.; A new demethylated metabolite, extracted from erythromycin-induced rabbit liver microsomes incubation media, isolated by HPLC and identified by FAB/MS and NMR, is described . Moreover, NMR spectra suggest the existence of tautomeric forms of this O-demethylated metabolite of FK506.

J Med Chem, 1992 Dec 25, 35(26), 4842 - 5
The conformation of 6-methoxyerythromycin A in water determined by proton NMR spectroscopy; Steinmetz WE et al.; The proton NMR spectrum of an aqueous solution of 6-methoxyerythromycin A (2) has been assigned and nuclear Overhauser effects have been obtained from a series of NOESY spectra . Carbon-13 antisymetric spin-lattice relaxation times have been measured for the methylene and methine carbons . The NMR data show that 2 is present exclusively in the keto form and has a conformation very similar to that reported for erythromycin A (1) in the solid and solution phases.

Chem Biol Interact, 1992 Dec, 85(2-3), 215 - 27
pH effects on the N-demethylation and formation of the cytochrome P-450 iron II nitrosoalkane complex for erythromycin derivatives; Delaforge M et al.; The effects of pH on access to the cytochrome P-450 active site, N-demethylation and formation of the cytochrome P-450 Fe(II)-RNO metabolite complex for a series of erythromycin derivatives were examined . Studies were performed with dexamethasone-treated rat liver microsomes containing large amounts of cytochrome P-450 3A isozymes . In addition to factors such as hydrophobicity or hindrance around the dimethyl-amino function, the ionisation state of the N(CH3)2 group played an important role in the recognition and metabolism of the substrate by cytochrome P-450 . Esterification of the desosamine in the beta position of the N(CH3)2 group leads to lower pKa values for the R--N+ H(CH3)2 <--> {R--N (CH3)2} + H+ equilibrium . At physiological pH, the amine group is mainly in the unprotonated form . Consequently, easier access to the protein active site and significant formation of cytochrome P-450 Fe(II)-RNO metabolite complex are observed for these derivatives . These results led us to interpret the formation of cytochrome P-450 Fe(II)-RNO metabolite complex as a series of multiple steps equilibria depending on the ionisation state of the N(CH3)2 group, the partition coefficient of the substrate between the microsomal layer and the aqueous media and a series of metabolic reactions leading partially to the final inhibitory nitrosoalkane-cytochrome P-450 Fe(II) complex.

Naunyn Schmiedebergs Arch Pharmacol, 1992 Dec, 346(6), 701 - 6
Erythromycin and motilin stimulate sphincter of Oddi motility and inhibit trans-sphincteric flow in the Australian possum; Saccone GT et al.; The actions of erythromycin lactobionate and porcine motilin on trans-sphincteric flow and simultaneous sphincter of Oddi motility were studied in 15 anaesthetized Australian Brush-tailed possums (Trichosurus vulpecula) . Erythromycin (25-200 micrograms/kg) and motilin (25-200 ng/kg) were administered as graded doses by close intraarterial injection . Trans-sphincteric flow was measured as inflow and outflow . Both motilin and erythromycin decreased trans-sphincteric inflow (both P < 0.0001) and outflow (P < 0.0001 and P = 0.0017 respectively) in a dose-dependent manner . The highest dose of each agent abolished trans-sphincteric flow . These agents increased sphincter of Oddi phasic contraction frequency and basal pressure up to 2 and 3 fold respectively (P < 0.05) . The amplitude of the sphincter of Oddi phasic contractions were not influenced in any consistent fashion by either agent . The durations of the responses (trans-sphincteric inflow) elicited by erythromycin and motilin were dose dependent (P = 0.0225 and P = 0.0001 respectively) . The actions of erythromycin (200 micrograms/kg) or motilin (100 ng/kg) on trans-sphincteric flow and sphincter of Oddi motility were not influenced by neural blockade with tetrodotoxin . These findings support the hypothesis that erythromycin acts as a motilin agonist and both substances increase the resistance to flow through the sphincter of Oddi by raising the basal pressure and frequency of contractions.

Ann Pharmacother, 1992 Dec, 26(12), 1507 - 11
Incidence and cost of hospital admissions secondary to drug interactions involving theophylline; Hamilton RA et al.; OBJECTIVE: To determine the incidence and cost of hospital admissions for theophylline toxicity, which occurred as a result of the concurrent use of one of the following medications: cimetidine, erythromycin, or ciprofloxacin . DESIGN: Retrospective chart review (18 months, between June 1989 and November 1990) . SETTING: A Department of Veterans Affairs Medical Center . PARTICIPANTS: All patients who were receiving theophylline chronically (913 patients) and also had a prescription for cimetidine (124 patients with 140 treatment courses), erythromycin (66 patients with 93 treatment courses), or ciprofloxacin (39 patients with 59 treatment courses) dispensed . INTERVENTIONS: Each patient's medical record was reviewed to identify hospital admissions within 30 days following the dispensing of the interacting drug . MAIN OUTCOME MEASURES: Admissions were considered to be related to theophylline toxicity if appropriate signs and symptoms were present and the theophylline concentration was above 20 micrograms/mL or had increased significantly from the concentration obtained prior to introduction of the interacting drug . RESULTS: One patient who received cimetidine and one who received ciprofloxacin were admitted for theophylline toxicity (2 of 292 potential interactions, 0.81 percent) . Admissions were for 16 and 13 days, respectively, and total costs for the two admissions were $12,864.22 or $44.00, respectively, per potential interaction . The entire admission was not for theophylline toxicity; it appeared that iatrogenic factors contributed to the duration . CONCLUSIONS: The incidence of hospital admissions secondary to theophylline drug interactions with cimetidine, ciprofloxacin, or erythromycin is low, but the admissions represent considerable expense, even when distributed among all patients at risk for the interactions.

Biol Mass Spectrom, 1992 Dec, 21(12), 675 - 87
Determination of erythromycin A in salmon tissue by liquid chromatography with ion-spray mass spectrometry; Pleasance S et al.; A reverse-phase liquid chromatography/mass spectrometry (LC/MS) method, incorporating gradient elution, is described for the characterization of residual erythromycin A and its metabolites in salmon tissue . The method uses ion-spray, a mild atmospheric pressure ionization technique which provides an abundant protonated molecule well suited for selected ion monitoring experiments . Tandem mass spectrometry (MS/MS) using collision-induced dissociation was used to provide structural information . The LC/MS method was tested for the analysis of salmon tissue spiked with erythromycin A at levels between 0.01 and 1 p.p.m . A simple extraction and clean-up procedure, slightly modified from that described by Takatsuki et al . (J . Assoc . Off . Anal . Chem . 70, 708 (1987)), was used in this work . Using selected ion and selected reaction monitoring techniques, the LC/MS and LC/MS/MS methods provided detection limits of < 10 and 50 ng g-1, respectively . Confirmatory full-scan LC/MS and LC/MS/MS spectra were obtained at the 0.5 and 1 microgram g-1 levels, respectively . Using a combination of these techniques, the presence of residual erythromycin A was confirmed in the tissue of fish administered medicated feed containing the antibiotic . In addition, several metabolites and degradation products of erythromycin A, including anhydro-erythromycin and N-demethyl-erythromycin, were detected and where possible confirmed by comparison with authentic compounds . Although this analytical method has been shown to afford the necessary sensitivity and precision, application of these techniques to high-throughput quantitative analyses will require development of an improved clean-up procedure and preferably also of a suitable surrogate internal standard.

J Fla Med Assoc, 1992 Dec, 79(12), 821 - 2
Erythromycin associated hearing loss in a patient with prior cis-platinum induced ototoxicity; Wallach PM et al.; A case is reported of reversible sensorineural hearing loss associated with intravenous erythromycin treatment . Cis-platinum induced high frequency hearing loss developed nine months previously during treatment for stage IV papillary cystadenocarcinoma . Renal and hepatic function were normal; however, serum erythromycin levels were elevated . Clinical recovery promptly followed discontinuation of erythromycin.

Carcinogenesis, 1992 Dec, 13(12), 2205 - 10
Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats; Guo Z et al.; Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, has been shown to inhibit chemical carcinogenesis, possibly due to its ability to block the activation or to enhance the detoxification of chemical carcinogens . The present study was conducted to elucidate the biochemical mechanisms involved by characterizing the effects of PEITC on phase I and phase II xenobiotic-metabolizing enzymes . A single dose of PEITC to F344 rats (1 mmol/kg) decreased the liver N-nitrosodimethylamine demethylase (NDMAd) activity (mainly due to P450 2E1) by 80% at 2 h and the activity of NDMAd remained decreased by 40% at 48 h after treatment . The liver pentoxyresorufin O-dealkylase (PROD) activity and P450 2B1 protein level were elevated 10- and 7-fold at 24 h after treatment respectively . The liver microsomal ethoxyresorufin O-dealkylase (EROD) (mainly due to P450 1A) and erythromycin N-demethylase (mainly due to P450 3A) activities were decreased at 2-12 h after treatment and recovered afterwards . The lung microsomal PROD and EROD activities were not significantly affected; whereas, the nasal microsomal PROD and EROD activities were decreased by 40-50% . After a treatment with PEITC, the rates of oxidative metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were decreased in liver microsomes by 40-60% at 2 h and recovered gradually; the rates in lung microsomes were markedly decreased by 60-70% at 2 h and remained at the decreased level at 24 h; and the rates in nasal mucosa microsomes were decreased gradually with the lowest activities observed at 18 h (50%) followed by a gradual recovery . Furthermore, the treatment with PEITC resulted in a maximal 5-fold increase of NAD(P)H:quinone oxidoreductase and 1.5-fold increase of glutathione S-transferase activities in the liver, but the activities of these two enzymes were not significantly affected in the lung and nasal mucosa . The sulfotransferase activity in the liver was decreased by 32-48% at 24-48 h after treatment; the nasal activity was increased by 1.8- to 2.5-fold, but the lung activity was not significantly changed . The hepatic UDP glucuronosyltransferase activity was slightly decreased at 2 h but slightly increased at 48 h after treatment, but no changes were observed for the lung and nasal activities . The study demonstrates that PEITC selectively affects xenobiotic-metabolizing enzymes in the liver, lung and nasal mucosa and it is especially effective in inhibiting the P450-dependent oxidation of NNK in the lung and of NDMA in the liver.

Pediatr Infect Dis J, 1992 Dec, 11(12), 1026 - 30
Prophylaxis of ophthalmia neonatorum: comparison of silver nitrate, tetracycline, erythromycin and no prophylaxis; Chen JY; From November, 1989, to October, 1991, 4544 neonates were born at our hospital . Neonatal ocular prophylaxis immediately after birth was used with 1% tetracycline ophthalmic ointment in 1156 neonates, 0.5% erythromycin ophthalmic ointment in 1163 neonates and 1% silver nitrate drops in 1082 neonates . No prophylaxis for neonatal conjunctivitis was given to 1143 neonates . A total of 302 infants (6.7%) developed conjunctivitis during the first 4 weeks of life . Between December, 1991, and January, 1992, 425 neonates were born at our hospital and all were given 0.5% erythromycin ophthalmic ointment twice in the first 24 hours after birth for ocular prophylaxis . Thirty-one (7.3%) infants developed conjunctivitis during the neonatal period . The incidence rates of neonatal chlamydial conjuctivitis in the tetracycline, erythromycin, silver nitrate, no prophylaxis and erythromycin twice groups were 1.3, 1.5, 1.7, 1.6 and 1.4%, respectively . We conclude that neonatal ocular prophylaxis with erythromycin (one or two doses) or tetracycline or silver nitrate does not significantly reduce the incidence of neonatal chlamydial conjunctivitis compared with that in those given no prophylaxis.

Med J Malaysia, 1992 Dec, 47(4), 309 - 10
Chlamydia pneumoniae respiratory infection in a child--a case report; Lum L et al.; A case of respiratory infection in a child due to Chlamydia pneumoniae is reported . The diagnosis was made by the detection of chlamydial antigen in the tracheal secretion and a significant increase in C . pneumoniae antibody titre . The infection responded well to erythromycin therapy.

Can J Physiol Pharmacol, 1992 Dec, 70(12), 1610 - 7
Dose-dependent, mechanism-based inactivation of cytochrome P450 monooxygenases in vivo by 1-aminobenzotriazole in liver, lung, and kidney of untreated, phenobarbital-treated, and beta-naphthoflavone-treated guinea pigs; Knickle LC et al.; The mechanism-based inactivation of the cytochrome P450 (P450) dependent monooxygenase system was studied in vivo in liver, lung, and kidney of untreated, phenobarbital-treated, and beta-naphthoflavone-treated guinea pigs 24 h after administration of 1-aminobenzotriazole (1-100 mg/kg, i.p.) . Microsomal isozyme-selective or -specific monooxygenase activities were inhibited in a dose-dependent manner in all three organs . In the liver of untreated and phenobarbital-treated animals, 7-pentoxyresorufin O-depentylation (catalyzed primarily by P450 2Bx, an orthologue of rabbit P450 2B4/rat 2B1) was inhibited more than 7-ethoxyresorufin O-deethylation (P450 1A1), 4-aminobiphenyl N-hydroxylation (P450 1A2), erythromycin N-demethylation (P450 3A), or benzphetamine N-demethylation; in beta-naphthoflavone-treated animals, 4-amino-biphenyl N-hydroxylation activity was preferentially inhibited . In lung, the order of inactivation of monooxygenase activities was 4-aminobiphenyl N-hydroxylation (4Bx, the orthologue of rabbit 4B1) > 7-pentoxyresorufin O-depentylation activity (2Bx) > 7-ethoxyresorufin O-deethylation (1A1; for example 72, 53, and 29% inactivation, respectively, in phenobarbital-treated animals at 100 mg/kg) . In all three tissues the loss in spectrally assayed P450 content corresponds quite well to the inhibition of monooxygenase activities . Thus, these studies show that 1-aminobenzotriazole is an effective inactivator of the pulmonary, hepatic, and renal P450 systems in guinea pigs following i.p . administration, and that P450 1A2 (liver) and P450 4Bx (lung), isozymes efficient for the oxidation of primary aromatic amines, are preferentially inactivated.

Nihon Kyobu Shikkan Gakkai Zasshi, 1992 Dec, 30(12), 2075 - 81
{Tumor associated carbohydrate antigens in bronchoalveolar lavage fluid in patients with diffuse panbronchiolitis}; Mukae H et al.; It is known that tumor associated carbohydrate antigens are significantly increased in the serum of patients with diffuse panbronchiolitis (DPB) . We investigated carbohydrate antigens (SLX, CA19-9) in bronchoalveolar lavage fluid (BALF) obtained from 24 patients with DPB . The concentrations of SLX and CA19-9 were significantly higher in BALF from patients with DPB than those from healthy subjects (7 cases) and patients with pulmonary sarcoidosis (16 cases) . No significant correlation was observed between either SLX or CA19-9 concentrations in the serum and BALF, and no significant correlation was observed between the concentrations of these carbohydrate antigens in BALF and clinical findings . Immunohistochemical study of SLX and CA19-9 in open lung biopsy specimens obtained from patients with DPB showed expression of SLX and CA19-9 on the bronchiolar surface epithelial cells and mucinous exudates in air spances . These results indicate that carbohydrate antigens are presumably increased in the pulmonary lesions of patients with DPB, and this increase causes high levels of these antigens in the serum . Furthermore, we investigated the change of concentrations of SLX and CA19-9 in BALF obtained from patients with DPB after erythromycin (EM) treatment . The concentrations of these two antigens were decreased after EM treatment.

J Fam Pract, 1992 Nov, 35(5), 517 - 23
A comparison of the gastrointestinal side effects of two forms of erythromycin; Anastasio GD et al.; BACKGROUND . The gastrointestinal (GI) side effects of erythromycin frequently limit therapy and compliance . PCE Dispertab, a more expensive brand of erythromycin, has been promoted as a well-tolerated new dosage form; however, no studies compare its GI side effects with those of other forms of erythromycin . We compared erythromycin PCE (particles-in-tablet) with E.E.S . (erythromycin ethylsuccinate) to determine whether there is a difference in the incidence and severity of GI side effects . METHODS . This was a multicenter, prospective, single-blind, randomized trial . Observers, but not participants, were blinded to the brand of erythromycin taken until after data analysis . We enrolled ambulatory patients who were at least 18 years old and weighed at least 90 lb for whom erythromycin had been prescribed at a dosage of 1.0 g/d . Subjects were given either the particles-in-tablet form, 333 mg three times daily, or the ethylsuccinate form, 400 mg four times daily, for 10 days and asked to report efficacy, compliance, and the frequency and severity of four GI symptoms (abdominal pain, nausea, vomiting, and diarrhea) in a daily diary . RESULTS . There were no significant differences between the particles-in-tablet and ethylsuccinate forms in incidence of GI side effects (63% and 61%, respectively), average daily GI symptom severity score (0.62 and 0.68, respectively), and GI-related discontinuations (8.5% and 8.2%, respectively) . The incidence of moderate or severe nausea was 5% for the particles-in-tablet form and 25% for the ethylsuccinate form (P < .001) . CONCLUSIONS . Although ethylsuccinate caused a higher incidence of moderate to severe nausea, there were no differences in the three main outcome measures: incidence of GI side effects, average daily GI-symptom severity score, and GI-related discontinuations . Therefore, we support prescribing erythromycin ethylsuccinate as a first line of treatment because it costs less.

Biochem Pharmacol, 1992 Nov 3, 44(9), 1745 - 56
Nature of cytochromes P450 involved in the 2-/4-hydroxylations of estradiol in human liver microsomes; Kerlan V et al.; Kinetics of the 2- and 4-hydroxylations of estradiol (E2) by human liver microsomal samples were studied to determine the major P450 isoform involved in these endogenous reactions . Thirty human liver microsomal samples were analysed . Metabolism of 25 microM {14C}E2 produced 2-hydroxy and 4-hydroxy derivatives with a ratio of 3.2 +/- 1.5 and a great inter-individual variation . Kinetic analysis of the 2- and 4-hydroxylations of E2 exhibited a curvilinear double reciprocal plot with an apparent Km of 15 microM . Further experiments demonstrated that alpha-naphthoflavone, testosterone and progesterone increased the 2-hydroxylation activity, suggesting the involvement of a substrate activation mechanism . These two hydroxylations of E2 were shown to be catalysed by cytochrome P450 with an apparent dissociation constant Ks of 0.8 microM . These 2- and 4-hydroxylations inter-correlated significantly (r = 0.93; N = 30) . The 2-hydroxylation of E2 correlated with four monooxygenase activities known to be supported by P450 3A4/3A5, namely nifedipine oxidation (r = 0.78; N = 29); erythromycin N-demethylation (r = 0.69; N = 27), testosterone 6 beta-hydroxylation (r = 0.66; N = 25) and tamoxifen N-demethylation (r = 0.64; N = 29) . On the other hand, E2-hydroxylations did not correlate with activities supported by P450 1A2 and P450 2E1 . Furthermore, drugs as cyclosporin, diltiazem, triacetyl-oleandomycin and 17 alpha-ethynylestradiol inhibited more than 90% of the E2-hydroxylations at concentrations < 250 microM, while weak inhibition was shown with 500 microM cimetidine and no significant inhibition with caffeine, phenacetin and omeprazole . Finally, 2- and 4-hydroxylations of E2 correlated significantly with the content of P450 3A4/3A5 immunodetected by a monoclonal antibody anti-human P450-nifedipine (r = 0.84; N = 28) . E2-hydroxylation activities were inhibited by more than 80% with polyclonal anti-human anti-P450-nifedipine . Preincubation of human liver microsomes with 100 microM gestodene (a suicide substrate of P450 3A4) inactivated this P450 isoform and accordingly allowed evaluation of the contribution of other P450 isoforms to the E2 metabolism to about 21% (+/- 17%, N = 29) . All these results taken together suggest that P450 3A4/3A5 are the major forms involved in the formation of catecholestrogens in the human liver microsomes.

Antimicrob Agents Chemother, 1992 Nov, 36(11), 2559 - 61
In vitro activity of Ro 23-9424 against clinical isolates of Legionella species; Edelstein PH et al.; Agar and broth microdilution MICs of Ro 23-9424 that inhibited 90% of 22 Legionella clinical isolates tested were 0.64 and 0.08 micrograms/ml, respectively; respective erythromycin values were 1.0 and 0.12 micrograms/ml . Ro 23-9424 (1 microgram/ml) was slightly more active than the same erythromycin concentration in a macrophage system, for both Legionella pneumophila strains studied.

Respir Med, 1992 Nov, 86(6), 503 - 5
Audit of the use of erythromycin in the treatment of community-acquired lower respiratory infections; Jolley AE et al.; The British Thoracic Society (BTS) guidelines for the treatment of community-acquired pneumonia recommend initial therapy with a betalactam antibiotic, with the addition of erythromycin if there are features of an atypical pneumonia . To see if these guidelines were being followed, a prospective study was undertaken of all adult patients admitted to hospital over a 3-month period who were given erythromycin for a community-acquired lower respiratory tract infection . Erythromycin was given to 62 patients who could be fully assessed . Continued prescription of erythromycin was justified in 10 (16%)--two patients with penicillin allergy, two with M . catarrhalis infection and one patient with legionnaires disease . Five patients had infections severe enough on admission to warrant combined therapy in line with the BTS recommendations . Five patients had erythromycin stopped on day 2 . Erythromycin was prescribed on admission and continued unnecessarily in 47/62 patients, showing that the BTS recommendations are not being followed correctly.

Am J Vet Res, 1992 Nov, 53(11), 2071 - 6
Effect of treatment with erythromycin and rifampin during the acute stages of experimentally induced equine ehrlichial colitis in ponies; Palmer JE et al.; Sixteen healthy ponies were inoculated IV with Ehrlichia risticii-infected P388D1 mouse monocytes . Of the 16 ponies, 15 developed clinical signs of equine ehrlichial colitis . Twenty-four hours after onset of fever (rectal temperature > 38.8 C), 7 ponies were treated with 25 mg of erythromycin stearate/kg of body weight and 10 mg of rifampin/kg, given orally every 12 hours for 5 days . The remaining 8 ill ponies served as nontreated controls . All ponies were observed for progression of clinical signs typical of equine ehrlichial colitis . Within 12 hours of initiation of treatment, 4 of the 7 treated ponies had rectal temperature < 38.4 C and, within 24 hours, 6 of the 7 ponies had rectal temperature < 38.3C . In contrast, all control ponies had rectal temperature > 39.2 C at 24 hours (P < 0.05) . Of the 7 treated ponies, 4 no longer had signs of mental depression after the second day of treatment, and only 1 of the 7 ponies had mild signs of depression after the third day of treatment . In contrast, control ponies had high mental depression score during the observation period (P < 0.05) . Feed intake improved in ponies of the treatment group, with feed intake of 4 of the 7 ponies returning to normal; the other 3 ponies were only mildly anorectic by the second day of treatment . Control ponies progressively decreased their feed intake during the observation period (P < 0.05) . One control pony and 2 treated ponies developed diarrhea before the treatment/observation period began . Only 1 treated pony developed diarrhea after treatment began . Of the 8 control ponies, 7 developed diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)

Am J Physiol, 1992 Nov, 263(5 Pt 1), G683 - 9
Sphincter of Oddi regulates flow by acting as a variable resistor to flow; Liu YF et al.; Two models of transsphincteric flow and a model evaluating pumping activity were established in the anesthetized Australian brush-tailed possum to determine whether the sphincter of Oddi (SO) acts as a resistor or as a pump . A simple model of transsphincteric flow (inflow only) demonstrated that at physiological common bile duct (CBD) pressure, 9.5 +/- 0.3 cmH2O (n = 7), transsphincteric flow occurred between SO pressure waves (n = 10) . A second more complex transsphincteric flow model was established that permitted simultaneous measurements of inflow, outflow, CBD pressure, SO basal pressure, SO contraction frequency, and amplitude . At physiological CBD pressure, inflow always equaled outflow (157.0 +/- 11.2 and 156.4 +/- 11.4 microliters/min, respectively; n = 7) . The SO displayed regular contractions superimposed on a basal pressure of 1.1 +/- 0.4 mmHg . Contraction amplitude was 12.6 +/- 3.0 mmHg and the frequency was 3.6 +/- 0.4 contractions/min (n = 7) . Pressure waves recorded in the CBD corresponded to the SO contractions and reflected SO activity . Transsphincteric flow occurred between SO contractions and was obstructed by these contractions . Stimulation of SO activity (basal pressure and contraction frequency) with intra-arterial injections of motilin (200 ng/kg) or erythromycin (200 micrograms/kg) abolished transsphincteric flow . Reduction in SO contraction frequency to 72.7 +/- 7.2% (P < 0.01, paired t test) after administration of Cisapride (2 mg/kg iv) increased transsphincteric flow to 147.6 +/- 12.3% (n = 7, P < 0.05, paired t test) . In six possums, possible SO pumping action was evaluated . A manometer was connected to the CBD, and a second manometer was connected to the duodenum surrounding the papilla.(ABSTRACT TRUNCATED AT 250 WORDS)

J Clin Invest, 1992 Nov, 90(5), 1871 - 8
Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes; Kolars JC et al.; Enzymes within the P450IIIA (CYP3A) subfamily appear to account for significant "first pass" metabolism of some drugs in the intestine . To identify which of the known P450IIIA genes are expressed in intestine, enterocyte RNA was hybridized on Northern blots with synthetic oligonucleotides complementary to hypervariable regions of hepatic P450IIIA4, P450IIIA5, and P450IIIA7 cDNAs . Hybridization was detected only with the P450IIIA4-specific oligonucleotide . The identity of the hybridizing mRNA was confirmed to be P450IIIA4 by direct sequencing of a DNA fragment amplified from enterocyte cDNA by the polymerase chain reaction . To determine if enterocyte P450IIIA4 is inducible, biopsies of small bowel mucosa were obtained from five volunteers before and after they received 7d of treatment with rifampin, a known inducer of P450IIIA4 in liver . Rifampin treatment resulted in a five- or eightfold mean increase (P < 0.05) in the biopsy concentration of P450IIIA4 mRNA when normalized for content of sucrase isomaltase or intestinal fatty acid binding protein mRNAs, respectively . Rifampin also induced P450IIIA immunoreactive protein in enterocytes in each of the subjects, as judged by immunohistochemistry, and resulted in a 10-fold increase in P450IIIA4-specific catalytic activity (erythromycin N-demethylation) in the one patient studied . Our identification of inducible P450IIIA4 in enterocytes may in part account for drug interactions characteristic of P450IIIA4 substrates and suggests a strategy for controlling entry into the body of a major class of xenobiotics.

Dig Dis Sci, 1992 Nov, 37(11), 1671 - 7
Effect of erythromycin on gallbladder emptying in diabetic patients with and without autonomic neuropathy and high levels of motilin; Fiorucci S et al.; A reduction of gallbladder emptying in response to neural or hormonal stimulation has been reported in patients with diabetes mellitus . Decreased gallbladder emptying may be a key factor in the pathogenesis of gallbladder stones . Few drugs, if any, are able to stimulate gallbladder emptying . However, in a previous study we demonstrated that erythromycin, a macrolide antibiotic, stimulates gallbladder emptying and motilin release in healthy human subjects by an atropine-sensitive pathway . Therefore, the present study was designed to evaluate the effect of erythromycin on gallbladder emptying and motilin release in diabetic patients with or without cardiac autonomic neuropathy (AN) . Thirteen diabetic patients, six with AN, and 10 healthy subjects were enrolled in the study protocol . Gallbladder emptying was determined by sonography after ingestion of a standard meal and during infusion of erythromycin alone or together with 6 micrograms/kg/hr atropine . We found that 100 mg/hr erythromycin caused a significant reduction in gallbladder volume in both healthy subjects and diabetic patients . The ejection fraction (mean +/- SE) of 45.3 +/- 8.2% and 37.3 +/- 5.0% was similar . The presence of AN had no influence on gallbladder emptying induced by erythromycin . Basal motilin plasma levels were 111.5 +/- 14.5 pmol/liter in diabetic patients and 63.3 +/- 6.0 pmol/liter in healthy subjects (P < 0.01) . However, patients with AN had higher (130.0 +/- 11.9 pmol/liter) motilin plasma levels than patients without (74.0 +/- 9.4 pmol/liter, P < 0.01) . Erythromycin administration caused an approximately twofold increase in plasma motilin concentrations in healthy subject and patients without AN, but did not stimulate motilin release in neuropathic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Clin Pharmacol Ther, 1992 Nov, 52(5), 471 - 8
Erythromycin breath test predicts oral clearance of cyclosporine in kidney transplant recipients; Turgeon DK et al.; It has been shown recently that cyclosporine is largely metabolized by P450IIIA (CYP3A), an enzyme whose catalytic activity varies significantly among patients . To determine whether heterogeneity in P450IIIA activity contributes to interpatient differences in cyclosporine dosing requirements, the oral pharmacokinetics of the drug were determined in 20 stable kidney transplant recipients . P450IIIA activity was then measured in each patient by use of the erythromycin breath test . In the 16 patients who were at steady state, the logarithm of the apparent oral clearance of cyclosporine correlated significantly with the rate of 14CO2 exhaled in breath after intravenous administration of {14C N-methyl}erythromycin (r = 0.55, p = 0.03) . No significant correlations existed between apparent oral clearance and age, high-density lipoprotein cholesterol or low-density lipoprotein cholesterol, or hematocrit in these patients . We conclude that heterogeneity in P450IIIA activity significantly contributes to interpatient differences in dosing requirements of cyclosporine in kidney transplant patients.

Dig Dis Sci, 1992 Nov, 37(11), 1678 - 84
Erythromycin stimulates gallbladder emptying and motilin release by atropine-sensitive pathways; Fiorucci S et al.; The effect of administering different doses of erythromycin on gallbladder emptying and plasma concentrations of immunoreactive motilin was investigated in healthy volunteers . Erythromycin was infused for 30 min at four different doses: 20, 50, 100, and 1000 mg/hr . Gallbladder volume was determined by ultrasound scanning every 10 min for 60 min . All doses, except 20 mg/hr, provoked a significant reduction in gallbladder volume (P < 0.01) . The gallbladder emptying peak occurred after 20 min infusion . It was approximately 40-45% of basal volume and 60-70% of the emptying observed after a standard meal . At 100 mg/hr, erythromycin caused a 2.5-fold increase in plasma motilin concentration, which reached a peak after 30 min infusion . Plasma motilin peaked following maximum gallbladder emptying in all subjects . To evaluate whether cholinergic pathways were implicated in the action of erythromycin, 100 mg/hr erythromycin was infused together with 6 micrograms/kg/hr atropine . Atropine inhibited both gallbladder emptying and motilin release (P < 0.001) . Infusion of 1 microgram/kg/hr somatostatin had the same inhibitory effects (P < 0.001) . Our results suggest that atropine acts by inhibiting an erythromycin-activated cholinergic neural mechanism . Somatostatin could exert its inhibitory effect by blocking the release of acetylcholine from neural terminations.

Can J Physiol Pharmacol, 1992 Nov, 70(11), 1491 - 5
Motilin and the postprandial motility of the antrum; Boivin M et al.; This study was designed to establish whether the rise in plasma motilin observed after a meal in humans can influence the postprandial motor activity of the antrum . Antroduodenal postprandial motility profiles and indices obtained from 5 controls and 5 subjects infused with exogenous synthetic motilin (0.1 microgram.kg-1) or with the motilin receptor agonist erythromycin lactobionate (200 mg) were compared . Motilin infusion increased plasma motilin concentrations about 5 times above the physiological range but failed to modify the normal postprandial contractile response . On the other hand, in 4 of the 5 subjects, erythromycin induced an intense motor response that mimicked phase III of the migrating motor complex . Our study demonstrates that, during the postprandial period, motilin antral receptors can be stimulated only with doses of motilin exceeding the physiological plasma concentrations, and that the motor effect obtained did not mimic the usual postprandial motility pattern . Our results, therefore, do not support the proposal that the postprandial motility of the antrum is regulated by the plasma levels of motilin.

Int J Clin Pharmacol Ther Toxicol, 1992 Nov, 30(11), 540 - 2
The effect of the new immunosuppressive drug FK506 on the formation of secondary metabolites of cyclosporin A; Bauer S et al.; Interactions of FK506 with the cyclosporin A (CsA) metabolism are described . These interactions were not differentiated between the primary and secondary part of metabolism . The combination-therapy with cyclosporin A and diltiazem has shown, that not only the blood levels of CsA were increased, but also the blood levels of the primary CsA-metabolite M17 . In the presented in in-vitro-investigations 1.7 microM tritium-labelled CsA was incubated for 90 min with human liver microsomes . The inhibitory effect of FK506 (6 microM) was observed with coincubation under the same conditions . The metabolites were quantified by detection of radioactivity of the elution-fractions after HPLC . The results showed strong inhibition on the formation of both, the primary and secondary CsA-metabolites by FK506 . With the same concentration diltiazem and erythromycin exhibited only an inhibition of the formation of secondary CsA-metabolites . In clinical investigations with FK506 in combination with CsA it is necessary to control blood levels of CsA and also its primary metabolites.

Biochem Pharmacol, 1992 Oct 6, 44(7), 1461 - 4
Effect of serum-free medium on cytochrome P450-dependent metabolism and toxicity in rat cultured hepatocytes; Hammond AH et al.; Cytochrome P450 (P450)-dependent activities in homogenates of rat hepatocytes cultured for 96 hr in serum-free and serum-containing medium were compared . Benzphetamine and erythromycin N-demethylases, 7-methoxy- and propoxy-coumarin O-dealkylases, p-nitrophenol hydroxylase and 7-ethoxy- and pentoxy-resorufin O-dealkylases were all maintained at higher levels in hepatocytes cultured in serum-free medium, although there was some selectivity with respect to the extent of the maintenance relative to the activities in fresh cells . The toxicities of coumarin, precocene I and precocene II to 24 hr hepatocyte cultures, determined as decreased survival, were also shown to be increased in serum-free medium . However, the magnitude of the difference between media with respect to the toxicity of precocene II was decreased in hepatocytes cultured for 72 hr . The observed increase in toxicity is consistent with the improved maintenance of P450 in hepatocytes cultured in serum-free medium, although there is still a selective decline in P450 activities and toxicity with increased time in culture . The activity of alcohol dehydrogenase and the toxicity of allyl alcohol were similar in hepatocytes cultured in serum-free and serum-containing medium for 96 hr . The absence of serum did not affect the non-protein sulphydryl content of the cultures.

Ethiop Med J, 1992 Oct, 30(4), 207 - 14
Relapsing fever in children--demographic, social and clinical features; Daniel E et al.; Louse-borne relapsing fever (LBRF) is an acute febrile illness endemic Ethiopia . To date reports of childhood LBRF are few . The demographic, social and clinical features of eighty children with LBRF admitted to Ethio-Swedish Children's Hospital, Addis Abeba between 1989 and 1991 is presented . The mean age of patients was 8.8 years (range 4 months to 15 years) . The male to female ratio was 1.2:1 . Seventy-seven (97%) patients came from Addis Abeba . They came from poor families living in overcrowded homes . Fever, headache, right upper quadrant pain, chills and rigors were common symptoms . Fever and hepatosplenomegaly were common signs . Three drug regimens were used in the treatment of patients . A combination of penicillin and tetracycline, chloramphenicol alone and erythromycin alone, all given for 3 days . There was only one death . The literature on LBRF in adults is reviewed and the results are compared (1).

Liver, 1992 Oct, 12(5), 344 - 50
Immunoquantification of cytochrome P-450 3A on rat paraffin-embedded liver tissue; Horsmans Y et al.; The cytochrome P-450 3A family is involved in the metabolism of several drugs, including nifedipine, cyclosporine, quinidine and erythromycin . The purpose of this study was to develop a reliable method to obtain a relative quantification of cytochrome P-450 3A apoproteins in rat liver specimens by immunocytochemistry and to correlate such quantification to erythromycin N-demethylase activity, a biochemical pathway sustained by that enzymatic system . Thirty-six male Wistar rats were treated with an injection of either saline or dexamethasone phosphate (10, 30 or 50 mg/kg), a potent inducer of cytochrome P-450 3A . Specimens taken from the same lobe were processed for immunocytochemistry and determination of erythromycin N-demethylase activity . Paraffin sections were treated with a polyclonal antiserum directed against cytochrome P-450 3A . The density of cytochrome P-450 3A immunostaining measured by an automatic image analyzer increased with the dose of dexamethasone pretreatment, and with the erythromycin N-demethylase activity, both parameters being closely correlated . Our data indicate that in rats, when cytochrome P-450 3A is concerned, there is a close correlation between the results of immunoquantitation and biochemical activity . This suggests that such a method of investigation might be used on small paraffin-embedded liver specimens obtained by needle biopsy.

Mol Pharmacol, 1992 Oct, 42(4), 695 - 702
Regiochemical differences in cytochrome P450 isozymes responsible for the oxidation of methylenedioxyphenyl groups by rabbit liver; Kumagai Y et al.; The cytochrome P450 isozymes catalyzing the oxidation of the methylenedioxyphenyl compounds methylenedioxybenzene (MDB) and methylenedioxyamphetamine (MDA) have been investigated in rabbit liver preparations . The aromatic ring in MDB undergoes both demethylenation to catechol and aromatic hydroxylation to sesamol, whereas that in MDA undergoes only demethylenation to dihydroxyamphetamine . Formation of catechol and sesamol from MDB in microsomal incubation mixtures was enhanced about 5- and 3-fold, respectively, by pretreatment of the rabbits with phenobarbital, which induced CYP2B4 and CYP4B1 . The cytochrome P450 isozyme responsible for aromatic hydroxylation of MDB was induced by beta-naphthoflavone and was inhibited by alpha-naphthoflavone . Microsomal demethylenation of MDA was minimally sensitive to pretreatment of the rabbits with phenobarbital, beta-naphthoflavone, pyrazole, or rifampicin . However, MDA competitively inhibited the N-demethylation of erythromycin . Antibodies against CYP2B4, but not those against CYP4B1, caused a marked inhibition of the demethylenation and aromatic hydroxylation of MDB . Antibodies against CYP2C3 did not inhibit the demethylenation of MDA, nor did substrates or inhibitors of the CYP2D family except for bufuralol . MDB and MDA were both capable of forming metabolic intermediate complexes, and the rate of complex formation was accelerated by phenobarbital induction . Reconstitution experiments with CYP2B4 suggested that phenobarbital-inducible complex formation from MDA was not due to the carbene pathway involving the methylenedioxy group but was due to oxidation of the amino group . These results indicate that CYP2B4 oxidizes different regions of methylenedioxyphenyl compounds depending on their structure . MDB undergoes oxidation at the methylenedioxy group (major) and the benzene ring (minor) . MDA is oxidized at the alkylamino side chain at the nitrogen and alpha-carbon . The results suggested that one or more constitutive isoforms (probably unknown) of cytochrome P450 present in rabbit liver microsomes are primarily responsible for MDA demethylenation but that CYP3A6 contributes slightly.

Aliment Pharmacol Ther, 1992 Oct, 6(5), 589 - 95
Oral or intravenous erythromycin has no effect on human distal colonic motility; Jameson JS et al.; Erythromycin is a prokinetic agent for the lower oesophageal sphincter, the stomach, the gallbladder and the small bowel, acting directly on motilin receptors . Its effect on pressure activity of the human colon has not been investigated . Eight healthy volunteers were studied on 2 occasions and given intravenous or oral erythromycin, or placebo in a single-blind, randomized crossover study . Sigmoid pressure activity was measured using a 4-lumen water perfused system placed sigmoidoscopically at 50, 45, 30 and 15 cm from the anal verge . The pressures were analysed for activity index (mmHg.min) for the 35 cm colonic study segment using dedicated software . No significant difference was found in the activity index following oral erythromycin (500 mg) or placebo, or following intravenous erythromycin 1.8 mg/kg or placebo . A further 8 subjects were studied in a single-blind crossover study to determine the effect of oral erythromycin (500 mg) b.d . on colonic transit, measured with radio-opaque markers and a single abdominal X-ray . Mean or segmental colonic transit times were not statistically significantly different (Student's paired t-test) in the subjects on placebo or erythromycin . This lack of effect of erythromycin on the distal large intestine may indicate the absence of receptors for motilin in that part of the gut.

Ann Otol Rhinol Laryngol Suppl, 1992 Oct, 157, 16 - 20
Erythromycin inhibition of lipopolysaccharide-stimulated tumor necrosis factor alpha production by human monocytes in vitro; Iino Y et al.; The mechanism of clinical effectiveness of low-dose and long-term erythromycin (EM) treatment for diffuse panbronchiolitis, sinobronchial syndrome, and associated otitis media with effusion was investigated by studying the effects of EM on tumor necrosis factor alpha (TNF-alpha) production by cultured human monocytes stimulated with lipopolysaccharide . At concentrations of 0.1 microgram/mL or more, EM inhibited TNF-alpha release from human monocytes stimulated by lipopolysaccharide in a dose-dependent manner . Of the other macrolides tested, roxithromycin, an EM derivative, also showed significant inhibition of TNF-alpha production, whereas josamycin failed to inhibit TNF-alpha release from monocytes . Nonmacrolidic drugs such as minocycline hydrochloride, ofloxacin, or penicillin G had no significant effect on TNF-alpha production . These results suggest that the clinical improvement of chronic respiratory diseases by EM may depend on the suppression of production of inflammatory cytokines such as TNF-alpha.

Int J Rad Appl Instrum B, 1992 Oct, 19(7), 803 - 6
Evaluation of 99mTc-erythromycin and 99mTc-streptomycin sulphate for the visualization of inflammatory lesions; Ercan MT et al.; 99mTc-erythromycin (E) and 99mTc-streptomycin sulphate (SS) were prepared with greater than 98% labelling efficiency . The labels were stable up to 24 h of testing, using ITLC-SG strips and acetone and saline as solvents . The biodistributions of both radiopharmaceuticals versus 67Ga-citrate were studied in mice with turpentine-induced abscesses at 6 days post-induction . The mice were sacrificed at 1, 3 and 6 h post-injection of 15 MBq of 99mTc-E or 99mTc-SS . Mice injected with 67Ga-citrate were sacrificed at 4 and 24 h . The maximum abscess-to-muscle ratios obtained by biodistribution studies were 2.36 +/- 1.04 (6 h), 2.38 +/- 0.38 (6 h) and 4.76 +/- 2.04 (4 h) with 99mTc-E, 99mTc-SS and 67Ga-citrate, respectively . The maximum abscess-to-contralateral tissue ratios by ROIs over respective areas on scintigrams were 2.38 +/- 0.16 (6 h), 3.21 +/- 0.14 (3 h) and 3.24 +/- 0.92 (24 h) for 99mTc-E, 99mTc-SS and 67Ga-citrate, respectively . The uptake mechanism might be infiltration into interstitial space due to increased capillary permeability.

Hepatology, 1992 Oct, 16(4), 937 - 42
Effect of loxiglumide and atropine on erythromycin-induced reduction in gallbladder volume in human subjects; Jebbink MC et al.; This study was undertaken to investigate the effect of erythromycin, a motilin agonist with prokinetic activity, on fasting gallbladder volume . To evaluate the mechanism of action of erythromycin on gallbladder motility, erythromycin (3.5 mg/kg.20 min, intravenously) was infused on three separate occasions: during cholinergic blockage with atropine (0.005 mg/kg.hr), during cholecystokinin receptor blockade with loxiglumide (10 mg/kg.hr) and during saline solution infusion (control) . Atropine, loxiglumide and saline solution infusions were started 3 hr before administration of erythromycin and were continued for 3 hr thereafter . Gallbladder volumes (measured by ultrasonography), plasma cholecystokinin levels (radioimmunoassay) and plasma pancreatic polypeptide levels (radioimmunoassay) were determined at regular intervals for 6 hr in six healthy volunteers . During the 3-hr infusion before administration of erythromycin, both loxiglumide and atropine significantly increased gallbladder volumes--from 18 +/- 2 to 37 +/- 3 cm3 (p less than 0.05) and from 17 +/- 3 to 24 +/- 2 cm3 (p less than 0.05), respectively--whereas saline solution did not significantly affect gallbladder volume . During control saline solution infusion, erythromycin induced prolonged gallbladder contraction that was significant (p less than 0.05) between 60 and 180 min and reached a maximum of 45% +/- 8% at 150 min . Plasma cholecystokinin levels were not affected by erythromycin . Erythromycin induced a significant (p less than 0.05) increase in plasma pancreatic polypeptide levels, from 12 +/- 1 pmol/L to 34 +/- 3 pmol/L . Loxiglumide did not prevent the erythromycin-induced reduction in gallbladder volume . Atropine markedly reduced the effect of erythromycin, causing slight but significant (p less than 0.05) gallbladder volume reductions (18% +/- 4%) between 150 and 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Zhonghua Jie He He Hu Xi Za Zhi, 1992 Oct, 15(5), 266 - 8, 317
{A clinical study of 50 cases of Legionnaires disease}; Wang BF; The clinical features and X-ray manifestations of 50 cases of legionnaires disease were analysed . 8 cases might be due to nosocomial infection through breathing in flying particles of the saliva or phlegm . According to the main clinical features, this disease could be divided into common pneumonia type; acute gastroenteritis type; encephalopathy type; shock type; acute renal insufficiency type . The differential diagnosis of legionnaires disease with mycoplasmal pneumonia, pneumococcal pneumonia and infiltrative pulmonary tuberculosis was also discussed . The first choice for treatment is erythromycin or erythromycin with rifampicin.

J Pharm Biomed Anal, 1992 Oct-Dec, 10(10-12), 851 - 60
Analysis of erythromycin estolate by liquid chromatography; Cachet T et al.; A method is described for the determination of erythromycin estolate by liquid chromatography . A C18 reversed-phase column (25 x 0.46 cm i.d.) was used with acetonitrile-tetrabutylammonium sulphate (pH 6.5, 0.2 M)-phosphate buffer (pH 6.5, 0.2 M)-water {x:5:5:(90-x), v/v/v/v} 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% (v/v) was used . The column was heated at 35 degrees C, the flow rate was 1.5 ml min-1 and UV detection was performed at 215 nm . The main component, erythromycin A propionate, was separated from all other components which were present in commercial samples . The impurities most frequently observed were the propionate ester of erythromycin C and the amide N-propionyl-N-demethyl-erythromycin A . Erythromycin A was shown to be present in specialties.

Drugs, 1992 Oct, 44(4), 537 - 53
Diabetic gastroparesis . A critical reappraisal of new treatment strategies; Drenth JP et al.; Delayed gastric emptying, gastroparesis, is one of the sequelae of diabetes mellitus . Symptoms may include postprandial nausea, epigastric pain, bloating, vomiting, early satiety and unpredictable blood sugar fluctuations . Nowadays diagnosis is made by the measurement of gastric emptying with a radionuclide test meal . Using this technique some 50% of diabetic patients show signs of disordered gastric emptying . Relief is best delivered by agents promoting gastric emptying . In phase II single-dose studies metoclopramide, domperidone, cisapride, erythromycin and renzapride were all able to enhance gastric evacuation of solid and liquid meals in patients with diabetic gastroparesis . A few short term studies support the efficacy of domperidone and renzapride, but long term trials are lacking . Erythromycin, mimicking the potent gastrokinetic effect of motilin, may hold considerable promise for the future . Experience with erythromycin in diabetic gastroparesis is nonetheless very limited . To some extent the therapeutic effectiveness of metoclopramide and cisapride has been established in placebo-controlled trials . In trials with a placebo-controlled crossover design, however, only metoclopramide showed a sustained positive effect . Metoclopramide, which combines gastrokinetic and antiemetic properties seems, so far, the best therapeutic option in diabetic gastroparesis . Cisapride may be considered as a good alternative in cases where limited efficacy or side effects preclude the use of metoclopramide.

Antimicrob Agents Chemother, 1992 Oct, 36(10), 2304 - 9
Azithromycin-induced block of elementary body formation in Chlamydia trachomatis; Engel JN; The mechanism of action of azithromycin on the murine strain of Chlamydia trachomatis grown in tissue culture epithelial cells is addressed . Azithromycin at a concentration of 100 ng/ml inhibits chlamydial growth in tissue culture, a value that agrees well with prior in vitro data from human strains of C . trachomatis grown in tissue culture . By morphological criteria, the block to chlamydial growth appears to occur early in its life cycle . Azithromycin is not directly toxic to chlamydial elementary bodies but does inhibit chlamydial protein synthesis in chlamydia-infected cells . This inhibition appears quite general in nature and is rapid . It is further shown that azithromycin does not directly inhibit mRNA synthesis . Azithromycin blocks chlamydial protein synthesis in host cell-free chlamydial reticulate bodies in a manner similar to its inhibition in infected cells, albeit at slightly higher concentrations . The inhibition of chlamydial protein synthesis following a brief exposure to azithromycin is more long lasting than that following a brief exposure to erythromycin.

Ann Intern Med, 1992 Sep 15, 117(6), 476 - 81
Minocycline-induced cell-mediated hypersensitivity pneumonitis; Guillon JM et al.; OBJECTIVE: To identify the cause of a hypersensitivity pneumonitis and to determine its pathogenesis . DESIGN: Case study . SETTING: Intensive care unit of a referral hospital . PATIENT: A 51-year-old man with chronic bronchitis who developed a hypersensitivity pneumonitis within 1 month after exposure to minocycline, amoxicillin, and erythromycin . INTERVENTION: Sequential bronchoalveolar lavages after reexposure to minocycline and amoxicillin . MEASUREMENTS: Immunologic analysis of the phenotype and function of alveolar lymphocytes . RESULTS: Reexposure to minocycline but not to amoxicillin was followed by an interstitial pneumonitis . Sequential bronchoalveolar lavages showed a transient rise of eosinophils and neutrophils and a persistent alveolar lymphocytosis . Alveolar lymphocytes consisted predominantly of CD8+ but also CD4+ cells . Two CD8+ lymphocyte subsets were identified: CD8+ D44+ cytotoxic T cells that increased rapidly after the drug was resumed and CD8+ CD57+ suppressor T cells that predominated 11 days after the drug's withdrawal . In-vitro assays showed the presence of a lymphocyte-mediated specific cytotoxicity against minocycline-bearing alveolar macrophages . CONCLUSION: These results support the hypothesis of a central role of T lymphocytes in the pathogenesis of drug-related hypersensitivity pneumonitis.

Clin Pharmacol Ther, 1992 Sep, 52(3), 231 - 8
Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin; Honig PK et al.; Terfenadine is a nonsedating H1-antagonist that when overdosed, used with hepatic compromise, or when given with ketoconazole results in accumulation of parent terfenadine, prolongation of the QT interval, and torsades de pointes in susceptible patients . Nine subjects were given the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral erythromycin (500 mg every 8 hours) . All subjects increased metabolite concentrations after the addition of erythromycin for 1 week . The maximum concentration of metabolite increased by a mean of 107% and the mean metabolite area under the concentration-time curve increased by 170% . Three subjects accumulated unmetabolized terfenadine after administration of erythromycin for 1 week . Electrocardiographic data revealed changes in QT intervals and ST-U complexes in a subset of subjects who accumulated terfenadine . We conclude that erythromycin alters the metabolism of terfenadine, leading to accumulation of terfenadine in certain individuals that is associated with altered cardiac repolarization.

J Bacteriol, 1992 Sep, 174(18), 5860 - 8
Regulation of the macrolide-lincosamide-streptogramin B resistance gene ermD; Hue KK et al.; The erythromycin resistance gene ermD, which encodes an rRNA methylase protein, has an unusually long leader region (354 nucleotides) . Previously, a single promoter-proximal leader peptide coding sequence was recognized from the nucleotide sequence, and erythromycin-induced ribosome stalling in this sequence was proposed to be required for the induction of methylase translation . We characterized spontaneously occurring and in vitro-constructed leader region mutations in an effort to understand the function of various segments of the long ermD leader region . A second leader peptide coding sequence was identified, and the location of insertion and point mutations that expressed ermD methylase constitutively suggested that translation of the second leader peptide is controlled by ribosome stalling in the first leader peptide . From Northern RNA blot analysis of ermD transcription, it appears that regulation of ermD expression is not by transcriptional attenuation.

Pediatr Dermatol, 1992 Sep, 9(3), 251 - 4
Painful, plaque-like, pitted keratolysis occurring in childhood; Shah AS et al.; Pitted keratolysis is a superficial infection of the soles of the feet that is almost always asymptomatic . A painful variant of this disorder was reported to occur in adult males during military service . We report painful, plaque-like, pitted keratolysis in two children . Treatment with topical erythromycin was curative.

J Antimicrob Chemother, 1992 Sep, 30(3), 339 - 48
The anti-inflammatory effect of erythromycin in zymosan-induced peritonitis of mice; Mikasa K et al.; The anti-inflammatory effect of erythromycin was investigated using zymosan-induced peritonitis in mice . When mice were given erythromycin 10 mg/kg/day po for 28 days, a marked suppression of inflammatory responses, including the reduced influx of leucocytes, plasma exudation and prostaglandin E2 synthesis, was observed . However, neither a 7-day treatment with erythromycin nor a 28-day treatment with clindamycin suppressed the response . The anti-inflammatory activity induced after a 28-day treatment with erythromycin was comparable to the anti-inflammatory effect conferred by a 2-day treatment with dexamethasone 40 microgram/mouse/day . Thus, these data confirm previous studies which show that erythromycin can exert an anti-inflammatory effect when used over long periods of time.

An Esp Pediatr, 1992 Sep, 37(3), 184 - 6
{Pertussis . Study of an epidemic}; Montiano Jorge JI et al.; Forty-six children seen during 1989 with the clinical diagnosis of Pertussis are reviewed in this study . In 64.5% of the cases the Bordet-Gengou medium nasopharyngeal culture was positive for B . pertussis . Two age groups showed more susceptibility to B . pertussis, children under one year of age (70%) and of more than five years of age (20%) . The disease was of more severity among infants younger than two months of age (apnea, choking spells, etc.) . Most infants needed to be admitted to the hospital . All patients received therapy with erythromycin, salbutamol (80%) and general supportive medical care . No deaths or other medical sequelae were observed.

Res Vet Sci, 1992 Sep, 53(2), 191 - 7
Antipyrine, erythromycin and oxytetracycline disposition in experimental fasciolosis; Burrows GE et al.; The effects of fasciolosis on drug disposition were studied by administration of antipyrine, erythromycin and oxytetracycline to sheep and cattle . Fasciolosis was produced by administration of 200 or 400 metacercariae (MC) of Fasciola hepatica to sheep and 500 MC to cattle . The disease was subsequently confirmed by determination of plasma glutamate dehydrogenase and gamma-glutamyl transferase and identification and quantitation of mature flukes in the liver at necropsy . Acute or subacute fasciolosis in sheep was accompanied by a significant decrease in the elimination rate constant (beta) and increase in the elimination half-time (t 1/2) for antipyrine and erythromycin when compared with controls or infected sheep which had been treated with the anthelmintic luxabendazole . An increase in apparent volume of distribution (Vd) was seen only for erythromycin in sheep given 400 MC . There were no changes in the disposition of oxytetracycline in sheep with either acute or subacute infection and no effects on disposition of the three test drugs in chronically infected sheep . With early chronic disease in calves, only the disposition of oxytetracycline was affected; not that of antipyrine or erythromycin.

Obstet Gynecol Clin North Am, 1992 Sep, 19(3), 539 - 49
Erythromycin; Graham EM; Even with the continuing emergence of new antibiotics, erythromycin continues to be used extensively in obstetrics and gynecology . It is inexpensive, with a long history of usage and proven safety . When oral erythromycin preparations are given in the correct dose and with proper timing in relation to meals, no individual preparation offers a significant therapeutic advantage . Its uses include the treatment of respiratory tract infections, chlamydial and other genital tract infections in pregnancy, puerperal mastitis, and acute conjunctivitis of the newborn.

J Formos Med Assoc, 1992 Sep, 91(9), 912 - 5
Diffuse panbronchiolitis: report of a case; Chu YC et al.; A 33-year-old male presented with a productive cough of yellowish sputum which he had had for several years and progressive dyspnea on exertion that had been present for one year . Physical examination on admission disclosed clubbing of the fingers, diffuse inspiratory crackles and some rhonchi on auscultation . Plain chest film showed diffuse fine nodular lesions in both lungs . Pulmonary function tests demonstrated obstructive ventilatory impairment with a positive bronchodilator response . A CT scan of the chest showed diffuse fine nodular infiltrations in both lung fields . Arterial blood gas analysis of the patient, while breathing room air, revealed mild hypoxemia . The histologic findings of an open lung biopsy specimen were compatible with a diagnosis of diffuse panbronchiolitis . The patient was treated with erythromycin and a bronchodilator, and was regularly followed at the outpatient department . In this report, clinical manifestations, diagnostic criteria and recent advances in the treatment of diffuse panbronchiolitis are discussedPublication Types:

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