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