Crit Care Med, 2003 May, 31(5), 1338 - 46 Cytochrome P450 3A4 activity after surgical stress; Haas CE et al.; OBJECTIVE: To evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery . DESIGN: Prospective, open-label study with each patient serving as his or her own control . SETTING: University-affiliated, acute care, general hospital . PATIENTS: A total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n = 5), complete or partial colectomy (n = 6), or peripheral vascular surgery with graft (n = 5) . INTERVENTIONS: Cytochrome P450 3A4 activity was estimated using the carbon-14 {14C}erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery . Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge . Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha . Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room . MEASUREMENTS AND MAIN RESULTS: ERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups . There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p =.06) . The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (r(s) = -.541, p =.03) and log interleukin-6 area under the curve from 0 to 72 hrs (r(s) = -.597, p =.014) . Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% +/- 5.2% vs . 74.7% +/- 5.1%, p <.001) . CONCLUSIONS: Acute inflammation after elective surgery was associated with a significant decline in cytochrome P450 3A4 activity, which is predictive of clinically important changes in the metabolism of commonly used drugs that are substrates for this enzyme. Zhonghua Er Bi Yan Hou Ke Za Zhi, 2002 Apr, 37(2), 127 - 9 {Effect of erythromycin on apoptosis of eosinophils in nasal polyps in vitro}; Tang J et al.; OBJECTIVE: To study the effect of erythromycin on apoptosis of eosinophils in nasal polyps in vitro . METHODS: Fifteen nasal polyp biopsies were collected during nasal polypectomy . The specimens were cultured with erythromycin in RPMI1640, and cultured without erythromycin as control group . The explants in both groups were taken out at 1, 3, 5 day after culture . The apoptosis of cells was detected by terminal deoxynucleotidyl transferasemediated dUTP nick endlabeling(TUNEL), eosinophils were identified by morphology and serial sections stained with HE, then the apoptosis index (AI) of eosinophils was calculated . RESULTS: The AI of eosinophils in nasal polyps after cultured for 1,3,5 days with erythromycin were (31.77 +/- 9.52)%, (32.67 +/- 9.44)% and (50.34 +/- 8.78)% respectively . In control group, the AI of eosinophils were (29.18 +/- 7.31)%, (29.82 +/- 12.03)% and (42.25 +/- 8.08)% respectively . There were significant difference between two groups at 5 day after culture(P < 0.05) . CONCLUSION: Erythromycin promoted apoptosis of eosinophils in nasal polyps in vitro. Drugs Today (Barc), 2001 Apr, 37(4), 215 - 227 Desloratadine: A preclinical and clinical overview; Norman P et al.; A new competitive histamine H(1)-receptor antagonist with superior binding affinity at this receptor as compared with other common antihistamines, desloratadine is the active metabolite of loratadine, the most extensively used agent of this class . Under development for the treatment of allergic rhinitis and urticaria and currently awaiting regulatory approval in the United States, desloratadine was recently approved and became commercially available in Europe for the treatment of allergic disease . Desloratadine is at least 50-fold more potent in vitro and appears to be 10-fold more potent in vivo than loratadine . The new antihistamine is metabolized to 3-hydroxydesloratadine, which retains biological activity . Absorption of orally administered desloratadine is dose proportional, and desloratadine achieves steady-state concentrations after approximately 5 doses with once-daily administration . This is consistent with mean half-life values of 24-27 h and a 24-h dosing interval . The absorption of desloratadine is not affected by food and there are no clinically relevant drug-drug interactions . In randomized, double-blind, placebo-controlled clinical trials, a single 5 mg dose of desloratadine conferred significant relief of seasonal allergic rhinitis (SAR) symptoms - including the complaint of nasal congestion - within hours of the first dose, and these effects were sustained both for the entire 24-h dosing interval and up to 2-4 weeks with once-daily treatment (5 mg/day) . In addition, patients with seasonal exacerbations of mild to moderate asthma derived similar clinical benefits from desloratadine, with significant, first-dose relief of both SAR-related complaints such as nasal congestion as well as asthma symptoms . In addition, beta(2) agonist requirements for symptom management were significantly reduced from baseline in these asthma patients when treated with the 5 mg/day desloratadine regimen as compared with placebo . Also experiencing marked relief of symptoms upon treatment with desloratadine were patients with chronic idiopathic urticaria, who exhibited significant first-dose relief of pruritus and sustained reductions in this symptom, numbers of lesions (and size of largest hive) and sleep disturbances, with a marked improvement in their ability to carry out activities of daily living . The clinical benefits of desloratadine in the above clinical settings were accompanied by general improvements in quality of life . Desloratadine does not cross the blood-brain barrier, as demonstrated by both human studies using cognitive indices as well as work in animal models . Desloratadine is well tolerated, and no significant drug-related (or food-related) adverse effects were noted when the agent was administered together with cytochrome P450 inhibitors (e.g., ketoconazole, erythromycin) . Administration of desloratadine has not been shown to cause any significant changes in cardiac activity at therapeutic doses, even at 9-fold higher doses, or in the presence of P450 inhibitors . Nor does administration of desloratadine lead to sedation, even in the presence of alcohol . (c) 2001 Prous Science . All rights reserved. J Pharm Biomed Anal, 2003 Jun 1, 32(2), 233 - 49 Fast separations on monolithic silica columns: method transfer, robustness and column ageing for some case studies; van Nederkassel AM et al.; Six separation methods, developed on conventional silica high performance liquid chromatography (HPLC) columns were transferred to monolithic silica columns of 5 and 10 cm length . The transferred methods include the separation of an alkylbenzene mixture, the separations of drugs from their impurities (nimesulide, tetracycline, phenoxymethylpenicillin and erythromycin) and the separation of a green tea extract . The transfer of the first three methods was successful while for the latter three it was not . Increasing the flow rate up to 9 ml/min (where possible) inversely decreased the analysis time of the successfully transferred methods to 48 s (alkylbenzene mixture) 1.8 min (nimesulide mixture) and 3 min (tetracycline mixture) while still reasonable well separated peaks were obtained . The robustness and repeatability of the transferred and accelerated separations was found to be acceptable . Despite the use of flow rates up to 9 ml/min and frequent mobile phase changes with pH values varying from 3.5 to 7, the column performance was found to be rather constant and the column ageing to be minimal. Reprod Toxicol, 2003 May-Jun, 17(3), 255 - 61 Maternal drug use in early pregnancy and infant cardiovascular defect; Kallen BA et al.; The purpose of the paper is to identify maternal drug use that may be associated with an increased risk for cardiac defects in the offspring . A case-control study was performed with cases (cardiovascular defects without known chromosome anomalies) being identified from three Swedish health registers (n=5015) and controls being all infants born in Sweden during the period 1 July 1995-2001 (n=577,730) . Information on drug exposure was obtained by interview in early pregnancy . Associations between maternal drug use and infant cardiovascular defect were identified for insulin, antihypertensives, fertility drugs, erythromycin, naproxen, anticonvulsants, nitrofurantoin, clomipramine, and budesonide in nasal preparations . Some of these associations are probably due to confounding from underlying disease or complaint, some may be due to multiple testing, some may be true drug effects . Further studies are needed to verify or reject these associations. Life Sci, 2003 Jun 6, 73(3), 327 - 35 Effect of age and photoperiodic conditions on metabolism and oxidative stress related markers at different circadian stages in rat liver and kidney; Martin C et al.; It has been shown that some cytochrome P450-dependent enzyme activities could present daily fluctuations, particularly CYP3A isoenzymes which are enhanced during the dark period . The aim of this study was to investigate whether age and photoperiodic conditions at different circadian stages could influence these fluctuations . Young mature (10 weeks) and old (22 months) Wistar rats were initially exposed to light-dark cycles 12:12 during 4 weeks, and secondly 18:6 for either one week or six weeks . Erythromycin N-demethylase (CYP3A-dependent), 7-ethoxycoumarin O-deethylase (CYP1A-dependent) and aniline 4-hydroxylase (CYP2E-dependent) activities were determined in liver and kidney microsomes at different hours after darkness onset (HADO) . In addition, liver and kidney GSH, GSHPx, ATP, TBARS were determined . During the LD 12:12 cycle, while no significant modification was observed in CYP1A- and 2E-dependent enzyme activities as functions of HADO, erythromycin N-demethylase activity (CYP3A-dependent) showed a significant increase during the second third of the dark period in both young and old rats . After switching to a LD 18:6 cycle, this variation was still observed during second third of the dark period, to a lesser but still significant degree, with no difference between one week and six weeks exposure to the new photoperiod . It can be noted that the old rats showed a significantly lower level of erythromycin N-demethylase activity than the young rats, in parallel to a decrease in GSH, GSHPx and ATP, and an increase in TBARS.These results confirm the lower resistance of old animals to oxidative stress . The observed variations in metabolism parameters underline the need for study designs in pharmaco-toxicology taking into account the possible risks induced by circadian changes, especially in aged subjects. Dig Dis Sci, 2003 Mar, 48(3), 488 - 97 Effect of altering gastric emptying on postprandial plasma glucose concentrations following a physiologic meal in type-II diabetic patients; Gonlachanvit S et al.; The purpose of this study was to determine the effects of altering gastric emptying on postprandial plasma glucose concentration after a physiologic meal in patients with type II diabetes mellitus (T II DM) . Nine T II DM patients underwent a double-blind, randomized, three-way crossover study, receiving erythromycin 200 mg, morphine 8 mg, or normal saline (placebo) intravenously prior to ingestion of a radiolabeled, dual-isotope, solid-liquid meal . Gastric emptying of solids and liquids and serial plasma glucose, glucagon, and serum insulin concentrations were measured at baseline and for 5 hr after meal ingestion . Erythromycin accelerated and morphine delayed solid- and liquid-phase gastric emptying compared to placebo (P < 0.05) . During the first hour, the postprandial plasma glucose concentrations were higher after erythromycin (P < 0.05) and lower after morphine (P < 0.05) compared to placebo . The peak postprandial plasma glucose concentration was higher after erythromycin (P = 0.05) and lower after morphine (P < 0.05) compared to placebo . In conclusion, pharmacologic acceleration of gastric emptying resulted in higher postprandial glucose concentrations, while delaying gastric emptying resulted in lower postprandial glucose concentrations after a physiologic meal in T II DM . These results suggest that administration of opiate analgesics or prokinetic agents to diabetic patients may alter glucose control . Modifying gastric emptying may be helpful in achieving glucose control in T II DM. Di Yi Jun Yi Da Xue Xue Bao . 2003 May;23(5):490, 493. {Sclerotherapy for renal cyst using erythromycin and procaine via renal puncture guided by B-ultrasound: report of 1,000 cases}; Ou XX et al.; Our experience of sclerotherapy for renal cyst injection of erythromycin and procaine via ultrasound-guided renal puncture is reported . The total efficiency reached 96% with low recurrence rate in the 1,000 cases receiving this therapy, suggesting that this approach is a simple, accurate and effective renal cysts with minimized postoperative complications treatment. J Pharm Pharm Sci, 2003 Jan-Apr, 6(1), 1 - 12 Experimental estimation of the role of P-Glycoprotein in the pharmacokinetic behaviour of telithromycin, a novel ketolide, in comparison with roxithromycin and other macrolides using the Caco-2 cell model; Pachot JI et al.; PURPOSE: The aim of this study was to examine the transport mechanism of telithromycin in comparison with erythromycin, azithromycin, clarithromycin and roxithromycin . METHODS: These antibiotics were examined in Caco-2 cell monolayers in order to demonstrate the potential involvement of P-GP in the absorption process, using verapamil as a P-GP competitor . A model using concentration equilibrium conditions was developed to delineate passive and active permeability components of telithromycin and roxithromycin transport in order to predict absorption in humans . RESULTS: Comparison of telithromycin Papp(AB)/Papp(BA) ratios with those of the other antibiotics indicated that an efflux pump was involved which limited the transport of the macrolides to a greater extent than that of telithromycin . Modulation of Caco-2 transport of these antibiotics by verapamil and their reciprocal effect upon verapamil transport confirmed the involvement of P-GP and demonstrated that two substrates of P-GP may increase the transport of each other . Under concentration equilibrium conditions, both roxithromycin and telithromycin exhibited high mean Papp values for passive diffusion which extrapolated to 88% and 77% predicted human absorption respectively, if the involvement of P-GP was ignored . Both Km and Vm values suggested that saturation of P-GP by telithromycin may occur at a lower dose level in humans than with roxithromycin (Km= 9.8 microM, Vm= 0.3 microM and Km= 45 microM, Vm= 1.1 microM, respectively) . At 4.10(-5) M of either telithromycin or roxithromycin the passive flux was respectively 48% and 16% greater than the active efflux . CONCLUSIONS: The high absorption potential of telithromycin combined with the low Km and Vm values and the high dose level suggest that in humans the efflux pump may not limit ketolide absorption and that the interaction with other P-GP substrates may not significantly increase its oral absorption. Respirology, 2003 Jun, 8(2), 249 - 51 A case of Legionella pneumophila pneumonia complicated by miliary tuberculosis; Uchida K et al.; A 47-year-old woman was admitted to hospital with severe Legionella pneumonia . The respiratory symptoms improved dramatically and the X-rays revealed a decrease in the diffuse chest infiltrates after treatment with erythromycin and rifampicin . However, chest CT scans showed that the reticulonodular opacities persisted for several weeks after the onset of pneumonia . Two months after admission, the chest X-rays showed the progression of small nodules in both lungs and there was increasing respiratory distress . A diagnosis of miliary tuberculosis was confirmed . The present case should alert physicians to this potentially confusing combination of respiratory pathogens. CNS Drugs, 2003, 17(7), 513 - 32 Clinically important drug interactions with zopiclone, zolpidem and zaleplon; Hesse LM et al.; Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population . Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency . The newer hypnosedatives include zolpidem, zaleplon and zopiclone . These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines . This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone . The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted.Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation . Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin . Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required . Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs.Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone . The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this . Another explanation may be a difference in CYP metabolism . While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation. Kyobu Geka, 2003 May, 56(5), 381 - 4 {Perioperative management of patient with pulmonary operation associated with interstitial pneumonia}; Osawa H et al.; The prognosis of patients complicated with interstitial pneumonia (IP) who undergo pulmonary operations is very poor if acute exacerbation occurs after the operation . We have experienced 6 cases in which operations were performed on lungs complicated with IP The first patient died due to acute exacerbation, but the subsequent 5 patients had good postoperative courses due to 1) short-term administration of low-dose steroid before and after the operation, 2) avoidance of administration of high concentration of oxygen during and after the operation, and 3) administration of erythromycin before and after the operation, 4) N-acetylcysteine inhalation and administration of dl-alpha-tocopherylnicotinate before and after the operation . It is thought that careful management of such patients is needed to prevent acute exacerbation even after discharge from hospital. J Diabetes Complications, 2003 May-Jun, 17(3), 141 - 4 Improvement of esophageal and gastric motility after 2-week treatment of oral erythromycin in patients with non-insulin-dependent diabetes mellitus; Chang CT et al.; Forty-five patients with non-insulin-dependent diabetes mellitus (NIDDM) were enrolled in the study . Before and after the 2-week treatment course of oral erythromycin, esophageal (the mean transit time, MTT) and gastric motility (the halftime of gastric emptying, GETt1/2) were evaluated by radionuclide labeled liquid and solid meals . Meanwhile, the fasting blood sugar (FBS) levels were monitored . After a 2-week erythromycin treatment, MTT shortened from 9.32+/-1.12 to 6.28+/-0.91 s and GETt1/2 shortened from 210.2+/-24.3 to 128.3+/-30.1 min . Meanwhile, FBS decreased from 198.2+/-30.1 to 121.5+/-21.3 mg/dl (P value <.05) . We conclude that a 2-week treatment course of oral erythromycin can significantly improve esophageal and gastric motility which results in a better control of blood sugar in patients with NIDDM. J Am Chem Soc, 2003 May 14, 125(19), 5671 - 6 Expression and kinetic analysis of the substrate specificity of modules 5 and 6 of the picromycin/methymycin polyketide synthase; Yin Y et al.; Picromycin synthase (PICS) is a multifunctional, modular polyketide synthase (PKS) that catalyzes the conversion of methylmalonyl-CoA to narbonolide and 10-deoxymethynolide, the macrolide aglycone precursors of the antibiotics picromycin and methymycin, respectively . PICS modules 5 and 6 were each expressed in Escherichia coli with a thioesterase domain at the C-terminus to allow release of polyketide products . The substrate specificity of PICS modules 5+TE and 6+TE was investigated using N-acetylcysteamine thioesters of 2-methyl-3-hydroxy-pentanoic acid as diketide analogues of the natural polyketide chain elongation substrates . PICS module 5+TE could catalyze the chain elongation of only the syn diketide (2S,3R)-4, while PICS module 6+TE processed both syn diastereomers, (2S,3R)-4 and (2R,3S)-5, with a 2.5:1 preference in k(cat)/K(m) for 5 but did not turn over either of the two anti diketides . The observed substrate specificity patterns are in contrast to the 15-100:1 preference for 4 over 5 previously established for several modules of the closely related erythromycin PKS, 6-deoxyerythronolide B synthase (DEBS). Clin Pharmacol Ther, 2003 May, 73(5), 427 - 34 Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease; Dowling TC et al.; BACKGROUND: The cytochrome p450 (CYP) oxidative enzyme system, located primarily in the liver and small intestine, is responsible for metabolism and detoxification of numerous endogenous and exogenous substances . The most abundant CYP enzyme, CYP3A, is known to be involved in the metabolism of more than 200 commonly used medications . In experimental models of renal failure, both hepatic function and CYP enzyme content are reduced; however, direct evidence in humans is lacking . Evaluation of drug metabolism in patients with end-stage renal disease is important because these patients use a large number of medications and are at risk of adverse reactions and drug-drug interactions . METHODS: We measured hepatic CYP3A activity at baseline and after rifampin (INN, rifampicin) enzyme induction in 12 patients with end-stage renal disease and 12 healthy, age-matched controls . Hepatic CYP3A phenotype was characterized with the erythromycin breath test, and enzyme induction capacity was evaluated with a short course of rifampin (600 mg/d for 6 days) . RESULTS: The end-stage renal disease group had 28% lower baseline erythromycin breath test values than controls (P <.05); however, enzyme induction capacity after rifampin administration was similar between groups (P =.70) . CONCLUSION: The findings suggested that one mechanism by which patients with end-stage renal disease are at increased risk of drug toxicity is reduced activity of the CYP3A enzyme pathway. J Am Chem Soc, 2003 May 7, 125(18), 5366 - 74 Mechanistic analysis of acyl transferase domain exchange in polyketide synthase modules; Hans M et al.; Many polyketides are synthesized by a class of multifunctional enzymes called type I modular polyketide synthases (PKSs) . Several reports have described the power of predictively altering polyketide structure by replacing individual PKS domains with homologues from other PKSs . For example, numerous erythromycin analogues have been generated by replacing individual methylmalonyl-specific acyl transferase (AT) domains of the 6-deoxyerythronolide B synthase (DEBS) with malonyl-, ethylmalonyl-, or methoxymalonyl-specific domains . However, the construction of hybrid PKS modules often attenuates product formation both kinetically and distributively . The molecular basis for this mechanistic imperfection is not understood . We have systematically analyzed the impact of replacing an AT domain of DEBS on acyl-AT formation, acyl-CoA:HS-NAc acyl transferase activity, acyl-CoA:ACP acyl transferase activity (nucleophile charging), acyl-SNAc:ketosynthase acyl transferase activity (electrophile charging), and beta-ketoacyl ACP synthase activity (condensation) . As usual, domain junctions were located in interdomain regions flanking the AT domain . Kinetic analysis of hybrid modules containing either malonyl transferase or methylmalonyl transferase domains revealed a 15-20-fold decrease in overall turnover numbers of the hybrid modules as compared to the wild-type module . In contrast, both the activity and the specificity of the heterologous AT domains remained unaffected . Moreover, no defects could be detected in the ability of the heterologous AT domains to catalyze acyl-CoA:ACP acyl transfer . Single turnover studies aimed at directly probing the ketosynthase-catalyzed reaction led to two crucial findings . First, wild-type modules catalyzed chain elongation with comparable efficiency regardless of whether methylmalonyl-ACP or malonyl-ACP were the nucleophilic substrates . Second, chain elongation in all hybrid modules tested was seriously attenuated relative to the wild-type module . Our data suggest that, as currently practiced, the most deleterious impact of AT domain swapping is not on the substrate specificity . Rather, it is due to the impaired ability of the KS and ACP domains in the hybrid module to catalyze chain elongation . Consistent with this proposal, limited proteolysis of wild-type and hybrid modules showed major differences in cleavage patterns, especially in the region between the KR and ACP domains. Int J Infect Dis, 2003 Mar, 7(1), 35 - 8 Phenotypic diversity of enterotoxigenic Escherichia coli (ETEC) isolated from cases of travelers' diarrhea in Kenya; Shaheen HI et al.; BACKGROUND: The aim of this study was to characterize phenotypically enterotoxins, colonization factors (CFs) and the antibiotic susceptibility of enterotoxigenic Escherichia coli (ETEC) strains isolated from cases of acute diarrhea that occurred in Europeans traveling to resorts in Mombasa, Kenya; this information is critical for the development of vaccines and empirical treatment . METHODS: Over a 1-year period from 1996 to 1997, five E . coli-like colonies were obtained from each of 463 cases with acute diarrhea . These strains were characterized for enterotoxins using GM-1 ELISA, for CFs using a dot-blot assay, and for antibiotic susceptibility using antibiotic disks . RESULTS: Of 164 strains characterized for ETEC phenotype, 30 (18%) expressed heat-labile toxin (LT) only, 83 (51%) heat-stable toxin (ST) only, and 51 (31%) both LT and ST . Analysis for CF expression demonstrated that 107 (65%) of the strains were positive for CFs, including CFA/IV (46%), CFA/II (35%), and CFA/I (5%), while less than 4% expressed less common CFs . All ETEC strains tested were resistant to erythromycin and sensitive to ceftriaxone . Over one-third of the strains were resistant to sulfamethoxazole-trimethoprim or tetracycline . Six strains were resistant to nalidixic acid; none of these were resistant to ciprofloxacin . CONCLUSIONS: Cumulatively, our findings indicate that ETEC in this region comprises a highly diverse group of bacterial enteropathogens, and that the development of prophylactic agents against ETEC faces major challenges because of this diversity. Jpn Heart J, 2003 Mar, 44(2), 225 - 34 Drug interaction between mosapride and erythromycin without electrocardiographic changes; Katoh T et al.; QT prolongation and torsades de pointes have been documented in patients administered cisapride and its blocking of potassium channels in myocytes has been suggested as the mechanism . An interaction with cytochrome P450 CYP3A4 inhibitor drugs like macrolide and azole antifungals is also thought to be a possible mechanism . Since mosapride has characteristics similar to cisapride, we examined the effects of mosapride on the electrocardiogram and pharmacokinetics before and after its coadministration with erythromycin . Ten healthy male volunteers were repeatedly administered mosapride 15 mg/day for 7 days followed by coadministration with erythromycin 1200 mg/day for 7 days . Coadministration with erythromycin resulted in a 1.6-fold increase in the Cmax of mosapride and prolongation of t(1/2) from 1.6 to 2.4 hours, indicating the inhibition of mosapride metabolism . However, there were no significant differences in the QT interval and QTc between mosapride alone and concomitant use with erythromycin . There was no correlation between the electrocardiographic parameters and plasma mosapride concentrations, and no case exceeded the upper limit of the normal range of QTc . Although there was a certain pharmacokinetic interaction between mosapride and erythromycin, their coadministration did not affect the electrocardiogram at all, indicating a reduced likelihood of severe clinical adverse events like QT prolongation and torsades de pointes. AJR Am J Roentgenol, 2003 May, 180(5), 1305 - 10 Time-resolved three-dimensional MR imaging of gastric emptying modified by IV administration of erythromycin; Lauenstein TC et al.; OBJECTIVE: The aim of our study was to assess the effect of IV erythromycin on gastric emptying and subsequent small-bowel filling using three-dimensional (3D) MR imaging in both healthy subjects and patients with functional dyspepsia . SUBJECTS AND METHODS: Six healthy volunteers and six patients with symptoms of functional dyspepsia ingested 10 mL of gadopentetate dimeglumine mixed into 500 mL of a liquid nutrient . On two separate days, gastric emptying was determined using 3D volume measurements that were obtained every 5 min for as long as 25 min on 3D T1-weighted gradient-echo MR imaging with and without the use of IV erythromycin . Gastric volumes and filling of the small bowel were quantified on the 3D data sets using semiautomatic software . RESULTS: Delineation of the bright gastric lumen proved easy . After 25 min, a significant decrease in gastric volumes could be seen in examinations performed with and without erythromycin . In healthy volunteers, gastric volumes decreased significantly more after the administration of erythromycin . In three patients with functional dyspepsia, MR imaging revealed reduced rates of gastric emptying . The administration of erythromycin resulted in a significantly faster rate of gastric emptying in two of those three patients . CONCLUSION: Three-dimensional MR imaging is a feasible method of assessing gastric volumes and diagnosing delayed gastric emptying . In patients with reduced rates of gastric emptying, 3D MR imaging may be an appropriate tool with which to monitor therapeutic approaches, such as the use of prokinetic agents like erythromycin. Eur J Clin Pharmacol, 2003 May, 59(1), 51 - 6 Epub 2003 Apr 01. The effect of erythromycin on the pharmacokinetics of rosuvastatin; Cooper KJ et al.; RATIONALE OBJECTIVE: To examine in vivo the effect of erythromycin on the pharmacokinetics of rosuvastatin {an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase} . Erythromycin is a potent inhibitor of CYP3A4 that markedly increases circulating levels of some other HMG-CoA reductase inhibitors . METHODS: In this randomised, double-blind, two-way cross-over, placebo-controlled trial 14 healthy volunteers were given 500 mg erythromycin or placebo four times daily for 7 days . A single dose of 80 mg rosuvastatin was co-administered on day 4 of dosing . Plasma concentrations of rosuvastatin and active and total HMG-CoA reductase inhibitors were measured up to 96 h after dosing . RESULTS: Eleven volunteers had data available from both dosing periods . There was no increase in rosuvastatin plasma exposure following co-administration with erythromycin compared to placebo . In fact, following co-administration with erythromycin, rosuvastatin geometric least square mean AUC((0-t)) and C(max) were 20% and 31%, respectively, lower than with placebo . Individual treatment ratios for AUC((0-t)) ranged from 0.48 to 1.17, and for C(max) ranged from 0.33 to 2.19 . Essentially all of the circulating active HMG-CoA reductase inhibitors and most (>94%) of the total inhibitors were accounted for by rosuvastatin . Erythromycin did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin . CONCLUSIONS: Erythromycin did not produce any increase in rosuvastatin plasma exposure . This indicates that CYP3A4 metabolism is not an important clearance mechanism for rosuvastatin, a result consistent with previous findings . The small decreases in rosuvastatin AUC((0-t)) and C(max) that occurred as a consequence of short-term treatment with erythromycin are unlikely to have relevance to long-term treatment with rosuvastatin. J Ind Microbiol Biotechnol, 2003 Aug, 30(8), 480 - 8 Epub 2003 Apr 16. Rapid engineering of polyketide overproduction by gene transfer to industrially optimized strains; Rodriguez E et al.; Development of natural products for therapeutic use is often hindered by limited availability of material from producing organisms . The speed at which current technologies enable the cloning, sequencing, and manipulation of secondary metabolite genes for production of novel compounds has made it impractical to optimize each new organism by conventional strain improvement procedures . We have exploited the overproduction properties of two industrial organisms- Saccharopolyspora erythraea and Streptomyces fradiae, previously improved for erythromycin and tylosin production, respectively-to enhance titers of polyketides produced by genetically modified polyketide synthases (PKSs) . An efficient method for delivering large PKS expression vectors into S . erythraea was achieved by insertion of a chromosomal attachment site ( attB) for phiC31-based integrating vectors . For both strains, it was discovered that only the native PKS-associated promoter was capable of sustaining high polyketide titers in that strain . Expression of PKS genes cloned from wild-type organisms in the overproduction strains resulted in high polyketide titers whereas expression of the PKS gene from the S . erythraea overproducer in heterologous hosts resulted in only normal titers . This demonstrated that the overproduction characteristics are primarily due to mutations in non-PKS genes and should therefore operate on other PKSs . Expression of genetically engineered erythromycin PKS genes resulted in production of erythromycin analogs in greatly superior quantity than obtained from previously used hosts . Further development of these hosts could bypass tedious mutagenesis and screening approaches to strain improvement and expedite development of compounds from this valuable class of natural products. Scand J Infect Dis, 2003, 35(2), 104 - 6 Risk of infantile hypertrophic pyloric stenosis after maternal postnatal use of macrolides; Sorensen HT et al.; A case report has suggested that exposure to erythromycin through breast milk might cause infantile hypertrophic pyloric stenosis . This study therefore examined whether macrolides, transmitted via breast milk, increase the risk of infantile hypertrophic pyloric stenosis in neonates . A population-based cohort study was conducted, based on data from a prescription registry, the Danish Birth Registry and North Jutland County's hospital discharge registry, Denmark, and comprising 1166 pregnant women who had been prescribed macrolides from birth to 90 d postnatally, and 34,690-41,778 pregnant women as controls . The odds ratios for infantile hypertrophic pyloric stenosis varied between 2.3 and 3.0 according to different periods of postnatal exposure, and after stratification for gender they were 10.3 {95% confidence interval (95% CI) 1.2-92.3} for girls and 2.0 (95% CI 0.5-8.4) for boys . The use of macrolides during breast-feeding increases the risk of infantile hypertrophic pyloric stenosis. Trop Gastroenterol, 2002 Jul-Sep, 23(3), 122 - 4 Effect of erythromycin and cisapride on emptying of the vagally denervated intrathoracic stomach; Narasimhan R et al.; BACKGROUND: Subsequent to esophagectomy and reconstruction among patients with esophageal cancers, the intrathoracic denervated stomach acts as a passive conduit without peristalsis . OBJECTIVE: The study was designed to assess the impact of two prokinetic drugs viz . erythromycin and cisapride on the emptying of vagally denervated intrathoracic stomach . METHODS: Twenty consecutive patients of carcinoma esophagus, who had undergone one stage transhiatal oesophagectomy with cervical esophagogastrostomy and were disease free at three months postoperative follow-up, were included in the study . These patients were randomised into two groups of ten each . The patients in group A received erythromycin, while patients in group B received cisapride . The gastric emptying was studied by scintigraphy, using a standard test meal containing 99m Tc sulphur colloid labelled 'IDLIS' {rice based radio labelled food} before and after the drug treatment . RESULTS: The pre and post treatment mean gastric half emptying time of the patients in the erythromycin group was 52.6 min and 49.7 min (p > 0.1) and in cisapride group it was 53.76 and 26.4 min respectively (p < 0.05) . Intergroup comparison of the difference was not statistically significant . CONCLUSION: Cisapride is an effective prokinetic agent in the treatment of gastric stasis of the vagally denervated intrathoracic stomach. World J Gastroenterol, 2003 Apr, 9(4), 779 - 83 Relative efficacy of some prokinetic drugs in morphine-induced gastrointestinal transit delay in mice; Suchitra AD et al.; AIM: To study the relative efficacy of cisapride, metoclopramide, domperidone, erythromycin and mosapride on gastric emptying (GE) and small intestinal transit (SIT) in morphine treated mice . METHODS: Phenol red marker meal was employed to estimate GE and SIT in Swiss albino mice of either sex . The groups included were control, morphine 1 mg/kg (s.c . 15 min before test meal) alone or with (45 min before test meal p.o.) cisapride 10 mg/kg, metoclopramide 20 mg/kg, domperidone 20 mg/kg, erythromycin 6 mg/kg and mosapride 20 mg/kg . RESULTS: Cisapride, metoclopramide and mosapride were effective in enhancing gastric emptying significantly (P<0.001) whereas other prokinetic agents failed to do so in normal mice . Metoclopramide completely reversed morphine induced delay in gastric emptying followed by mosapride . Metoclopramide alone was effective when given to normal mice in increasing the SIT . Cisapride, though it did not show any significant effect on SIT in normal mice, was able to reverse morphine induced delay in SIT significantly (P<0.001) followed by metoclopramide and mosapride . CONCLUSION: Metoclopramide and cisapride are most effective in reversing morphine-induced delay in gastric emptying and small intestinal transit in mice respectively. Toxicology, 2003 May 1, 187(1), 49 - 65 Cytochrome P450 expression and testosterone metabolism in the liver of deer; Sivapathasundaram S et al.; Cytochrome P450 expression in cervine liver was investigated using chemical probes and Western blot analysis, and compared with the rat . Deer liver, when compared with rat liver, was characterised by high ethoxyresorufin O-deethylase, coumarin 7-hydroxylase and, to a lesser extent, erythromycin N-demethylase activities; in contrast, deer liver exhibited low debrisoquine 4-hydroxylase, chlorzoxazone 6-hydroxylase and, particularly, lauric acid hydroxylase activities . Ethoxyresorufin O-deethylase activity in deer was markedly inhibited by alpha-naphthoflavone, but was relatively resistant to inhibition by furafylline . Coumarin 7-hydroxylase was inhibited by 8-methoxypsoralen . Western blot analysis using antibodies to rat CYP1A recognised a single, highly expressed protein . Kinetic analysis indicated that a single enzyme is likely to be responsible for the high ethoxyresorufin O-deethylase activity in deer liver . Probing of cervine hepatic microsomes with antibodies to rat CYP2A2 showed that apoprotein levels were higher in the deer compared with the rat . Eadie-Hofstee plot analysis indicated that more than one enzyme catalyses the 7-hydroxylation of coumarin . Western blot analysis using antibodies to rat CYP2B, rat CYP2C11, human CYP2D6, rat CYP3A and rat CYP4A1 revealed in each case the presence of single, poorly expressed, proteins in deer liver . In contrast, when antibodies to rat CYP2E1 were used, a highly expressed single protein was observed . Cervine hepatic microsomes metabolised testosterone to generate androstenedione and a number of hydroxylated products, the major hydroxylation sites being the 2beta-, 6beta- and possibly the 12-position . In summary, this is the first study showing that deer liver expresses all xenobiotic-metabolising cytochrome P450 families, but the level of expression differs from that of the rat . Int J Gynaecol Obstet, 2003 Apr, 81(1), 41 - 5 Management of non-neoplastic ovarian cysts with sclerotherapy; Kafali H et al.; OBJECTIVE: To evaluate sclerotherapy with alcohol and erythromycin in the management of simple ovarian cysts . METHODS: Twenty-four simple ovarian cysts were subjected to sclerotherapy with alcohol and erythromycin . All procedures were performed under local anesthesia and in an outpatient setting . Cytological examination was carried out in all cases and two patients were excluded from the study because of suspicious cytological results . The patients were followed up monthly with color Doppler sonography for more than 12 months . RESULTS: Cyst fluid was serous in 17 cases and dark-chocolate colored in seven cases . The volume of aspirated fluid ranged from 100 to 220 ml . The size of ovarian masses and cyst-wall thickness ranged from 5.5 to 8.5 cm and 1.5 to 5 mm, respectively . Cytological analysis of 15 cysts revealed acellular sediment, seven cysts were compatible with endometrioma, and two were reported as suspicious . During the 12-month follow-up, seven cyst recurrences were detected . CONCLUSION: Aspiration and sclerotherapy with alcohol and erythromycin are followed by a relatively high recurrence rate when the aspirate is bloody . However, patients with a simple cyst that is painful or liable to torsion could benefit from sclerotherapy . Such patients, who are at low risk for malignancy, are relieved with sclerotherapy while avoiding surgery. Cardiovasc Toxicol, 2002, 2(3), 195 - 208 Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs; Al-Wabel NA et al.; The cardiovascular effects of cisapride administered intravenously at escalating doses with and without pretreatment with erythromycin were evaluated in morphine/chloralose anesthetized dogs . Dogs were instrumented to permit simultaneous recording of ECGs, left ventricular (LVP) and aortic (AoP) pressures, as well as programmed electrical stimulation (PES) . Escalating intravenous doses of cisapride from 2 to 8 mg/kg (four times the recommended therapeutic dose) increased the heart rate (HR) and prolonged the corrected QT interval (QTc) (p < 0.05) compared to controls . Pretreatment with erythromycin failed to enhance the effect of cisapride on either HR or QTc . Cisapride with or without erythromycin pretreatment had no effect on AoP, but depressed indices of left ventricular contractility (dP/dt(max) decreased while PEP/ET increased) compared to controls . No dogs developed spontaneous arrhythmias, and arrhythmias were not inducible by PES . Cisapride with or without erythromycin pretreatment altered the orientation of the T-wave vector (p < 0.05) compared to controls, indicating a primary effect of cisapride on ventricular repolarization . The QTc and T wave changes observed were consistent with the known action of cisapride on canine I(Kr) channels. J Huazhong Univ Sci Technolog Med Sci, 2002, 22(2), 144 - 7 The effects of cholecystojejunostomy and biliary drainage on biliary motor; Zheng Q et al.; Simulating physiological neuronal and hormonal conditions during digestive and interdigestive periods, the study identified the changes of the motility of biliary system including bile duct and sphincter of Oddi (SO) before and after cholecystojejunostomy . Thirty-five rabbits were divided into five groups randomly . The experimental groups received the venous injection of CCK 10 ng/kg, erythromycin 10 mg/kg, atropine 3 micrograms/kg and L-NAME 10 mg/kg respectively . Each rabbit underwent manometry through introducing a three-lumen catheter via the papilla retrogradely, using the low-compliance papillary infusion system . Then the gallbladder and the upper segment of the jejunum was anastomosed and the manometric procedures repeated after one week . SO basal pressure was increased, contraction amplitude decreased, contraction time shortened after cholecystojejunostomy . L-NAME, CCK and erythromycin could all excite SO . L-NAME could increase basal pressure and contraction amplitude, CCK increase basal pressure contraction amplitude and frequency, and erythromycin increase contraction amplitude, respectively . But comparing with that before cholecystojejunostomy, the increasing extent was decreased . The tensional and spontaneous contractions of the SO were under the control of the neural and hormonal mechanism . The anastomosis of gallbladder and jejunum and the drainage of bile made the tensional contraction stronger, but the spontaneous contraction weakened after the operation due to the decreases of the sensitivity of SO to hormonal factors . The clinical symptoms may not be relieved when the patients with SO dysfunction accepted cholecystojejunostomy. Cardiovasc Drugs Ther, 2002 Jul, 16(4), 327 - 33 The influence of magnesium on the electrophysiological effects of erythromycin in the isolated Guinea pig heart; Lueger A et al.; There have been several case reports that erythromycin can prolong the QT interval, resulting in torsades de pointes . As magnesium is well established in the treatment of torsades de pointes, we aimed to investigate how this trace element influences the electrophysiological effects of erythromycin . The effects of erythromycin and magnesium on cardiac conduction and refractoriness were evaluated in isolated guinea pig hearts perfused by the method of Langendorff . Erythromycin was given in concentrations of 10, 30 and 100 microM . In the magnesium group MgSO4 was elevated to 3.4 mM . Magnesium at a concentration of 3.4 mM did not affect cardiac conduction and refractoriness . Erythromycin prolongs the QT interval in a dose-dependent manner . The prolongation of the QT interval by erythromycin was diminished by the elevated magnesium concentration (3.4 mM) at high rates (pacing cycle length 180 vs . 220 ms) . The most pronounced effect of erythromycin (100 microM) was the prolongation of the atrial effective refractory period . This effect was nearly abolished by the elevated magnesium concentration (129.0 +/- 8.3% vs . 41.9 +/- 10.6%, P < 0.01, n = 6, x +/- SEM) . In summary, magnesium minimizes the effects of erythromycin on the repolarization period in the ventricle and on the effective refractory period of the atrium. Nihon Kokyuki Gakkai Zasshi, 2002 Oct, 40(10), 837 - 9 {Mycoplasma pneumoniae pneumonia with a tumorous shadow on chest radiography--a case report}; Onodera A et al.; A 16-year-old woman was admitted with a 1-week history of increasing cough and fever . Chest radiography and computed tomography revealed a tumorous shadow in the right upper lung field . Serologic testing provided evidence of a Mycoplasma pneumoniae infection . The clinical findings did not improve after 3 days of minocycline treatment, or after another 3 days in which levofloxacin was administered in combination with minocycline . The patient gradually improved after treatment with erythromycin replaced the minocycline treatment . This was a rare case of Mycoplasma pneumoniae pneumonia with a tumorous shadow in the chest radiograph. Circulation, 2003 Mar 18, 107(10), 1355 - 8 Drugs that induce repolarization abnormalities cause bradycardia in zebrafish; Milan DJ et al.; BACKGROUND: Drug-induced QT prolongation and torsades de pointes remain significant and often unpredictable clinical problems . Current in vitro preclinical assays are limited by biological simplicity, and in vivo models suffer from expense and low throughput . METHODS AND RESULTS: During a screen for the effects of 100 small molecules on the heart rate of the zebrafish, Danio rerio, we found that drugs that cause QT prolongation in humans consistently caused bradycardia and AV block in the zebrafish . Of 23 such drugs tested, 18 were positive in this initial screen . Poor absorption explained 4 of 5 false-negative results, as demonstrated by microinjection . Overall, 22 of 23 compounds that cause repolarization abnormalities were positive in this assay . Antisense "knockdown" of the zebrafish KCNH2 ortholog yielded bradycardia in a dose dependent manner confirming the effects of reduction of repolarizing potassium current in this model . Classical drug-drug interactions between erythromycin and cisapride, as well as cimetidine and terfenadine, were also reproduced . CONCLUSION: This simple high-throughput assay is a promising addition to the repertoire of preclinical tests for drug-induced repolarization abnormalities . The genetic tractability of the zebrafish will allow the exploration of heritable modifiers of such drug effects. J Biol Chem, 2003 May 16, 278(20), 18695 - 701 Epub 2003 Mar 10. Multiple interactions involving the amino-terminal domain of yeast mtRNA polymerase determine the efficiency of mitochondrial protein synthesis; Rodeheffer MS et al.; The amino-terminal domain (ATD) of Saccharomyces cerevisiae mitochondrial RNA polymerase has been shown to provide a functional link between transcription and post-transcriptional events during mitochondrial gene expression . This connection is mediated in large part by its interactions with the matrix protein Nam1p and, based on genetic phenotypes, the mitochondrial membrane protein Sls1p . These observations led us to propose previously that mtRNA polymerase, Nam1p, and Sls1p work together to coordinate transcription and translation of mtDNA-encoded gene products . Here we demonstrate by specific labeling of mitochondrial gene products in vivo that Nam1p and Sls1p indeed work together in a pathway that is required globally for efficient mitochondrial translation . Likewise, mutations in the ATD result in similar global reductions in mitochondrial translation efficiency and sensitivity to the mitochondrial translation inhibitor erythromycin . These data, coupled with the observation that the ATD is required to co-purify Sls1p in association with mtDNA nucleoids, suggest that efficient expression of mtDNA-encoded genes in yeast involves a complex series of interactions that localize active transcription complexes to the inner membrane in order to coordinate translation with transcription. Can Vet J, 2003 Jan, 44(1), 65 - 6 Protein-losing enteropathy caused by Lawsonia intracellularis in a weanling foal; Bihr TP; A 5-month-old Morgan filly was presented to the Atlantic Veterinary College with a history of lethargy, fever, depression, anorexia, and dependent ventral edema . Diagnostic tests revealed severe inflammation, hypoproteinemia, and thickened small intestinal loops . Protein-losing enteropathy caused by Lawsonia intracellularis was diagnosed and treated successfully with erythromycin-rifampin. J Oral Maxillofac Surg, 2003 Mar, 61(3), 310 - 6 The efficacy of azithromycin in the treatment of acute infraorbital space infection; Al-Belasy FA et al.; PURPOSE: In this study, we aimed to evaluate the role of azithromycin in the treatment of acute infraorbital space infection . MATERIALS AND METHODS: Sixty patients (39 men and 21 women; age range, 18 to 47 years) who had acute infraorbital space infection with pain, swelling, and general malaise were included in the study . After initial surgical therapy, patients were randomly allocated to receive either 500 mg azithromycin once daily for 3 days, 250 mg erythromycin stearate every 6 hours for 3 days, or no antibiotic . Patients were assessed at the time of admission and after 1, 2, 3, and 7 days . Pain, swelling, cervical lymphadenopathy, and sublingual temperature were assessed at each visit . Data were collected, and all groups were compared for differences in pain and swelling using the Mann-Whitney U test and for differences in lymphadenopathy and sublingual temperature using Fisher's exact test . RESULTS: At the time of admission, no 2 groups were statistically different at the.05 level in relation to age, gender, and presenting clinical signs or symptoms . At days 2 and 3, patients who received azithromycin had a significant reduction in pain (P =.002 and P =.02, respectively) and swelling (P =.001 and P =.013, respectively) compared with those who received no antibiotic . At day 3, patients who received erythromycin had a significant reduction in pain (P =.03) and swelling (P =.046) compared with those who received no antibiotic . In a comparison of the patients who received azithromycin with those who received erythromycin, there was no significant difference (P >.05) in the reduction of pain at any time of the study . However, at day 2, patients who received azithromycin had a significantly greater reduction in swelling (P =.002) than those who received erythromycin . In relation to the percentage of the patients with cervical lymphadenopathy and raised sublingual temperature (>37.2 degrees C), no 2 groups were statistically different at any time of the study . After 3 days of treatment, patients who received the antibiotics were clinically improved, and all patients (n = 60 patients) reviewed after 7 days had resolution of their clinical signs and symptoms . CONCLUSION: This study emphasizes the importance of surgical drainage and proves that both azithromycin and erythromycin are effective adjunctive treatments in the therapy of relatively mild odontogenic orofacial infections . J Agric Food Chem, 2003 Mar 12, 51(6), 1534 - 8 Liquid chromatography analysis of erythromycin A in salmon tissue by electrochemical detection with confirmation by electrospray ionization mass spectrometry; Billedeau SM et al.; A rapid and sensitive method is described for the quantitation of erythromycin A (EA) in edible salmon tissue by liquid chromatography (LC) analysis using either electrochemical detection (ED) or electrospray ionization mass spectrometric (ESI/MS) detection . The salmon tissue is extracted with 10 mM ammonium formate . The extract is then purified by solid phase extraction using a hydrophilic-lipophilic balanced (HLB) polymeric-based C18 packing, followed by partitioning of EA into methylene chloride at alkaline pH, evaporation, and final dilution . The mean recoveries of EA at 50, 100, 200, and 400 ppb levels in fortified salmon tissue were 63.8 +/- 6.0 and 75.5 +/- 5.4% by LC-ED and LC-ESI/MS, respectively . There was no evidence of formation of the anhydro-EA (m/z 716) decomposition product of EA (m/z 734) that was reported to occur by other published methods. J Antimicrob Chemother, 2003 Mar, 51(3), 651 - 8 Stability and compatibility study of cefepime in comparison with ceftazidime for potential administration by continuous infusion under conditions pertinent to ambulatory treatment of cystic fibrosis patients and to administration in intensive care units; Baririan N et al.; Cefepime has been examined for stability, potential liberation of degradation products and compatibility with other drugs under conditions mimicking its potential use by continuous infusion in cystic fibrosis and intensive care patients (5-12% w/v solutions; temperatures from 20 to 37 degrees C; 1 h contact at 25 degrees C with other drugs frequently co-administered by intravenous route to these types of patients) . Ceftazidime was used as a comparator based on a previous normative study with this antibiotic for the same indications . Based on a limit of max . 10% degradation, cefepime can be considered stable for a maximum of 24 h at 25 degrees C, but for only approximately 14 h at 30 degrees C, and for <10 h at 37 degrees C . Cefepime released so far unidentified degradation products if maintained at >30 degrees C for >12 h as shown from a marked increase in pH and from the development of a strong red-purple colour . Incompatibilities were observed with erythromycin, propofol, midazolam, phenytoin, piritramide, theophylline, nicardipine, N-acetylcysteine and a concentrated solution of dobutamine . We conclude that: (i) cefepime cannot be used safely by continuous infusion if containers are kept for more than a few hours at 37 degrees C (as will be the case for cystic fibrosis patients if using portable pumps carried under clothes); (ii) caution must be exercised in intensive care patients if the temperature and co-administration of other drugs is not kept under tight control . The nature and safety of the cefepime degradation products need to be studied further. J Pharmacol Exp Ther, 2003 May, 305(2), 608 - 14 Epub 2003 Feb 11. Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor; Janovick JA et al.; We expressed a test system of wild-type (WT) rat (r) and human (h) gonadotropin-releasing hormone (GnRH) receptors (GnRHRs), including naturally occurring (13) and manufactured (five) "loss-of-function" mutants of the GnRHR . These were used to assess the ability of different GnRH peptidomimetics to rescue defective GnRHR mutants and determine their effect on the level of membrane expression of the WT receptors . Among the manufactured mutants were the shortest rGnRHR C-terminal truncation mutant that resulted in receptor loss-of-function (des(325-327)-rGnRHR), two nonfunctional deletion mutants (des(237-241)-rGnRHR and des(260-265)-rGnRHR), two nonfunctional Cys mutants (C(229)A-rGnRHR and C(278)A-rGnRHR); the naturally occurring mutants included all 13 full-length GnRHR point mutations reported to date that result in full or partial human hypogonadotropic hypogonadism . The 10 peptidomimetics assessed as potential rescue molecules ("pharmacoperones") are from three differing chemical pedigrees (indoles, quinolones, and erythromycin-derived macrolides) and were originally developed as GnRH peptidomimetic antagonists . These structures were selected for this study because of their predicted ability to permeate the cell membrane and interact with a defined affinity with the GnRH receptor . All peptidomimetics studied with an IC(50) value (for hGnRHR) <or=2.3 nM had measurable efficacy in rescuing GnRHR mutants, and within a single chemical class, this ability correlated to these IC(50) values . Erythromycin-derived macrolides with IC(50) values as high as 669.5 nM showed efficacy as rescue compounds . The ability to rescue a particular receptor was a reasonable predictor of the ability to rescue others, even across species lines, although particular mutants could not be rescued by any of the drugs tested. Antimicrob Agents Chemother, 2003 Mar, 47(3), 1047 - 51 Influence of P-glycoprotein inhibitors on accumulation of macrolides in J774 murine macrophages; Seral C et al.; The influence of inhibitors of P-glycoprotein (verapamil {VE}, cyclosporine {CY}, and GF120918 {GF}) on the cell handling of macrolides (erythromycin {ERY}, clarithromycin {CLR}, roxithromycin {ROX}, azithromycin {AZM}, and telithromycin {TEL}) was examined in J774 murine macrophages . The net influx rates of AZM and TEL were increased from 2- to 3.5-fold in the presence of these inhibitors, but their efflux was slowed only marginally . At 3 h, the inhibitors increased the levels of AZM, ERY, and TEL accumulation approximately three- to fourfold (the effect of VE, however, was lower) but did not influence CLR accumulation (the inhibitors had an intermediate behavior on ROX accumulation) . The effect was concentration dependent (half-maximal increases in the level of accumulation of AZM were obtained with GF, CY, and VE at 0.5, 5, and 10 micro M, respectively) . ATP depletion also caused an approximately threefold increase in the level of accumulation of AZM . Two inhibitors of MRP (probenecid {2.5 mM} and gemfibrozil {0.25 mM}) had no effect . Monensin (a proton ionophore) completely suppressed the accumulation of AZM in control cells as well as in cells incubated in the presence of VE, demonstrating that transmembrane proton gradients are the driving force causing the accumulation of AZM in both cases . Yet, VE did not alter the pH of the lysosomes (approximately 5) or of the cytosol (approximately 7.1) . P-glycoprotein was detected by immunostaining at the cell surface as well as in intracellular vacuoles (endosomes and lysosomes) . The data suggest that the influx of AZM, ERY, TEL, and ROX is adversely influenced by the activity of P-glycoprotein in J774 macrophages, resulting in suboptimal drug accumulation. Prescrire Int, 2003 Feb, 12(63), 8 - 11 Telithromycin: new preparation . A needless addition to the other macrolides; Oral erythromycin and symptomatic relief of gastroparesis: a systematic review; Department of Internal Medicine, St . Joseph's Hospital, Chicago, Illinois, USAOBJECTIVE: Erythromycin is a motilin agonist that greatly increases the fractional rate of gastric emptying . Although a number of studies document the efficacy of erythromycin in improving gastric emptying, little information exists concerning symptom improvement in patients with gastroparesis . The aim of this study was to review clinical trials of erythromycin to determine the efficacy of this agent in producing symptom relief in patients with gastroparesis . METHODS: A MEDLINE search from 1966 to 2001 was performed to identify all clinical trials using erythromycin in patients with gastroparesis . The search was further limited to clinical trials using symptom assessment as an endpoint . References from index citations were reviewed to identify additional studies . The search was conducted independently by two authors, and discrepancies were resolved by consensus opinion . RESULTS: Thirty-five clinical trials were identified, and five met inclusion criteria . One study each involved gastroparesis caused by surgery and systemic sclerosis . Three studies evaluated patients with diabetic or idiopathic gastroparesis . No study used symptoms as a primary endpoint . Improvement was reported in 26 of 60 (43%) patients . Individual symptom scores were available for 23 of 60 subjects in these studies, and symptom improvement was seen in 11 of 23 (48%) patients . One study compared erythromycin and metoclopromide in an open-label, crossover fashion, and found no difference between the two agents . All studies were methodologically weak and highly subject to bias . Four of five studies were open-label trials . Sample sizes in all studies were < or =13 subjects, and treatment duration was < or =4 wk in all studies . CONCLUSIONS: Although clearly a potent prokinetic, limited data exist concerning efficacy of erythromycin in treating gastroparesis . Small sample sizes, uncontrolled designs, short duration, and inadequate symptom assessment limit available studies . Well-designed trials designed to assess symptom relief in gastroparesis are needed. Eur J Drug Metab Pharmacokinet, 2002 Oct-Dec, 27(4), 281 - 7 Rapidly distinguishing reversible and irreversible CYP450 inhibitors by using fluorometric kinetic analyses; Yan Z et al.; In this study we have evaluated the reliability of a fluorescence-based method used for rapid identification of irreversible CYP inhibitors (mechanism-based inhibitors) . This was accomplished by comparing the time-dependence pattern of IC50 values from fluorometric kinetic measurements . For irreversible CYP inhibitors, IC50 values decreased as incubation proceeded . This was due to progressive inactivation of corresponding enzymes by reactive metabolites generated during the incubation . This change pattern was confirmed using a number of known irreversible CYP inhibitors, including furafylline, midazolam, erythromycin, clarithromycin, oleandomycin, 17alpha-ethynylestradiol and verapamil . The pattern was different in reversible inhibition, depending upon the compounds tested in the fluorometric kinetic assay . For some compounds, such as clotrimazole, IC50 values remained relatively stable, whereas other compounds, such as miconazole, terfenadine and ketoconazole showed a significant increase with incubation time . Monitoring tested compounds by LC-MS/MS during the incubation confirmed that increases of IC50 were probably caused by the loss of inhibitors, resulting from either metabolic degradation, or non-specific binding to microsomal proteins. Yao Xue Xue Bao, 2001 May, 36(5), 321 - 4 {Effects of 18 alpha-glycyrrhizic acid on rat liver cytochrome P450 isoenzymes and phase II transferase}; Yang J et al.; AIM: To study the effect of 18 alpha-glycyrrhizic acid (18 alpha-GL) on hepatic microsomal drug metabolizing enzymes in rats . METHODS: 18 alpha-GL (12.5, 50.0 mg.kg-1.d-1) were given i.p . to male Wistar rats for 3, 6 or 12 consecutive days . The rats were sacrificed 24 h after the last dose and the liver microsomes were prepared for analysis of cytochrome P450 (CYP) isozymes and phase II transferase activites . RESULTS: Aniline hydroxylase (CYP2E1) activities in the rats treated with 18 alpha-GL (12.5, 50.0 mg.kg-1) for 6 days decreased dose-dependently by up to 53.2%; For 3, 6 or 12 days 7-ethoxyresorufin O-deethylase (CYP1A1) activities in the rats of 50 mg.kg-1 dose group decreased time-dependently by 17.6%, 38.3% and 47.3%, respectively; Erythromycin N-demethylase (CYP3A) activities was significantly inhibited from 23.1% to 34.3% . UDP-glucuronosyltransferase activities toward 7-hydroxy-4-methylcoumarin significantly increased ranging from 19.3% to 29.9% . UDP-glucuronosyltransferase activities toward 4-phenylphenol in the rats treated with 18 alpha-GL (12.5, 50.0 mg.kg-1) for 6 days increased by 45.9% and 70.3% . Glutathione S-transferase (GST) activities in the rats treated with 18 alpha-GL (12.5, 50.0 mg.kg-1) for 6 days increased by 13.7% and 48.3% in dose-dependent manner . CONCLUSION: 18 alpha-GL inhibited rat liver microsomal cytochrome P450 while induced phase II transferase. Clin Ther, 2002 Dec, 24(12), 2126 - 36 An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme A reductase inhibitors on health care utilization: a Canadian population-based study; Einarson TR et al.; BACKGROUND: Cytochrome P450-related drug interactions can lead to adverse effects that may affect health care resource utilization . OBJECTIVE: The purpose of this study was to quantify the impact of drug interactions involving hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) on health care resource utilization . METHODS: Using the Manitoba Health Research database, we identified patients who had used statins between January 1, 1995, and March 31, 1998 . New statin users (NSUs) were those who received a first prescription for a statin after April 30, 1995; old statin users (OSUs) were those who had a statin prescription before January 1, 1995 . The number of hospitalizations, physician visits, and prescriptions, and their associated costs to the Manitoba health care system were calculated . Statin interacters were defined as users with >1 prescription for an interacting drug while receiving a statin . Interacting drugs were classified into 2 groups: group A included drugs whose levels increased as a result of the statin prescription; drugs in group B increased statin levels . The Wilcoxon rank-sum test was used to analyze differences by statin on health care resource use . RESULTS: A total of 28,705 statin users (18, 181 NSUs and 10,524 OSUs) were identified . During the study period, 24,496 (85.3%) individuals took 1 statin, 3751 (13.1%) took 2 statins, and 458 (1.6%) took 3 to 5 statins . The most common coadministered group A interacting drugs were diclofenac (5.8%), amitriptyline (4.9%), warfarin (4.5%), and ibuprofen (1.8%) . The most common group B interacting drugs were erythromycin (8.2%), omeprazole (5.5%), cimetidine (3.6%), and clarithromycin (3.5%) . Statin interacters consumed significantly more health care resources than did noninteracters for both incident and prevalent analyses (P < 0.001) . In the prevalent analysis (NSUs + OSUs), pravastatin users taking interacting drugs had significantly fewer hospitalizations (mean, 1.3), fewer physician visits (mean, 24.2), and lower health care costs (mean, 5,526 dollars) compared with prevalent users of lovastatin (1.7, 28.0, and 6,925 dollars, respectively) and fewer physician visits than simvastatin users (25.6, P < 0.001) . In the incident analysis, pravastatin users had significantly less physician visits (20.8 vs 23.5, P < 0.001) and lower health care costs (4,739 dollars vs 6,323 dollars, P < 0.001) than lovastatin users . CONCLUSION: Pravastatin was associated with fewer hospitalizations, physician visits, and overall health care resource utilization in prevalent users than lovastatin, possibly due to a lack of drug interaction effects. Br J Nutr, 2003 Feb, 89(2), 189 - 200 The combined effects of garlic oil and fish oil on the hepatic antioxidant and drug-metabolizing enzymes of rats; Chen HW et al.; This present study was designed to investigate the combined modulatory effect of garlic oil (GO) and fish oil (FO) on the antioxidant and drug metabolism systems . Rats were fed either a low-maize oil (MO) diet (50 g MO/kg), high-MO diet (235 g MO/kg) or high-FO diet (205 g FO+ 30 g MO/kg) and received different doses of GO (0-200 mg/kg body weight) three times per week for 6 weeks . Fatty acid analysis showed that 20 : 5n-3 and 22 : 6n-3 were incorporated into serum lipid at the expense of 18 : 2n-6 and 20 : 4n-6 in rats fed the high-FO diet . GO dose-dependently increased hepatic glutathione S-transferase (GST), glutathione reductase, superoxide dismutase (SOD) and ethoxyresorufin O-deethylase (EROD) activities, but decreased glutathione peroxidase and N-nitrosodimethylamine demethylase (NDMAD) activities (P<0.05) . With the exception of glutathione peroxidase, the activities of glutathione reductase, SOD, GST, EROD and NDMAD were modulated by the dietary fat . The high-FO group had greater SOD and EROD activity than either MO-fed group; it also had greater NDMAD activity than the low-MO group (P<0.05) . GST activity was higher in rats fed high-FO or high-MO diets than rats fed the low-MO diet . Change in erythromycin demethylase activity, however, was not caused by either dietary fat or GO . Immunoblot assay showed that GO dose-dependently enhanced the protein level of the Ya, Yb1, Yc isoenzymes of GST and cytochrome P450 (CYP) 1A1 and 3A1, but GO suppressed CYP2E1 expression . Regardless of the dosage of GO, the high-FO diet increased CYP1A1, CYP3A1 and CYP2E1 levels compared with the high- and low-MO diets . Accompanying the changes observed in immunoblots, CYP1A1 and CYP3A1 mRNA levels were increased by GO in a dose-dependent manner and also increased additively in combination with FO feeding . These present results indicate that co-administration of GO and FO modulates the antioxidant and drug-metabolizing capacity of animals and that the effect of GO and FO on drug-metabolizing enzymes is additive. Jpn J Antibiot, 2000 Jun, 53 Suppl B, 111 - 6 {Azithromycin in the field of dermatology}; Arata J; Azithromycin (AZM) is a new macrolides antibiotic that has a 15-membered ring structure obtained by introducing methyl-substituted nitrogen into a 14-membered ring lactone of erythromycin(EM) . This article reviewed and summarized the clinical studies in the treatment of skin and skin structure infections conducted in Japan and abroad of AZM. Curr Drug Targets Infect Disord, 2002 Dec, 2(4), 355 - 70 Natural and acquired macrolide resistance in mycobacteria; Doucet-Populaire F et al.; The genus Mycobacterium contains two of the most important human pathogens, Mycobacterium tuberculosis and Mycobacterium leprae, the etiologic agents of tuberculosis and leprosy, respectively . Other mycobacteria are mostly saprophytic organisms, living in soil and water, but some of them can cause opportunistic infections . The increasing incidence of tuberculosis as well as infections with non-tuberculous mycobacteria (NTM) in AIDS patients has renewed interest in molecular mechanisms of drug resistance in these pathogens . Mycobacteria show a high degree of intrinsic resistance to most common antibiotics . For instance, species from the M . tuberculosis complex (MTC) are intrinsically resistant to macrolides . Nevertheless, some semi-synthetic macrolides as the erythromycin derivatives clarithromycin, azithromycin and most recently the ketolides, are active against NTM, particularly Mycobacterium avium, and some of them are widely used for infection treatment . However, shortly after the introduction of these new drugs, resistant strains appeared due to mutations in the macrolide target, the ribosome . The mycobacterial cell wall with its specific composition and structure is considered to be a major factor in promoting the natural resistance of mycobacteria to various antibiotics . However, to explain the difference in macrolide sensitivity between the MTC and NTM, the synergistic contribution of a specific resistance mechanism might be required, in addition to possible differences in cell wall permeability . This mini-review summarizes the current knowledge on the natural and acquired macrolide resistance in mycobacteria, gives an overview of potential mechanisms implicated in the intrinsic resistance and brings recent data concerning a macrolide resistance determinant in the MTC. Obes Surg, 2002 Dec, 12(6), 765 - 72 The effect of erythromycin on bile excretion and proximal small bowel motility following divided gastric bypass surgery: a prospective randomized placebo-controlled trial; Wilkinson NW et al.; BACKGROUND: No conclusive data exists supporting the use of any prokinetic agent in the postoperative setting . The study was designed to examine the effect of erythromycin on small bowel motility in a placebo-controlled trial of post gastric bypass patients utilizing a standardized nuclear medicine test . METHODS: A consecutive series of 21 patients undergoing elective gastric bypass surgery for morbid obesity between September 1999 and March 2001 were enrolled in this prospective double-blind randomized controlled trial . Standard open, divided gastric bypass was performed . Patients were randomized to receive either erythromycin 250 mg i . v . (11 patients) or placebo (10 patients) every 8 hours . On postoperative day 2, a hepatic iminodiacetic acid (HIDA) scan was obtained . Tracer movement through the biliary tree and proximal small bowel was quantified and compared . RESULTS: Tracer clearance from the liver and biliary tree was no different between groups from time of injection through 1 hour . Tracer material clearance from the duodenum into the jejunum was no different between the erythromycin and control groups at 1 hour, 37% +/- 13% and 37% +/- 22% respectively (P = 0.95) . At 4 hours, clearance was greater in the erythromycin group, 77% +/- 6%, compared to control, 60% +/- 20% (P = 0.036) . The rate of tracer change between hour 1 and 4 (slope) was steeper in the erythromycin group (P = 0.048) . CONCLUSIONS: Erythromycin increases intestinal transit in the postoperative setting. Yao Xue Xue Bao, 2002 Oct, 37(10), 753 - 7 Effects of dimethyl diphenyl bicarboxylate on the metabolism and hepatotoxicity of aflatoxin B1 in rats; Lu H et al.; AIM: To study the effect of antihepatitis drug, dimethyl diphenyl bicarboxylate (DDB) on the metabolism and hepatotoxicity of aflatoxin B1(AFB1) in rats . METHODS: Rats were given orally DDB 300 mg.kg-1.d-1 for 3 days and then injected intraperitioneally with AFB1 1.5 mg.kg-1 . Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were examined 16 hours after the injection of AFB1 . The in vitro metabolism of AFB1 by DDB-pretreated rat liver microsome was investigated by HPLC assay . RESULTS: DDB (300 mg.kg-1) pretreatment provided significant protection against AFB1 hepatotoxicity as evidenced by the decrease of AFB1-elevated serum marker enzymes in rats . Pretreatment with DDB was shown to slightly increase the level of AFM1, the less toxic metabolite . DDB significantly increased the liver cytochrome P450 content, P450 isozyme 2B1-mediated 7-pentoxyresorufin O-dealkylase (PROD) activity, cytosolic glutahione (GSH) level and GSH S-transferase (GST) activities . In addition, DDB slightly increased P450 isozymes, 3A-mediated erythromycin-demethylase and 1A-mediated 7-ethoxyresorufin O-deethylase (EROD) activities . CONCLUSION: The results indicate that DDB protected rats against AFB1 hepatotoxicity by increasing the detoxifying metabolism of AFB1 in the liver. Dermatology, 2003, 206(1), 37 - 53 Update and future of systemic acne treatment; Zouboulis CC et al.; Systemic treatment is required in patients with moderate-to-severe acne, especially when acne scars start to occur . Antibiotics with anti-inflammatory properties, such as tetracyclines (oxytetracycline, tetracycline chloride, doxycycline, minocycline and limecycline) and macrolide antibiotics (erythromycin and azithromycin) are the agents of choice for papulopustular acne, even though the emerging resistant bacterial strains are minimizing their effect, especially regarding erythromycin . Systemic antibiotics should be administered during a period of 8-12 weeks . In severe papulopustular and in nodulocystic/conglobate acne, oral isotretinoin is the treatment of choice . Hormonal treatment represents an alternative regimen in female acne, whereas it is mandatory in resistant, severe pubertal or post-adolescent forms of the disease . Compounds with anti-androgenic properties include estrogens combined with progestins, such as ethinyl estradiol with cyproterone acetate, chlormadinone acetate, desogestrel, drospirenone, levonogestrel, norethindrone acetate, norgestimate, and other anti-androgens directly blocking the androgen receptor (flutamide) or inhibiting androgen activity at various levels, corticosteroids, spironolactone, cimetidine, and ketoconazole . After 3 months of treatment control of seborrhea and acne can be obtained . Low-dose corticosteroids (prednisone, prednisolone, or dexamethasone) are indicated in patients with adrenal hyperandrogenism or acne fulminans . New developments and future trends represent low-dose long-term isotretinoin regimens, new isotretinoin formulations (micronized isotretinoin), isotretinoin metabolites, combination treatments to reduce toxicity, insulin-sensitizing agents, 5alpha-reductase type 1 inhibitors, antisense oligonucleotide molecules, and, especially, new anti-inflammatory agents, such as lipoxygenase inhibitors . J Med Assoc Thai, 2002 Nov, 85 Suppl 4, S1177 - 82 Oral erythromycin for treatment of feeding intolerance in preterm infants: a preliminary report; Sekteera W et al.; Feeding intolerance is a common problem in preterm infants resulting in a prolonged hyperalimentation which is associated with an increased risk of serious and sometimes even life threatening complications, including cholestasis jaundice, liver impairment, nutritional deficiency, biochemical rickets and catheter-related septicaemia . Erythromycin, a commonly used macrolide antibiotic, has been reported as having potent prokinetic properties and enhancing gastrointestinal motor activity . The authors, therefore, conducted a preliminary study of oral erythromycin for the treatment of feeding intolerance in preterm infants to evaluate the safety and efficacy of this drug . AIM: To evaluate the safety and efficacy of oral erythromycin as a prokinetic agent in promoting enteral feeding in preterm infants with feeding intolerance . METHOD: Preterm infants, gestational age (GA) < or = 36 wk, who met the feeding intolerance criteria, were enrolled in the study . Inclusion criteria included infants who received enteral feeding less than half of full feeding or less than 75 ml/kg/day by day 14 post-natal age or gastric residual > or = 50 per cent of a given amount of feeding, more than 2 consecutive feeds by day 7 post-natal age . All patients received oral erythromycin ethylsuccinate 12 mg/kg every six hours for 2 days, then 3 mg/kg every six hours for 5 days . The times taken to establish full enteral feeding after the drug treatment and time to stop hyperalimentation were recorded . Potential adverse effects of erythromycin were assessed . Response to treatment was defined as decreased gastric residual < 30 per cent of a similar amount of the previous feed and was able to continue to full feeding . RESULTS: Ten preterm infants were enrolled in this study with a mean GA of 30.8 weeks (26-35), mean birth weight of 1,489 g (range 900-2,560 g) and mean age at entry of 9.2 days (range 7-12 days) . Nine of 10 infants responded to treatment within 24 hours . The average time to establish full enteral feeding after the drug treatment was 6.6 days (range 4-10 days) . None of the infants developed adverse effects such as vomiting, diarrhea, or pyloric stenosis . CONCLUSION: The preliminary data indicates that oral erythromycin is effective and safe in facilitating enteral feeding in preterm infants with feeding intolerance . Infants can achieve full feeding within a week after treatment, and this may shorten the course of hyperalimentaiton . Further randomized controlled trials are warranted. Trans Am Ophthalmol Soc, 2002, 100, 61 - 5; discussion 65-6 The dehiscent Hughes flap: outcomes and implications; Bartley GB et al.; PURPOSE: The modified Hughes procedure is used to reconstruct full-thickness lower eyelid defects . A tarsoconjunctival flap from the upper eyelid replaces the posterior lamella, whereas a skin graft, a skin flap, or a skin-muscle flap restores the anterior lamella . The conjunctival pedicle from the upper eyelid is divided after vascularization of the reconstructed lower eyelid is judged to be adequate (traditionally, at least 3 weeks postoperatively) . This study reviews the outcomes of patients in whom the conjunctival flap prematurely dehisced . METHODS: Eight patients were identified during a 15-year interval . The posterior lamellar defects ranged in size from 13 to 30 mm horizontally and 5 to 8 mm vertically . The average age at the time of eyelid reconstruction was 72 years (range, 60-84 years) . Flap dehiscence, resulting in each case from accidental trauma, occurred between 1 and 11 days postoperatively . Surgical repair of the dehiscence was unsuccessfully attempted in one case; otherwise, the eyelids were permitted to heal spontaneously with the application of erythromycin ophthalmic ointment as the sole therapy . RESULTS: Although the result was satisfactory in each case, one patient, who had dry eyes from Sjogren's syndrome, required secondary surgery to treat mild lagophthalmos and lower eyelid retraction . Follow-up ranged from 3 to 122 months (median, 6.5 months) . CONCLUSIONS: The ultimate functional and aesthetic outcomes after premature, traumatic dehiscence of a Hughes flap were surprisingly good, suggesting that elective division of the conjunctival pedicle in routine cases can be performed relatively soon after the primary reconstructive procedure. Crit Care Med, 2003 Jan, 31(1), 39 - 44 Intravenous erythromycin facilitates bedside placement of postpyloric feeding tubes in critically ill adults: a double-blind, randomized, placebo-controlled study; Griffith DP et al.; OBJECTIVE To evaluate the efficacy of intravenous erythromycin as a method to facilitate feeding tube placement into the small intestine in critically ill patients.DESIGN Double blind, randomized, controlled trial.SETTING Medical and surgical intensive care units in an academic medical center.PATIENTS Prospective cohort of 36 consecutive adults requiring intensive care unit care and enteral tube feeding for nutritional support.INTERVENTION Infusion of a single dose of intravenous erythromycin (500 mg) or saline before placement of 10-Fr feeding tubes using a standardized active bedside protocol.MEASUREMENTS AND MAIN RESULTS We determined the success rate of feeding tube placement into or beyond the second portion of the duodenum and the time required for this procedure by experienced nurses . The feeding tube was considered to be postpyloric when the tip was in the second portion of the duodenum or beyond . The predictive value of a serial step-up in gastrointestinal aspirate pH from < or = 5.0 to > or = 6.0 was also determined . Use of intravenous erythromycin significantly improved the rate of feeding tube placement into the duodenum or jejunum (erythromycin group, 13 of 14 patients or 93% vs . the control group, 12 of 22 patients or 55%; p < .03) . Erythromycin administration also significantly decreased the procedure time from 25 +/- 3 to 15 +/- 2 mins (p < .04) . Feeding tube placement into either duodenum or jejunum was confirmed in all 18 patients with a pH step-up from < or = 5.0 to > or = 6.0 . CONCLUSION: A single bolus dose of intravenous erythromycin facilitates active bedside placement of postpyloric feeding tubes in critically ill adult patients. Hunan Yi Ke Da Xue Xue Bao, 2001 Feb 28, 26(1), 62 - 4 {Classification of urogenital tract infection in 518 cases and drug sensitivity analysis}; Li BH et al.; In 518 cases with urogenital tract infection detected with mycoplasma identification susceptibility testing reagent box, 308 cases (59.4%) were infected by ureaplasma urealyticum (Uu), 21 cases (4.1%) were infected by mycoplasma hominis (Mh), and 189 cases (36.5%) were infected by both Uu and Mh . Drug sensitivity to the macrolides (erythromycin, roxithromycin, josamycin, azithromycin), the tetracyclines (doxycycline, minocin), and the quinolines (ofloxacin, ciprofloxacin) were detected at the same time . The results showed that the sensitivity to various antibiotics in Uu infection was different from that in Mh infection . Macrolides were more sensitive for Uu infection, and quinolines were more sensitive for Mh infection, while the mixed infection of Mh and Uu had resistance to most antibiotics. Cochrane Database Syst Rev . 2003;(1):CD002086. Minocycline for acne vulgaris: efficacy and safety; Garner SE et al.; BACKGROUND: Minocycline is a tetracycline antibiotic that is commonly used in the treatment of moderate to severe acne vulgaris . Although it is more convenient for patients to take than first-generation tetracyclines, as it only needs to be taken once or twice a day and can be taken with food, it is more expensive . Concerns have also been expressed over its safety following the deaths of two patients taking the drug . There is a lack of consensus among dermatologists over the relative risks and benefits of minocycline . As most acne prescribing is undertaken by general practitioners, it is important that guidelines issued to them are based on the best available evidence rather than personal judgements . OBJECTIVES: To collate and evaluate the evidence on the clinical efficacy of minocycline in the treatment of inflammatory acne vulgaris . Specific objectives were to compare the efficacy of minocycline with other drug treatments for acne and to collate information on the incidence of adverse drug reactions . SEARCH STRATEGY: Randomised controlled trials (RCTs) of minocycline for acne vulgaris were identified by searching the following electronic databases; MEDLINE, EMBASE, Biosis, Biological Abstracts, International Pharmaceutical Abstracts, Cochrane Skin Group's Trial Register, Theses Online, BIDS ISI Science Citation Index, National Research Register, Current Controlled Trials and Bids Index to Scientific and Technical Proceedings . Other strategies used were scanning the references of articles retrieved, hand-searching of major dermatology journals and personal communication with trialists and drug companies . SELECTION CRITERIA: To be eligible for the review, studies had to be RCTs comparing the efficacy of minocycline at any dose to active or placebo control, in subjects with inflammatory acne vulgaris . Diagnoses of papulo-pustular, polymorphic and nodular acne were also accepted . Trials were not excluded on the basis of language . DATA COLLECTION AND ANALYSIS: 27 randomised controlled trials met the inclusion criteria and were included in this review . The comparators used were placebo (2 studies), oxytetracycline (1), tetracycline (6), doxycycline (7), lymecycline (2), topical clindamycin (3), topical erythromycin/zinc (1), cyproterone acetate/ ethinyloestradiol (1), oral isotretinoin (2), topical fusidic acid (1) and there was one dose response study . Two studies are ongoing and it remains to be clarified whether one further study is a RCT . Major outcome measures used in the trials included lesion counts, acne grades/severity scores, doctors' and patients' global assessments, adverse drug reactions and drop out rates . The quality of each study was assessed independently by two assessors and an effect size calculated where possible . An additional three RCTs and three safety studies were identified by searches conducted in November 2002; these will be reviewed for a major update in early 2003 when it is anticipated that the results of the two ongoing studies will be available . MAIN RESULTS: The trials were generally small and of poor quality and in many cases the published reports were inadequate for our purpose . Pooling of the studies was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data . Although minocycline was shown to be an effective treatment for acne vulgaris, in only two studies was it found to be superior to other tetracyclines . Both of these were conducted under open conditions and had serious methodological problems . A third study showed it to be more effective than 2% fusidic acid, applied topically, against inflammatory lesions in mild to moderate acne . Differences in the way adverse drug reactions were identified could have accounted for the wide variation between studies in numbers of events reported . This meant that no overall evaluation could be made of incidence rates of adverse events associated with minocycline therapy . No RCT evidence was found to support the benefits of minocycline in acne resistant to other therapies and the dose response has only been evaluated up to eight weeks of therapy . REVIEWER'S CONCLUSIONS: Minocycline is likely to be an effective treatment for moderate acne vulgaris, but this review found no reliable RCT evidence to justify its continued use first-line, especially given the price differential and the concerns that still remain about its safety . Its efficacy relative to other acne therapies could not be reliably determined due to the poor methodological quality of the trials and lack of consistent choice of outcome measures . Similarly the relative risk of adverse drug reactions could not be ascertained reliably and no recommendations can be made concerning the appropriate dose that should be used . It is hoped that this review will highlight the inadequacy of acne trials in general and encourage improvements in methodological quality and standards of reporting. Br J Clin Pharmacol, 2003 Jan, 55(1), 86 - 93 Effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function; Orlando R et al.; AIMS: The objectives of this study were: (i) to evaluate the effect of a cytochrome P450 (CYP) 3A4 inhibitor, erythromycin, on the pharmacokinetics of intravenous lignocaine and its two pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX); (ii) to assess whether the effects of the erythromycin inhibitory action on lignocaine clearance and the results of the MEGX liver function test depend on liver functional status; and (iii) to determine the effects of both moderate and severe liver dysfunction on the disposition kinetics of lignocaine . METHODS: The study was carried out on 10 healthy volunteers, and 10 Child's class A and 10 class C cirrhotic patients, according to a double-blind, randomized, two-way crossover design . On day 1 of the investigation, all subjects received three oral doses of erythromycin (600 mg of the ethylsuccinate ester) or placebo, and two further doses on day 2 . One hour after the fourth dose, subjects were given 1 mg kg-1 lignocaine intravenously . Timed plasma samples were then obtained until 12 h for determination of the concentrations of lignocaine, MEGX and GX . RESULTS: Erythromycin caused statistically significant, although limited, modifications of lignocaine and MEGX pharmacokinetic parameters . In healthy volunteers, lignocaine clearance was decreased from 9.93 to 8.15 ml kg-1 min-1{mean percentage ratio (95% CI), 82 (65-98)} and the half-life was prolonged from 2.23 to 02.80 h {mean percentage ratio (95% CI), 130 (109-151)}; MEGX area under the concentration-time curve from 0 h to 12 h was increased from 665 to 886 ng ml-1 h {mean percentage ratio (95% CI), 129 (102-156)} . Quantitatively similar modifications were observed in the two cirrhotic groups . GX concentrations were lowered in all study groups, although not to statistically significant extents . Erythromycin coadministration caused no appreciable interference with the results of the MEGX test . Only in patients with Child's grade C liver cirrhosis were lignocaine kinetic parameters significantly altered with respect to healthy volunteers . Thus, clearance was approximately halved, steady-state volume of distribution was increased, and terminal half-life was more than doubled . CONCLUSIONS: Although erythromycin only modestly decreases lignocaine clearance, it causes a concomitant elevation of the concentrations of its pharmacologically active metabolite MEGX . A pharmacodynamic study following lignocaine infusion to steady state appears necessary to assess the actual clinical relevance of these combined effects . The degree of liver dysfunction has no influence on the extent of the erythromycin-lignocaine interaction, whereas it markedly influences the extent of the changes in lignocaine pharmacokinetics . These findings indicate that no dose adjustment is needed in patients with moderate liver cirrhosis, whereas the lignocaine dose should be halved in patients with severe cirrhosis. Biotechnol Bioeng, 2003 Mar 20, 81(6), 640 - 9 Modeling the performance of pilot-scale countercurrent chromatography: scale-up predictions and experimental verification of erythromycin separation; Booth AJ et al.; Biosynthesis of polyketide antibiotics, such as erythromycin A (EA), can result in the formation of analogues of the main compound that are chemically and structurally extremely similar . The large-scale purification of these antibiotics by conventional high-performance liquid chromatography (HPLC) can be prohibitively expensive due to the large volume of both solvent and adsorbent required . This study examines the feasibility of using a novel pilot-scale countercurrent chromatography (CCC) machine as an alternative to HPLC . CCC is a low-pressure (typically <4000 kN m(-2)) liquid-liquid chromatographic technique that allows the separation of solutes on the basis of their partitioning between two immiscible liquid phases . The effects of mobile phase flow rate, column rotational speed, and sample injection volume on the attainable yield and purity of EA were investigated . Our results show that, at a mobile phase flow rate of 40 mL min(-1), a rotational speed of 1200 rpm, and an injection volume of 100 mL (10 g total erythromycin), EA could be satisfactorily fractionated with a purity of approximately 92% (w/w) and a recovery yield of approximately 100% (w/w) . The total solute throughput was estimated to be 0.41 kg day(-1) . More importantly, we demonstrated simple and predictive linear scale-up of the CCC separation based on data obtained from a single laboratory-scale CCC chromatogram, and verified this experimentally . The retention time and peak width of the target compound at the pilot scale could be predicted to within 4% for operation at a range of mobile-phase flow rates and injection volumes . This predictable nature of CCC separations, unlike HPLC methods, can greatly reduce process development times and enable a complete process-scale operating scenario to be planned . J Comb Chem, 2003 Jan-Feb, 5(1), 67 - 72 Synthesis and screening of a molecularly imprinted polymer library targeted for penicillin G; Cederfur J et al.; A library of molecularly imprinted polymers (MIPs) was synthesized by radical bulk polymerization using the beta-lactam antibiotic penicillin G as the template . Diversity of the library was obtained by combining various functionalized monomers and cross-linkers and by varying the stoichiometry and the concentration of the components in the prepolymerization mixtures . The library was screened for selectivity to penicillin G by a radioligand binding assay and was compared to a corresponding control library . The best MIP candidate, showing the highest selectivity for penicillin G, was prepared from methacrylic acid and trimethylolpropane trimethacrylate as the functionalized monomer and cross-linker, respectively . Cross-reactivity studies with other beta-lactam antibiotics showed a low cross-reactivity of penicillin V (15%), ampicillin (16%), and amoxicillin (19%) . Nafcillin and oxacillin showed less cross-reactivity (<1%) . Cross-reaction with a cephalosporin antibiotic (cephapirin) and structurally nonrelated antibiotics (chloramphenicol, tetracycline, dapsone, and erythromycin) was less than 0.01%. Pharmacotherapy, 2003 Jan, 23(1), 5 - 8 Erythromycin accelerates gastric emptying in a dose-response manner in healthy subjects; Boivin MA et al.; STUDY OBJECTIVES: To evaluate whether a dose-response curve exists for erythromycin, determine the lowest effective dose of erythromycin needed to improve gastric motility, and compare erythromycin's effectiveness with that of metoclopramide in improving gastric emptying . DESIGN: Randomized, crossover, multiintervention trial . SETTING: Inpatient clinical research center . SUBJECTS: Ten healthy volunteers (four men, six women) from the general population . INTERVENTION: On each study day, the subjects were infused with erythromycin 0.75 mg/kg, 1.5 mg/kg, or 3.0 mg/kg; metoclopramide 10 mg; or placebo, in random order . Subjects then drank Ensure 200 ml mixed with acetaminophen 1.5 g . Gastric emptying was estimated by comparing the area under the curve after 60 minutes for acetaminophen absorption using four timed blood draws . MEASUREMENTS AND MAIN RESULTS: Erythromycin increased gastric emptying in a dose-response manner . Erythromycin 3.0 mg/kg and metoclopramide 10 mg were associated with statistically significant increases in liquid gastric emptying compared with placebo . During infusion, nausea and stomach cramping were associated with the 3.0-mg/kg dose of erythromycin; drowsiness was associated with metoclopramide . CONCLUSION: In patients requiring intravenous erythromycin for gastric motility, the 3.0-mg/kg dose seems the most effective, with a reasonable side effect profile. Clin Infect Dis, 2003 Jan 15, 36(2), 225 - 8 Epub 2002 Dec 31. Pneumonitis associated with Ureaplasma urealyticum in children with cancer; Buckingham SC et al.; We describe 3 pediatric patients with cancer who had clinical and radiographic evidence of pneumonitis and for whom cultures of bronchoalveolar lavage fluid specimens yielded Ureaplasma urealyticum . Two of the patients died; for the surviving patient, clinical improvement coincided temporally with administration of erythromycin . Immunocompromised patients with pneumonitis of unclear etiology should have respiratory secretions cultured for mycoplasmas and should receive empiric therapy that includes a macrolide antibiotic. Curr Treat Options Gastroenterol, 2003 Feb, 6(1), 3 - 11 Small Bowel Diverticulosis: An Overlooked Entity; Gross SA et al.; Small bowel diverticulosis (SBD) is a rare entity . Most cases of diverticulosis are asymptomatic . SBD is often discovered incidentally during contrast studies and endoscopy . When patients report chronic gastrointestinal symptoms such as abdominal pain, bloating, flatulence, and anemia, SBD is often an overlooked diagnosis . Patients requiring treatment for SBD are those with complications such as malabsorption, hemorrhage, obstruction, and acute inflammation with abscess or rarely perforation . Malabsorption can be managed with broad-spectrum antibiotics and vitamin supplementation . Hemorrhage is treated conservatively with resuscitation efforts, but recurrent bleeding requires surgery . Enteroliths causing obstruction in the duodenum can be relieved by endoscopy, that is, by manipulation, but jejunoileal obstruction requires a resection . Pseudo- obstruction may be managed with prokinetics such as metoclopramide, erythromycin, and the 5-hydroxytryptamine 4 agonist tegaserod . Uncomplicated cases of SBD are treated with bowel rest and antibiotics . However, perforation or abscess formation not amenable to percutaneous drainage mandates surgical resection . Any patient with a triad of anemia, abdominal pain, and an abdominal radiograph with dilated loops of small bowel merits SBD in the differential diagnosis. J Clin Microbiol, 2003 Jan, 41(1), 428 - 31 Phenotypes and genotypes of erythromycin-resistant pneumococci in Italy; Montanari MP et al.; Of 120 erythromycin-resistant pneumococci isolated in Italian hospitals, 39 (32.5%) were M-type isolates, carrying the mef gene alone . The mef gene was also detected, together with erm(AM), in one constitutively resistant isolate and in five isolates of the partially inducible phenotype . Among the 45 mef-positive isolates, 25 (55.6%) carried mef(A) and 20 (44.4%) carried mef(E) as observed from PCR-restriction fragment length polymorphism analysis of a 1,743-bp amplicon . The same result was obtained by a similar method applied to a more common 348-bp amplicon. Circulation, 2003 Jan 7, 107(1), 32 - 7 Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction; Lau WC et al.; BACKGROUND: We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing . Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4 . METHODS AND RESULTS: Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer . Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner . Percent platelet aggregation was 34+/-23, 58+/-15 (P=0.027), 74+/-10 (P=0.002), and 89+/-7 (P=0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively . Erythromycin attenuated platelet aggregation inhibition (55+/-12 versus 42+/-12% platelet aggregation; P=0.002), as did troleandomycin (78+/-18 versus 45+/-18% platelet aggregation; P<0.0003), whereas rifampin enhanced platelet aggregation inhibition (33+/-18 versus 56+/-20% platelet aggregation, P=0.001) . CONCLUSIONS: CYP3A4 activates clopidogrel . Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation . Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel. Encephale, 2002 Nov-Dec, 28(6 Pt 1), 567 - 9 {Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs}; Senechal A et al.; Clozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia . However, according to different epidemiological studies clozapine can induce neutropenia in less than 3% of patients and may represent a major problem for the management of treatment-resistant patients not responding to conventional or other atypical antipsychotics . Recently, a few case of neutropenia have been reported following the addition of other medications to clozapine, notably paroxetine, risperidone, trimethoprim-sulfamethoxazole and erythromycin . In our report we present the case of Mr A., a 40-year-old Caucasian patient with a 20-year history of paranoid schizophrenia . After numerous trials with conventional antipsychotics, partial remission of psychotic symptoms was obtained with clozapine . Over the past eight years during his treatment with clozapine, the patient presented 2 episodes of neutropenia . The first episode came five years after starting clozapine and was attributed to the addition 6 weeks earlier of haloperidol (2 mg/day) to clozapine (250 mg/day) and divalproex (1,500 mg/day) . Recently, one week after the addition of risperidone (2 mg/day) to clozapine (550 mg/day), leukocytes count dropped from 12 100/mm(3) to 5 700/mm(3) and neutrophils from 7 400/mm(3) to 900/mm(3) . The patient was also taking haloperidol (4 mg/day), methotrimeprazine (35 mg/day), procyclidine (5 mg/day) and valproic acid (1,500 mg/day) . Twelve days after discontinuation of risperidone, leukocytes and neutrophils count increased to 11,100/mm(3) and 6,300/mm(3) respectively while the treatment with clozapine was continued . The first eighteen weeks of treatment represent the period where the risk of neutropenia is the highest . In our patient neutropenia occurred 5 and 7 years after starting clozapine . It is proposed that the two neutropenic episode were precipitated by adding respectively haloperidol and risperidone to clozapine . Also, divalproex can potentially cause a decrease in white blood cell count and may have contributed to the two neutropenic episode . It is suggested that drug interactions may be responsible for neutropenia in clozapine treated patients and that clozapine should not necessarily be discontinued in the presence of neutropenia . Also we propose that hematological surveillance should be done on a weekly basis for 4 to 6 weeks following the addition of psychotropic drugs known for their potential to cause neutropenia when associated with clozapine . Therefore polypharmacy may contribute to cause neutropenia in clozapine treated patients and that discontinuation of an antipsychotic should be done before introducing another one. J Cardiovasc Pharmacol, 2003 Jan, 41(1), 14 - 24 Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: importance of triangulation, reverse use dependence, and instability; Hondeghem LM et al.; Drug-induced proarrhythmia is a rare but potentially lethal adverse drug reaction . To test whether the SCREENIT system (an automated computerized test apparatus), using an isolated perfused heart obtained from female rabbits, could correctly identify agents that lengthen the action potential duration (APD) and drugs known to induce proarrhythmia, 14 drugs (penicillin G, haloperidol, adriamycin, indapamide, verapamil, aspirin, lidocaine, clomipramine, propranolol, erythromycin, quinidine, terfenadine, amiodarone, and thioridazine) were coded and submitted for a blinded test . Of these drugs, eight are reported to induce QT prolongation in the clinic (adriamycin, clomipramine, quinidine, amiodarone, and thioridazine), while three do not lengthen and three shorten the QT . To test for reproducibility, four drugs were given in duplicate (haloperidol, aspirin, erythromycin, and terfenadine) . The drug effects on monophasic APD, conduction, instability (index of variability of APD), triangulation (index of duration of fast repolarization), and reverse use dependence were measured at five drug concentrations (0.05, 0.15, 0.5, 1.5, and 5 mg/l) . All 14 blinded drugs, in the concentrations used, were correctly identified as to their effects on APD and conduction . The drugs eliciting drug-induced proarrhythmia in patients were also identified as promoting instability, triangulation, and reverse use dependence in the rabbit heart . Importantly, none of the safe agents was labeled as proarrhythmic, and the results were very consistent between duplications . In conclusion, SCREENIT correctly identifies prolongation of APD, accurately separates safe agents form proarrhythmic drugs, and has highly reproducible results . Thus, the isolated perfused rabbit heart can be a valuable tool in a preclinical proarrhythmia test battery in drug development. Antimicrob Agents Chemother, 2003 Jan, 47(1), 48 - 53 Fourteen-member macrolides promote the phosphatidylserine receptor-dependent phagocytosis of apoptotic neutrophils by alveolar macrophages; Yamaryo T et al.; An inflammation of the airway of patients with diffuse panbronchiolitis (DPB), is characterized by dense neutrophil infiltration . Resolution of the inflammation can be achieved by the removal of apoptotic n