Erythromycin

Zhonghua Liu Xing Bing Xue Za Zhi, 2001 Aug, 22(4), 293 - 5
{Clinic intervention study on urogenital mycoplasma infection of pregnant women}; Ye Y et al.; OBJECTIVE: To explore the hypothesis of pathogenic relationship between urogenital mycoplasma infection and adverse perinatal outcomes . METHODS: Four hundred and eighty-eight mycoplasma-positive pregnant women detected by culture method were randomly divided into erythromycine-intervention group and non-intervention group . Comparison was made on rate of reverse sero-conversion, of vertical transmission to mycoplasma and adverse perinatal outcomes incidence between groups . RESULTS: Ureaplasma urealyticum sero-conversion rate and rate of vertical-transmission in intervention group were significantly lower than in non-intervention group (P < 0.05) . The incidences rates of preturm labor, post partum fever, puerperal infection and neonate pneumonia in intervention group were significantly lower than in non-intervention group (P < 0.05) . CONCLUSION: Erythromycin is effective in control of ureaplasma urealyticum infection among pregnant women through cutting off vertical transmission passway and lowering adverse perinatal outcomes against ureaplasma urealyticum.

Hautarzt, 2001 Oct, 52(10 Pt 2), 980 - 4
{Acute generalized cat scratch disease in myelodysplastic syndrome}; von Kobyletzki G et al.; In patients with normal immunity, cat scratch disease typically develop a papule at the portal of entry and no other cutaneous features . A 73 year old male patient with a myelodysplastic syndrome developed generalized petechial, papular and, vasculitic skin lesions in association with cat scratch disease . After the diagnosis was established by identifying the causative organism in a lymph node biopsy, the patient was treated with erythromycin for three weeks resulting in progressive clearance of the skin lesions . Apart from the soluble IL-2 receptor, no other serologic inflammatory parameters were elevated . IgG antibodies against Bartonella henselae and Bartonella quintana increased only slightly during acute exacerbation of the disease, but significantly increased some months later . The diagnosis was established by the positive staining of the lymph node biopsy using the Warthin-Starry stain.

Cardiovasc Drugs Ther, 2001, 15(3), 211 - 8
Safety of HMG-CoA reductase inhibitors: focus on atorvastatin; Bernini F et al.; Statins effectively lower LDL-cholesterol and some members of this class have been shown to reduce the risk of major cardiovascular events and total mortality in patients with or at risk for coronary heart disease . Statins are in general well tolerated . Withdrawal rates related to adverse events are low (< or =3%) . The most common adverse events are mild gastrointestinal symptoms . Elevated serum transaminase levels occur infrequently (< or = 1.5%) . These are generally asymptomatic, reversible and rarely require drug withdrawal . Statins do not cause adverse endocrine effects, do not alter glycemic control in diabetic patients, and do not increase cancer risk . Dose-related myopathy and/or rhabdomyolysis also occurs very rarely, although the risk is increased by concomitant administration of cyclosporine, niacin, fibrates, or by CYP3A4 isoenzyme inhibitors (e.g . erythromycin, systemic azole antifungal agents etc.) with statins metabolized by this isoenzyme . The pharmacokinetics of the individual statin should be considered in patients receiving polypharmacological treatments, to minimize the risk of unfavorable drug interactions . Atorvastatin is well tolerated in long-term treatment of dyslipidemia and is characterized by a safety profile similar to the other available statins.

Int J Antimicrob Agents, 2001 Nov, 18(5), 427 - 31
Tolerability of 3-day, once-daily azithromycin suspension versus standard treatments for community-acquired paediatric infectious diseases; Treadway G et al.; Tolerability of azithromycin oral suspension, 10 mg/kg once daily for 3 days, was assessed in paediatric patients (< or = 18 years) with respiratory or skin and soft-tissue infections . Of 2425 patients evaluated, 1213 received azithromycin and 1212 received standard regimens of amoxycillin/clavulanic acid, cefaclor, cefixime, ceftriaxone, clarithromycin, erythromycin, or penicillin V . The incidence of treatment-related adverse events was significantly lower in patients receiving azithromycin than comparators (7.9 vs . 11.5%, P=0.003), while discontinuation rates were similar (1.0 and 1.1%, respectively) . Significantly fewer gastrointestinal events were recorded for azithromycin than comparators (6.5 vs . 9.9%, P=0.002), and their duration was significantly shorter (mean 2.3 vs . 5.0 days, P=0.0001) . Azithromycin paediatric oral suspension is well tolerated and associated with significantly fewer adverse events than comparators.

Antimicrob Agents Chemother, 2001 Dec, 45(12), 3644 - 6
Newer macrolides as empiric treatment for acute Q fever infection; Gikas A et al.; The effectiveness of newer macrolides in acute Q fever for 113 patients was recorded . The mean times to defervescence were 2.9 days for doxycycline and 3.3, 3.9, 3.9, and 6.4 days for clarithromycin, roxithromycin, erythromycin, and beta-lactams, respectively (P < 0.01 for macrolides versus beta-lactams) . We conclude that macrolides may be an adequate empirical antibiotic therapy for acute Q fever.

Drugs, 2001, 61(13), 1893 - 9
Role of erythromycin for treatment of incipient chronic lung disease in preterm infants colonised with Ureaplasma urealyticum; Buhrer C et al.; Ureaplasma urealyticum is frequently isolated from tracheal aspirates of very low birthweight infants who go on to develop chronic lung disease . The use of erythromycin has been advocated in ventilated very low birthweight infants who are colonised with U . urealyticum, although the association between U . urealyticum and chronic lung disease remains controversial . There are only two randomised, controlled trials involving a total of 37 U . urealyticum-positive very low birthweight infants . Both trials failed to demonstrate a reduction in the incidence of chronic lung disease after 7 or 10 days of erythromycin . On the other hand, there are reports of rare but serious adverse effects of erythromycin in newborn infants including sudden cardiovascular compromise and hypertrophic pyloric stenosis . We conclude that, at present, there is insufficient evidence to support the use of erythromycin for the treatment of incipient chronic lung disease in very low birthweight infants colonised with U . urealyticum.

Pacing Clin Electrophysiol, 2001 Oct, 24(10), 1575 - 6
Risk of torsades de pointes from oral erythromycin with concomitant carbimazole (methimazole) administration; Koh TW; There are many reports of intravenous erythromycin causing QT prolongation and torsades de pointes, but this complication is seldom ascribed to orally administered erythromycin, which is by far the most commonly prescribed route . This report describes a case of torsades de pointes associated with oral erythromycin as a result of a previously undescribed interaction with carbimazole, an antithyroid drug that is metabolized to the active drug methimazole, and the potential pharmacokinetic and pharmacodynamic mechanisms are highlighted.

Can J Physiol Pharmacol, 2001 Oct, 79(10), 848 - 53
Differential effects of phenobarbital on the constitutive and inducible expression of P450 2B and 3A subfamilies in sheep tissues; Dupuy J et al.; The activity and expression of cytochromes P450 were determined in liver, kidneys, lungs, duodenum, jejunum, ileum, and caecum of adult Lacaune sheep . High expression of total P450, benzphetamine and erythromycin demethylase activities, and P450 2B isoforms, as two distinct proteins that were detected and called P4502 Bm and P4502 Bx, was found in the lungs (in addition to liver) . By contrast, the P450 3A subfamily was only expressed in liver and duodenal mucosa of untreated sheep . Phenobarbital (PB) treatment led to significant increases in all measured hepatic parameters and in total P450 of each investigated organ with the exception of ileum and caecum . Benzphetamine demethylase activity increased in liver and kidneys, correlating with the expression of the two P450 2B proteins, which were also induced in duodenum and ileum . By contrast, benzphetamine demethylase activity and expression of the P450 2B isoforms in lungs were unchanged by PB treatment . Erythromycin demethylation activity and P450 3A subfamily expression was increased only in liver of PB-treated sheep.

J Biotechnol, 2002 Jan 18, 92(3), 217 - 28
Saccharopolyspora erythraea-catalyzed bioconversion of 6-deoxyerythronolide B analogs for production of novel erythromycins; Carreras C et al.; A method was developed for the large-scale bioconversion of novel 6-deoxyerythronolide B (6-dEB) analogs into erythromycin analogs . Erythromycin biosynthesis in Saccharopolyspora erythraea proceeds via the formation of a polyketide aglycone, 6-dEB, which is subsequently glycosylated, hydroxylated and methylated to yield the antibiotic erythromycin A . A modular polyketide synthase (PKS) directs 6-dEB synthesis using a dedicated set of active sites for the condensation of each of seven propionate units . Strategies based on genetic manipulation and precursor feeding are available for the efficient generation of novel 6-dEB analogs using a plasmid-based system in Streptomyces coelicolor . 6-dEB and 13-substituted 6-dEB analogs produced in this manner were fed to S . erythraea mutants which could not produce 6-dEB, yet retained their 6-dEB modification systems, and resulted in the generation of erythromycin A and 13-substituted erythromycin A analogs . Erythromycin B, C and D analogs were observed as intermediates of the process . Dissolved oxygen, temperature, the specific aglycone feed concentration, and pH were found to be important for obtaining a high yield of erythromycin A analogs . Cultivation conditions were identified which resulted in the efficient bioconversion of 6-dEB analogs into erythromycin A analogs, which this process demonstrated at the 100 l scale.

Intern Med, 2001 Oct, 40(10), 1064 - 7
Legionnaires' disease associated with habitual drinking of hot spring water; Tominaga M et al.; A 57-year-old man presented with pneumonia, respiratory distress, and myelodysplastic syndrome . A diagnosis of Legionnaires' disease due to Legionella pneumophila (L . pneumophila) was established . The patient had long been drinking tap water via a conduit from a hot spring resource, from which L . pneumophila was also isolated . Both the patient's strain and the water strain of L . pneumophila were identified as serogroup 1, and the genetic relatedness between the two strains as seen by pulsed-field gel electrophoresis was 87% . The patient was successfully treated with erythromycin, fluoroquinolone, and rifampicin . This case raises an important issue on public health represented by legionellosis in Japan.

Vutr Boles, 2000, 32(4), 13 - 7
{Macrolides: pharmacology and clinical use}; Draganov V et al.; Members of macrolides are Erythromycin, Oleandomycin, Spiramycin, Roxithromycin, Josamycin, Midecamycin, Clarithromycin, Azithromycin and Dirithromycin . This review present mechanism of action, pharmacokinetic, adverse drug reactions and main clinical uses of the macrolides.

Ann Surg, 2001 Nov, 234(5), 668 - 74
Low-dose erythromycin reduces delayed gastric emptying and improves gastric motility after Billroth I pylorus-preserving pancreaticoduodenectomy; Ohwada S et al.; OBJECTIVE: To test the hypothesis that early and low doses of erythromycin reduce the incidence of early delayed gastric emptying (DGE) and induce phase 3 of the migratory motor complex in the stomach after Billroth I pylorus-preserving pancreaticoduodenectomy (PPPD) . SUMMARY BACKGROUND DATA: Delayed gastric emptying is a leading cause of complications after PPPD, occurring in up to 50% of patients . High doses of erythromycin (200 mg) accelerate gastric emptying after pancreaticoduodenectomy and reduce the incidence of DGE, although they induce strong contractions that do not migrate to the duodenum . METHODS: Thirty-one patients were randomly assigned to either the erythromycin or control groups . The patients received erythromycin lactobionate (1 mg/kg) every 8 hours, or H2-receptor antagonists and gastrokinetic drugs from days 1 to 14 after surgery . On postoperative day 30, gastroduodenal motility was recorded in 14 patients . RESULTS: Preoperative, intraoperative, and postoperative factors were comparable in the erythromycin and control groups . The erythromycin group had a shorter duration of nasogastric drainage, earlier resumption of eating, and a 75% reduction in the incidence of DGE . Erythromycin was an independent influence on nasogastric tube removal, and preservation of the right gastric vessels was a significant covariate . Low doses of erythromycin induced phase 3 of the migratory motor complex and phase 3-like activity, with the same characteristics as spontaneous phase 3, in 86% of patients: two had quiescent stomachs and the others had spontaneous phase 3 or phase 3-like activity . CONCLUSIONS: Low doses of erythromycin reduced the incidence of DGE by 75% and induced phase 3 of the migratory motor complex after Billroth I PPPD . Low doses of erythromycin are preferable to high doses in the unfed period after PPPD.

Am J Physiol Gastrointest Liver Physiol, 2001 Nov, 281(5), G1214 - 20
Pressure-geometry relationship in the antroduodenal region in humans; Faas H et al.; Understanding of the control mechanisms underlying gastric motor function is still limited . The aim of the present study was to evaluate antral pressure-geometry relationships during gastric emptying slowed by intraduodenal nutrient infusion and enhanced by erythromycin . In seven healthy subjects, antral contractile activity was assessed by combined dynamic magnetic resonance imaging and antroduodenal high-resolution manometry . After intragastric administration of a 20% glucose solution (750 ml), gastric motility and emptying were recorded during intraduodenal nutrient infusion alone and, subsequently, combined with intravenous erythromycin . Before erythromycin, contraction waves were antegrade (propagation speed: 2.7 +/- 1.7 mm/s; lumen occlusion: 47 +/- 14%) . Eighty-two percent (51/62) of contraction waves were detected manometrically . Fifty-four percent of contractile events (254/473) were associated with a detectable pressure event . Pressure and the degree of lumen occlusion were only weakly correlated (r(2) = 0.02; P = 0.026) . After erythromycin, episodes of strong antroduodenal contractions were observed . In conclusion, antral contractions alone do not reliably predict gastric emptying . Erythromycin induces strong antroduodenal contractions not necessarily associated with fast emptying . Finally, manometry reliably detects ~80% of contraction waves, but conclusions from manometry regarding actual contractile activity must be made with care.

Early Hum Dev, 2001 Dec, 65(2), 91 - 6
The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants; Costalos C et al.; The aim of the study was to determine the effect of a low oral dose of erythromycin on whole gastrointestinal transit time {WGTT} . Erythromycin {EM} {1.5 mg/kg, 6 hourly} or placebo was given first over 7 days in a double blind randomized crossover study of 21 preterm infants with feed intolerance . Median {range} birth weight was 1420 {690, 2200} g and postconceptual age 32 . 5 {20, 36.4} weeks . WGTT was assessed on day 3 of each treatment, by timing the transit of carmine red through the gut . Treatments were compared using Student's paired t test . RESULTS: WGTT was significantly shorter following EM treatment as compared to placebo: mean {SD} 10.16 {4.6} h vs . 15 . 9 {7.2} h, p<0.01 . CONCLUSION: Oral low-dose EM significantly shortens WGTT of feed-intolerant preterm infants.

Chem Biol Interact, 2001 Oct 25, 138(1), 85 - 106
alpha-Naphthoflavone acts as activator and reversible or irreversible inhibitor of rabbit microsomal CYP3A6; Boek-Dohalska L et al.; This report describes the effect of alpha-naphthoflavone (alpha-NF), a known substrate, inhibitor and activator of several cytochromes P450 (CYP), on rabbit CYP3A6 . Hepatic microsomes of rabbit pretreated with rifampicine (RIF), enriched with CYP3A6, as well as purified CYP3A6 reconstituted with isolated NADPH:CYP reductase were used as enzymatic systems in this study . The data from difference spectroscopy experiments showed that alpha-NF does yield a type I binding spectrum . This compound is oxidized by microsomal CYP3A6 into two metabolites (5,6-epoxide and trans-7,8-dihydrodiol) . While alpha-NF is a substrate of CYP3A6, it also acts as an enzyme modulator . Under the conditions used, stimulation of 17beta-estradiol 2-hydroxylation by alpha-NF was observed . In contrast, this compound reversibly inhibited N-demethylation of erythromycin and tamoxifen, competitively with respect to these substrates, having the K(i) values of 51.5 and 18.0 microM, respectively . Moreover, alpha-NF was found to be an effective inactivator of progesterone and testosterone 6beta-hydroxylation catalyzed by CYP3A6 in RIF-microsomes . In addition, time- and concentration-dependent inactivation of human CYP3A4-mediated 6beta-hydroxylation of testosterone by alpha-NF, was determined . The inactivation of CYP3A6 followed pseudo-first-order kinetics and was dependent on both NADPH and alpha-NF . The concentrations required for half-maximal inactivation (K(i)) were 80.1 and 108.5 microM and the times required for half of the enzyme to be inactivated were 10.0 and 11.9 min for 6beta-hydroxylation of progesterone and testosterone, respectively . The loss of the enzyme activity was not recovered following dialysis, while 90% of the ability to form a reduced CO complex remained . This indicates the binding of alpha-NF to a CYP apoprotein molecule rather than to a heme moiety . Protection from inactivation was seen in the presence of all tested CYP3A substrates . Progesterone and testosterone protected CYP3A6 against inactivation competitively with respect to inactivator, erythromycin non-competitively and 17beta-estradiol showed a mixed type of protection . Here, we described for the first time that alpha-NF is capable of irreversible inhibition of microsomal rabbit CYP3A6 and human CYP3A4 . The obtained results strongly suggest that the CYP3A active center contains at least two and probably three distinct binding sites for substrates.

Kansenshogaku Zasshi, 2001 Sep, 75(9), 808 - 11
{Two patients with Bartonella henselae infection from a dog}; Murano I et al.; Two patients were reported as having been infected with Bartonella henselae after having contact with a dog . Both of the patients owned a dog, but had no contact with cats . One patient was a 10-year-old boy who had experienced a fever of 38-39 degrees C for 11 days, as well as having bilateral cervical lymphadenopathy . The boy's serum IgM antibodies to B . henselae were negative on the 6th and 16th day of his illness, whereas his IgG value, using indirect fluorescence antibody (IFA) method, was found to be elevated from 1:256 to 1:1,024 . B . henselae DNA was detected, by PCR method, in swabs from the gingiva and buccal membrane of the dog with which the boy had been in contact . The boy was first treated with cefdinir (300 mg daily) for 6 days without beneficial effect . He responded, however, to minocycline (100 mg daily) with symptom resolution in four days . The other patient was a 64-year-old man who had experienced a fever of 38-39 degrees C for 27 days, as well as having right inguinal lymphadenopathy . The man's serum IgM antibody to B . henselae was negative, although his IgG value, determined by IFA, was 1:1,024 . In addition, B . henselae DNA was detected, by PCR method, in parafin-embedded tissue obtained from the biopsied inguinal lymph nodes . The man was treated with cefazolin (2 g daily) . His fever resolved, but his lymph nodes remained swollen . After a regimen of erythromycin (1,200 mg daily), the swelling in his inguinal lymphnodes gradually disappeared . Careful review of suspected CSD victims' history of contact with animals is important in making a prompt diagnosis of B . henselae infection.

Pharmacotherapy, 2001 Oct, 21(10), 1192 - 5
Effects of metronidazole on hepatic CYP3A4 activity; Haas CE et al.; STUDY OBJECTIVE: To evaluate the effect of a short course of oral metronidazole, commonly used for bowel-preparation regimens, on hepatic cytochrome P450 (CYP) 3A4 activity, as measured by the {14C N-methyl}-erythromycin breath test (ERMBT) in healthy volunteers . DESIGN: Prospective, nonrandomized, interventional study SETTING: University-affiliated, community, teaching hospital . SUBJECTS: Five healthy male volunteers . INTERVENTION: Subjects underwent a baseline ERMBT in the morning before receiving three oral doses of metronidazole 500 mg administered at 3 P.M., 7 P.M., and 11 P.M . Repeat ERMBTs were performed at 24, 72, and 96 hours after the initial ERMBT . Changes in ERMBT values were compared with baseline results using Freidman's repeated-measures analysis of variance on ranks . MEASUREMENTS AND MAIN RESULTS: The ERMBT values did not change significantly compared with baseline (p=0.82) . Median (range) ERMBT values expressed as a percentage of baseline at 24, 72, and 96 hours were 110.3 (96.2-136.9), 101.3 (99.3-115.0), and 101.8 (95.5-116.3), respectively CONCLUSION: A short course of oral metronidazole does not result in a significant change in hepatic CYP3A4 activity as measured by the ERMBT.

Ned Tijdschr Geneeskd, 2001 Sep 22, 145(38), 1828 - 31
{Erythromycin for premature rupture of membranes is beneficial for infant}; Buitendijk SE; In the 'Overview of the role of antibiotics in curtailing labour and early delivery' (ORACLE I)-trial in women with premature rupture of membranes, the use of erythromycin was found to be associated with a decrease in the primary composite outcome (neonatal death, chronic lung disease or major cerebral abnormality on ultrasound; p = 0.08) and in single adverse neonatal outcomes (p = 0.02) when compared to placebo . The positive results were more significant in the singleton group (p = 0.02 for the composite outcome), while no effects were found in twin pregnancies . The combination of amoxycillin and clavulanic acid, with or without erythromycin, was associated with some improvements in outcome, but was also accompanied by a higher rate of neonatal necrotising enterocolitis . Another trial (ORACLE II) found no effects of antibiotic use in women with premature labour with intact membranes . Although both trials were of good quality, the stratification into singleton and twin pregnancies should have been done more consistently . Because premature rupture of membranes in singleton pregnancies is more likely to be associated with a pre-existing infection than in multiple pregnancies, the potential benefit of treatment with antibiotics is larger in singleton pregnancies.

Microbiol Immunol, 2001, 45(8), 617 - 20
Characteristics of macrolide-resistant Mycoplasma pneumoniae strains isolated from patients and induced with erythromycin in vitro; Okazaki N et al.; Some patients with Mycoplasma pneumoniae infection are clinically resistant to antibiotics such as erythromycin, clarithromycin, or clindamycin . We isolated M . pneumoniae from such patients and found that one of three isolates showed a point mutation in the 23S rRNA gene . Furthermore, 141 EM-sensitive clinical isolates of M . pneumoniae were cultured in broth medium containing 100 microg/ml of erythromycin (EM) . Among 11 EM-resistant strains that grew in the medium, point mutations in the 23S rRNA were found in 3 strains at A2063G, 5 strains at A2064G and 3 strains at A2064C . The relationship between the point mutation pattern of these EM-resistant strains and their resistance phenotypes to several macrolide antibiotics was investigated.

N Z Med J, 2001 Aug 24, 114(1138), 374 - 7
Treatment practices for chlamydial infection in New Zealand; Bennett S et al.; AIMS: To identify prescribing and treatment practices for chlamydial infection in New Zealand . METHODS: Postal survey to doctors and nurses at all sexual health, family planning, student and youth health centres, and randomly selected general practitioners . RESULTS: There was considerable variation in treatment regimes used for chlamydial infection with few respondents treating in accordance with international guidelines regarding dose, frequency, and duration of treatment . Doxycycline (88.4%) was most commonly used to treat uncomplicated chlamydial infection in non-pregnant patients . Most respondents (70.2%) stipulated doxycycline for longer durations than the seven day regimen international guidelines recommend, with doxycycline 100 mg twice a day for ten days most frequently specified . Among the 259 respondents who would treat pregnant women with erythromycin, 51 different treatment regimens were specified, and 51.7% recorded regimens less than that recommended by international guidelines . When treating a patient presumptively, the majority of respondents tested for chlamydial infection . In contrast to other respondents, sexual health clinic staff rarely provide patients with a prescription for a patient's partner without seeing the partner . CONCLUSIONS: Standardised treatment guidelines are required for patients diagnosed with chlamydial infection . Guidelines should include recommendations for the treatment of partners, and encourage the laboratory confirmation of diagnosis.

Crit Care Med, 2001 Oct, 29(10), 1916 - 9
Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill; Boivin MA et al.; OBJECTIVE: To determine whether adding erythromycin to a gastric feeding regimen could render it as effective in meeting nutritional needs as transpyloric feeding . DESIGN: Randomized, controlled study . SETTING: University hospital medical, surgical, and neurologic care intensive care units . PATIENTS: Critically ill patients, requiring a projected 96 hrs of enteral feeding, who had no specific indication for tube location (gastric or transpyloric) . Eighty patients were randomized . INTERVENTIONS: Patients were randomized to gastric feeding with erythromycin (200 mg iv) given every 8 hrs or feeding through a transpylorically placed feeding tube . Goal rate and feeding advancement were determined by protocol . MEASUREMENTS AND MAIN RESULTS: During the 96-hr period, the gastric group received 74% of their goal calories and the transpyloric group received 67% . The only day on which gastric feedings were superior was the first study day, where the gastric group attained 55% of their goal, compared with 44% in the transpyloric group . This 1-day difference was the result of an initial failure of tube placement in some subjects . Exclusion of these patients did not change overall results . Nutritional indexes, length of stay in the intensive care unit, ventilator dependence, and survival were not different between the two groups . CONCLUSIONS: Gastric feeding with erythromycin as a prokinetic is equivalent to transpyloric feeding in meeting the nutritional goals of the critically ill.

Int J Antimicrob Agents, 2001, 18 Suppl 1, S71 - 6
Comparative safety of the different macrolides; Rubinstein E; The macrolides are generally well tolerated when used for the treatment of acute infections . Even when given long term for prophylaxis, there are few discontinuations due to side-effects . There are isolated reports of QT(c) prolongation in patients treated with erythromycin and other 14-membered-ring macrolides . Since the 14-membered-ring macrolides are metabolized by P450 isoenzymes, there is the potential for interaction with other therapeutic agents also metabolized in this way . Pharmacokinetic studies have demonstrated interactions between either erythromycin or clarithromycin and cyclosporin, cisapride, pimozide, disopyramide, astemizole, carbamazepine, midazolam, digoxin, hydroxymethylglutaryl-coenzyme A reductase inhibitors (i.e . 'statins') and warfarin . In patients receiving such concurrent therapy, azithromycin may be superior to erythromycin and clarithromycin.

Br J Anaesth, 2001 Jun, 86(6), 869 - 71
Gastric residual volume in children: a study comparing efficiency of erythromycin and metoclopramide as prokinetic agents; Zatman TF et al.; Metoclopramide may be used to stimulate gastric emptying when anaesthetizing children for emergency operations . Unfortunately, metoclopramide is associated with extrapyramidal side effects . Erythromycin, a motilin receptor agonist, is a prokinetic agent but its use has been little investigated in children . This randomized double-blind study compared the effects of premedication with oral metoclopramide 0.15 mg kg(-1) or erythromycin 1 mg kg(-1) on gastric emptying in 80 children undergoing tonsillectomy . Pre-operative fluids, premedication and anaesthetic technique were standardized and gastric volume was measured with an orogastric tube . Post-operative nausea and vomiting was recorded . Metoclopramide and erythromycin produced similar gastric volumes (0.29 and 0.24 ml kg(-1)) and there was no difference in post-operative vomiting . In the erythromycin group there were more patients with negative aspirates (45.9%) than in the metoclopramide group (35.1%), but the difference was not statistically significant . These results indicate that erythromycin may be as effective as metoclopramide as a prokinetic agent.

Wien Klin Wochenschr, 2001 Aug 16, 113(15-16), 593 - 6
Efficacy of macrolides vs . metronidazole against Entamoeba histolytica clinical isolates; Georgopoulos A et al.; Current treatment of Entamoeba histolytica infection requires the use of several agents that are effective at different sites of the body . Commonly administered agents such as nitroimidazoles have a high rate of gastrointestinal side effects and their use is restricted during pregnancy . In order to offer new choices, four macrolide antibiotics (erythromycin, clarithromycin, azithromycin, josamycin) and metronidazole were tested for their in vitro activity against E . histolytica . Ten clinically isolated strains from an endemic area (Santo Domingo, Dominican Republic) were tested after polyxenical culture . Protozoan viability was significantly reduced by josamycin after 24 and 48 hours of incubation at a concentration of > or = 50 mg/l, which was slightly higher than that of metronidazole (25 mg/l) . No resistance to metronidazole was found . The antiamebic activity of azithromycin, clarithromycin and erythromycin was significant at drug concentrations > or = 100 mg/l . High doses of josamycin, which is a very well tolerated drug, may serve as a useful therapeutic agent in the presence of E . histolytica infection.

Arch Intern Med, 2001 Sep 10, 161(16), 2021 - 6
Risk of cataract in patients treated with statins; Schlienger RG et al.; BACKGROUND: Studies in dogs showed that some hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are associated with cataract when administered in excessive doses . Clinical safety data of statins regarding cataract development in humans have been of limited value so far . OBJECTIVE: To determine whether long-term use of statins is associated with an increased risk of cataract . METHODS: We conducted a case-control analysis using data from the United Kingdom-based General Practice Research Database . The main outcome was a first-time diagnosis of cataract and/or cataract extraction in patients aged 40 to 79 years . Controls were matched to cases on age, sex, practice, calendar time, and duration of medical history in the database . Use of statins, fibrates, or other lipid-lowering drugs was compared with nonuse of any lipid-lowering drug, stratified by exposure duration and dose . RESULTS: We identified 7405 cases and 28 327 controls . Long-term use of statins (eg, > or =30 prescriptions) was not associated with an increased cataract risk (adjusted odds ratio {OR}, 0.9; 95% confidence interval {CI}, 0.5-1.6), nor was use of fibrates or of other lipid-lowering drugs (adjusted OR, 0.5; 95% CI, 0.3-1.1; and OR, 0.7; 95% CI, 0.1-5.6, respectively) . We found evidence that concomitant use of simvastatin and erythromycin, a potent inhibitor of simvastatin metabolism, is associated with an increased cataract risk (adjusted odds ratio, 2.2; 95% confidence interval, 1.2-4.1) . CONCLUSIONS: Our study provides evidence that long-term use of therapeutic statin doses does not increase the risk of developing cataract . Concomitant use of erythromycin and simvastatin may increase the cataract risk.

Xenobiotica, 2001 Aug-Sep, 31(8-9), 469 - 97
Role of transport proteins in drug absorption, distribution and excretion; Ayrton A et al.; 1 . The molecular and functional characterization of transport proteins is emerging rapidly and significant numbers of drugs have been shown to be substrates or inhibitors . The purpose of this review is to highlight the in vivo preclinical and clinical evidence that supports a role for transport proteins in attenuating the absorption, distribution and excretion (ADE) of drugs . 2 . For absorption, a clear role has emerged for P-glycoprotein in limiting permeability across the gastrointestinal tract . As a result, a wide variety of drugs suffer from incomplete, variable and non-linear absorption . Similarly, at the blood-brain barrier a range of drugs has limited brain penetration due to P-glycoprotein-mediated efflux, which can limit therapeutic effectiveness of CNS agents . In the liver, transport proteins are present on the sinusoidal membrane that can be the rate-limiting step in hepatic clearance for some drugs . Mechanistic studies clearly suggest a key role and broad substrate specificity for the OATP family of sinusoidal transporters . Mainly ATP-dependent transport proteins such as P-glycoprotein and MRP2 govern active biliary excretion . 3 . Drug-drug interactions have been demonstrated involving inhibition or induction of transport proteins . Clinically significant interactions in the gastrointestinal tract and kidney have been observed with inhibitors such as ketoconazole, erythromycin, verapamil, quinidine, probenecid and cimetidine . Clinically significant inhibition at the blood-brain barrier is more difficult to demonstrate, relying on pharmacodynamic and toxicodynamic changes, but an example is quinidine increasing loperamide-induced central effects in humans . 4 . This review highlights the emerging role of transport proteins in ADE of drugs and suggests these need to be considered, in drug discovery and development, with respect to variability in drug disposition and response.

Curr Opin Investig Drugs, 2001 Apr, 2(4), 555 - 7
GM-611 (Chugai Pharmaceutical); Peeters TL; GM-611 is an erythromycin derivative that acts as an agonist at the motilin receptor . It is being developed by Chugai as a potential treatment for gastric motility disorder {169036}, as well as reflux esophagitis, non-ulcer dyspepsia and diabetic gastroparesis {347963} . GM-611 is in phase II trials in the US for reflux esophagitis {322624}, {347955}, {399349} . GM-611 acts by a novel mechanism whereby it stimulates and promotes peristalsis in the stomach and other segments of the gastrointestinal tract {334994} . The drug was shown to produce a dose-dependent sustained depolarization of rabbit duodenal smooth muscle . Depolarization appeared to be associated with activation of monovalent cation-selective channels {273336} . In December 2000, Credit Suisse First Boston predicted that successful development of GM-611 could lead to sales over $500 million {400228}.

Int J Clin Pharmacol Ther, 2001 Sep, 39(9), 369 - 82
Drug interactions of the statins and consequences for drug selection; Boger RH; Cholesterol-lowering drugs such as HMG-CoA reductase inhibitors ("statins") are increasingly used in hypercholesterolemic patients who suffer from multiple concomitant diseases, and are therefore taking multiple drugs . The statins do not differ in their mechanism of action (pharmacodynamics), but there are differences in the affinity to the target enzyme as well as differences in pharmacokinetic properties, which need to be considered when choosing a statin for a specific patient . The most critical side effect of statins is development of myopathy, which becomes evident as muscle pain, weakness, and elevation of serum creatine kinase activity . The incidence of myopathy is usually low . However, myopathy and rhabdomyolysis are more frequent when statins are combined with other drugs that inhibit cytochrome P450-dependent metabolism of statins in the liver (e.g., itraconazole, erythromycin) . Drug interactions can thus significantly increase the risk associated with statin therapy . Oral bioavailability of the statins varies considerably . Besides the absolute rate of oral bioavailability, it is important to know the relative difference between intestinal absorption rate and rate of oral bioavailability in order to assess the potential for drug-drug interactions . Statins that are not metabolized by a single cytochrome P450 isoenzyme, and have a high bioavailability, are the least prone to drug interactions.

Curr Gastroenterol Rep, 2001 Oct, 3(5), 433 - 6
Update on acute colonic pseudo-obstruction; Eaker EY; Acute colonic pseudo-obstruction is characterized by distention of the colon in the absence of mechanical obstruction . This presentation is typically related to recent surgery, severe illness, or medication . Nasogastric and rectal tube decompression and correction of electrolyte abnormalities are the standard of care . Colonoscopic decompression, performed in a number of these cases, was felt to be unwarranted in many situations and is associated with a high recurrence rate . Medical management beyond conservative measures has been limited . Medical therapy with pharmacologic agents such as erythromycin, metoclopromide, and cisapride was of limited use . Recent findings confirm that an older agent, neostigmine, provides excellent results, including colonic decompression and clinical improvement after administration . This suggests a new standard of care.

Kaohsiung J Med Sci, 2001 Jun, 17(6), 331 - 5
Legionnaires' disease in an immunocompetent young adult; Tsai HC et al.; Infection with Legionella pneumophila (LP) is a rare cause of pneumonia in previously healthy young adults . Pleural effusion is relatively common in Legionnaires' disease but is usually clinically insignificant . Herein we describe an immunocompetent, 19-year-old female with LP respiratory infection that presented with pleural effusion and mild interstitial infiltrates in the lower lungs . She received 3 weeks' treatment with erythromycin and rifampin and recovered completely . Diagnosis was based on serology testing with a four-fold rise of the antibody titer in the acute and convalescent phase . Legionnaires' disease should be considered in the differential diagnosis of culture-negative pleural effusion in immunocompetent young adults.

Clin Pharmacol Ther, 2001 Sep, 70(3), 247 - 54
Population pharmacokinetics of everolimus in de novo renal transplant patients: impact of ethnicity and comedications; Kovarik JM et al.; BACKGROUND: Everolimus is a macrolide immunosuppressant intended for acute rejection prophylaxis after kidney transplantation . METHODS: A total of 5260 blood samples were collected in the context of two randomized, double-blind, multicenter efficacy trials in 673 patients over a 6-month period after kidney transplantation . The data were evaluated in a nonlinear mixed-effects model . The influence of demographic characteristics (age, weight, sex, and ethnicity) and of comedications on everolimus exposure was explored . RESULTS: For a reference 44-year-old, 71-kg Caucasian kidney allograft recipient receiving everolimus as part of a cyclosporine (INN, ciclosporin)-prednisone immunosuppressive regimen, the absorption rate constant was 6.07 h(-1) (standard error {SE}, 0.70 h(-1)), the apparent clearance was 8.8 L/h (SE, 0.2 L/h), and the apparent central distribution volume was 110 L (SE, 5 L) . There were no clinically relevant influences of age, weight, or sex on clearance . No significant difference in clearance was detected for Asian patients, whereas black patients had an average clearance that was 20% higher than that of nonblack patients . Patients concomitantly receiving erythromycin or azithromycin had an average 19% lower clearance . One patient receiving itraconazole had a 74% reduction in clearance . After we accounted for covariates, the remaining interindividual variability in clearance was 27% and the variability for distribution volume was 36% . The combined intraindividual and assay/measurement residual error in everolimus blood concentrations was 31% . CONCLUSIONS: Dose adjustment of everolimus on the basis of weight does not appear necessary . Black patients may need a higher dose to achieve exposure that is similar to that of nonblack patients . Concomitant administration of potent inhibitors of the cytochrome P450 isozyme CYP3A may reduce everolimus clearance and increase its blood concentrations.

Clin Pharmacol Ther, 2001 Sep, 70(3), 228 - 36
Ethnic differences and relationships in the oral pharmacokinetics of nifedipine and erythromycin; Yu KS et al.; OBJECTIVE: Our objective was to investigate ethnic differences in the oral pharmacokinetics of nifedipine and erythromycin, both typical cytochrome P4503A (CYP3A) substrates, in Koreans and Caucasians and to identify the nature of any correlations between the pharmacokinetic parameters of the two drugs . METHODS: Twenty healthy male volunteers (10 Koreans and 10 Caucasians) received single oral doses of nifedipine (10 mg) or erythromycin (500 mg) in a randomized 2-way crossover study . Pharmacokinetic evaluations were performed, and parameters were compared for the two ethnic groups . During the nifedipine study period, hemodynamic measurements were conducted to determine the pharmacodynamic relevance of the pharmacokinetic differences . RESULTS: Koreans showed area under the concentration-time curves (AUCs) for both drugs that were 1.6 to 1.7 times higher than those of Caucasians . This difference decreased to 1.3 when normalized for body weight . Significant correlation between the AUCs of the two drugs was not evident . Hemodynamic changes after nifedipine administration paralleled those of the pharmacokinetic differences, with significantly greater decreases in blood pressure and total peripheral resistance noted in Koreans . CONCLUSIONS: Koreans showed significantly lower oral clearances of nifedipine and erythromycin, probably because of genetic differences attributed to the CYP3A enzymes.

Antimicrob Agents Chemother, 2001 Oct, 45(10), 2798 - 806
Cellular uptake of two fluoroketolides, HMR 3562 and HMR 3787, by human polymorphonuclear neutrophils in vitro; Abdelghaffar H et al.; We analyzed the cellular accumulation of two new fluoroketolides, HMR 3562 and HMR 3787, by human polymorphonuclear neutrophils (PMN) in vitro . Both compounds were rapidly taken up by PMN, with a cellular-to-extracellular concentration ratio (C/E) of about 141 (HMR 3562) and 117 (HMR 3787) at 5 min, and this was followed by a plateau at 60 to 180 min, with a C/E of >300 at 180 min . Both ketolides were mainly located in PMN granules (about 75%) and egressed slowly from loaded cells (about 40% at 60 min), owing to avid reuptake . Uptake was moderately sensitive to external pH, and activation energy was also moderate (about 70 kJ/mol) . As with other macrolides and ketolides, the existence of an active transport system was suggested by (i) the strong interindividual variability in uptake kinetics, suggesting variability in the number or activity of a transport protein; (ii) the saturation kinetics characteristic of a carrier-mediated transport system (V(max), about 2,300 ng/2.5 x 10(6) PMN/5 min; K(m), about 50 microg/ml); (iii) the inhibitory effects of Ni(2+) (a blocker of the Na+-Ca(2+) exchanger), phorbol myristate acetate (a protein kinase C activator), and H89 (a protein kinase A inhibitor) . Although these two ketolides are more related to HMR 3647 (telithromycin), it is interesting that the presence of a fluoride gave these molecules a cellular pharmacokinetics more like those of HMR 3004 than those of HMR 3647 . The macrolide transport system has not been yet elucidated, but our data confirm that, despite variations in chemical structure, all erythromycin A derivatives share a transmembrane transport system.

Chest, 2001 Sep, 120(3), 730 - 3
Erythromycin and common cold in COPD; Suzuki T et al.; STUDY OBJECTIVES: To investigate whether erythromycin therapy lowers the frequency of the common cold and subsequent exacerbation in patients with COPD . DESIGN: Prospective, randomized, controlled, but not blinded, trial . PATIENTS: One hundred nine patients with COPD were enrolled into the study . Patients were randomly assigned to erythromycin therapy or to no active treatment in September 1997 . Patients then were observed for 12 months, starting in October, during which time the risk and frequency of catching common colds and COPD exacerbations were investigated . Fifty-five patients received erythromycin at study entry (erythromycin group) . The remaining 54 patients received no active treatment (control group) . MEASUREMENTS AND RESULTS: The mean (+/- SE) number of common colds for 12 months was significantly lower in the erythromycin group than in the control group (1.24 +/- 0.07 vs 4.54 +/- 0.02, respectively, per person; p = 0.0002) . Forty-one patients (76%) in the control group experienced common colds more than once, compared to 7 patients (13%) in the erythromycin group . The relative risk of developing two or more common colds in the control group compared with that in the erythromycin group was 9.26 (95% confidence interval {CI}, 3.92 to 31.74; p = 0.0001) . Thirty patients (56%) in the control group and 6 patients (11%) in the erythromycin group had one or more exacerbations . The relative risk of experiencing an exacerbation in the control group compared with that in the erythromycin group was 4.71 (95% CI, 1.53 to 14.5; p = 0.007) . Significantly more patients were hospitalized due to exacerbations in the control group than in the erythromycin group (p = 0.0007) . CONCLUSION: Erythromycin therapy has beneficial effects on the prevention of exacerbations in COPD patients.

Mol Microbiol, 2001 Sep, 41(5), 1091 - 9
The pleuromutilin drugs tiamulin and valnemulin bind to the RNA at the peptidyl transferase centre on the ribosome; Poulsen SM et al.; The pleuromutilin antibiotic derivatives, tiamulin and valnemulin, inhibit protein synthesis by binding to the 50S ribosomal subunit of bacteria . The action and binding site of tiamulin and valnemulin was further characterized on Escherichia coli ribosomes . It was revealed that these drugs are strong inhibitors of peptidyl transferase and interact with domain V of 23S RNA, giving clear chemical footprints at nucleotides A2058-9, U2506 and U2584-5 . Most of these nucleotides are highly conserved phylogenetically and functionally important, and all of them are at or near the peptidyl transferase centre and have been associated with binding of several antibiotics . Competitive footprinting shows that tiamulin and valnemulin can bind concurrently with the macrolide erythromycin but compete with the macrolide carbomycin, which is a peptidyl transferase inhibitor . We infer from these and previous results that tiamulin and valnemulin interact with the rRNA in the peptidyl transferase slot on the ribosomes in which they prevent the correct positioning of the CCA-ends of tRNAs for peptide transfer.

J Vet Pharmacol Ther, 2001 Aug, 24(4), 251 - 9
Pharmacokinetics and microsomal oxidation of praziquantel and its effects on the P450 system in three-month-old lambs infested by Fasciola hepatica; Giorgi M et al.; Praziquantel (PZQ) is a broadly effective trematocide and cestocide, widely employed in veterinary and human medicine . In view of several differences in both its pharmacokinetic profile in different animal species and in the cytochrome P450-dependent system between ruminant and nonruminant species, the present study was undertaken to determine the pharmacokinetics of this drug, its effects on the P450 system and the involvement of cytochrome P450 in its metabolism in 3-month-old lambs infested by Fasciola hepatica . Following both oral and i.m . administration, PZQ disposition was best described by a linear one-compartment open model with a rapid absorption and elimination . Although the PZQ dose used by the i.m . route was only half of that used by the oral route, the mean PZQ plasma concentration was higher after i.m . than after oral treatment . Oral treatment with 30 mg/kg/day of PZQ did not modify the mono-oxygenase activities tested, whilst the administration of PZQ at a dose of 60 mg/kg/day for 2 days caused a significant decrease in the P450 3A-dependent erythromycin N-demethylase and 6beta testosterone hydroxylase activities . From the incubation of microsomes from lambs not treated with PZQ, a single metabolite (PZQ 11b-OH or PZQ 1-OH) was identified by GC/MS analysis . By selective inhibition of the 3A subfamily performed with triacetyloleandromycin, the production of this metabolite declined by about 90% suggesting a prominent role of P450 3A isoforms in this oxidation . These features indicate that agents or drugs which are able to modulate P450 3A-dependent catalysis may interfere with the metabolism, bioavailability and therapeutic effects of PZQ.

J Chromatogr A, 2001 Aug 10, 926(1), 97 - 104
Confirmatory method for macrolide residues in bovine tissues by micro-liquid chromatography-tandem mass spectrometry; Draisci R et al.; A new confirmatory method for three macrolides (tylosin, tilmicosin and erythromycin) in bovine muscle, liver and kidney by micro-LC-MS-MS using an atmospheric pressure ionisation source and an ionspray interface has been developed . Roxithromycin was used as internal standard . The molecular related ions, {M+2H}2+, at m/z 435 for tilmicosin, and {M+H}+, at m/z 734 and 916 for erythromycin and tylosin, respectively, were the precursor ions for collision-induced-dissociation and two diagnostic product ions for each macrolide were identified for the unambiguous confirmation by selected reaction monitoring LC-MS-MS . Precision values (relative standard deviations) were all below 14.9%, whereas the overall accuracy (relative error) ranged from -17.7 to -9.8% for tylosin, from -17.5 to -10.7% for tilmicosin and from -19.6 to -13.7% for erythromycin, in all the investigated bovine tissues . The limits of quantification were 30 (muscle) or 40 (liver, kidney) microg kg(-1), 20 (muscle) or 150 (liver, kidney) microg kg(-1), 50 (muscle, liver) or 80 (kidney) microg kg(-1), 20 (muscle, liver) or 50 (kidney) microg kg(-1) for tylosin, tilmicosin, erytromycin and roxithromycin, respectively.

J Toxicol Sci, 2001 Aug, 26(3), 141 - 50
Climbazole is a new potent inducer of rat hepatic cytochrome P450; Kobayashi Y et al.; We examined the effect of climbazole on the induction of rat hepatic microsomal cytochrome P450 (P450), and compared the induction potency with other N-substituted azole drugs such as clorimazole . We found that climbazole is found to be a potent inducer of rat hepatic microsomal P450 as clorimazole . Induced level of P450 by climbazole was almost similar in extent to clorimazole when compared with other imidazole drugs in a dose- and time-dependent manner . Parallel to the increase in P450, climbazole increased aminopyrine and erythromycin N-demethylase, ethoxycoumarin O-deethylase, and androstenedione 16 beta- and 15 alpha/6 beta hydroxylase activities; however, clorimazole did not induce aminopyrine N-demethylase activity irrespective of its marked increase in P450 content . Immunoblot analyses revealed that climbazole induced CYP2B1, 3A2 and 4A1 . The present findings indicate that climbazole is a new potent inducer of hepatic microsomal P450 and drug-metabolizing enzymes like clorimazole, but it may have some differential mechanism(s) for these enzymes' induction in rat liver.

Biochem Biophys Res Commun, 2001 Sep 14, 287(1), 198 - 203
Gene expression profiles of human small airway epithelial cells treated with low doses of 14- and 16-membered macrolides; Yamanaka Y et al.; Although long-term treatment with low doses of 14-membered macrolides is widely applied in management of patients with chronic inflammatory diseases, e.g., diffuse panbronchiolitis, chronic bronchitis, or chronic lung damage in newborns, the physiological mechanisms underlying the action of macrolides in these conditions are unclear . To clarify the pathological basis of these diseases and also to aid in the design of novel drugs to treat them, we chose to investigate the molecular target(s) of macrolides . Our experiments involved long-term culture of human small airway epithelial cells (hSAEC) in media containing 14-membered macrolides erythromycin (EM) or clarithromycin (CAM), or a 16-membered macrolide, josamycin (JM), which lacks clinical anti-inflammatory effects . We then analyzed gene expression profiles in the treated cells using a cDNA microarray consisting of 18,432 genes . We identified nine genes whose expression was significantly altered during 22 days of culture with EM, and seven that were altered by CAM in that time . Four of those genes revealed similar behavior in cells treated with either of the 14-membered macrolides, but not JM . The products of these four genes may be candidates for mediating the ability of 14-membered macrolides to suppress chronic inflammation .

Appl Microbiol Biotechnol, 2001 Aug, 56(3-4), 414 - 9
Disruption of a gene encoding a putative gamma-butyrolactone-binding protein in Streptomyces tendae affects nikkomycin production; Engel P et al.; A 2.6-kb BamHI fragment from the genome of the wild-type, nikkomycin-producing strain of Streptomyces tendae ATCC 31160 was cloned and sequenced . This 2.6-kb BamHI fragment corresponds to the DNA site where transposon Tn4560 had inserted to create a nikkomycin-nonproducing mutant . A possible ORF of 660 nucleotides was found in this 2.6-kb BamHI fragment, in which the third base of each codon was either G or C in 92% of the codons . The deduced amino acid sequence coded by this ORF (TarA, tendae autoregulator receptor) shows strong homology with several Gamma-butyrolactone-binding proteins that negatively regulate antibiotic production in other streptomycetes and have a helix-turn-helix DNA-binding motif . A portion (179 nucleotides) of tarA that encodes the helix-turn-helix motif was replaced with ermE, and wild-type S . tendae was transformed with this construct borne in pDH5, a gene-disruption vector . Southern hybridization indicated that ermE had inserted in the 2.6-kb BamHI region in one isolate that is erythromycin resistant . Northern hybridization indicated that tarA disruption significantly increased the amount of disrupted-tarA mRNA . This suggests that TarA negatively regulates its own synthesis . Nikkomycin production by the tarA disruptant was delayed but reached the wild-type level after longer incubation in production medium.

Zh Mikrobiol Epidemiol Immunobiol, 2001 Mar-Apr, (2), 36 - 40
{Etiology, clinical manifestations, and epidemiology in community-acquired respiratory infection in children in the Khabarovsk region}; Kholodok GN et al.; Clinico-epidemiological analysis and etiological verification of the outbreak of respiratory infection among school children in a rural district of the Khabarovsk territory, registered in spring 1997, were made . According to clinical signs, one-third of the patients had whooping cough, while the rest of the children exhibited the signs of respiratory infection with the symptoms of longering bronchitis . A half of the children had not been vaccinated against whooping cough, as they had been given injections of adsorbed DT vaccine with reduced antigen content . Etiologically, the diagnosis of whooping cough was confirmed in 57% of the patients with 47.4% of them having Bordetella pertussis monoinfection and 52.6% having mixed infection, mainly in combination with chlamydiosis . Whooping cough took an abnormal course under these circumstances . Treatment with erythromycin produced a good effect.

Cir Pediatr, 2001 Jul, 14(3), 98 - 102
{Anorexia nervosa or somatic disease}; Garcia Aroca J et al.; We have studied 18 patients with anorexia nervosa with antroduodenal manometry for 24 hours and also 24 hours oesophageal pH studies . After the first 12 hours of measurements we started treatment with Cisapride (n = 8) or Erythromycin (n = 10) in a blind study . The results of measurements reveal a severe gastroesophageal reflux in 4 patients . Antroduodenal manometry showed dysfunctions in gastric motility, without relation with weight loss or duration of the disease . Cisapride and more so Erythromycin favor gastrointestinal motility.

J Infect, 2001 Apr, 42(3), 206 - 7
Legionella pneumonia and bacteraemia in association with protein-losing enteropathy after Fontan operation; Cheung YF et al.; A 20-year-old young man suffered from severe protein-losing enteropathy 4 years after Fontan operation . His postoperative haemodynamics were unfavourable in terms of poor myocardial contractility and moderate atrioventricular prosthetic paravalvar leakage . A 2-week trial of steroid therapy for protein-losing enteropathy was given without success . The clinical course was complicated by Legionella pneumophila pneumonia and bacteraemia, which respond to the combination therapy with intravenous erythromycin and ciprofloxacin . The vulnerability of the patient to infection was related to an immuno-deficiency state secondary to protein-losing enteropathy and steroid therapy . Steroids should be used with caution in the management of protein-losing enteropathy after Fontan operation .

J Laryngol Otol, 2001 Aug, 115(8), 622 - 8
Reversible ototoxic effect of azithromycin and clarithromycin on transiently evoked otoacoustic emissions in guinea pigs; Uzun C et al.; The possible cochlear toxicity of systemically applied macrolides--erythromycin (ER), azithromycin (AZ) and clarithromycin(CL)--was investigated in guinea pigs by measuring transiently evoked otoacoustic emissions (TEOAEs) . A single dose of 125 mg/kg intravenous (i.v.) ER caused no change in TEOAEs in guinea pigs (p>0.05), whereas AZ (45 mg/kg orally) and CL (75 mg/kg i.v.) reversibly reduced the emission response (p<0.05) . The reversible reduction of TEOAE responses due to AZ and CL, which is in accordance with the clinical picture of AZ and CL ototoxicity, could likely be attributable to the transient dysfunction of outer hair cells . The present study reveals that at least one ototoxic effect of AZ and CL is on the inner ear . The results may also encourage planning clinical researches on TEOAE monitoring in patients receiving high doses of AZ or CL.

J Antimicrob Chemother, 2001 Sep, 48(3), 403 - 5
In vitro activity of telithromycin, a new ketolide, against Chlamydia pneumoniae; Miyashita N et al.; The in vitro activity of telithromycin, a new ketolide, was compared with those of roxithromycin, azithromycin, clarithromycin and erythromycin A against 20 strains of Chlamydia pneumoniae . The MICs and minimal chlamydiacidal concentrations of telithromycin for the 20 C . pneumoniae strains both ranged between 0.031 and 0.25 mg/L . Telithromycin was twice as active as roxithromycin, azithromycin and erythromycin A, but less active than clarithromycin . These results appear to indicate that telithromycin is an effective antibiotic that should play some role in the treatment of respiratory tract infections caused by C . pneumoniae.

Acta Obstet Gynecol Scand, 2001 Aug, 80(8), 697 - 701
Effects of erythromycin on stretch-induced contractile activity of isolated myometrium from pregnant women; Celik H et al.; BACKGROUND: Despite the fact that preterm labor and birth account for the vast majority of neonatal morbidity and mortality the currently available treatment options are still far from satisfactory . The aim of this study was to investigate the effects of erythromycin on stretch-induced contractions of pregnant human myometrial strips, obtained at cesarean section . METHOD: Myometrial strips were suspended in an organ bath under 3 g tension and the effects of erythromycin (0.1, 0.2, 0.5, 1.0 mM) on stretch-induced isometric contractions were evaluated . Results were statistically analyzed using Kruskal Wallis analysis of variance and Wilcoxon Rank tests where appropriate . RESULTS: Erythromycin caused a significant decrease in the peak amplitude, while causing an increase in frequency of stretch-induced myometrial contractions in a dose dependent manner in vitro . CONCLUSIONS: Results from this preliminary study suggest that erythromycin may have additional beneficial effects in infection related preterm labor cases, however, further studies are needed for clarifying the usefulness of erythromycin as a tocolytic agent.

Nihon Kokyuki Gakkai Zasshi, 2001 Jun, 39(6), 446 - 51
{A case of Coxiella burnetii pneumonia in an adult}; Miyashita N et al.; A 49-year-old man visited our hospital complaining of a continuous high-grade fever and cough which had appeared during his stay in Indonesia . He was admitted on the same day because his laboratory data showed marked inflammatory changes and his chest radiograph revealed an infiltrative shadow in the right upper lung field . Initial treatment with beta-lactams was not effective and both his symptoms and his chest radiograph worsened . However, treatment with erythromycin clearly had an effect . Then, we carried out several tests for detection of atypical pathogens including Mycoplasma and Chlamydia . Finally, the case was diagnosed as one of Coxiella burnetii pneumonia because the DNA of C . burnetii was detected from his sera and seroconversion of C . burnetii--specific antibody was observed among paired serum samples . C . burnetii is one of the most commonly recognized pathogens among community-acquired pneumonias in Western countries, but in Japan, reports of community-acquired C . burnetii pneumonia have been rare . This difference may be due to the features of Q fever, in which there are large differences in frequency and form from country to country and among areas of the same country . Surveillance of C . burnetii pneumonia in Japan and different area will be required.

Acta Paediatr, 2001 Aug, 90(8), 904 - 8
A placebo-controlled trial of low-dose erythromycin to promote feed tolerance in preterm infants; Oei J et al.; The aim of this study was to assess the efficacy of erythromycin, a motilin agonist, in promoting enteral feed tolerance in preterm infants of < or = 32 wk gestation . Eligible infants were randomized to receive either low-dose (2.5 mg kg(-1) per dose 6 hourly) oral erythromycin ethylsuccinate or placebo for 10 d from the time of the first oral feed . The data from 22 erythromycin and 21 placebo infants were analysed . Birthweights (erythromycin 1,216 +/- 380 g, placebo 1,355 +/- 228 g, p = 0.25), gestation (erythromycin 28.6 +/- 2.2 wk, placebo 29.3 +/- 1.7 wk, p = 0.24) and other clinical variables were not different between the groups . Almost all infants were fed expressed breast milk . Erythromycin infants had significantly fewer episodes of large residual gastric aspirates (>30% of the previous 6 h worth of feeds) over 10 d (erythromycin 1.1 +/- 1.9, placebo 3.6 +/- 2.2 episodes, p = 0.0007) . Infants in the erythromycin group achieved full oral feeds more quickly (6.0 +/- 2.3 vs 7.9 +/- 3.5 d, p = 0.04) . There were no significant differences between the groups with regard to the number of days on total parenteral nutrition or to the time needed to regain birthweight . One enrolled infant from each group died of necrotizing enterocolitis . CONCLUSION: Low-dose erythromycin promoted gastric emptying and feed tolerance in premature infants at a lower gestational age than previously reported . Increased exposure to broad-spectrum antibiotics may not be free of risk . Further studies are recommended to assess its efficacy in premature infants with established feed intolerance.

Biopharm Drug Dispos, 2000 Nov, 21(8), 331 - 8
Effects of physostigmine on the pharmacokinetics of intravenous parathion in rats; Hurh E et al.; It was reported that the area under the plasma concentration-time curve from time zero to time infinity (AUC) of parathion was significantly smaller, and the time-averaged total body clearance (Cl) of parathion was significantly faster after intravenous administration of parathion to rats pretreated with dexamethasone than those in control rats . This was supported by significantly faster intrinsic clearance of parathion to form paraoxon in hepatic microsomal fraction of rats pretreated with dexamethasone . The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible hepatic cytochrome P450 (CYP) 3A in rats . The purpose of this study is to explain the protective effects of physostigmine against paraoxon toxicity by suppressing CYP3A, and hence, decreasing formation of a toxic metabolite, paraoxon . The pharmacokinetic changes of parathion and paraoxon were investigated after intravenous administration of parathion, 3 mg/kg, to control Sprague-Dawley rats, and the rats pretreated with physostigmine (100 microg/kg, intraperitoneal injection 30 min before parathion administration) . After a 1-min intravenous infusion of parathion to rats pretreated with physostigmine, the AUC of parathion (60.4 compared with 73.7 microg min/mL) was significantly greater, Cl of parathion (49.7 compared with 40.7 mL/min/kg) was significantly slower, and amount of paraoxon recovered from liver, mesentery and large intestine at 5 min was smaller than those in control rats . Based on in vitro rat hepatic microsomal studies, physostigmine inhibited significantly the erythromycin N-demethylase activity (1.03 compared with 0.924 nmol/mg protein/min), mainly mediated by hepatic cytochrome P450 3A in rats . The above data suggested that the formation of paraoxon was inhibited in rats pretreated with physostigmine by inhibiting CYP3A .

J Agric Food Chem, 2001 Aug, 49(8), 3709 - 12
Procedure to evaluate the stability during processing and storage of a medicated premix and medicated farm feed: erythromycin thiocyanate; Bernabeu JA et al.; In this paper, a stability study of a medicated premix and medicated farm feed containing erythromycin thiocyanate was planned . No drug degradation was detected during the medicated farm feed processing . In the medicated premix stability study, significant drug degradation was detected only at 40 degrees C and 75% relative humidity . Because after 2 years of storage at 25 degrees C and 60% relative humidity no degradation of erythromycin thiocyanate was detected, this period of time is proposed as the premix shelf life . In the medicated farm feed stability study, drug degradation was detected under accelerated conditions, but it was not detected under long-term storage conditions for 3 months . Therefore, the proposed shelf life of the medicated farm feed is 3 months, as this is time enough to be consumed . The planned stability study-storage conditions, testing frequency, and proposed data evaluation-allowed an easy and reliable evaluation of veterinary medicine stability.

Gut, 2001 Sep, 49(3), 395 - 401
Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial; Talley NJ et al.; INTRODUCTION: Erythromycin, a motilin agonist, is a potent prokinetic . ABT-229 is a specific motilin agonist that dose dependently accelerates gastric emptying . Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus . We aimed to evaluate the efficacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying . METHODS: Patients with type 1 diabetes and postprandial symptoms were randomised (n=270) . Based on a validated C(13) octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata . Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline . A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0-800 mm) from baseline to the final visit . RESULTS: The treatment arms were similar regarding baseline characteristics . There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline -169, -101, -155, -143, and -138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat) . The results were not significantly different in those with and without delayed gastric emptying . The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo . Overall, 63% of patients on placebo reported a good or excellent global response, and this was not different from the active treatment arms . CONCLUSIONS: The motilin agonist ABT-229 was not efficacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying.

Mol Cell, 2001 Jul, 8(1), 181 - 8
The polypeptide tunnel system in the ribosome and its gating in erythromycin resistance mutants of L4 and L22; Gabashvili IS et al.; Variations in the inner ribosomal landscape determining the topology of nascent protein transport have been studied by three-dimensional cryo-electron microscopy of erythromycin-resistant Escherichia coli 70S ribosomes . Significant differences in the mouth of the 50S subunit tunnel system visualized in the present study support a simple steric-hindrance explanation for the action of the drug . Examination of ribosomes in different functional states suggests that opening and closing of the main tunnel are dynamic features of the large subunit, possibly accompanied by changes in the L7/L12 stalk region . The existence and dynamic behavior of side tunnels suggest that ribosomal proteins L4 and L22 might be involved in the regulation of a multiple exit system facilitating cotranslational processing (or folding or directing) of nascent proteins.

Clin Pharmacokinet, 2001, 40(7), 501 - 7
Clinical pharmacokinetics of mizolastine; Lebrun-Vignes B et al.; Mizolastine is a new histamine H1 receptor antagonist . Mizolastine 10 mg/day is effective in allergic rhinitis and chronic idiopathic urticaria . In young healthy volunteers, absorption of mizolastine is rapid with time (tmax) to peak concentration (Cmax) of about 1 hour . The absolute bioavailability of mizolastine 10mg tablets is about 65% . Distribution is rapid with a mean distribution half-life of 1.5 to 1.9 hours . Mizolastine is >98% bound to serum albumin and the apparent volume of distribution is between I and 1.4 L/kg . Mizolastine is extensively metabolised by hepatic glucuronidation and sulphation, with no major active metabolite, and excreted in faeces . The terminal elimination half-life (t1/2beta) is 7.3 to 17.1 hours . The apparent oral clearance after a repeated oral dose of 10mg is 6.02 L/h, with steady state reached from day 3 and no accumulation between days 1 and 7 . Cmax and area under the concentration-time curve (AUC) are linearly related to dose . Mizolastine appears in vivo to be a relatively weak inhibitor of cytochrome P450 2E1, 2C9, 2D6 and 3A4 . In vivo, no interactions were observed between mizolastine and lorazepam or ethanol . A significant increase in Cmax and trough plasma concentration (Cmin) of digoxin occurred after coadministration with mizolastine, without change in AUC, tmax or clinical parameters . Significant increases in theophylline Cmin and AUC were observed after coadministration with mizolastine . Mizolastine Cmax and AUC were increased when coadministered with erythromycin, with no change in t1/2beta . Concomitant administration of mizolastine and ketoconazole increased mizolastine AUC values with no change in t1/2beta . In a population analysis of the pharmacokinetics of mizolastine in patients with allergies, parameter values were close to those in healthy volunteers, except for duration of absorption, which was almost doubled in the patients . Bodyweight and creatinine clearance were found to have little influence on oral clearance, and no influence of liver transaminases was found on clearance and distribution . Pharmacokinetic parameters of mizolastine in elderly individuals were similar to those observed in healthy young volunteers . In patients with chronic renal insufficiency, t1/2beta was prolonged by 47% compared with young healthy volunteers . In patients with cirrhosis, tmax was longer, Cmax was lower, distribution half-life was prolonged and AUC was 50% higher than in healthy volunteers . In pharmacodynamic-pharmacokinetic trials, the percentage of wheal and flare inhibition was found to correlate with mizolastine Cmin values . No direct relationship was found between drug concentrations in skin blister fluid and antihistamine activity.

Mutat Res, 2001 Sep 1, 480-481, 171 - 8
Inhibitory effect of naringin on the micronuclei induced by ifosfamide in mouse, and evaluation of its modulatory effect on the Cyp3a subfamily; Alvarez-Gonzalez I et al.; Naringin (Nar) is a flavonone found in high amount in grapefruit . In in vitro studies to determine its antimutagenicity results have been both positive and negative . On the other hand, an increase in the bioavailability of some medicaments have been observed when these are ingested together with grapefruit . It has been suggested that the effect may be related to the inhibition of the human enzyme Cytochrome P450 (CYP) 3A4 by Nar, an enzyme with a high aminoacid sequence homology with the Cyp3a in mouse . The present study was designed for three main purposes: (1) to determine whether Nar has a genotoxic effect in mouse in vivo . This was evaluated by measuring the rate of micronucleated polychromatic erythrocytes (MNPE); (2) to determine its antigenotoxic and its anticytotoxic potential on the damage produced by ifosfamide (Ifos) . The first study was done by scoring the rate of MNPE, and the second one by establishing the index polychromatic erythrocytes/normochromatic erythrocytes (PE/NE); and (3) to explore whether its antigenotoxic mechanism of action is related to an inhibitory effect of Nar on the expression of the Cyp3a enzyme, an effect which could avoid the biotransformation of Ifos . A single oral administration was used for all groups in the experiment: three groups were given different doses of Nar (50, 250, and 500 mg/kg), other groups received the same doses of Nar plus an administration of Ifos (60 mg/kg), another group treated with distilled water and another with Ifos (60 mg/kg) were used as negative and positive controls, respectively . The micronuclei and the cell scoring were made in blood samples taken from the tail of the animals at 0, 24, 48, 72, and 96 h . The results showed that Nar was neither genotoxic nor cytotoxic with the doses tested, but Ifos produced an increase in the rate of MNPE at 24 and 48 h . The highest value was 24+/-1.57 MNPE per thousand cells at 48 h . The index PE/NE was significantly reduced by Ifos at 24 and 48 h . Concerning the antigenotoxic capacity of Nar, a significant decrease was observed in the MNPE produced by Ifos at the three tested doses . This effect was dose-dependent, showing the highest reduction in MNPE frequency (54.2%) at 48 h with 500 mg/kg of Nar . However, no protection on the cytotoxicity produced by Ifos was observed . Immunoblot analysis was used to assess the Cyp3a expression in liver and intestinal microsomes from mouse exposed orally to Nar . An induction in the Cyp3a protein was observed in both intestinal and hepatic microsomes from treated mice . This induction correlated with an increase in erythromycin N-demethylase activity . These data suggest that other mechanism(s) are involved in the antigenotoxic action of naringin.

J Clin Pharmacol, 2001 Aug, 41(8), 852 - 60
The risk of liver damage associated with minocycline: a comparative study; Seaman HE et al.; Using the General Practice Research Database, the authors performed (1) a cohort analysis comparing the incidence of liver dysfunction in new users of minocycline with new users of oxytetracycline/tetracycline and (2) a case control study assessing antibiotic exposure in new cases of liver dysfunction and controls without liver dysfunction . In new users, the incidence of liver dysfunction in those exposed to minocycline was 1.04 cases/10,000 exposed person months (EPM) and 0.69 cases/10,000 EPM in those exposed to oxytetracycline/tetracycline (relative risk 1.51 {CI95: 0.63, 3.65}) . The risk in both groups was greatest in the first month of use . The adjusted odds ratio (ORadj) of liver dysfunction associated with exposure to minocycline compared with nonuse was 2.10 (CI95: 1.30, 3.40); for oxytetracycline/tetracycline, the ORadj was 1.46 (CI95: 0.81, 2.64); and for exposure to erythromycin, the ORadj was 1.64 (CI95: 0.71, 3.80) . The authors thus support a weak association between the use of oral antibiotics and liver dysfunction in patients with acne . The risk associated with exposure to minocycline appears to be very small . The cohort analysis demonstrated that any risk associated with minocycline was not significantly greater than that associated with oxytetracycline/tetracycline exposure.

Prescrire Int . 2001 Feb;10(51):16.
Erythromycin-induced pyloric stenosis in infants; Choosing a macrolide: drug interactions must be taken into account; (1) Some macrolides carry a strong risk of potentially severe drug interactions . (2) Erythromycin is the macrolide with the biggest risk of interactions . (3) Spiramycin is the macrolide with the smallest risk of interactions . Azithromycin and dirithromycin also seem to have a low risk of interactions, but they are far more recent and therefore less well known . (4) In first-line use, unless there are specific indications, a macrolide with a low risk of interactions should be used.

Antimicrob Agents Chemother, 2001 Sep, 45(9), 2643 - 7
Stability and compatibility of ceftazidime administered by continuous infusion to intensive care patients; Servais H et al.; The stability and compatibility of ceftazidime have been examined in the context of its potential use in concentrated solutions for continuous infusion in patients suffering from severe nosocomial pneumonia and receiving other intravenous medications by the same route . Ceftazidime stability in 4 to 12% solutions was found satisfactory (<10% degradation) for 24 h if kept at a temperature of 25 degrees C (77 degrees F) maximum . Studies mimicking the simultaneous administration of ceftazidime and other drugs as done in clinics showed physical incompatibilities with vancomycin, nicardipine, midazolam, and propofol and a chemical incompatibility with N-acetylcystein . Concentrated solutions (50 mg/ml) of erythromycin or clarithromycin caused the appearance of a precipitate, whereas gentamicin, tobramycin, amikacin, isepamicin, fluconazole, ketamine, sufentanil, valproic acid, furosemide, uradipil, and a standard amino acid solution were physically and chemically compatible.

Xenobiotica, 2001 May, 31(5), 265 - 75
Cooperativity of alpha-naphthoflavone in cytochrome P450 3A-dependent drug oxidation activities in hepatic and intestinal microsomes from mouse and human; Emoto C et al.; 1 . The effects of several CYP3A substrates (alpha-naphthoflavone (alphaNF), terfenadine, midazolam, erythromycin) on nifedipine oxidation and testosterone 6beta-hydroxylation activities were investigated in hepatic and intestinal microsomes from mouse and human . 2 . alphaNF (10 microM) and terfenadine (100 microM) inhibited nifedipine oxidation activities (at substrate concentration of 100 microM) in mouse hepatic microsomes to approximately 50%, but not in mouse intestinal microsomes . alphaNF (30 microM) stimulated nifedipine oxidation activities in mouse and human intestinal microsomes and in human hepatic microsomes to approximately 1.3-1.8-fold . Inhibitory potencies (50% inhibition concentration, IC50) of midazolam and erythromycin for nifedipine oxidations were calculated to be approximately 90 microM in human intestinal microsomes . In contrast, testosterone (100 microM) stimulated the nifedipine oxidation activities approximately 1.5-fold in hepatic and intestinal microsomes from mouse and human . 3 . alphaNF showed different effects on the kinetic parameters including the Hill coefficients of nifedipine oxidation and testosterone 6beta-hydroxylation catalysed by hepatic and intestinal microsomes from mouse and human . Cooperativity in nifedipine oxidation was increased by the addition of alphaNF to pooled human hepatic microsomes, but little effects of alphaNF could be observed in individual human intestinal microsomes . 4 . These results suggest that CYP3A enzymes in liver and intestine might have different characteristics and that observations from hepatic microsomes should not be directly applicable to intestine metabolism in some cases . Studies of drug-drug interactions of CYP3A substrates are recommended to be performed using intestinal samples.

Ir J Med Sci, 2001 Apr-Jun, 170(2), 126 - 31
Electrogastrography: a non-invasive measurement of gastric function; Lawlor PM et al.; BACKGROUND: Electrogastrography (EGG) is the non-invasive measurement of gastric electrical activity . With the development of modern technology, improved recording and automated analysis, it is a reliable and accurate technique for the measurement of gastric myoelectrical activity providing information about the frequency and regularity of the gastric slow wave . AIM: The aim of this report is to evaluate its role in clinical practice . METHODS: The literature is reviewed and its role investigated . RESULTS: EGG has been successfully used in the investigation of gastroparesis, non-ulcer dyspepsia (NUD), gastric emptying (GE) disorders and diabetes mellitus (DM) . EGG also provides an insight into the effect of medications on gastric function, e.g . edrophonium, cisapride, erythromycin and proton-pump inhibitors (PPI) . CONCLUSIONS: EGG has a developing role in the assessment of gastric dysfunction and on the effect of medical treatment . The effect of surgery and anaesthesia on gastric myoelectric activity is less clear.

Curr Treat Options Gastroenterol, 2001 Apr, 4(2), 179 - 191
Gastric Dysmotility and Gastroparesis; McCallum RW et al.; Nutrition support in gastroparesis begins with encouraging smaller volume, low-fat, low-fiber meals and, if necessary, liquid caloric supplements . There should be a low threshold for placing a jejunal feeding tube either by laparoscopy or mini-laparotomy . Parenteral nutrition should be used only briefly during hospitalization and not encouraged or sustained as an outpatient . Metoclopramide is now the prokinetic of choice for patients who can tolerate this agent; subcutaneous administration is an important method that allows for continued guaranteed absorption . Low-dosage erythromycin also has a prokinetic role alone or in combination with metoclopramide . Domperidone, a centrally acting antiemetic and prokinetic, is only be available to US citizens who can access sources in Canada or Mexico . Antiemetics should be used extensively because nausea is a very severe debilitating symptom, which is under-appreciated and under-treated by physicians . We recommend scopolamine patches to gain maximal absorption, in spite of vomiting and unpredictable oral intakes . The 5-hydroxytryptamine-3 (5-HT3) antagonists ondansetron and granisetron are the most powerful agents . Relief bands using the P6 acupuncture point are useful adjunct . Special vigilance should be paid to situations that can undermine medical therapy or result in breakthrough symptoms, such as hyperglycemic events in patients with diabetes, migraine headaches, cyclic nausea and vomiting, menstrual cycles, rumination syndrome (psychogenic vomiting), and elevated herpes simplex titers . Most excitingly, the era of gastric electrical stimulation has arrived for patients not responding to standard medical therapy . The dramatic improvement in nausea and vomiting, as well as a sustained evidence of improved quality of life, gastric emptying, nutritional status, and decreased hospitalizations by this device are documented by long-term follow-up of more than a year for patients in this country and world-wide.

Am J Gastroenterol, 2001 Jul, 96(7), 2041 - 50
Effects of low doses of erythromycin on the 13C Spirulina platensis gastric emptying breath test and electrogastrogram: a controlled study in healthy volunteers; DiBaise JK et al.; OBJECTIVE: Electrogastrography and stable isotope gastric emptying breath tests (GEBTs) are relatively simple, noninvasive tests of gastric motor function that may be useful in monitoring the effects of therapeutic interventions . It was our primary objective to examine the effects of low dose i.v . erythromycin on the results of the 13C Spirulina platensis GEBT and electrogastrography . We were also interested in evaluating the reproducibility of these tests . METHODS: In 10 healthy subjects (five female, ages 23-37 yr), we simultaneously performed the GEBT, using a prepackaged meal (340 kcal), and electrogastrography on each of four different occasions separated by at least 1 wk . After performance of baseline studies, they were repeated in random order after the infusion of 50 mg of erythromycin (Er50), 100 mg erythromycin (Er100), and a placebo (saline) . Breath samples were obtained at baseline and at 75, 90, and 180 min after the meal and T1/2 and Tlag calculated . Electrogastrography recordings began 30 min before the test meal and continued for 2 h after the meal . RESULTS: Baseline and placebo T1/2 and Tlag were similar . Er50 resulted in a modest acceleration of gastric emptying (T1/2 Er50 vs baseline vs placebo = 104.0 vs 132.7 vs 125.5 min) and reduction in lag time (Tlag Er50 vs baseline vs placebo = 47.2 vs 61.5 vs 56.2 min) . A similar decrease was seen in response to Er100 . The baseline and placebo fasting and fed electrogastrography parameters were similar . After infusion of Er100, the percentage of normal slow waves in the first postprandial hour decreased relative to baseline and placebo (percent normogastria Er100 vs baseline vs placebo = 64.1+/-7.5 vs 82.4+/-6.4 vs 79.7+/-5.5) . This corresponded with an increase in percent tachygastria during the same period and an overall decrease in the mean dominant frequency . Similar but less striking changes were seen after administration of Er50 . Replicate GEBTs showed a high degree of reproducibility both within and between individuals for T1/2 and Tlag . In contrast, replicate electrogastrograms revealed moderate to high variability for all parameters except the dominant frequency . CONCLUSION: The stable isotope GEBT utilizing 13C S . platensis demonstrates responsiveness to the prokinetic effects of low dose i.v . erythromycin and good reproducibility.

Pharm Res, 2001 May, 18(5), 652 - 5
Development of a generalized, quantitative physicochemical model of CYP3A4 inhibition for use in early drug discovery; Riley RJ et al.; PURPOSE: To examine the structure-activity relationships for the inhibition of the activity of recombinant human CYP3A4 and to establish a generalized, quantitative physicochemical model for use in early drug discovery . METHODS: Inhibition of the activity of recombinant human CYP3A4 (erythromycin N-demethylase) by 30 diverse chemicals was studied using enhanced throughput methodology . RESULTS: There was a general, strong correlation between the IC50 value determined against erythromycin N-demethylase activity and lipophilicity (LogD7.4) (r2 = 0.68, p <0.0001) . This relationship was strengthened further by subdividing the structures studied into two distinct subpopulations of chemistry within the dataset . These could be identified by the absence (r2 = 0.80, p <0.0001) or presence (r2 = 0.69, p <0.0001) of a sterically uninhindered N-containing heterocycle, more specifically a pyridine, imidazole, of triazole function . The presence of these structural motifs increased the potency of CYP3A4 inhibition by approximately 10-fold for a given lipophilicity (LogD7.4.value) . More detailed analyses of AstraZeneca compounds demonstrated that the inhibitory potency of the pyridine structure can be attenuated through direct steric effects or electronic substitution resulting in a modulation of the pKa of the pyridine nitrogen, thereby influencing its ability to interact with the CYP heme . CONCLUSIONS: A generalized, quantitative model is proposed for the inhibition of the major drug metabolizing enzyme, CYP3A4 . This model indicates the importance of lipophilicity and rationalizes increased potency arising through additional interactions with the heme iron . These general relationships were shown to be applicable to a selection of compounds of interest to several early research projects.

J Am Chem Soc, 2001 Mar 21, 123(11), 2495 - 502
Precursor-directed biosynthesis of 16-membered macrolides by the erythromycin polyketide synthase; Kinoshita K et al.; Streptomyces coelicolor CH999/pJRJ2 harbors a plasmid encoding DEBS(KS1 degrees ), a mutant form of 6-deoxyerythronolide B synthase that is blocked in the formation of 6-deoxyerythronolide B (1, 6-dEB) due to a mutation in the active site of the ketosynthase (KS1) domain that normally catalyzes the first polyketide chain elongation step of 6-dEB biosynthesis . Administration of (2E,4S,5R)-2,4-dimethyl-5-hydroxy-2-heptenoic acid, N-acetylcysteamine thioester (6) an unsaturated triketide analogue of the natural triketide chain elongation intermediate to cultures of S . coelicolor CH999/pJRJ2 results in formation of a 16-membered macrolactone, which is isolated in the hemiketal form 33 . The formation of the octaketide 33 indicates that the triketide substrate has been processed by DEBS module 2 as if it were a diketide analogue . The substrate specificity of this novel reaction has been explored by the incubation of three additional analogues of the unsaturated triketide 6, compounds 18, 31, and 32, with S . coelicolor CH999/pJRJ2, resulting in the formation of the corresponding macrolactones 34, 35, and 36 . By contrast, the unsaturated triketide 10, lacking a methyl group at C-2, did not give rise to any detectable macrolactone product when incubated with S . coelicolor CH999/pJRJ2.

Gut, 2001 Aug, 49(2), 203 - 8
Perception of changes in wall tension of the proximal stomach in humans; Piessevaux H et al.; BACKGROUND: Hypersensitivity to distension of the stomach is a frequent finding in functional dyspepsia . During gastric distension studies both wall tension and elongation are increased . AIM: We wished to distinguish changes in wall tension from changes in elongation in the genesis of perception of mechanical stimuli originating from the proximal stomach in healthy subjects . SUBJECTS AND METHODS: Twenty six volunteers were studied using gastric barostat and antroduodenal manometry . In 14 subjects, stepwise isobaric and isovolumetric distensions were performed before and during erythromycin infusion . In all volunteers, on a separate occasion, phasic contractions of the proximal stomach were detected as intraballoon pressure increases during fixed volume inflation . These contractions were matched with perception changes during two 10 minute periods, before and during administration of erythromycin . RESULTS: Erythromycin significantly lowered the perception and discomfort thresholds during stepwise gastric distension . During fixed volume inflation, erythromycin increased the number and amplitude of fundic contractions and enhanced their perception from 51.1 (7.4)% to 64.0 (4.7)% . The proportion of perception score increases coinciding with fundic contractions increased from 47.3 (0.7)% to 81.5 (0.5)% . The amplitude of correctly identified isolated fundic pressure waves was higher compared with non-identified waves . CONCLUSIONS: These results support the hypothesis that changes in gastric wall tension may be involved in the genesis of symptoms originating from the stomach.

Chest, 2001 Jul, 120(1), 198 - 202
Centrilobular nodules correlate with air trapping in diffuse panbronchiolitis during erythromycin therapy; Yamada G et al.; BACKGROUND: Low-dose erythromycin therapy improves airflow limitation and airway inflammation in patients with diffuse panbronchiolitis (DPB) . However, to our knowledge there has been no study to determine whether physiologic improvement during erythromycin therapy correlates with radiologic findings . Study objective: To clarify whether improvement in pulmonary function correlates with specific changes on chest CT . DESIGN: The relationship between five CT findings and five pulmonary function parameters was evaluated before and 3 months after low-dose erythromycin therapy in 24 patients with DPB retrospectively . RESULTS: After erythromycin therapy, the predicted percentage of vital capacity (%VC; 87.0 +/- 3.07% vs 98.9 +/- 3.39%; p = 0.00006) and 50% of the maximum midexpiratory flow rate of FVC (1.41 +/- 0.26 L/s vs 1.61 +/- 0.27 L/s; p = 0.03) significantly increased, and the residual volume/total lung capacity ratio (RV/TLC%; 44.5 +/- 1.93% vs 40.7 +/- 1.83%; p = 0.0019) significantly decreased, but the FEV(1) to FVC ratio and 25% of the maximum expiratory flow rate of FVC did not . In five CT findings, centrilobular nodules (3.7 +/- 0.4 vs 1.5 +/- 0.3; p = 0.0001), peripheral bronchiolar wall thickness (3.8 +/- 0.3 vs 2.6 +/- 0.4; p = 0.0007), and peripheral bronchiolectasis (2.8 +/- 0.3 vs 2.2 +/- 0.4; p = 0.0058) had significantly improved, whereas low attenuation area and central bronchiectasis had not . There were positive correlations of improved scores of centrilobular nodules with improved %VC (r = 0.58, p = 0.0062) and RV/TLC% (r = 0.64, p = 0.0022) . CONCLUSIONS: Decreased air trapping in DPB correlates with an improvement of centrilobular nodules, which reflects the obstructive lesions of bronchioles during the erythromycin therapy.

Allergol Immunopathol (Madr), 2001 Jan-Feb, 29(1), 31 - 2
Immediate reaction to clarithromycin; Gangemi S et al.; We present the case of bronchospastic reaction to clarithromycin had during a drug challenge test . Personal allergic history was negative for respiratory allergies and positive for adverse drug reactions to general and regional anesthesia and to ceftriaxone . After the administration of 1/4 of therapeutic dose of clarithromycin the patient showed dyspnea, cough and bronchospasm in all the lung fields . The positivity of the test was confirmed by the negativity to the administration of placebo . The quickness and the clinical characteristic of the adverse reaction suggest a pathogenic mechanism of immediate-type hypersensitivity . On reviewing the literature we have found no reports of bronchospastic reaction to clarithromycin . Macrolides are a class of antibiotics mainly used in the last years in place of beta-lactams because of a broad spectrum of action and a low allergic power . In fact, there are few reports on allergic reactions to these molecules . Clarithromycin is one of the latest macrolides, characterised by the presence of a 14-carbon-atom lactone ring as erythromycin, active on a wide spectrum of pathogens.

Dermatol Surg, 2001 Jul, 27(7), 648 - 53; discussion 653-4
Artificial skin for closure and healing of wounds created by skin cancer excisions; Prystowsky JH et al.; BACKGROUND: A dermal regeneration template indicated for life-threatening third-degree burn injuries is a product with potential application to smaller wounds to aid in healing and closure of complex excision sites . OBJECTIVE: To assess the effectiveness of dermal regeneration template for closure of skin cancer excision sites that would have otherwise required complicated closures . METHODS: Five patients, 61-84 years old, with skin cancer surgery yielding a total of six wounds were treated with the dermal regeneration template to close and heal their wounds . RESULTS: Four of five patients had complete healing (five of six wounds) with cosmetically acceptable results . The one treatment failure was application of the dermal regeneration template over exposed skull where inadequate neodermis formed . Successful healing was observed in five complex skin cancer excision sites including two wounds in previously irradiated grafted skin, a large and deep temporal defect, a wide excision in the supraclavicular region, and an excision down to cartilage on the antihelix of the ear . No infections were noted, although in four of five patients prophylactic oral antibiotics (either erythromycin or cephalexin) were prescribed postoperatively for 1-2 weeks . CONCLUSION: The product simplified wound care, subjectively appeared to decrease pain and postoperative bleeding, and yielded cosmetically acceptable wound repair . Autografting was not necessary; wounds healed in 2-4 months by epithelialization over neodermis after removal of the silicone layer . Furthermore, the product was a convenient long-term dressing and healing device for wounds where complex repairs, autografts, and/or flaps would otherwise be considered for closure.

J Am Chem Soc, 2001 Jul 11, 123(27), 6465 - 74
Assessing the balance between protein-protein interactions and enzyme-substrate interactions in the channeling of intermediates between polyketide synthase modules; Wu N et al.; 6-Deoxyerythronolide B synthase (DEBS) is the modular polyketide synthase (PKS) that catalyzes the biosynthesis of 6-deoxyerythronolide B (6-dEB), the aglycon precursor of the antibiotic erythromycin . The biosynthesis of 6-dEB exemplifies the extraordinary substrate- and stereo-selectivity of this family of multifunctional enzymes . Paradoxically, DEBS has been shown to be an attractive scaffold for combinatorial biosynthesis, indicating that its constituent modules are also very tolerant of unnatural substrates . By interrogating individual modules of DEBS with a panel of diketides activated as N-acetylcysteamine (NAC) thioesters, it was recently shown that individual modules have a marked ability to discriminate among certain diastereomeric diketides . However, since free NAC thioesters were used as substrates in these studies, the modules were primed by a diffusive process, which precluded involvement of the covalent, substrate-channeling mechanism by which enzyme-bound intermediates are directly transferred from one module to the next in a multimodular PKS . Recent evidence pointing to a pivotal role for protein-protein interactions in the substrate-channeling mechanism has prompted us to develop novel assays to reassess the steady-state kinetic parameters of individual DEBS modules when primed in a more "natural" channeling mode by the same panel of diketide substrates used earlier . Here we describe these assays and use them to quantify the kinetic benefit of linker-mediated substrate channeling in a modular PKS . This benefit can be substantial, especially for intrinsically poor substrates . Examples are presented where the k(cat) of a module for a given diketide substrate increases >100-fold when the substrate is presented to the module in a channeling mode as opposed to a diffusive mode . However, the substrate specificity profiles for individual modules are conserved regardless of the mode of presentation . By highlighting how substrate channeling can allow PKS modules to effectively accept and process intrinsically poor substrates, these studies provide a rational basis for examining the enormous untapped potential for combinatorial biosynthesis via module rearrangement.

Ann Thorac Surg, 2001 Jun, 71(6), 1786 - 91
Bile exposure of the denervated stomach as an esophageal substitute; Gutschow CA et al.; BACKGROUND: Both the supine position and the existence of a gastric drainage procedure are suspected to promote reflux of duodenal juice into the denervated intrathoracic stomach . Erythromycin has been shown to weaken pyloric resistance to gastric outflow and to enhance antral motility, gastric emptying, and gallbladder contractility . METHODS: The presence of bile in the gastric transplant of 79 patients was monitored over a 24-hour period with use of the Bilitec 2000 optoelectronic device 3 to 195 months after subtotal esophagectomy . Ten patients were reinvestigated after a 3-year period . Five groups were studied: group I: n = 12, no gastric drainage, never given erythromycin, group 2: n = 40, gastric drainage, never given erythromycin, group 3: n = 7, no gastric drainage, given erythromycin, group 4: n = 13, gastric drainage, given erythromycin, and group 5: n = 7, no longer given erythromycin (with or without gastric drainage) . The percentage of time gastric bile absorbance was more than 0.25 was calculated for the total, supine, and upright periods of recording in reference to data from 25 healthy volunteers . RESULTS: The Bilitec test was pathologic in 9 of the 12 patients of group 1 whereas it was normal in three . Gastric exposure to bile was longer in group I patients than in controls for the total (p = 0.012) and supine (0.036) periods, but the difference did not reach statistical significance for the upright period (p = 0.080) . Bile exposure in group 4 did not significantly differ from controls (total: p = 0.701; supine: p = 0.124; upright: p = 0.712) . Bile exposure for the total period did not significantly differ whether patients were taking erythromycin or the drug had been discontinued at the time of the study (p = 0.234); and it tended to decrease with time in patients investigated twice (p = 0.046) . CONCLUSIONS: Gastric exposure to bile after truncal vagotomy and transposition of the stomach up to the neck is pathologic in three quarters of patients . It is more marked in the supine than in the upright position and tends to decrease with time . The addition of a gastric drainage procedure in combination with erythromycin therapy tends to normalize gastric exposure to bile . The effects of erythromycin may persist after discontinuation of the drug.

Expert Opin Investig Drugs, 2001 Mar, 10(3), 547 - 60
Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug; Agrawal DK; Desloratadine is a biologically active metabolite of the second-generation antihistamine loratadine . Desloratadine is a highly selective peripheral H1 receptor antagonist that is significantly more potent than loratadine . Results of in vitro and in vivo studies have suggested that desloratadine has anti-allergic effects that are unrelated to its ability to antagonise the effects of histamine . Desloratadine inhibits the expression of cell adhesion molecules, inhibits the generation and release of inflammatory mediators and cytokines, attenuates eosinophil chemotaxis, adhesion and superoxide generation . Studies in animals indicate that desloratadine does not cross the blood-brain barrier and therefore does not cause sedation and does not impair cognition or psychomotor performance . Desloratadine has an excellent overall safety profile . It has no effect on QRS and QTc intervals and does not cause arrhythmias . Desloratadine is not associated with any significant changes in gastrointestinal function . In clinical studies, oral desloratadine is rapidly absorbed and bioavailability is not affected by ingestion with food or grapefruit juice . The half-life of desloratadine in humans is 27 h; the linear kinetic profile is unaltered by race or gender . Desloratadine is not a substrate for P-glycoprotein or organic anion transport polypeptide and the drug does not appear to be metabolised to a significant extent by the cytochrome P450 CYP3A4 pathway . It therefore may be safely administered with ketoconazole, erythromycin, fluoxetine, or azithromycin . Clinically, desloratadine effectively controls both nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR), including nasal congestion . Desloratadine also provides significant relief of SAR symptoms in patients with co-existing asthma and is effective in the treatment of chronic idiopathic urticaria . Desloratadine improves quality of life and is well-tolerated.

Rev Mal Respir, 2001 Apr, 18(2), 193 - 6
{Sinobronchial syndrome}; Courbot A et al.; The sinobronchial syndrome consists of chronic sinusitis and chronic nonspecific inflammation of the lower airways, typically chronic bronchitis, bronchiectasis and diffuse panbronchiolitis . This airway disease of unknown etiology is not related to smoking . It is common in Japan and is poorly described in western countries . We report a case in a non-Asian patient . The known efficacy of long-term low-dose erythromycin therapy justifies careful diagnosis of sinobronchial syndrome in patients of non-Asian ethnic origin.

Br J Clin Pharmacol, 2001 Jun, 51(6), 591 - 600
Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers; Khaliq Y et al.; AIMS: To evaluate the pharmacokinetic interaction between ritonavir and mefloquine . METHODS: Healthy volunteers participated in two separate, nonfasted, three-treatment, three-period, longitudinal pharmacokinetic studies . Study 1 (12 completed): ritonavir 200 mg twice daily for 7 days, 7 day washout, mefloquine 250 mg once daily for 3 days then once weekly for 4 weeks, ritonavir restarted for 7 days simultaneously with the last mefloquine dose . Study 2 (11 completed): ritonavir 200 mg single dose, mefloquine 250 mg once daily for 3 days then once weekly for 2 weeks, ritonavir single dose repeated 2 days after the last mefloquine dose . Erythromycin breath test (ERMBT) was administered with and without drug treatments in study 2 . RESULTS: Study 1: Ritonavir caused less than 7% changes with high precision (90% CIs: -12% to 11%) in overall plasma exposure (AUC(0,168 h)) and peak concentration (Cmax) of mefloquine, its two enantiomers, and carboxylic acid metabolite, and in the metabolite/mefloquine and enantiomeric AUC ratios . Mefloquine significantly decreased steady-state ritonavir plasma AUC(0,12 h) by 31%, Cmax by 36%, and predose levels by 43%, and did not affect ritonavir binding to plasma proteins . Study 2: Mefloquine did not alter single-dose ritonavir pharmacokinetics . Less than 8% changes in AUC and Cmax were observed with high variability (90%CIs: -26% to 45%) . Mefloquine had no effect on the ERMBT whereas ritonavir decreased activity by 98% . CONCLUSIONS: Ritonavir minimally affected mefloquine pharmacokinetics despite strong inhibition of CYP3A4 activity from a single 200 mg dose . Mefloquine had variable effects on ritonavir pharmacokinetics that were not explained by hepatic CYP3A4 activity or ritonavir protein binding.

Eur J Clin Pharmacol, 2001 May, 57(2), 115 - 21
The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients; Grub S et al.; OBJECTIVE: The aim of this study was to compare the effect of ketoconazole, erythromycin and rifampicin on the pharmacokinetics of saquinavir soft-gelatin formulation (Fortovase; FTV) in healthy volunteers with that in HIV-infected patients at steady state after administration of 1200 mg three times daily . METHODS: In two open-labelled, randomised, crossover studies pharmacokinetic parameters were calculated in healthy volunteers who received on one occasion multiple doses of 1200 mg FTV three times daily alone and on the other occasion in combination with multiple doses of either 400 mg ketoconazole once daily or 600 mg rifampicin once daily . In another open-labelled, multicentre study, 33 HIV-infected patients underwent a pharmacokinetic assessment after 36-51 weeks of treatment with FTV and were then given additionally multiple doses of either 200 mg ketoconazole once daily, 250 mg erythromycin four times daily or 600 mg rifampicin once daily . Pharmacokinetic parameters of saquinavir were determined again at the end of the combination treatment . RESULTS: In healthy volunteers, coadministration of ketoconazole increased saquinavir area under the curve from time 0 to 8 h (AUC0-8 h) by 190% (95% CI: 90-343) whereas coadministration with rifampicin resulted in a decrease for AUC0-8 h by 70% (95% CI: 50-82) . In HIV-infected patients, coadministration of ketoconazole and erythromycin increased AUC0-8 h of saquinavir by 69% (95% CI: 14-150) and 99% (95% CI: 33-198), respectively . When saquinavir was given together with rifampicin, exposure of saquinavir in terms of AUC0-8 h was decreased by 46% (95% CI: 18-65) compared with the baseline assessment . CONCLUSION: Interactions of saquinavir with ketoconazole, erythromycin and rifampicin were observed in healthy volunteers as well as patients . The effects observed in patients, however, appear to be less pronounced . The enzyme induction caused by rifampicin might lead to subtherapeutic levels of saquinavir and this finding appears to be of clinical relevance.

Respiration, 2001, 68(3), 319 - 22
Chronic bronchiolitis with associated eosinophilic lung disease (eosinophilic bronchiolitis); Takayanagi N et al.; We encountered an adult patient with dyspnea, eosinophilia and bronchiolitis . He was diagnosed as having diffuse panbronchiolitis, and was treated with erythromycin for 3 years, but his symptoms had gradually worsened . Bronchoalveolar lavage showed marked eosinophilia, and video-assisted thoracoscopic lung biopsy revealed chronic bronchiolitis with associated eosinophilic lung disease (eosinophilic bronchiolitis) . To our knowledge, no case of eosinophilic bronchiolitis has been reported in the literature .

ANZ J Surg, 2001 Feb, 71(2), 98 - 102
Erythromycin enhances oesophageal motility in patients with gastro-oesophageal reflux; Chrysos E et al.; BACKGROUND: Intravenous (i.v.) erythromycin enhances gastric emptying and oesophageal motility in both healthy and disease situations, acting either as a motilin or acetylcholine agonist . The purpose of the present paper was to investigate any possible effect of i.v . erythromycin on oesophageal motility in patients with gastro-oesophageal reflux (GOR) . METHODS: In 15 patients with GOR (proven on 24-h ambulatory oesophageal pH measurement), standard oesophageal manometry was performed after i.v . injection of placebo and 200 mg erythromycin, in a random blind fashion . RESULTS: Erythromycin significantly increased lower oesophageal sphincter (LOS) pressure from 17 +/- 5 to 41 +/- 10 mmHg (P < 0.001), without affecting the postdeglutition relaxation of LOS . Erythromycin also increased the amplitude (from 79 +/- 34 to 97 +/- 40 mmHg; P < 0.001), duration (from 3.4 +/- 0.6 to 3.8 +/- 0.6 s; P = 0.005), velocity (from 3.1 +/- 0.8 to 3.5 +/- 1.15 cm/s; P = 0.0047) and strength (from 149 +/- 84 to 201 +/- 103 mmHg.s; P < 0.001) of peristalsis at 5 cm proximal to the LOS . Similarly, the drug increased the amplitude of peristalsis at 10 and 15 cm proximal to the LOS (from 70 +/- 39 to 77.4 +/- 37 mmHg; P = 0.049 and from 36 +/- 20 to 49 +/- 36 mmHg; P = 0.004, respectively) and the duration of peristalsis at the same levels (from 3.1 +/- 0.6 to 3.3 +/- 0.5 s; P = 0.011, and from 2.7 +/- 0.6 to 3 +/- 0.5 s; P = 0.003, respectively) . CONCLUSION: Intravenously administered erythromycin improves impaired oesophageal motility in patients with GOR . This observation might be of clinical use.

Bioorg Med Chem Lett, 2001 Jun 18, 11(12), 1477 - 9
Erythromycin biosynthesis . The 4-pro-S hydride of NADPH is utilized for ketoreduction by both module 5 and module 6 of the 6-deoxyerythronolide B synthase; Yin Y et al.; Incubation of chirally deuterated NADPH with 6-deoxyerythronolide B synthase (DEBS) modules 5 and module 6 and analysis of the derived triketide lactones established that the two ketoreductase domains, KR5 and KR6, are both specific for the 4-pro-S hydride of the nicotinamide cofactor.

Naturwissenschaften, 2001 Mar, 88(3), 93 - 101
Multimodular biocatalysts for natural product assembly; Schwarzer D et al.; Nonribosomal peptides and polyketides represent a large class of natural products that show an extreme structural diversity and broad pharmacological relevance . They are synthesized from simple building blocks such as amino or carboxy acids and malonate derivatives on multimodular enzymes called nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), respectively . Although utilizing different substrates, NRPSs and PKSs show striking similarities in the modular architecture of their catalytic domains and product assembly-line mechanism . Among these compounds are well known antibiotics (penicillin, vancomycin and erythromycin) as well as potent immunosuppressive agents (cyclosporin, rapamycin and FK 506) . This review focuses on the modular organization of NRPSs, PKSs and mixed NRPS/PKS systems and how modules and domains that build up the biosynthetic templates can be exploited for the rational design of recombinant enzymes capable of synthesizing novel compounds.

Acta Vet Hung, 2001, 49(2), 125 - 30
Characterisation of some Ornithobacterium rhinotracheale strains and examination of their transmission via eggs; Varga J et al.; The biochemical characteristics and antibiotic susceptibility of 12 Ornithobacterium rhinotracheale strains isolated from chickens and turkeys suffering from respiratory clinical signs and the survival of some isolates on egg-shell and within chicken eggs during hatching were examined . All O . rhinotracheale strains showed typical biochemical characteristics . Among the 16 drugs examined, penicillin G, ampicillin (MICs ranging from < or = 0.06 microgram/ml to 1 microgram/ml), ceftazidim (with MICs from < or = 0.06 microgram/ml to 0.12 microgram/ml), erythromycin, tylosin, tilmicosin (with some exceptions MICs ranged from < or = 0.06 microgram/ml to 1 microgram/ml) and tiamulin (MICs varied from < or = 0.06 microgram/ml to 2 micrograms/ml) were the most effective . Lincomycin, oxytetracycline and enrofloxacin also gave good inhibitions, but with most strains in a higher concentration (MICs ranged in most cases from 2 micrograms/ml to 8 micrograms/ml) . The other antibiotics inhibited the growth of O . rhinotracheale only in very high concentrations (colistin) or not at all (apramycin, spectinomycin, polymyxin B) . At 37 degrees C, O . rhinotracheale did not survive on egg-shell for more than 24 hours, while upon inoculation into embryonated chicken eggs it killed embryos by the ninth day, and from the 14th day post-inoculation no O . rhinotracheale could be cultured from the eggs at all . These results suggest that O . rhinotracheale is not transmitted via eggs during hatching.

Mol Microbiol, 2001 May, 40(4), 951 - 62
Erythromycin inhibition of 50S ribosomal subunit formation in Escherichia coli cells; Usary J et al.; The effects of erythromycin on the formation of ribosomal subunits were examined in wild-type Escherichia coli cells and in an RNase E mutant strain . Pulse-chase labelling kinetics revealed a reduced rate of 50S subunit formation in both strains compared with 30S synthesis, which was unaffected by the antibiotic . Growth of cells in the presence of {14C}-erythromycin showed drug binding to 50S particles and to a 50S subunit precursor sedimenting at about 30S in sucrose gradients . Antibiotic binding to the precursor correlated with the decline in 50S formation in both strains . Erythromycin binding to the precursor showed the same 1:1 stoichiometry as binding to the 50S particle . Gel electrophoresis of rRNA from antibiotic-treated organisms revealed the presence of both 23S and 5S rRNAs in the 30S region of sucrose gradients . Hybridization with a 23S rRNA-specific probe confirmed the presence of this species of rRNA in the precursor . Eighteen 50S ribosomal proteins were associated with the precursor particle . A model is presented to account for erythromycin inhibition of 50S formation.

Saudi Med J, 2000 Sep, 21(9), 860 - 3
Isolation of Moraxella catarrhalis in patients at King Khalid University Hospital, Riyadh; Babay HA; OBJECTIVE: A retrospective study was carried out to assess the clinical significance of Moraxella catarrhalis (M . catarrhalis) isolated from 32 specimens received from patients seen during a 2 year period . METHODS: The identity of isolates was confirmed by DNAse production and reduction of nitrate to nitrite . Susceptibility testing and B-lactamase production was carried out for each isolate . RESULTS: Twenty three of the patients were adults and 9 were children . Twelve (37%) of the isolates were from the sputum of patients aged more than 50 years with a clinical diagnosis of pneumonia, bronchitis or bronchiactesis . Six (18%) had M . catarrhalis isolated from sputum and had underlying cardiac, liver diseases or diabetes mellitus . The organism was isolated from the blood of one patient with pneumonia and one with leukaemia . It was also isolated from patients with sinusitis, conjunctivitis or otitis media . Twenty seven (84%) of the 32 strains produced B-lactamase, resistance to erythromycin and clindamycin was detected in 13% of the isolates . All isolates were susceptible to ciprofloxacin, tetracycline, trimethoprim-sulfamethoxazle, gentamicin, chloramphenicol, polymyxin B and neomycin . CONCLUSION: This study showed that M . catarrhalis can be an important respiratory tract pathogen in adults and children, able to invade the blood stream of patients with predisposing respiratory conditions and underlying systemic illnesses, as well as immunocompetent patients . Since most strains produce B-lactamase, antibiotic therapy should be guided by in-vitro susceptibility tests.

J Antibiot (Tokyo), 2001 Mar, 54(3), 278 - 84
Synthesis of 14,15-dehydroerythromycin A ketolides: effects of the 13-substituent on erythromycin tautomerism; Fardis M et al.; A ketolide was prepared from 14,15-dehydroerythromycin A by two different routes . The first approach involving oxidation of the 3-OH of 3-descladinosyl-14,15-dehydroerythromycin A 2'-O-acetate gave unexpectedly high levels of 3,11-double oxidation . This may be due to greater formation of the 9,12-hemiketal in 14,15-dehydroerythromycin A and concomitant exposure of the 11-OH group for oxidation . NMR studies of 14,15-dehydroerythromycin A support this hypothesis, revealing a 9:1 ratio of 9-ketone to 9,12-hemiketal in CDCl3 and a 1:1 ratio in CD3OD as contrasted with the corresponding tautomer ratios of 30:1 in CDCl3, and 6: 1 in CD3OD with erythromycin A . Alteration of the 13-substituent on the erythronolide A ring from ethyl to vinyl thus favors formation of the 9,12-hemiketal . A second route to the ketolides was developed based on these findings, in which the 11-OH is eliminated prior to oxidation of the 3-OH.

J Pharm Pharmacol, 2001 May, 53(5), 643 - 51
In-vivo kinetics of the interaction between midazolam and erythromycin in rats, taking account of metabolic intermediate complex formation; Takedomi S et al.; To predict, quantitatively, the extent of drug interaction during repeated administration of a metabolic inhibitor, we analysed the effects of erythromycin treatment under several regimens on the area under the concentration curve (AUC) of midazolam in rats . Midazolam was administered into the portal vein 12 h after erythromycin treatment for 1, 2 or 3 days, or 12, 24, 36, 48, 72 and 96 h after erythromycin treatment for 4 days, and the plasma-concentration profiles of midazolam were analysed to assess the AUC . Moreover, the contents of total cytochrome P450 and inactive metabolic intermediate (MI) complex were simultaneously quantitated . While the AUC value of midazolam was not affected by the administration of erythromycin for 1 day, repeated administration of erythromycin evoked an increase in AUC ratio (AUC in erythromycin-treated rats/AUC in vehicle-treated rats), which reached a maximum value of 1.99 at 12 h after 4 days' treatment with erythromycin . The total content of cytochrome P450 in liver microsomes was unaffected by erythromycin treatment . Although the MI complex was undetectable after 1 day's treatment with erythromycin, its content increased with duration of erythromycin treatment, and the complex disappeared after the end of erythromycin treatment with a half-life of 12.3 h . In conclusion, the interaction between erythromycin and midazolam could be well predicted when the formation of MI complex in the liver was taken into account.

Toxicol Lett, 2001 May 19, 121(3), 179 - 90
Effects of fumonisin B1 present in Fusarium moniliforme culture material on drug metabolising enzyme activities in ducks; Raynal M et al.; The effects of fumonisin B1 (0, 5, 15 and 45 mg/kg/day), obtained from culture material of Fusarium moniliforme, on drug metabolising enzyme activities were investigated in four groups of five growing ducks by daily oral administration over 12 days . No lethality or sign of toxicosis occurred . The liver and kidney weights were increased, whereas microsomal and cytosolic tissue fractions were unaffected . Although the total microsomal P450 content was unaffected, benzphetamine, ethylmorphine, erythromycin N-demethylases and ethoxyresorufin O-deethylase activities were together increased (respectively by 114, 242, 57 and 27% with 5 mg/kg/day and 1024, 969, 200 and 147% with 45 mg/kg/day) . By contrast, aminopyrine and nitrosodimethylamine N-demethylases, methoxyresorufin and pentoxyresorufin O-dealkylases, and UDP-glucuronyltransferase activities were only increased by using 45 mg/kg/day, whereas glutathione S-transferases activities remained unaffected.

Clin Pharmacokinet, 2001, 40(4), 263 - 81
Clinical pharmacokinetics of fluvastatin; Scripture CD et al.; Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models . Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract . After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile . Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites . The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood . CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite . Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues . The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance . Age and gender do not appear to affect the disposition of fluvastatin . CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors . Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively . The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance . In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo . In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac . The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin . These alterations have not been shown to be clinically significant . There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents . Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.

BETA . 1999 Apr;12(2):3.
Protease inhibitors and sildenafil (Viagra) should not be combined; Highleyman L; AIDS: The European Agency for the Evaluation of Medicinal Products (EMEA) issued a warning in April 1999, about potential adverse effects when the impotence drug sildenafil (Viagra) is taken with protease inhibitors . In particular, sildenafil and Ritonavir in combination results in significantly increased plasma levels of sildenafil for up to 24 hours after the drug is taken . There are similar reactions with other drugs, including Saquinavir, Erythromycin, and Itraconazole . The EMEA recommends that anyone taking protease inhibitors refrain from sildenafil, and that anyone taking sildenafil not exceed 25 mg in a 48-hour period .

Chem Biol, 2001 May, 8(5), 475 - 85
Engineering a polyketide with a longer chain by insertion of an extra module into the erythromycin-producing polyketide synthase; Rowe CJ et al.; BACKGROUND: Modular polyketide synthases catalyse the biosynthesis of medically useful natural products by stepwise chain assembly, with each module of enzyme activities catalysing a separate cycle of polyketide chain extension . Domain swapping between polyketide synthases leads to hybrid multienzymes that yield novel polyketides in a more or less predictable way . No experiments have so far been reported which attempt to enlarge a polyketide synthase by interpolating additional modules . RESULTS: We describe here the construction of tetraketide synthases in which an entire extension module from the rapamycin-producing polyketide synthase is covalently spliced between the first two extension modules of the erythromycin-producing polyketide synthase (DEBS) . The extended polyketide synthases thus formed are found to catalyse the synthesis of specific tetraketide products containing an appropriate extra ketide unit . Co-expression in Saccharopolyspora erythraea of the extended DEBS multienzyme with multienzymes DEBS 2 and DEBS 3 leads to the formation, as expected, of novel octaketide macrolactones . In each case the predicted products are accompanied by significant amounts of unextended products, corresponding to those of the unaltered DEBS PKS . We refer to this newly observed phenomenon as 'skipping' . CONCLUSIONS: The strategy exemplified here shows far-reaching possibilities for combinatorial engineering of polyketide natural products, as well as revealing the ability of modular polyketide synthases to 'skip' extension modules . The results also provide additional insight into the three-dimensional arrangement of modules within these giant synthases.

Pediatr Dermatol, 2001 Mar-Apr, 18(2), 131 - 4
Primary cutaneous Mycobacterium kansasii infection in a child; Chaves A et al.; A 6-year-old girl with a primary cutaneous form of Mycobacterium kansasii infection is presented . Disseminated infection and immune deficiency were excluded in our patient . She was successfully treated with surgical excision and oral erythromycin . Primary cutaneous M . kansasii is an exceedingly rare infection in children.

Semin Gastrointest Dis, 2001 Apr, 12(2), 113 - 24
Drug-induced cholestasis; Chitturi S et al.; The spectrum of drug-induced cholestasis ranges from 'bland' reversible cholestasis to chronic forms due to the vanishing bile duct syndrome . Agents known for many years to cause cholestasis include estrogens and anabolic steroids, chlorpromazine, erythromycin, and the oxypenicillins; structurally similar congeners of these drugs (tamoxifen, newer macrolides) may also cause cholestasis . Contemporary drugs linked to cholestastic liver injury include ticlopidine, terfenadine, terbinafine, nimesulide, irbesartan, fluoroquinolones, cholesterol-lowering 'statins,' and some herbal remedies (greater celandine, glycyrrhizin, chaparral) . Amoxillin-clavulanate, ibuprofen, and pediatric cases of the vanishing bile duct syndrome are recent additions to a long list of drugs associated with the vanishing bile duct syndrome . Particular human leukocyte antigen profiles have recently been identified among those who have developed cholestasis with specific drugs (tiopronin and amoxicillin-clavulanate), and the mechanistic relevance of these genetic associations is being explored . The treatment of drug-induced cholestasis is largely supportive . The offending drug should be withdrawn immediately . Cholestyramine or ursodeoxycholic acid are used to alleviate pruritus, with rifampicin and opioid antagonists being reserved for those who fail first line therapy . Nutritional support is essential for those with prolonged cholestasis, a subgroup who are at risk of developing biliary cirrhosis and liver failure . Timely referral for liver transplant assessment is crucial in these patients.

J Cardiovasc Pharmacol, 2001 May, 37(5), 607 - 18
The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis; Gintant GA et al.; Torsade de pointes is a rare but potentially fatal ventricular arrhythmia associated with drug-induced delayed repolarization and prolongation of the QT interval . To determine if the arrhythmogenic potential of noncardiac drugs can be assessed in vitro, we evaluated the effects of 12 drugs on the action potential duration (APD) of cardiac Purkinje fibers and compared results with clinical observations . APD changes in canine and porcine fibers were evaluated under physiologic conditions (37 degrees C, {K+}0 = 4 mM) using standard microelectrode techniques . Six of seven drugs associated with QT prolongation or torsade de pointes in man (cisapride, erythromycin, grepafloxacin, moxifloxacin, sertindole, and sotalol) affected concentration-dependent prolongation of the APD in canine fibers during slow stimulation (2-s basic cycle length), attaining greater than 15% prolongation at high concentrations (> or = 10-fold clinically encountered plasma levels) . Each of five drugs not linked clinically to QT prolongation and torsade de pointes (azithromycin, enalaprilat, fluoxetine, indomethacin, and pinacidil) failed to attain 15% prolongation, with fluoxetine, indomethacin, and pinacidil abbreviating the APD . Drugs eliciting the greatest prolongation also demonstrated prominent reverse rate-dependent effects . The antihistamine terfenadine (linked to dose-dependent QT prolongation and torsade de pointes clinically) only minimally prolonged the APD in canine and porcine fibers (and exerted no effect on midmyocardial fibers from left ventricular free wall) at supratherapeutic concentrations . On the basis of concentration-dependent APD prolongation and reverse rate-dependent effects, this Purkinje fiber model detects six of seven drugs linked clinically to acquired long QT syndrome and torsade de pointes, and clears each of five drugs not associated with repolarization abnormalities (overall 92% accuracy), validating the utility of this Purkinje fiber model in the preclinical evaluation of QT prolongation and proarrhythmic risk by noncardiac drugs.

Cardiovasc Res, 2001 May, 50(2), 345 - 53
Phase 2 prolongation, in the absence of instability and triangulation, antagonizes class III proarrhythmia; Hondeghem LM et al.; OBJECTIVE: To evaluate whether prolongation of the plateau of the action potential duration, in the absence of instability and triangulation, can reverse the proarrhythmia elicited by a class III antiarrhythmic agent . METHODS: The effects of almokalant, erythromycin and their combination, on cardiac electrophysiological parameters (action potential duration (APD), instability, triangulation and ectopics) were evaluated in isolated hearts from female albino rabbits . In this study, proarrhythmia was estimated quantitatively by number of ectopic beats . RESULTS: Erythromycin lengthened the APD primarily by a prolongation of the plateau, while having only minor effects upon phase 3 repolarization . The prolongation did not induce much instability, triangulation or reverse use dependence and, as expected, erythromycin did not induce significant proarrhythmia . Almokalant also lengthened APD, but it did not lengthen the plateau; instead, it prolonged phase 3 repolarization . The prolongation markedly triangulated the action potential, elicited much instability and marked reverse use dependence . This combination of effects induced very marked proarrhythmia . When almokalant and erythromycin were combined, their effects upon APD appeared additive: both the plateau and the repolarization phase were prolonged . However, the larger prolongation of APD did not lead to more proarrhythmia; this suggests that a prolongation of APD is not proarrhythmic per se . On the contrary, proarrhythmia as a function of APD prolongation was reduced in the presence of erythromycin (P<0.05) . CONCLUSION: Instability plus triangulation consistently lead to serious proarrhythmia especially when combined with reverse use dependence, but prolongation of APD in itself is not necessarily proarrhythmic . In fact, APD prolongation in the absence of instability and triangulation can be antiarrhythmic.

Intern Med, 2001 Apr, 40(4), 345 - 8
Fulminant Mycoplasma pneumoniae pneumonia; Takiguchi Y et al.; A 64-year-old woman, who was previously in good health was admitted because of progressive respiratory distress . Her chest radiograph revealed bilateral widespread alveolar infiltrates . She was given a diagnosis of pneumonia caused by Mycoplasma pneumoniae serologically, acute respiratory distress syndrome, and disseminated intravascular coagulation . She died of multiple organ failure despite intensive therapy with mechanical ventilation, intravenous erythromycin and corticosteroids, continuous hemodiafiltration, and plasma exchange . Although Mycoplasma pneumoniae infection is usually a benign self-limited disease, this case emphasizes its potentially serious nature even in normal healthy individuals.

JPEN J Parenter Enteral Nutr, 2001 May-Jun, 25(3), 160 - 5
Efficacy of erythromycin for postpyloric placement of feeding tubes in critically ill children: a randomized, double-blind, placebo controlled study; Gharpure V et al.; BACKGROUND: Erythromycin enhances gastric emptying and has been suggested to facilitate nasoenteric feeding tube placement in adults . Our primary objective was to evaluate the effect of erythromycin on the transpyloric passage of feeding tubes in critically ill children, and second, to evaluate the effect of erythromycin on the distal migration of duodenal feeding tubes . METHODS: Seventy-four children were randomly assigned to receive erythromycin lactobionate (10 mg/kg) IV or equal volume of saline placebo 60 minutes before passage of a flexible weighted tip feeding tube . Abdominal radiographs were obtained 4 hours later to assess tube placement . If the tube was proximal to the third part of the duodenum, two additional doses of erythromycin/placebo were administered 6 hours apart . Those receiving additional doses had repeat radiographs 14 to 18 hours after tube placement . RESULTS: The number of postpyloric feeding tubes was similar in the erythromycin and placebo treated groups 4 hours after tube insertion (23/37 vs 27/37, p = .5) . Of those with prepyloric tubes at 4 hours, none in the erythromycin group and 3 in the placebo group had the tube migrate to the postpyloric position by 14 to 18 hours (p < .05) . Of those with postpyloric tubes proximal to the third part of the duodenum at 4 hours, additional doses of erythromycin did not cause more tubes to advance further into the intestine than did placebo (p = .6) . CONCLUSIONS: Erythromycin does not facilitate transpyloric passage of feeding tubes in critically ill children . The distal migration of duodenal tubes further into the small bowel is also not enhanced by erythromycin.

Clin Pharmacokinet, 2001, 40(3), 151 - 8
The erythromycin breath test for the prediction of drug clearance; Rivory LP et al.; The erythromycin breath test (EBT) is a putative probe of cytochrome P450 (CYP) 3A4 activity in vivo . Therefore, the EBT might prove useful for the individualisation of doses of drugs that have a low therapeutic window (for example the immunosuppressants or cytotoxics) and are metabolised by CYP3A4 . However, there is a lack of consensus as to how the EBT should be used to predict total body clearance (CL), and the results so far have been largely disappointing . We argue that the required assumption that individuals produce 5 mmol of CO2/min per m2 at rest is one of the problems with the existing EBT, as the literature suggests significant variability and possible gender differences in this parameter . An examination of the EBT with a simple compartment model suggests that alternative parameters could be more useful in the prediction of CL . In particular, there is theoretical support for the use of the time-point at which breath radioactivity is maximal (tmax) as a correlate for CL . This is in agreement with our recent study of the pharmacokinetics of erythromycin in patients with cancer.

Zhonghua Jie He He Hu Xi Za Zhi, 1998 May, 21(5), 284 - 6
{The long-term effect of double embolization of bronchial artery on patients with hemoptysis}; Ling C et al.; OBJECTIVE: To investigate the long-term effect of bronchial arterial embolization with different material and procedure on patients with hemoptysis . METHOD: Seventy two cases were divided into two groups, one received the double embolization of bronchial artery, the other group used single gelfoam embolization . In double embolization group, the mixture containing gelfoam microspheres (0.5 mm x 0.5 mm), erythromycin and high osmalality sodium chloride were firstly used to embolize the terminal vessels, the gelfoam particle (1 mm x 1 mm) was then used to embolize the main trunk of bronchial artery . RESULT: After 2-4.8 years following up, it turned out that the cure rate and general effectiveness were: the double embolization group 83%, 100% respectively, the single gelfoam embolization group 61%, 95% . By comparison, there were significant difference on cure rate between these two groups(P < 0.05) . CONCLUSION: The bronchial arterial double embolization will increase the long-term effect obviously on patients with hemoptysis.

Chem Biol, 2001 Apr, 8(4), 329 - 40
Molecular basis of Celmer's rules: role of the ketosynthase domain in epimerisation and demonstration that ketoreductase domains can have altered product specificity with unnatural substrates; Holzbaur IE et al.; BACKGROUND: Polyketides are structurally diverse natural products with a range of medically useful activities . Non-aromatic bacterial polyketides are synthesised on modular polyketide synthase multienzymes (PKSs) in which each cycle of chain extension requires a different 'module' of enzymatic activities . Attempts to design and construct modular PKSs that synthesise specified novel polyketides provide a particularly stringent test of our understanding of PKS structure and function . RESULTS: We show that the ketoreductase (KR) domains of modules 5 and 6 of the erythromycin PKS, housed in the multienzyme subunit DEBS3, exert an unexpectedly low level of stereochemical control in reducing the keto group of a synthetic analogue of the diketide intermediate . This led us to construct a hybrid triketide synthase based on DEBS3 with ketosynthase domain ketosynthase (KS)5 replaced by the loading module and KS1 . The construct in vivo produced two major triketide stereoisomers, one expected and one surprising . The latter was of opposite configuration at three out of the four chiral centres: the branching alkyl centre was that produced by KS1 and, surprisingly, both hydroxyl centres produced by the reduction steps carried out by KR5 and KR6 respectively . CONCLUSIONS: These results demonstrate that the epimerising activity associated with module 1 of the erythromycin PKS can be conferred on module 5 merely by transfer of the KS1 domain . Moreover, the normally precise stereochemical control observed in modular PKSs is lost when KR5 and KR6 are challenged by an unfamiliar substrate, which is much smaller than their natural substrates . This observation demonstrates that the stereochemistry of ketoreduction is not necessarily invariant for a given KR domain and underlines the need for mechanistic understanding in designing genetically engineered PKSs to produce novel products.

J Microbiol Immunol Infect, 2001 Mar, 34(1), 76 - 8
Legionnaires' disease in a patient with rheumatoid arthritis; Chang CC et al.; A 62-year-old male with rheumatoid arthritis (RA) who was taking nonsteroid anti-inflammatory drug for controlling synovitis developed a flare of his arthritis, hepatitis, and pneumonia due to infection with Legionella pneumophila serotype 1 . Adult respiratory distress syndrome (ARDS) occurred following the development of pneumonia . After the introduction of erythromycin and ventilator support with positive end expiratory pressure (PEEP), his condition stabilized and he recovered gradually . We suggest that L . pneumophila should be considered early in the differential diagnosis of pneumonia in RA patients due to their immunocompromised status.

Arch Dis Child Fetal Neonatal Ed, 2001 May, 84(3), F177 - 82
Randomised controlled study of oral erythromycin for treatment of gastrointestinal dysmotility in preterm infants; Ng PC et al.; AIM: To evaluate the effectiveness of oral erythromycin as a prokinetic agent for the treatment of moderately severe gastrointestinal dysmotility in preterm very low birthweight infants . METHODS: A prospective, double blind, randomised, placebo controlled study in a tertiary referral centre of a university teaching hospital was conducted on 56 preterm infants (< 1500 g) consecutively admitted to the neonatal unit . The infants were randomly allocated by minimisation to receive oral erythromycin (12.5 mg/kg, every six hours for 14 days) or an equivalent volume of placebo solution (normal saline) if they received less than half the total daily fluid intake or less than 75 ml/kg/day of milk feeds by the enteral route on day 14 of life . The times taken to establish half, three quarters, and full enteral feeding after the drug treatment were compared between the two groups . Potential adverse effects of oral erythromycin and complications associated with parenteral nutrition were assessed as secondary outcomes . RESULTS: Twenty seven and 29 infants received oral erythromycin and placebo solution respectively . The times taken to establish half, three quarters, and full enteral feeding after the drug treatment were significantly shorter in the group receiving oral erythromycin than in those receiving the placebo (p < 0.05, p < 0.05 and p < 0.0001 respectively) . There was also a trend suggesting that more infants with prolonged feed intolerance developed cholestatic jaundice in the placebo than in the oral erythromycin group (10 v 5 infants) . None of the infants receiving oral erythromycin developed cardiac dysrhythmia, pyloric stenosis, or septicaemia caused by multiresistant organisms . CONCLUSIONS: Oral erythromycin is effective in facilitating enteral feeding in preterm very low birthweight infants with moderately severe gastrointestinal dysmotility . Treated infants can achieve full enteral feeding 10 days earlier, and this may result in a substantial saving on hyperalimentation . However, until the safety of erythromycin has been confirmed in preterm infants, this treatment modality should remain experimental . Prophylactic or routine use of this medication for treatment of mild cases of gastrointestinal dysmotility is probably not warranted at this stage.

J Clin Gastroenterol, 2001 May-Jun, 32(5), 394 - 9
Gastric emptying characteristics of a novel (13)C-octanoate-labeled muffin meal; Chey WD et al.; GOALS: Determine the gastric emptying characteristics of a novel, 350-kcal test meal consisting of two muffins, using scintigraphy and the 13C-octanoate breath test (OBT) . STUDY: Healthy volunteers underwent three studies on separate days within a 1-week period . On day 1, we measured emptying of the 350-kcal muffin test meal labeled simultaneously with 99mTc sulfur colloid and 13C-octanoate . On day 2, reproducibility of the OBT using a single-labeled 350-kcal test meal was assessed . On day 3, the effect of erythromycin on the 350-kcal OBT was determined . RESULTS: The mean (+/-SD) half-emptying time (T1/2) as measured by scintigraphy was 104 +/- 24 minutes, versus 212 +/- 52 minutes by OBT . There was a strong correlation between T1/2 determined by scintigraphy and the breath test (r = 0.83) . Multiple linear regression analysis identified a significant relationship between T1/2 determined by scintigraphy and the 90-and 180-minute breath samples . There was a strong correlation (r = 0.830, slope = 0.732 +/- 0.120 {SE}, intercept = 26.4 +/- 12.7) between the T1/2 obtained using the regression equation and the actual T1/2 obtained by scintigraphy . The mean T1/2 (+/-SD) for replicate determinations using the OBT was 209 +/- 52 minutes, compared with 196 +/- 42 minutes on days 1 and 2, respectively (not significant, p = 0.28, paired Student t test) . Treatment with erythromycin on day 3 produced a significant decrease in T1/2 (155 +/- 49 minutes, p = 0.002) . CONCLUSIONS: The 350-kcal muffin meal OBT provides a convenient, nonscintigraphic way of measuring solid-phase gastric emptying . Multiple linear regression appears promising as a method of analyzing OBT data and may allow for an abbreviated breath test protocol.

Appl Environ Microbiol, 2001 May, 67(5), 2136 - 8
Export of cytochrome P450 105D1 to the periplasmic space of Escherichia coli; Kaderbhai MA et al.; CYP105D1, a cytochrome P450 from Streptomyces griseus, was appended at its amino terminus to the secretory signal of Escherichia coli alkaline phosphatase and placed under the transcriptional control of the native phoA promoter . Heterologous expression in E . coli phosphate-limited medium resulted in abundant synthesis of recombinant CYP105D1 that was translocated across the bacterial inner membrane and processed to yield authentic, heme-incorporated P450 within the periplasmic space . Cell extract and whole-cell activity studies showed that the periplasmically located CYP105D1 competently catalyzed NADH-dependent oxidation of the xenobiotic compounds benzo{a}pyrene and erythromycin, further revealing the presence in the E . coli periplasm of endogenous functional redox partners . This system offers substantial advantages for the application of P450 enzymes to whole-cell biotransformation strategies, where the ability of cells to take up substrates or discard products may be limited.

Eur J Surg, 2001 Mar, 167(3), 188 - 94
Human stomach has a recordable mechanical activity at a rate of about three cycles/minute; Collard JM et al.; OBJECTIVE: To discover whether the human stomach contracts every 20 seconds or not . DESIGN: Manometric study . SETTING: Teaching hospital, Belgium . SUBJECTS: 10 healthy volunteers, and 31 patients who had had the whole stomach denervated and pulled up to the neck for oesophageal replacement . INTERVENTIONS: Analysis of selected strips of manometric tracings obtained with intraluminal perfused catheters . 13 patients were given erythromycin (1 g/day) by mouth . MAIN OUTCOME MEASURES: Estimation of the rate and frequency distribution according to amplitude of intraluminal pressure waves with the vertical axis of the tracings scaled up to reflect contractions within the gastric wall . RESULTS: Microwaves (<9 mmHg) that came in between conventional macrowaves (>9 mmHg) were found, showing that the human stomach undergoes mechanical activity (amplitude ranging from 0.2-310 mmHg) at the pacemaker's rate which varied from 2.43 to 3.60 cycles/minute from one subject to another . Phase I of the interdigestive motor complex contained microwaves only, phase II and the fed pattern consisted of a mixture of microwaves and macrowaves, and phase III contained macrowaves only . The fasting rate of mechanical activity was lower in patients who were given erythromycin than in those not given erythromycin (p = 0.003) and in healthy volunteers (p=0.002), and it increased significantly after a meal (p < 0.0001) . Microwaves in strips in which they were the most prominent were of higher amplitude in patients than in healthy volunteers (median: 3.5 compared with 2.5 mmHg; p < 0.0001) . CONCLUSIONS: The human stomach has mechanical activity at the rate at which the pacemaker generates electrical slow waves . The classic phases of the gastric motor activity seem to differ from each other by the frequency distribution of pressure waves according to amplitude rather than by the contraction rate . Weak mechanical activity is much more readily detectable after the stomach has been denervated and tailored for oesophageal substitution.

Xenobiotica, 2000 Dec, 30(12), 1111 - 21
NADH-dependent reduction of sulphamethoxazole hydroxylamine in dog and human liver microsomes; Trepanier LA et al.; 1 . Reduction of hydroxylamine drug metabolites by NADH-dependent hydroxylamine reductase (NDHR) has been suggested to be involved in the pathogenesis of idiosyncratic sulphonamide toxicity in humans . The dog represents a naturally occurring clinical model for sulphonamide toxicity in humans . he purpose of these studies, therefore, was to characterize the presence of hepatic NADH-dependent hydroxylamine reductase activity in the dog and to compare this activity with that found in humans . 2 . NDHR activity was characterized by the presence of two enzymes in both dog and human liver microsomes, with comparable estimates of Km (Km1 = 75 microM, Km2 = 404 microM in dog; Km1 = 69 microM, Km2 = 503 microM in human) . Estimates of maximal velocity were significantly, but not dramatically, higher for dog NDHR (Vmax1 = 2.09 nmole mg(-1) min(-1) Vmax2 = 4.58 nmole mg(-1) min(-1) compared with human NDHR (Vmax1 = 0.42 nmole mg(-1) min(-1), Vmax2 = 1.56 nmole mg(-1) min(-1)) . NDHR in dog, as in humans, preferred NADH to NADPH, was more active at pH 6.3 than at 7.4 and was not inhibited by carbon monoxide, azide, anaerobic conditions, the CYP substrate inhibitors tolbutamide, dextromethorphan, or erythromycin, or antibodies directed against CYP2C, CYP2D or CYP3A . 3 . It is concluded that two forms of NDHR are present in dog and humans with similar biochemical characteristics . Although NDHR activity has been attributed to a CYP2D isoform in pig, there is no evidence for involvement of CYP450 in the reduction of sulphamethoxazole hydroxylamine in either dogs or humans.

Ital Heart J Suppl, 2001 Mar, 2(3), 230 - 4
{Characteristics of a statine of the most recent generation}; Notarbartolo A et al.; LDL cholesterol levels are directly related to increased risk of cardiovascular disease . Several classes of drugs are available for the reduction of high cholesterol levels, but the highest efficacy has been demonstrated by HMG-CoA reductase inhibitors (statins) . Cerivastatin is a third generation, synthetic statin, characterized by the highest pharmacological and therapeutic potency among currently marketed statins, and whose lipid-lowering efficacy has been demonstrated in a number of large, multicenter trials . Along with improvements in triglycerides and HDL cholesterol, cerivastatin at the dosage of 0.4 mg/day achieved a mean 36% reduction in LDL cholesterol . Analysis of clinical trials indicates that the molecule has age and gender-related effects, with a greater cholesterol reduction in women than in men and in elderly than younger patients . Cerivastatin has a dual hepatic metabolism pathway, via the CYP3A4 and CYP2C8 isoenzymes of cytochrome P450; therefore no potentially significant drug interactions with other CYP3A4 inhibitors, for instance erythromycin and itraconazole, have been reported . Cerivastatin tolerability profile at dosages investigated is similar to that of placebo.

Chem Biol, 2001 Mar, 8(3), 253 - 63
Identification of a sugar flexible glycosyltransferase from Streptomyces olivaceus, the producer of the antitumor polyketide elloramycin; Blanco G et al.; BACKGROUND: Elloramycin is an anthracycline-like antitumor drug related to tetracenomycin C which is produced by Streptomyces olivaceus Tu2353 . Structurally is a tetracyclic aromatic polyketide derived from the condensation of 10 acetate units . Its chromophoric aglycon is glycosylated with a permethylated L-rhamnose moiety at the C-8 hydroxy group . Only limited information is available about the genes involved in the biosynthesis of elloramycin . From a library of chromosomal DNA from S . olivaceus, a cosmid (16F4) was isolated that contains part of the elloramycin gene cluster and when expressed in Streptomyces lividans resulted in the production of a non-glycosylated intermediate in elloramycin biosynthesis, 8-demethyl-tetracenomycin C (8-DMTC) . RESULTS: The expression of cosmid 16F4 in several producers of glycosylated antibiotics has been shown to produce tetracenomycin derivatives containing different 6-deoxysugars . Different experimental approaches showed that the glycosyltransferase gene involved in these glycosylation events was located in 16F4 . Using degenerated oligoprimers derived from conserved amino acid sequences in glycosyltransferases, the gene encoding this sugar flexible glycosyltransferase (elmGT) has been identified . After expression of elmGT in Streptomyces albus under the control of the erythromycin resistance promoter, ermEp, it was shown that elmG can transfer different monosaccharides (both L- and D-sugars) and a disaccharide to 8-DMTC . Formation of a diolivosyl derivative in the mithramycin producer Streptomyces argillaceus was found to require the cooperative action of two mithramycin glycosyltransferases (MtmGI and MtmGII) responsible for the formation of the diolivosyl disaccharide, which is then transferred by ElmGT to 8-DMTC . CONCLUSIONS: The ElmGT glycosyltransferase from S . olivaceus Tu2353 can transfer different sugars into the aglycon 8-DMTC . In addition to its natural sugar substrate L-rhamnose, ElmGT can transfer several L- and D-sugars and also a diolivosyl disaccharide into the aglycon 8-DMTC . ElmGT is an example of sugar flexible glycosyltransferase and can represent an important tool for combinatorial biosynthesis.

Pharm Res, 2000 Dec, 17(12), 1511 - 5
Hepatic disposition of fexofenadine: influence of the transport inhibitors erythromycin and dibromosulphothalein; Milne RW et al.; PURPOSE: To examine the disposition of fexofenadine in the isolated perfused rat liver and the influence of erythromycin and dibromosulphthalein (DBSP) on the hepatic uptake and biliary excretion of fexofenadine . METHODS: Livers from four groups of rats were perfused in a recirculatory manner with fexofenadine HCl added as a bolus (125, 250, 500, or 1000 microg) to perfusate . Livers from another three groups of rats were perfused with 250 microg of fexofenadine HCl . With one group as control, erythromycin (4.0 microg/ml) or DBSP (136 microg/ml) was added to the perfusate of the other groups . In all experiments, perfusate and bile were collected for 60 min; in addition, livers from the second experiment were retained for assay . Fexofenadine was determined in perfusate, bile, and homogenized liver by HPLC . RESULTS: The area under the curve (AUC) of fexofenadine was linearly related to concentration . It was unchanged from control (12,800 +/- 200 ng x h/ml) by erythromycin (14,400 +/- 2000 ng x h/ml), but was increased 95% by DBSP (25,000 +/- 2600 ng x h/ml, P <0.001) . The ratios of the concentrations of fexofenadine in liver/perfusate were decreased significantly by DBSP; those for bile/liver were increased by erythromycin . CONCLUSIONS: Erythromycin reduced the canalicular transport of fexofenadine into bile, whereas DBSP reduced uptake across the sinusoidal membrane.

J Clin Pharmacol, 1998 Dec, 38(12), 1137 - 43
Preliminary evaluation of progestins as inducers of cytochrome P450 3A4 activity in postmenopausal women; Tsunoda SM et al.; The effects of intramuscularly and orally administered medroxyprogesterone acetate on cytochrome P450 3A4 (CYP3A4) activity were investigated in twelve postmenopausal women in a randomized, crossover study . Unbound prednisolone clearance and the erythromycin breath test were used as markers of CYP3A4 activity . After 2 months of intramuscular progestin therapy, unbound prednisolone clearance increased by 25% in five of six subjects . Similarly, after intramuscular progestin therapy, results from the erythromycin breath test showed a 23% mean increase in CYP3A4 activity . In contrast, 2 months of oral progestin therapy had no effect on prednisolone pharmacokinetics or erythromycin metabolism . These results suggest that parenterally but not orally administered progestins may induce or activate the CYP3A4 enzyme system, leading to an increased metabolism of many CYP3A4 substrates.

J Allergy Clin Immunol, 2001 Apr, 107(4), 751 - 62
Desloratadine: A new, nonsedating, oral antihistamine; Geha RS et al.; Desloratadine is a new, selective, H(1)-receptor antagonist that also has anti-inflammatory activity . In vitro studies have shown that desloratadine inhibits the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, PGD(2), leukotriene C(4), tryptase, histamine, and the TNF-alpha-induced chemokine RANTES . Desloratadine also inhibits the induction of cell adhesion molecules, plateletactivating factor-induced eosinophil chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol myristate acetate-induced superoxide generation in vitro . In animals desloratadine had no effect on the central nervous, cardiovascular, renal, or gastrointestinal systems . Desloratadine is rapidly absorbed, has dose-proportional pharmacokinetics, and has a half-life of 27 hours . The absorption of desloratadine is not affected by food, and the metabolism and elimination are not significantly affected by the subject's age, race, or sex . There are no clinically relevant interactions between desloratadine and erythromycin, ketoconazole, or grapefruit juice . Desloratadine is not a significant substrate of the P-glycoprotein transport system . Once daily administration of desloratadine rapidly reduces the nasal and nonnasal symptoms of seasonal allergic rhinitis, including congestion . In patients with seasonal allergic rhinitis and concomitant asthma, desloratadine treatment was also associated with significant reductions in total asthma symptom score and use of inhaled beta(2)-agonists . Use of desloratadine in patients with chronic idiopathic urticaria was associated with significant reductions in pruritus, number of hives, size of the largest hive, and interference with sleep and daily activities . Clinical experience in over 2300 patients has shown that the adverse event profile of desloratadine is similar to that of placebo; desloratadine has no clinically relevant effects on electrocardiographic parameters, does not impair wakefulness or psychomotor performance, and does not exacerbate the psychomotor impairment associated with alcohol use.

Optometry, 2001 Mar, 72(3), 179 - 84
Recurrent phlyctenular keratoconjunctivitis: a forme fruste manifestation of rosacea; Blaustein BH et al.; BACKGROUND: Phlyctenular keratoconjunctivitis represents a delayed type hypersensitivity response to a systemic antigen within the body . METHODS: We present a case of symptomatic, recurrent, phlyctenular keratoconjunctivitis in an 8-year-old child . The patient's inflammation responded favorably to topical steroids at each episode, but no specific antigen could be identified . CONCLUSION: After observing the father's erythematous facial lesions, we attributed the child's ocular inflammation to rosacea (as a forme fruste manifestation) and treated her with systemic erythromycin . The symptoms were rapidly relieved and the disease process was arrested.

Eur J Clin Pharmacol, 2001 Jan-Feb, 56(11), 799 - 803
The effects of grapefruit juice on the pharmacokinetics of erythromycin; Kanazawa S et al.; OBJECTIVE: To study the effects of grapefruit juice on the pharmacokinetics of erythromycin . METHODS: The effects of grapefruit juice intake on the pharmacokinetics of erythromycin were investigated in six healthy male volunteers, who received 400 mg erythromycin with either water or grapefruit juice . The measurement of erythromycin in plasma samples were achieved by simple Sep-Pak CN cartridge extraction coupled with the electrochemical determination HPLC method, which was developed for the determination of erythromycin in human plasma in the present study . RESULTS: Grapefruit juice, compared with water intake, significantly (P<0.05) increased the mean Cmax value (1.65+/-0.94 versus 2.51+/-0.68 microg/ml) and the mean AUC0-12 value of erythromycin (5.92+/-3.25 versus 8.80+/-1.32microg.h/ml) . However, the Tmax and t1/2 values of erythromycin were not affected by grapefruit juice intake . CONCLUSION: These results indicate that the bioavailability of erythromycin was increased by the inhibitory effect of grapefruit juice on cytochrome P450 (CYP) 3A4-mediated metabolism in the small intestine.

Clin Ther, 2001 Feb, 23(2), 205 - 12
Comparison of the cumulative irritation potential of adapalene gel and cream with that of erythromycin/tretinoin solution and gel and erythromycin/isotretinoin gel; Queille-Roussel C et al.; BACKGROUND: Adapalene is a naphthoic acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris . OBJECTIVE: This study assessed the cumulative irritation potential of adapalene gel (0.1%) and adapalene cream (0.1%) compared with that of erythromycin (4%)/tretinoin (0.025%) solution, erythromycin (4%)/tretinoin (0.025%) gel, erythromycin (2%)/isotretinoin (0.05%) gel, and white petrolatum (negative control) . METHODS: This was a single-center, randomized, controlled, investigator-blinded, intraindividual comparison study in healthy subjects with normal skin . The cumulative irritation assay (patch test) was used to assess the potential for irritation (including erythema) of the treatments . Each subject received all study treatments, randomly applied under occlusion (patch), to sites on either side of the midline on the mid-thoracic area of the back . All patches were applied to the same sites throughout the study, unless the degree of reaction to the treatment or adhesive necessitated removal . For 3 weeks, each test material was applied daily, Monday through Friday, for approximately 24 hours; the Friday patches were left in place over the weekend for approximately 72 hours . RESULTS: All 36 subjects (26 men, 10 women; age, 18-49 years {mean, 30 years}) completed the study . In the course of the study, all subjects had > or =1 application discontinued prematurely on > or =1 site due to intolerance . There were no discontinuations with white petrolatum . All erythromycin/tretinoin gel patches were discontinued at day 10; 35 of 36 erythromycin/isotretinoin gel patches were discontinued at day 9; and 35 of 36 erythromycin/tretinoin solution patches were discontinued at day 11 or day 17 . The adapalene products, although slightly more irritating (mean cumulative irritation index, 0.25-1) than white petrolatum, were significantly less irritating than the erythromycin/tretinoin and erythromycin/isotretinoin products (P < 0.01) . CONCLUSIONS: Adapalene gel and cream were well tolerated, with possible benefits for compliance . Their low irritation potential should be considered when prescribing a topical retinoid for the treatment of acne vulgaris.

J Med Invest, 2001 Feb, 48(1-2), 97 - 101
Interferon-gamma activates outwardly rectifying chloride channels in the human bronchial epithelial cell line BEAS-2B; Ge N et al.; The mechanism of increased chloride currents by inflammatory cytokine, interferon-gamma (IFN-gamma), was investigated in cultured a human bronchial epithelial cell line (BEAS-2B) using cell-attached and inside-out patch configurations . The channel sensitive to chloride ion was activated by forskolin, an activator of adenylate cyclase, or 100 microM dibutyryl 5'-cyclic monophosphate in cell-attached configurations . The conductance of this channel was 40 +/- 4 pS in symmetrical 150 mM chloride solution between membrane potentials of 0 to mV, and this channel was blocked by 500 microM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), suggesting that this channel was an outwardly rectifying chloride channel (ORCC) . Treatment of 10-1000 U/ml IFN-gamma for 3 hours, but not IFN-alpha, significantly increased channel activities of ORCC, and this activation was observed at least 24 hours after treatment . Erythromycin, a macrolide antibiotic, at a concentration of 100 microM inhibited the activation of ORCC induced by IFN-gamma . The findings of the present study indicate that increased mucus secretion during inflammation might be partly due to activation of chloride permeability by cytokine and erythromycin might improve oversecretion of mucus from bronchial epithelium by blocking ORCC.

J Biochem Mol Toxicol, 2001, 15(2), 90 - 9
Cloning, sequencing, heterologous expression, and characterization of murine cytochrome P450 3a25*(Cyp3a25), a testosterone 6beta-hydroxylase; Dai D et al.; A full-length cDNA clone encoding a novel form of the cytochrome P450 3A subfamily (Cyp3a-25) has been isolated from a mouse liver cDNA library . The sequence contained 2010 base pairs and encoded a protein with 503 amino acids . The amino acid sequence shared greater identities with rat CYP3A18 (90%) and golden hamster CYP3A10 (81%) sequences than with known mouse sequences (Cyp3a-11, Cyp3a-13, Cyp3a-16, and Cyp3a-41 {68--70%}) . CYP3A25 was expressed in the Escherichia coli PCWori(+) expression vector following slight modifications of the N- and C-terminals of the cDNA . The purified CYP3A25 was recognized on an immunoblot by CYP3A1 antibody and has a molecular weight of 50 kD . CYP3A25 was catalytically active in the 6 beta-hydroxylation of testosterone and the N-demethylation of benzphetamine and erythromycin . It was demonstrated by RT-PCR that the CYP3A25 mRNA is present in both fetal and adult tissues, including liver, lung, intestines, kidney, and brain . Northern blotting demonstrated that expression is greatest in the liver and small intestine .

Food Addit Contam, 2000 Dec, 17(12), 1019 - 26
The effects of T-2 toxin exposure on liver drug metabolizing enzymes in rabbit; Guerre P et al.; High doses of T-2 toxin are known to decrease protein synthesis and mono-oxygenase activities in rat liver . The purpose of this study was to investigate whether exposure at a low dose could alter the normal metabolism of the xenobiotic by the liver . Three doses of T-2 toxin, dissolved in olive oil, were orally and daily administered to New Zealand white rabbits for five days . At 0.5 mg/kg, three of the five animals died, whereas only a weak decrease in body weight gain and moderate signs of toxicity occurred in rabbits receiving 0.25 mg/kg/day, and the body weight increased without signs of toxicity at 0.1 mg/kg/day . At 0.25 mg/kg/day, total liver microsomal P450 content, and the activities of aminopyrine and benzphetamine N-demethylases, pentoxyresorufin O-depentylase, glutathione S-transferases accepting 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene as substrates, were decreased . By contrast, ethylmorphine and erythromycin N-demethylases, ethoxyresorufin and methoxyresorufin O-dealkylases, aniline hydroxylase, and UDP-glucuronyltransferase accepting p-nitrophenol as substrate, were unaffected . The expression of P450 1A1, 1A2, 2A1, and 2B4, but not P450 2C3 and 3A6, were also decreased, whereas microsomal conjugated dienes, fluorescent substances, and malondialdehyde contents were increased . At 0.1 mg/kg/day, neither significant effects on drug metabolizing enzymes nor microsomal oxidative damages were obtained . Taken together, these results suggest that a short exposure time to the mycotoxin would not be associated with significant changes in the normal metabolism of xenobiotics by the liver.

Acta Otolaryngol, 2001 Jan, 121(1), 83 - 92
The anti-inflammatory effect of erythromycin and its derivatives, with special reference to nasal polyposis and chronic sinusitis; Cervin A; Macrolides have been used for decades as an important chemotherapeutic agent in the treatment of infectious diseases . In the last 10 years there has also been increasing interest in the interaction between macrolide antibiotics and the immune system . The aim of this review is to focus on the anti-inflammatory action of erythromycin and its derivatives in the treatment of chronic sinusitis and nasal polyps . Systematic clinical investigations have been few and to the author's knowledge there have been no placebo-controlled studies . However there have been, especially from Japan, a number of clinical reports stating that long-term, low-dose macrolide antibiotics are effective in treating chronic sinusitis incurable by surgery or glucocorticosteroid treatment, with an improvement in symptoms varying between 60% and 80% in different studies . In animal studies macrolides have increased mucociliary transport, reduced goblet cell secretion and accelerated apoptosis of neutrophils, all factors that may reduce the symptoms of chronic inflammation . There is also increasing evidence in vitro of the anti-inflammatory effects of macrolides . Several studies have shown macrolides to inhibit interleukin gene expression for IL-6 and IL-8 and also to inhibit the expression of intercellular adhesion molecule essential for the recruitment of inflammatory cells . There is also evidence in vitro, as well as clinical experience, showing that macrolides reduce the virulence and tissue damage caused by chronic bacterial colonization without eradicating the bacteria . The benefit of long-term, low-dose macrolide treatment seems to be that it is, in selected cases, effective when steroids fail . The exact mechanism of action is not known, but it probably involves downregulation of the local host immune response as well as a downgrading of the virulence of the colonizing bacteria . In the future, placebo-controlled studies should be performed to establish the efficacy of macrolides if this treatment is to be accepted as evidence-based medicine.

J Clin Pharmacol, 2001 Mar, 41(3), 324 - 9
Race but not age affects erythromycin breath test results in older hypertensive men; Schwartz JB; Erythromycin breath tests (ERBT) were performed to determine age and racial effects on CYP3A4-mediated hepatic clearance in hypertensive men (n = 43) in the clinical setting . Older hypertensive African American men (n = 19: 71 +/- 8 years, mean +/- SD) had faster ERBT clearance compared with Caucasian (n = 20: 72 +/- 6 years) hypertensive men (at 20 minutes after dosing: 0.042 +/- 0.01 percent dose/min exhaled vs . 0.033 +/- 0.013; at 60 minutes after dosing: 0.030 +/- 0.05 vs . 0.023 +/- 0.007 percent dose/min exhaled; ANOVA, p = 0.007), while age, smoking, and reported alcohol intake did not affect ERBT . The data suggest faster hepatic CYP3A-mediated clearance in African American men compared with Caucasian men, and that race may significantly affect CYP3A-mediated hepatic clearance in patients treated for hypertension.

Int J Environ Health Res, 2001 Mar, 11(1), 107 - 12
Verotoxin-producing Escherichia coli--an environment-induced emerging zoonosis in and around Calcutta; Chattopadhyay UK et al.; With changes in livestock management practices and food processing industry, along with changes in people's food habits, many diseases have emerged . Infection with verotoxin-producing Escherichia coli (VTEC) is one such illness . In the present study an attempt was made to isolate, identify and characterize VTEC strains with reference to the O157:H7 serotype from animal, human sources and some food products with the aid of the available modern methods . A total of 876 samples (330 animal, 184 human, 362 food samples) were screened for the presence of VTEC by conventional as well as PCR technique . Seventeen VTEC strains (12 animal, one human and four food samples) were isolated . The isolation rate was higher in diarrhoeic animals (6.02%), followed by diarrhoeic handler (3.12%) and raw beef (1.78%) samples . All strains showed the presence of the VT gene by PCR tests and were uniformly sensitive to common antibiotics except tetracycline, cephalexin, dicloxacillin, erythromycin and lincomycin . Since all strains were isolated from various sources of animal and human origin and all strains showed the presence of the VT gene and uniform antibiogram, a zoonotic association is suggested . This study marks the first report of isolation of VTEC strains from animal sources in India.

J Pharmacol Exp Ther, 2001 Apr, 297(1), 410 - 22
Metabolism of levo-alpha-Acetylmethadol (LAAM) by human liver cytochrome P450: involvement of CYP3A4 characterized by atypical kinetics with two binding sites; Oda Y et al.; levo-alpha-Acetylmethadol (LAAM) is a long-acting opioid agonist prodrug used for preventing opiate withdrawal . LAAM undergoes bioactivation via sequential N-demethylation to nor-LAAM and dinor-LAAM, which are more potent and longer-acting than LAAM . This study examined LAAM and nor-LAAM metabolism using human liver microsomes, cDNA-expressed CYP, CYP isoform-selective chemical inhibitors, and monoclonal antibody to determine kinetic parameters for predicting in vivo drug interactions, involvement of constitutive CYP isoforms, and mechanistic aspects of sequential N-demethylation . N-Demethylation of LAAM and nor-LAAM by human liver microsomes exhibited biphasic Eadie-Hofstee plots . Using a dual-enzyme Michaelis-Menten model, K(m) values were 19 and 600 microM for nor-LAAM and 4 and 450 microM for dinor-LAAM formation, respectively . LAAM and nor-LAAM metabolism was inhibited by the CYP3A4-selective inhibitors troleandomycin, erythromycin, ketoconazole, and midazolam . Of the cDNA-expressed isoforms examined, CYP2B6 and 3A4 had the highest activity toward LAAM and nor-LAAM at both low (2 microM) and high (250 microM) substrate concentrations . N-Demethylation of LAAM and nor-LAAM by expressed CYP3A4 was unusual, with hyperbolic velocity curves and Eadie-Hofstee plots and without evidence of positive cooperativity . Using a two-site model, K(m) values were 6 and 0.2 microM, 1250 and 530 microM, respectively . Monoclonal antibody against CYP2B6 inhibited CYP2B6-catalyzed but not microsomal LAAM or nor-LAAM metabolism, whereas troleandomycin inhibited metabolism in all microsomes studied . The ratio {dinor-LAAM/(nor-LAAM plus dinor-LAAM)} with microsomes and CYP3A4 decreased with increasing LAAM concentration, suggesting most dinor-LAAM is formed from released nor-LAAM that subsequently reassociates with CYP3A4 . Based on these results, we conclude that LAAM and nor-LAAM are predominantly metabolized by CYP3A4 in human liver microsomes, and CYP3A4 exhibits unusual multisite kinetics.

Drug Metab Dispos, 2001 Apr, 29(4 Pt 1), 443 - 52
Prediction of midazolam-CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data; Yamano K et al.; The extent of decreases in apparent hepatic clearance and intrinsic hepatic clearance of midazolam (MDZ) after intravenous administration of MDZ with concomitant oral administration of cimetidine (CIM), itraconazole (ITZ), or erythromycin (EM) was predicted using plasma unbound concentrations and liver unbound concentrations of inhibitors . When MDZ was concomitantly administered with CIM, the observed increase in MDZ concentration was successfully predicted using inhibition constants assessed by human liver microsome and liver-to-plasma unbound concentration ratios in rats . However, the extent of interaction with ITZ or EM was still underestimated even taking into account the concentrative uptake of inhibitors into liver . We could predict the degree of "mechanism-based" inhibition by EM on the hepatic metabolism of MDZ, after repeated administration of EM, by a physiological model incorporating the amount of active enzyme as well as the concentration of inhibitor . The maximum inactivation rate constant and the apparent inactivation constant of EM on MDZ metabolism were 0.0665 min(-1) and 81.8 microM, respectively . These kinetic parameters for the inactivation of the enzyme were applied to the physiological model with pharmacokinetic parameters of EM and MDZ obtained from published results . Consequently, we estimated that cytochrome P450 3A4 in the liver after repeated oral administration of EM was inactivated, resulting in 2.6-fold increase in the plasma concentration of MDZ . The estimated extent of increase in MDZ concentration in our study correlated well with the observed value based on metabolic inhibition by EM from published results.

Expert Opin Pharmacother, 2000 Jul, 1(5), 881 - 7
Pharmacotherapy of gastroparesis; Quigley EM; The evaluation and management of gastric motor dysfunction continues to represent a significant clinical challenge . The very definition of what constitutes a clinically relevant disturbance of gastric motility remains unclear . The spectrum of gastroparesis extends from those with classical symptoms and severe delay of gastric emptying to those with dyspepsia and a mild delay in emptying rate . Indeed, for many patients with dyspepsia, the role of gastric emptying delay in the pathogenesis of symptoms, remains unclear . Any assessment of the efficacy of any therapeutic class in gastroparesis must be mindful, therefore, of these variations in definition . For those individuals with severe established gastroparesis, therapeutic success often remains elusive and i.v . erythromycin and oral dopamine antagonists, or substituted benzamides, remain the best options for acute severe exacerbations and chronic maintenance therapy, respectively . Alternatives, currently under investigation, include a number of 5-HT4 agonists, macrolides devoid of antibiotic activity, CCK antagonists and gastric electrical stimulation . Other novel approaches include strategies to address some of the regional abnormalities in gastric motor function that have been identified in some patients with dyspepsia.

J Clin Neurosci, 2001 Mar, 8(2), 183 - 6
Multiple actinomyces brain abscesses: case report; Tsai MS et al.; A case of multiple cerebral abscesses caused by actinomyces is reported in a 37 year old male with mucoepidermoid carcinoma of the right lung . In conjunction with penicillin, sulfonamide and erythromycin, the patient underwent stereotactic surgery for aspiration of the brain abscesses under (CT) . The bacteria, considered to originate from the right lung, were identified from the abscess material obtained at surgery . Using proper therapy to control infection and intracranial pressure is important . A lon g term follow up with frequent computerised tomography evaluation has been conducted and the patient outcome has been successful recovery .

Allergy, 2001, 56 Suppl 65, 7 - 13
The pharmacologic profile of desloratadine: a review; Henz BM; Desloratadine is a new agent for the treatment of diseases such as seasonal allergic rhinitis and chronic urticaria . The pharmacologic profile of desloratadine offers particular benefits in terms of histamine H1-receptor binding potency and H1 selectivity . Desloratadine has a half-life of 21-24 h, permitting once-daily dosing . No specific cautions are required with respect to administration in renal or hepatic failure, and food or grapefruit juice have no effect on the pharmacologic parameters . No clinically relevant racial or sex variations in the disposition of desloratadine have been noted . In combination with the cytochrome P450 inhibitors, ketoconazole and erythromycin, the AUC and Cmax of desloratadine were increased to a small extent, but no clinically relevant drug accumulation occurred . With high-dose treatment (45 mg/day for 10 days), no significant adverse events were observed, despite the sustained elevation of plasma desloratadine levels . Specifically, desloratadine had no effects on the corrected QT interval (QTc) when administered alone, at high dose, or in combination with ketoconazole or erythromycin . Preclinical studies also show that desloratadine does not interfere with HERG channels or cardiac conduction parameters even at high dose . Desloratadine is nonsedating and free of antimuscarinic/anticholinergic effects in preclinical and clinical studies . Novel antiallergic and anti-inflammatory effects have also been noted with desloratadine, a fact which may be relevant to its clinical efficacy.

Yao Xue Xue Bao, 1997, 32(1), 5 - 10
{Involvement of cytochrome P4503A in the monohydroxylation of ring A of praziquantel in rat liver microsomes}; Zhang YJ et al.; The possibility of involvement of cytochrome P4503A (CYP3A) in the monohydroxylation of the ring A of praziquantel (PZQ) was studied by using CYP3A specific inducer dexamethasone (DEX), specific inhibitor triacetyloeandomycin (TAO) and the activity of erythromycin (ERY) and ethylmorphine (EMP) N-demethylase which are known to be marker for CYP3A enzyme activity as probes . In the liver microsomes obtained from rats pretreated with CYP3A inducer DEX with TAO treatment the content of uncomplexed P450 was decreased, the activity of ERY and EMP N-demethylase ws reduced, and simultaneously, the rate of formation of ring A monohydroxylate of PZQ was inhibited . Ring A monohydroxylate formation was competitively inhibited by TAO and ERY . The rates of ring A monohydroxylate formation were strongly correlated with the activity of N-demethylase of ERY and EMP . These results indicate that CYP3A is involved in the monohydroxylation of the ring A of PZQ.

Tenn Med, 2001 Mar, 94(3), 95 - 7
Cat bites: a source of rabies exposure in rural Tennessee; Lyman D; In summary, several errors occurred with this patient . One, the patient should have been treated prophylactically for P . multocida, as most cat bites become infected . In the patient not allergic to penicillin, augmentin is the drug of choice, not erythromycin . Two, rabies postexposure prophylaxis should have been advised immediately after assessing the significance of the exposure . A feral cat must be assumed to be rabid if it cannot be quarantined for 10 days . Therefore, the bite or scratch from such an animal constitutes a significant rabies exposure . Three, initial postexposure rabies prophylaxis must include both HRIG and the first of a series of either HDCV, RVA, or PCEC.

J Lab Clin Med, 2001 Mar, 137(3), 176 - 83
Effect of erythromycin on matrix metalloproteinase-9 and cell migration; Hashimoto N et al.; Erythromycin (EM) has an anti-inflammatory effect that may account for its clinical benefit in the treatment of chronic inflammatory diseases such as diffuse panbronchiolitis . To investigate the mechanism of this anti-inflammatory effect, we studied the relationship between the concentration of EM and matrix metalloproteinase-9 (MMP-9) activity, which is important in cell migration . We showed that EM suppressed the gelatinolytic activity of U937 cell-derived MMP-9 by using gelatin zymography, showed that expressions of MMP-9 protein and MMP-9 mRNA were down-regulated by EM in a dose-dependent manner, and showed that U937 migration was also suppressed by EM . We also demonstrated that EM treatment suppressed the gelatinolytic activity of MMP-9 in spleen macrophages . These findings suggest that the suppressive effect of EM on MMP-9 activity is one of the anti-inflammatory mechanisms that inhibit the migration of inflammatory cells into the inflammatory site.

J Assoc Physicians India, 1997 Nov, 45(11), 835 - 8
A study of gastric emptying in chronic renal failure; Alimchandani A et al.; In a prospective controlled study, 32 patient with chronic renal failure (CRF) and 11 healthy volunteers were evaluated for solid gastric emptying at our institute over a period of 2 years . The study sought to identify the incidence of abnormal gastric emptying in these patients, the factors influencing the development of abnormal gastric emptying and whether gastrointestinal symptoms correlated with abnormal gastric emptying . The efficacy of prokinetic drugs Cisapride and Erythromycin in improving delayed gastric emptying in these patients with CRF was also compared and evaluated . We observed delayed gastric emptying in 69% of our patients . About 50% of our patients with delayed gastric emptying had no gastrointestinal symptoms suggesting a poor correlation between the two . Delayed gastric emptying was observed frequently in patients with peripheral neuropathy and/or autonomic neuropathy . Gastric emptying in CRF appears to be independent of age, sex, duration of disease, BUN, creatinine and H . phylori infection . Oral Cisapride and Erythromcin are effective gastrokinetic agents in these patients . Identification of delayed gastric emptying in patients with CRF and treatment with these drugs may reduce gastrointestinal symptom related morbidity.

Gene, 2001 Jan 24, 263(1-2), 255 - 64
The Streptomyces venezuelae pikAV gene contains a transcription unit essential for expression of enzymes involved in glycosylation of narbonolide and 10-deoxymethynolide; Chen S et al.; In Streptomyces venezuelae, four polyketide synthase (PKS) polypeptides encoded by pikAI-pikAIV are used to generate 10 and 12-membered macrocyclic structures, narbonolide and 10-deoxymethynolide . Sequence analysis suggests these genes are translationally coupled with downstream genes, pikAV (encoding a type II thioesterase), desVIII-desVI (encoding enzymes responsible for production of the final glycosylated products pikromycin, narbomycin, methymycin and neomethymycin) and desR (a resistance gene) . Type II thioesterases have been suggested to have an editing function in polyketide biosynthesis and deletion of the corresponding genes often leads to decreased levels of polyketide production . Surprisingly an in-frame deletion of 687 bp of the 843 bp pikAV ORF led to a strain SC1022 that produced normal yields of polyketide products, but only in the aglycone form . Plasmid-based expression of the desVIII-VI and desR in the SC1022 strain completely restored production of glycosylated products, despite the absence of a functional pikAV gene product . Under these conditions the PikAV TEII therefore does not play an important role in polyketide biosynthesis, and its function remains an enigma . These observations also demonstrate that the region of pikAV DNA deleted in strain SC1022 contains a transcription unit essential for expression of the des genes . A sequence alignment of PikAV with members of the highly conserved type II thioesterases revealed a short divergent region at the carboxy terminus, suggesting a region of pikAV that might contain such a transcription unit . DNA containing this region of pikAV was shown to be able to increase plasmid-based expression of both crotonyl CoA reductase gene (ccr) and the erythromycin resistance gene (ermE) in S . venezuelae.

J Bacteriol, 2001 Mar, 183(6), 2071 - 80
MeaA, a putative coenzyme B12-dependent mutase, provides methylmalonyl coenzyme A for monensin biosynthesis in Streptomyces cinnamonensis; Zhang W et al.; The ratio of the major monensin analogs produced by Streptomyces cinnamonensis is dependent upon the relative levels of the biosynthetic precursors methylmalonyl-coenzyme A (CoA) (monensin A and monensin B) and ethylmalonyl-CoA (monensin A) . The meaA gene of this organism was cloned and sequenced and was shown to encode a putative 74-kDa protein with significant amino acid sequence identity to methylmalonyl-CoA mutase (MCM) (40%) and isobutyryl-CoA mutase (ICM) large subunit (36%) and small subunit (52%) from the same organism . The predicted C terminus of MeaA contains structural features highly conserved in all coenzyme B12-dependent mutases . Plasmid-based expression of meaA from the ermE* promoter in the S . cinnamonensis C730.1 strain resulted in a decreased ratio of monensin A to monensin B, from 1:1 to 1:3 . Conversely, this ratio increased to 4:1 in a meaA mutant, S . cinnamonensis WM2 (generated from the C730.1 strain by insertional inactivation of meaA by using the erythromycin resistance gene) . In both of these experiments, the overall monensin titers were not significantly affected . Monensin titers, however, did decrease over 90% in an S . cinnamonensis WD2 strain (an icm meaA mutant) . Monensin titers in the WD2 strain were restored to at least wild-type levels by plasmid-based expression of the meaA gene or the Amycolatopsis mediterranei mutAB genes (encoding MCM) . In contrast, growth of the WD2 strain in the presence of 0.8 M valine led only to a partial restoration (<25%) of monensin titers . These results demonstrate that the meaA gene product is significantly involved in methylmalonyl-CoA production in S . cinnamonensis and that under the tested conditions the presence of both MeaA and ICM is crucial for monensin production in the WD2 strain . These results also indicate that valine degradation, implicated in providing methylmalonyl-CoA precursors for many polyketide biosynthetic processes, does not do so to a significant degree for monensin biosynthesis in the WD2 mutant.

Bratisl Lek Listy, 2000, 101(11), 614 - 6
{Skin manifestations of Lyme borreliosis--occurrence, diagnosis, therapy}; Svecova D et al.; Eight genotypes of Borrelia burgdorferi are known currently . In Slovakia (Carpathian Euroregion) the most frequent genotypes are B . garini, B . afzelii, as well as B . valaisiana and B . lusitaniae . Infestation of the vector Ixodes ricinus is 3-30% . The most frequent early skin manifestation is erythema migrans (60-70%) . Borrelia burgdorferi is suggested to be the causative agent in sclerodermia circumscripta, lichen sclerosus et atrophicus, maybe also in urticaria chronica, granuloma anulare, erythema anulare, erythema nodosum . It can be the causative agent also in neurological diagnoses as e.g . chronic oligosymptomatic encephalopathy, "sclerosis multiplex-like" syndrome and fatigue syndrome, arthralgia, myalgia, seronegative indifferentiated oligoarthritis and fibromyalgies . The serological diagnosis has to be coincide with clinical findings . Used serological examinations are ELISA, Immunoblot, indirect immunofluorescence examination . PCR is an important contribution in examination of synovial fluid (85% detection) and cerebrospinal liquor (24-100%) . The importance of PCR is stressed in cases with mixed infections by several borrrelia genotypes . The first line treatment includes doxyciclin, amoxicilin, and erythromycin . The second line includes macrolides, cephalosporines . New perspectives are ascribed to active immunisation with recombined antigen OsA (LYMErix, ImuLyme).

Hum Exp Toxicol, 2000 Nov, 19(11), 623 - 31
Inhibitory effects of the medicinal herb, Thonningia sanguinea, on liver drug metabolizing enzymes of rats; Gyamfi MA et al.; In this study we examined the effect of the aqueous extract of Thonningia sanguinea (T.S.) on 7-ethoxyresorufin O-deethylase (EROD, CYP1A1), 7-pentoxyresorufin O-dealkylase (PROD, CYP2B1/2), 7-methoxyresorufin O-demethylase (MROD, CYP1A2), aniline hydroxylase (aniline, CYP2E1), p-nitrophenol hydroxylase (PNPH, CYP2E1) and erythromycin N-demethylase (ERDM, CYP3A1) in rat liver in vitro and in vivo . Although T.S . extract increased ERDM activity in induced rat liver microsomes, it showed a dose-dependent inhibitory effect in vitro on other P450 monooxygenase activities particularly EROD and PROD, which are mediated primarily by CYP1A1 and CYP2B1/2, respectively . PROD, EROD and MROD activities were also decreased by 18%, 19% and 40%, respectively, in hepatic microsomes prepared from rats treated with T.S . extract for 3 days . Kinetic analysis of CYP activity of 3-methylchloranthrene-induced microsomes demonstrated that T.S . inhibited EROD and MROD activities by a noncompetitive and competitive mechanism, respectively . The analysis of alterations produced by T.S . on PROD kinetic parameters in phenobarbital-induced microsomes suggested that the inhibition is noncompetitive . Pretreatment of rats with T.S . prolonged pentobarbital and phenobarbital sleeping time; however, plasma phenobarbital concentration determined on awakening showed no significant difference between control and T.S.-treated rats . T.S . was also found to be a potent inhibitor of the liver cytosolic glutathione S-transferase . These data suggest that selective modulation of CYP isoenzymes by T.S . might contribute to protection of the liver from xenobiotic-induced intoxication or to alteration of the action of drug(s) concomitantly administered besides its antioxidative properties.

Life Sci, 2000 Dec 15, 68(4), 431 - 43
Cocaine metabolism in human fetal and adult liver microsomes is related to cytochrome P450 3A expression; Ladona MG et al.; Cocaine N-demethylation to norcocaine was studied in human liver microsomes of different ages . Norcocaine was formed at a considerable rate in fetal (45.4+/-18.2 nmol/mg x hour, n = 8) and adult specimens (82.0+/-46.6 nmol/mg x hour, n = 15), p = 0.04 (Mann-Whitney) . Furthermore, the apparent Km values in fetal specimens (0.57 and 0.48 mM, n = 2) showed a higher affinity compared with those of adults (mean value 2.7 (1.8-4.25) mM, n = 4) . Estimated enzyme metabolic clearance with respect to P450 total content was higher in fetal than in adult liver microsomes (2.22 ml/nmol P450 x hour, and 0.18 (0.14-0.23) ml/nmol P450 x hour, respectively) . Several drugs, known to be CYP3A substrates, were used as potential inhibitors of cocaine metabolism . Midazolam, ergotamine and erythromycin showed strong inhibition (approx . 70 %) when used at concentrations of 500 microM (midazolam, erythromycin) or 200 microM (ergotamine) . The metabolism of 1 mM cocaine correlated strongly with immunodetected CYP3A protein determined by Western blotting in both fetal (r = 0.89, p = 0.19) and adult specimens (r = 0.82, p < 0.01) . These findings further support CYP3A as a major catalyst of norcocaine formation in human liver microsomes . These results are important given the potential risk of toxicity to the foetus of maternal cocaine abuse during pregnancy . Although the high Km values found in adult livers reduce the importance of this enzyme pathway in cocaine detoxication, this pathway would emerge as significant in circumstances of CYP3A induction and/or drug interactions leading to potential liver toxicity in chronic cocaine abusers.

Int J Clin Pract, 2000 Oct, 54(8), 504 - 8
Can prophylactic oral erythromycin reduce time to full enteral feeds in preterm neonates?
Patole SK, Almonte R, Kadalraja R, Tuladhar R, Muller R, Whitehall JS.
Efficacy of oral, prophylactic erythromycin in reducing the time to establish full enteral feeds (150 ml/kg/day) was assessed in neonates < 32 weeks, ready for enteral feeds . Seventy-three consecutive neonates were randomised to receive oral erythromycin ethyl succinate (n = 36) or placebo (n = 37) in a double-blind trial until full enteral feeds or 14 days of therapy were reached . A prospectively designed feeding regimen, including plan of action for signs of feed intolerance, was common for all enrolled neonates . The median gestational age, birth weight and postnatal age at start of feeds were 29 versus 30 weeks (p = 0.40), 1232 versus 1280 g (p = 0.96) and 5 versus 5 days (p = 0.84) for erythromycin and placebo group, respectively . Time to achieve full feeds was not significantly different in the two groups . (median times: erythromycin 93.5 versus placebo 104 hours, p = 0.60) . Erythromycin-related side-effects did not occur.

Acta Paediatr Suppl, 2000 Dec, 89(435), 11 - 6
Epidemiology of invasive and other pneumococcal disease in children in England and Wales 1996-1998; Miller E et al.; The results of enhanced national surveillance of pneumococcal disease in children < 15 y of age in England and Wales are reported for the period 1996-1998 . Of the 1985 cases of laboratory-confirmed invasive disease (annual incidence 6.6 per 100,000 overall and 39.7 per 100,000 in infants < 1 y of age), 485 (24%) were meningitis (annual incidence of 1.6 per 100,000 overall and 15.7 per 100,000 in infants <1 y of age) . Fifty-nine deaths in children with invasive disease were identified-3% of the total reports . Thirty-one different serogroups/types were identified, with organisms in the 7-valent conjugate vaccine responsible for 69% of the infections in children < 5 y of age: this rose to 77% and 82%, respectively, for the 9-and 11-valent vaccines . Resistance to penicillin varied from 2.3% to 6.2% in different years, but erythromycin resistance remained constant at 17% . The vast majority of resistant isolates were in vaccine serotype/groups . Computerized hospital admission records for all children < 15 y of age with a discharge diagnosis code indicating probable pneumococcal disease were also analysed for 1997 . The annual incidence for cases with a code specifically mentioning S . pneumoniae was 9.9 per 100,000 compared with 71.2 per 100,000 for lobar pneumonia; the mean duration of stay for both was < 1 wk . The incidence of admission for pneumococcal meningitis (1.9 overall and 19.6 for infants < 1 y of age) was similar to that derived from laboratory reports and resulted in an average duration of stay of 2 wk . CONCLUSION: This surveillance has confirmed the substantial burden of morbidity attributable to pneumococcal disease in British children and the potential public health benefits that could be achieved by the use of pneumococcal conjugate vaccines.

Jpn J Antibiot, 2000 Oct, 53(10), 615 - 22
{Relationship between the chemical structure of O-methyl erythromycin derivatives and their affinity to the lung}; Yoshida H et al.; Clarithromycin (CAM) was synthesized by selective methylation of the C-6-hydroxy group of erythromycin (EM), which had a high affinity to the lung . In the present study, the relationship between the chemical structure of derivatives of O-methyl group for the hydroxy group at 6, 11, 12 and 4"-position of the EM and their affinity to the lung was investigated . When each O-methyl EM derivatives was injected into the external jugular vein in rats, the lung levels were in decreasing order, 6,11,12,4"-OCH3 > 6,12-OCH3 > 6,11,4"-OCH3 > 6,4"-OCH3 > 6,11-OCH3 > 6-OCH3 > 11-OCH3 > EM . There was not a correlation between the lung affinity and dissociation constant (pKa) . It was found that substitution of a O-methyl group for the hydroxy group at each position afforded both the affinity to the lung and the lipophilicity . However, the levels of the increase were inconsistent for each substitution position . In the case of 6 and 12-position afforded higher affinity than that for 11 and 4"-position . A study of the effect of EM derivatives on the {14C}EM and {14C}CAM uptake process into the isolated lung cells was carried . The uptake of {14C}EM was not influenced by EM, CAM and 6,11,12,4"-OCH3 . On the other hand, the uptake of {14C}CAM was significantly inhibited in the presence of derivatives which had a O-methyl substitution at position 6, but was not influenced by an O-acethyl substitution . These findings suggest that CAM is transported via carrier-mediated system in the lung cells, which has a selective recognition the O-methyl group at position 6 . In addition, the uptake of {14C}CAM was further inhibited by the derivatives with O-methyl group at position 12.

Ugeskr Laeger, 2000 Dec 11, 162(50), 6856 - 7
{Acne neonatorum/acne infantum}; Holm EA et al.; Acne is generally considered to be a disease of adolescence . However 20% of newborns have acne neonatorum, which may to be overlooked because it is usually mild and transient . Acne can also be seen in infants and children, where the skin lesions are normally more severe . We describe a case of a ten-month-old boy with severe acne without other underlying diseases . Treatment with systemic erythromycin and local application with isotretinoin gel was moderately successful, but the eruption cleared when treated with isotretinoin 0.5 mg/kg.

J Bacteriol, 2001 Feb, 183(3), 1078 - 84
Cytoplasmic filament-deficient mutant of Treponema denticola has pleiotropic defects; Izard J et al.; In Treponema denticola, a ribbon-like structure of cytoplasmic filaments spans the cytoplasm at all stages of the cell division process . Insertional inactivation was used as a first step to determine the function of the cytoplasmic filaments . A suicide plasmid was constructed that contained part of cfpA and a nonpolar erythromycin resistance cassette (ermF and ermAM) inserted near the beginning of the gene . The plasmid was electroporated into T . denticola, and double-crossover recombinants which had the chromosomal copy of cfpA insertionally inactivated were selected . Immunoblotting and electron microscopy confirmed the lack of cytoplasmic filaments . The mutant was further analyzed by dark-field microscopy to determine cell morphology and by the binding of two fluorescent dyes to DNA to assess the distribution of cellular nucleic acids . The cytoplasmic filament protein-deficient mutant exhibited pleiotropic defects, including highly condensed chromosomal DNA, compared to the homogeneous distribution of the DNA throughout the cytoplasm in a wild-type cell . Moreover, chains of cells are formed by the cytoplasmic filament-deficient mutant, and those cells show reduced spreading in agarose, which may be due to the abnormal cell length . The chains of cells and the highly condensed chromosomal DNA suggest that the cytoplasmic filaments may be involved in chromosome structure, segregation, or the cell division process in Treponema.

Clin Pharmacol Ther, 2000 Dec, 68(6), 598 - 604
St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4; Durr D et al.; BACKGROUND: St John's Wort (hypericum perforatum) is an herbal medicine that is frequently used for therapy of mild depression . Recently, St John's Wort was reported to substantially decrease blood/plasma concentrations and efficacy of cyclosporine (INN, ciclosporin), indinavir, and digoxin . In this study we investigated the mechanisms of these St John's Wort-induced drug interactions . METHODS AND RESULTS: In a preclinical study, the administration of St John's Wort extract to rats during 14 days resulted in a 3.8-fold increase of intestinal P-glycoprotein/Mdrl expression and in a 2.5-fold increase in hepatic CYP3A2 expression (Western blot analyses) . In a clinical study, the administration of St John's Wort extract to 8 healthy male volunteers during 14 days resulted in an 18% decrease of digoxin exposure after a single digoxin dose (0.5 mg), in 1.4- and 1.5-fold increased expressions of duodenal P-glycoprotein/MDR1 and CYP3A4, respectively, and in a 1.4-fold increase in the functional activity of hepatic CYP3A4 (14C-erythromycin breath test) . CONCLUSIONS: These results indicate direct inducing effects of St John's Wort on intestinal P-glycoprotein/MDR1 (in rats and humans), hepatic CYP3A2 (in rats), and intestinal and hepatic CYP3A4 (in humans) . Therefore the results provide a mechanistic explanation for the previously observed drug interactions in patients and support the importance of intestinal P-glycoprotein/MDR1 in addition to intestinal and hepatic CYP3A4 for overall drug absorption and disposition in humans.

Neurogastroenterol Motil, 2001 Feb, 13(1), 27 - 35
Contractile effects and intracellular Ca2+ signalling induced by motilin and erythromycin in the circular smooth muscle of human colon; Van Assche G et al.; Motilin has excitatory effects on the colon of the rabbit and the dog, but little is known of its effect on the human colon . The aim of this study was to investigate the effects induced by motilin and erythromycin A (EMA) on muscle strips and on single cells from primary cultures from human colon . Isotonic contraction was recorded in circular muscle strips from macroscopically normal resection specimens of patients operated on for colonic neoplasm . Agonist-induced intracellular Ca2+ ({Ca2+}i) signalling was studied in primary cultures of colonic smooth-muscle cells using the ratiometric Ca2+ indicator Indo 1, on a laser-scanning confocal epifluorescence microscope . In circular muscle strips, norleucine13-porcine motilin ({Nle13}-pm)and EMA induced tonic contractions with an EC50 of 92 +/- 21 nmol L(-1) and 31 +/- 16 micromol L(-1), respectively . The maximal contraction was 21 +/- 4% (motilin) and 33 +/- 12% (EMA) of the response to 10(-4) mol L(-1) acetylcholine (ACh) . The motilin antagonist OHM-11526 (10(-5.5) mol L(-1)) abolished the effects of both {Nle13}-pm and EMA . Neither tetrodotoxin (10(-5.5) mol L(-1)), L-nitro-D-arginine methyl ester (L-NAME) (10(-3.5) mol L(-1)) nor guanethidine (10(-5) mol L(-1)) interfered with the effects of {Nle13}-pm or EMA . {Nle13}-pm (10(-11)-10(-6) mol L(-1)) induced rises of {Ca2+}i in cultured colonic myocytes . At 10(-6) mol L-1, 94% of the cells responded, and half of the cells responded at 1.4 nmol L(-1) {Nle13}-pm . 81% (35/43) and 95% (75/79) responded to EMA (10(-6) mol L(-1)) and acetylcholine (ACh, 10(-4) mol L(-1)), respectively . The motilin antagonist GM-109 inhibited motilin- and EMA-induced {Ca2+}i rises . In the absence of extracellular Ca2+, only 13% (7/52) of the cells responded to {Nle13}-pm (10(-6) mol L(-1)) vs . 90% (47/52) to ACh (10(-4) mol L(-1)) . Motilin and EMA have direct excitatory effects on circular smooth muscle from the human colon and these effects are mediated via a smooth-muscle motilin receptor . These findings suggest that motilin may regulate colonic motility and that motilides may have therapeutic potential for the treatment of colonic hypomotility.

Lung Cancer, 2001 Feb-Mar, 31(2-3), 331 - 4
Bronchorrhea revealing cervix adenocarcinoma metastastic to the lung; Epaulard O et al.; Copious bronchorrhea can be related to bronchioloalveolar carcinoma, but reports of bronchorrhea related to lung metastasis are rare . We report the case of a woman presenting lung metastases of a cervical adenocarcinoma revealed by bronchorrhea, eventually identified as ectopic cervical mucus . Treatment included anticancer drugs and erythromycin, the latter in order to reduce the bronchorrhea, with eventually poor efficacy . This observation illustrates the importance of respiratory signs in the post-therapeutic follow up of cancer, especially cough and bronchorrhea in adenocarcinoma.

Drug Metab Dispos, 2001 Feb, 29(2), 145 - 51
Pharmacokinetic interaction of cytochrome P450 3A-related compounds with rhodamine 123, a P-glycoprotein substrate, in rats pretreated with dexamethasone; Yumoto R et al.; The effect of pretreatment with dexamethasone (DEX) on drug-drug interactions between rhodamine 123 (Rho123), a P-glycoprotein (P-gp) substrate, and midazolam, a cytochrome P450 (CYP) 3A substrate, or verapamil, a P-gp/CYP3A substrate, was studied in rats . Rats were pretreated with DEX (100 mg/kg/day, oral) for 2 days . Western blot analysis with a monoclonal antibody for P-gp, C219, revealed that DEX pretreatment increased P-gp level in the intestine 1.9-fold, but not in the liver . In vitro metabolism study of erythromycin in microsomal suspensions indicated the 9.7-fold increase of CYP3A activity in the liver, but not in the intestine, by DEX pretreatment . In an in vivo study, DEX pretreatment increased P-gp-mediated exsorption clearance of Rho123 from blood to the intestinal lumen approximately 2-fold, but not biliary clearances, in good agreement with the results of Western blot analysis . In untreated rats, midazolam (100 microM) or verapamil (30 or 100 microM) added in the intestinal perfusate (single perfusion) decreased the exsorption clearance and biliary clearance of Rho123 by approximately 30 to 50% . In DEX-pretreated rats, however, the inhibitory potency of midazolam in the liver significantly decreased compared with that in untreated rats, although the potency in the intestine did not change . The inhibitory potency of verapamil decreased both in the intestine and liver by DEX pretreatment . In conclusion, it was demonstrated that DEX pretreatment affects not only P-gp-mediated disposition of Rho123 but also pharmacokinetic interactions of P-gp/CYP3A-related compounds with Rho123, probably because concentrations of substrates/inhibitors at target sites such as the intestine and liver are varied.

Antimicrob Agents Chemother, 2001 Feb, 45(2), 401 - 6
Erythromycin modulates eosinophil chemotactic cytokine production by human lung fibroblasts in vitro; Sato E et al.; Recent studies suggest that erythromycin can suppress the production of some cytokines and may be an effective treatment for asthma . Eosinophil chemotactic cytokines have been suggested to contribute to the pathogenesis of asthma by the recruitment of eosinophils . We hypothesized that erythromycin modulates eosinophil chemotactic cytokine production . To test the hypothesis, we evaluated the potential of erythromycin to modulate the release of eosinophil chemoattractants from the human lung fibroblast cell line HFL-1 . HFL-1 released eotaxin, granulocyte-macrophage colony-stimulating factor, and regulated and normal T-cell expressed and presumably secreted (RANTES) in response to interleukin-1beta or tumor necrosis factor alpha . Erythromycin attenuated the release of these cytokines and eosinophil chemotactic activity by the HFL-1 . The suppressive effect on eotaxin was the most marked of these cytokines . Erythromycin therapy also suppressed eotaxin mRNA significantly . These results suggest a mechanism that may account for the apparent beneficial action of macrolide antibiotics in the treatment of allergic airway disorders.

J Am Soc Nephrol, 2001 Feb, 12(2), 326 - 32
Downregulation of hepatic cytochrome P450 in chronic renal failure; Leblond F et al.; Chronic renal failure (CRF) is associated with a decrease in drug metabolism . The mechanism remains poorly understood . The present study investigated the repercussions of CRF on liver cytochrome P450 (CYP450) . Three groups of rats were defined: control, control paired-fed, and CRF . Total CYP450 activity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver microsomes . The regulation of liver CYP450 by dexamethasone and phenobarbital was assessed in CRF rats . Compared with control and control paired-fed rats, creatinine clearance was reduced by 60% (P: < 0.01) in CRF rats . Weight was reduced by 30% (P: < 0.01) in control paired-fed and CRF rats, compared with control animals . There was no difference in the CYP450 parameters between control and control paired-fed . Compared with control paired-fed rats, total CYP450 was reduced by 47% (P: < 0.001) in CRF rats . Protein expression of CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (>40%, P: < 0.001) in rats with CRF . The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the same in the three groups . Northern blot analysis revealed a marked downregulation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats . Although liver CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbital was present . N-demethylation of erythromycin was decreased by 50% in CRF rats compared with control (P: < 0.001) . In conclusion, CRF in rats is associated with a decrease in liver cytochrome P450 activity (mainly in CYP2C11, CYP3A1, and 3A2), secondary to reduced gene expression.

Dig Surg, 2000, 17(6), 578 - 580
Erythromycin and position facilitated placement of postpyloric feeding tubes in burned patients; Komenaka IK et al.; BACKGROUND: One of the main difficulties encountered in enteral nutrition in critically ill patients is the impaired gastric emptying: while the small bowel is ready the stomach is still 'lazy' . This paper describes a simple bedside method for postpyloric feeding tube placement, using a gastric prokinetic agent, erythromycin, and patient positioning . METHODS: In eight critically ill, burned patients a gastric feeding tube was placed in a reverse Trendelenburg, right lateral decubitus position . A dose of 250 mg of erythromycin was administered intravenously . RESULTS: In 13 out of 14 attempts, the tube passed into the duodenum, a success rate of 92% . CONCLUSIONS: Combining the prokinetic effects of erythromycin with proper patient positioning allows a rapid bedside transpyloric placement of feeding tubes .

Eur J Surg, 2000 Dec, 166(12), 942 - 8
Human stomach has a recordable mechanical activity at a rate of about three cycles/minute; Collard JM et al.; OBJECTIVE: To discover whether the human stomach contracts every 20 seconds or not . DESIGN: Manometric study . SETTING: Teaching hospital, Belgium . SUBJECTS: 10 healthy volunteers, and 31 patients who had had the whole stomach denervated and pulled up to the neck for oesophageal replacement . INTERVENTIONS: Analysis of selected strips of manometric tracings obtained with intraluminal perfused catheters . 13 patients were given erythromycin (1g/day) by mouth . MAIN OUTCOME MEASURES: Estimation of the rate and frequency distribution according to amplitude of intraluminal pressure waves with the vertical axis of the tracings scaled up to reflect contractions within the gastric wall . RESULTS: Microwaves (<9 mmHg) that came in between conventional macrowaves (>9 mmHg) were found, showing that the human stomach undergoes mechanical activity (amplitude ranging from 0.2-310 mmHg) at the pacemaker's rate which varied from 2.43 to 3.60 cycles/minute from one subject to another . Phase I of the interdigestive motor complex contained microwaves only, phase II and the fed pattern consisted of a mixture of microwaves and macrowaves, and phase III contained macrowaves only . The fasting rate of mechanical activity was lower in patients who were given erythromycin than in those not given erythromycin (p = 0.003) and in healthy volunteers (p = 0.002), and it increased significantly after a meal (p < 0.0001) . Microwaves in strips in which they were the most prominent were of higher amplitude in patients than in healthy volunteers (median: 3.5 compared with 2.5 mmHg; p < 0.0001) . CONCLUSIONS: The human stomach has mechanical activity at the rate at which the pacemaker generates electrical slow waves . The classic phases of the gastric motor activity seem to differ from each other by the frequency distribution of pressure waves according to amplitude rather than by the contraction rate . Weak mechanical activity is much more readily detectable after the stomach has been denervated and tailored for oesophageal substitution.

Am J Gastroenterol, 2000 Dec, 95(12), 3444 - 51
The effect of acute oral erythromycin on gallbladder motility and on upper gastrointestinal symptoms in gastrectomized patients with and without gallstones: a randomized, placebo-controlled ultrasonographic study; Portincasa P et al.; OBJECTIVE: Gastrectomy might be a risk factor for cholelithiasis and gallbladder stasis might play a major role . We studied fasting and postprandial gallbladder motility with 600 mg oral erythromycin or placebo in gastrectomized patients (with and without gallstones) and controls . METHODS: Seventeen patients operated on for gastric cancer (subtotal gastrectomy: n = 10, total gastrectomy: n = 7) were compared with 20 sex- and body-size matched healthy controls . Subjects randomly received erythromycin or placebo 30 min before the ingestion of a standard 200 ml liquid test meal . Gallbladder volume was estimated by ultrasonography until 120 min after test meal . A visual analog scale monitored GI perception of appetite, satiety, nausea, abdominal fullness and epigastric pain . RESULTS: Gastrectomized patients had increased fasting gallbladder volume (35.9 +/- 3.4 ml versus 21.0 +/- 1.4 ml, p = 0.0005) with faster postmeal emptying (T/2 14.8 +/- 1.1 min versus 23.5 +/- 1.5 min, p = 0.00019) than controls . Six patients developed small and asymptomatic gallstones, which did not influence gallbladder motility . In these patients, fasting gallbladder volume increased with time after surgery (r = +0.82, p = 0.047) . Perception of satiety, abdominal fullness, and epigastric pain after ingestion of the test meal were all significantly greater in patients than in controls . Erythromycin significantly enhanced gallbladder emptying during fasting (p = 0.001) and postprandially in both patients and controls (0.002 < p < 0.017) and significantly reduced postmeal satiety and epigastric discomfort in gastrectomized patients . CONCLUSIONS: Increased fasting volume might be a form of stasis, predisposing patients to gallstone formation . Erythromycin improves fasting and postprandial gallbladder emptying and decreases upper GI symptoms in gastrectomized patients.

Am J Gastroenterol, 2000 Dec, 95(12), 3388 - 92
The effect of erythromycin on human esophageal motility is mediated by serotonin receptors; Koutsoumbi P et al.; OBJECTIVE: Erythromycin exhibits prokinetic properties . The drug enhances esophageal and gastric motility by acting as a motilin agonist and promoting acetylocholine release . 5-HT3 receptors are involved in the spontaneously occurring migrating motor complex and the effect of erythromycin on antral motility in dogs . The aim of the study was to investigate the hypothesis that 5-HT3 receptors are also involved in the action of erythromycin on the human esophagus . METHODS: A total of 18 healthy volunteers underwent standard esophageal manometry on three different occasions in a double-blind, placebo-controlled, randomized manner, as follows: 1) after placebo, 2) after 200 mg of erythromycin i.v., and 3) after 200 mg of i.v . erythromycin subsequent to pretreatment with either 4 mg of i . v . ondansetron (serotonin receptor antagonist) (10 subjects) or 12 microg/kg of i.v . atropine (8 subjects) . RESULTS: Erythromycin significantly increased a) the amplitude of peristalsis at 5 cm (from 87 +/- 19 mm Hg to 108 +/- 26 mm Hg; p = 0.0007), 10 cm (from 72 +/- 24 mm Hg to 81 +/- 26 mm Hg; p = 0.016), and 15 cm (from 47 +/- 15 mm Hg to 55 +/- 17 mm Hg; p = 0.014) proximal to LES, b) the duration of peristalsis at 5 cm (from 4.5 +/- 0.9 s to 5.7 +/- 1.2 s; p < 0.0001) and 10 cm (from 4.1 +/- 1 s to 4.9 +/- 1 s; p < 0.0001) proximal to the LES and c) the strength of peristalsis at 5 cm proximal to the LES (from 180 +/- 49 mm Hg x s to 276 +/- 100 mm Hg x s; p < 0.0001), and decreased the velocity of peristalsis at distal esophagus (from 4.1 +/- 1 cm/s to 3.8 +/- 0.9 cm/s; p = 0.03) . In addition, erythromycin significantly increased the resting pressure of the LES (from 36 +/- 10 mm Hg to 44 +/- 12 mm Hg; p = 0.002) . Pretreatment with ondansetron totally reversed all of the effects of erythromycin to the placebo state . Pretreatment with atropine not only prevented the effects of erythromycin, but it reduced the amplitude and strength of peristalsis at the distal esophagus at significantly lower levels than after placebo . CONCLUSIONS: Erythromycin exerts its prokinetic action on the lower esophagus by stimulating cholinergic pathways . This action includes not only an increase in LES pressure, but significant increases in the amplitude and duration of esophageal peristalsis, as well . 5-HT3 receptors are also involved in this process.

Eur J Clin Pharmacol, 2000 Nov, 56(8), 575 - 9
CYP2D6 is involved in O-demethylation of diltiazem . An in vitro study with transfected human liver cells; Molden E et al.; OBJECTIVE: In a previous study of diltiazem (DTZ) pharmacokinetics in renal transplant patients, we speculated that a polymorphic enzyme could be involved in O-demethylation of diltiazem . The aim of this in vitro study was to investigate whether O-demethylation of DTZ is mediated by cytochrome P450-2D6 (CYP2D6) . METHODS: DTZ was incubated with transfected human liver epithelial (THLE) cells expressing CYP2D6 (T5-2D6 clone) . Metabolism of DTZ was studied over a concentration range of 12.5-400 microM and in the presence of quinidine (a CYP2D6 inhibitor) or erythromycin (a CYP3A4 inhibitor) . THLE cells lacking CYP2D6 activity (T5-neo clone) were used as control . The culture medium of the cells, in which DTZ was dissolved, was analysed for DTZ and metabolites prior to and after 8 h of incubation using high-performance liquid chromatography (HPLC, UV detection) . Authentic O-demethyl-DTZ (Mx) was not available, and this metabolite was therefore not identifiable . RESULTS: Desacetyl-O-demethyl-DTZ (M4) was exclusively produced during incubations of DTZ with THLE cells expressing CYP2D6 . The rate of M4 formation was described using Michaelis Menten kinetics in the concentration range of DTZ used . Production of M4 was inhibited by quinidine, but not erythromycin . An unidentified chromatographic peak, which was interpreted to be Mx, showed the same pattern of formation as M4 both in absence and presence of inhibitors . N-demethylated metabolites, formed by CYP3A4, were not observed in any of the cell lines . CONCLUSION: Evidence was provided in vitro that O-demethylation of DTZ is mediated by the polymorphic isoenzyme CYP2D6 . Involvement of CYP2D6 in the metabolism of DTZ may have clinical implications regarding pharmacokinetic variability and interactions.

J Mol Graph Model, 2000 Aug-Oct, 18(4-5), 497 - 511, 539-40
Development and screening of a polyketide virtual library for drug leads against a motilide pharmacophore; Siani MA et al.; A virtual library of macrocyclic polyketide molecules was generated and screened to identify novel, conformationally constrained potential motilin receptor agonists ("motilides") . A motilide pharmacophore model was generated from the potent 6,9-enol ether erythromycin and known derivatives from the literature . The pharmacophore for each molecular conformation was a point in a distance-volume space based on presentation of the putative binding moieties . Two methods, one fragment based method and the other reaction based, were explored for constructing the polyketide virtual library . First, a virtual library was assembled from monomeric fragments using the CHORTLES language . Second, the virtual library was assembled by the in silico application of all possible polyketide synthase enzyme reactions to generate the product library . Each library was converted to low-energy 3D conformations by distance geometry and standard minimization methods . The distance-volume metric was calculated for low-energy conformations of the members of the virtual polyketide library and screened against the enol ether pharmacophore . The goal was to identify novel macrocycles that satisfy the pharmacophore . We identified three conformationally constrained, novel polyketide series that have low-energy conformations satisfying the distance-volume constraints of the motilide pharmacophore.

Environ, Toxicol . Pharmacol. . 2000 Dec, 9(1-2), 31 - 37
Induction of cytochrome P450 enzymes by albendazole treatment in the rat; Asteinza J et al.; The anthelmintic drug albendazole (ABZ), methyl(5-(propylthio)-1H-benzimidazol-2-yl)carbamate, is a benzimidazole highly efficient in the treatment of neurocysticercosis . The effects of ABZ treatment (i.p . and p.o . administration) on the expression of several cytochrome P450 (CYP) enzymes were evaluated in rat liver in order to characterize the spectrum of altered CYP enzymes involved in the metabolism of environmental mutagens and carcinogens, after drug intake . Intraperitoneal administration of ABZ (50 mg/kg body weight/day/three days in corn oil) to rats, caused an induction of hepatic activities of CYP1A1-associated ethoxyresorufin O-deethylase (EROD) 65 fold, CYP1A2-associated methoxyresorufin O-demethylase (MROD) 6 fold, CYP2B1-associated penthoxyresorufin O-dealkylase (PROD) 4 fold, CYP2B2-associated benzyloxyresorufin O-dealkylase (BROD) 14 fold, as well as a partial reduction of CYP2E1-associated 4-nitrophenol hydroxylase (4-NPH) activity . CYP3A-associated erythromycin N-demethylase (END) activity was not modified under the same treatment conditions . Western blot analysis was conducted to explore if the increased catalytic activity was a result of an increased protein content; only CYP1A1/2 showed a visible increase in protein concentration after ABZ inoculation, therefore, the increased PROD and BROD activities could be attributed to the induction of CYP1A1/2 . Results with the two main metabolites of ABZ (15 mg/kg body weight/day/three days, i.p.) indicated that ABZ sulfoxide (ABZSO) but not ABZ sulfone (ABZSO(2)) displayed the same pattern of CYP induction than ABZ . Oral administration of ABZ at the human therapeutic dose of 20 mg/kg body weight/day/three days, produced an increase in CYP1A1/2 protein content 24 h after the first intake . The protein level remained high during the treatment, and up to 72 h after the last administration; basal protein levels were almost recovered 48 h later.

Pharmacotherapy, 2000 Dec, 20(12), 1486 - 98
Intolerance to intragastric enteral nutrition in critically ill patients: complications and management; MacLaren R; Compared with parenteral nutrition, early administration of enteral nutrition (EN) to critically ill patients improves clinical outcomes and reduces infection rates . Intragastric EN often is complicated by intolerance, as indicated by elevated volumes of aspirated gastric residuals . Conflicting data are available for the volume of residual that represents intolerance, but most clinicians use 150-200 ml to signify gastrointestinal motility dysfunction . Intolerance is associated with mortality . Data support an association between intragastric EN and aspiration pneumonia, but little information is available regarding the contributory effect of intolerance . Transpyloric migration of the feeding tube may facilitate tolerance but does not reduce the likelihood of aspiration pneumonia . Prokinetic agents (cisapride, erythromycin, metoclopramide) promote gastric emptying . Results of most studies are limited because patients did not receive or tolerated intragastric EN . Metoclopramide is the agent of choice for treating intolerance . Further studies are necessary before prokinetic drugs can be recommended for preventing intragastric EN-associated aspiration pneumonia.

J Med Microbiol, 2000 Dec, 49(12), 1097 - 102
Characterisation of drug resistance gene cassettes associated with class 1 integrons in clinical isolates of Escherichia coli from Taiwan, ROC; Chang CY et al.; The presence of class 1 integrons in clinical isolates of Escherichia coli was detected by PCR . Of 104 E . coli isolates from Kaohsiung, 54 (52%) carried class 1 integrons, with inserted DNA regions of 1-3 kb . These integrons were located on plasmids, as demonstrated by Southern hybridisation . DNA sequencing was used to identify the genetic content of the integron-variable regions . Different class 1 integrons contained various numbers, kinds and combinations of gene cassettes within their variable regions . These gene cassettes included those encoding resistance to trimethoprim (dfrIa, dfrV, dfr12 and dfr17), aminoglycosides (aadA1a, aadA2, aadA4 and aadB), chloramphenicol (cmlA), erythromycin (ereA2) and beta-lactams (blaP1) . An integron carrying three inserted cassettes - dfr12-orJF-aadA2 - was present in 33 (61%) of the 54 isolates with class 1 integrons . Gene cassettes encoding resistance were expressed phenotypically . The results indicate that class 1 integrons are widespread in clinical E . coli isolates in Taiwan . The types, combinations and frequency of the gene cassettes in integrons may reflect the specific selective pressures to which the isolates were exposed and could provide useful surveillance data for relation to antibiotic usage information.

Mol Gen Genet, 2000 Nov, 264(4), 477 - 85
Analysis of genes involved in 6-deoxyhexose biosynthesis and transfer in Saccharopolyspora erythraea; Doumith M et al.; Glycosylation represents an attractive target for protein engineering of novel antibiotics, because specific attachment of one or more deoxysugars is required for the bioactivity of many antibiotic and antitumour polyketides . However, proper assessment of the potential of these enzymes for such combinatorial biosynthesis requires both more precise information on the enzymology of the pathways and also improved Escherichia coli-actinomycete shuttle vectors . New replicative vectors have been constructed and used to express independently the dnmU gene of Streptomyces peucetius and the eryBVII gene of Saccharopolyspora erythraea in an eryBVII deletion mutant of Sac . erythraea . Production of erythromycin A was obtained in both cases, showing that both proteins serve analogous functions in the biosynthetic pathways to dTDP-L-daunosamine and dTDP-L-mycarose, respectively . Over-expression of both proteins was also obtained in S . lividans, paving the way for protein purification and in vitro monitoring of enzyme activity . In a further set of experiments, the putative desosaminyltransferase of Sac . erythraea, EryCIII, was expressed in the picromycin producer Streptomyces sp . 20032, which also synthesises dTDP-D-desosamine . The substrate 3-alpha-mycarosylerythronolide B used for hybrid biosynthesis was found to be glycosylated to produce erythromycin D only when recombinant EryCIII was present, directly confirming the enzymatic role of EryCIII . This convenient plasmid expression system can be readily adapted to study the directed evolution of recombinant glycosyltransferases.

Life Sci, 2000 Nov 10, 67(25), 3103 - 12
Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4; Chan WK et al.; Resveratrol, a phytoalexin found in red wine, has been shown to possess antioxidant and antimutagenic properties . Incubation of resveratrol with Sf9 insect microsomes containing baculovirus-derived human cytochrome P450 3A4 (CYP3A4) and NADPH-cytochrome P450 reductase showed that resveratrol inactivated CYP3A4 in a time- and NADPH-dependent manner . Resveratrol, erythromycin and troleandomycin inactivated CYP3A4 at a similar rate (as reflected by k(inact)) whereas the binding affinity to CYP3A4 (as reflected by K(I)) was in the order of: troleandomycin > erythromycin > resveratrol . (K(I) and k(inact) for CYP3A4 inactivation by resveratrol, erythromycin and troleandomycin are 20 microM and 0.20 min(-1), 5.3 microM and 0.12 min(-1) and 0.18 microM and 0.15 min(-1), respectively.) Fractionation studies of red wine showed that fractions that did not contain resveratrol inactivated CYP3A4 significantly . In addition, the resveratrol content in red wine used in the study was too low to account for the degree of CYP3A4 inactivation observed after red wine treatment . Inactivation studies using a variety of red wine types showed that the CYP3A4 inactivation did not correlate to their resveratrol content . In summary, data here showed that resveratrol is an effective mechanism-based inactivator of CYP3A4; however, it is not one of the main red wine constituents that are responsible for CYP3A4 inactivation by red wine . Nevertheless, inactivation of CYP3A4 by resveratrol may cause clinically relevant drug interactions with CYP3A4 substrates.

J AAPOS, 2000 Dec, 4(6), 379 - 80
Oral erythromycin treatment for childhood blepharokeratitis; Meisler DM et al.; Blepharokeratitis is a chronic external ocular and adnexal inflammatory condition marked by erythematous and edematous lid margins, lid margin crusting and scaling, meibomian gland inflammation and inspissation, and conjunctival hyperemia . The associated keratitis usually involves the inferior cornea and is characterized by punctate epithelial keratopathy and marginal stromal infiltrates . The inflammation sometimes leads to corneal thinning, scarring, and vascularization . The standard therapy for adult blepharokeratitis includes lid hygiene, topical cortico-steroid preparations, and topical antibiotics . Oral tetracycline and its analogues, doxycycline and minocycline, are used in adults to treat associated meibomian gland dysfunction . Whereas blepharitis is common in children, blepharokeratitis is rare and is often associated with severe ocular and psychosocial morbidity . Treatment of youths may be problematic because of poor compliance with lid hygiene and therapy that includes drops and ointment.(1) Furthermore, the use of tetracycline and its analogues is contraindicated in children aged less than 8 years because it may cause dental enamel abnormalities . Isolated case reports have suggested that erythromycin may be a reasonable alternative to tetracycline in childhood blepharokeratitis.(2,3) We report on the successful treatment of this condition with oral erythromycin in 5 children.

J Mol Biol, 2000 Dec 15, 304(5), 707 - 13
Conformational changes in the ribosome induced by translational miscoding agents; Jerinic O et al.; Ribosomes are dynamic complexes responsible for translating the genetic information encoded in mRNAs to proteins . The accuracy of this process is vital to the survival of an organism, and is often compromised by translational miscoding agents . Aminoglycosides are a group of miscoding agents that bind to the ribosome and reduce the fidelity of translation . Previous studies have shown that aminoglycosides alter the higher order structure of the ribosome . Here, we used a toeprinting assay to how that streptomycin, neomycin, kanamycin, gentamycin, and hygromycin B trigger conformational changes within Escherichia coli ribosome . Miscoding agents viomycin and 30% ethanol also cause similar structural changes within the ribosome . In contrast, antibiotics that do not cause miscoding, such as tetracycline, chloramphenicol, erythromycin, fusidic acid and spectinomycin, do not induce the conformational changes triggered by miscoding agents . Furthermore, ribosomes isolated from strains that are either streptomycin resistant or dependent for growth do not show these conformational changes in the presence of streptomycin . These results correlate structural changes in the ribosome induced by miscoding agents in vitro with their in vivo phenotype .

Thorax, 2001 Jan, 56(1), 62 - 4
Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin; Brennan S et al.; BACKGROUND: The aim of this study was to compare neutrophil migration in cystic fibrosis (CF) and non-CF populations and to investigate the effect of erythromycin on directed migration of neutrophils (PMNs) in CF . METHODS: PMNs were isolated and their migratory capacity in response to interleukin-8 (IL-8) or f-Met-Leu-Phe (fMLP) in the presence or absence of erythromycin (1-100 microg/ml) was assessed . RESULTS: CF derived PMNs showed significantly increased migration to IL-8 but not to fMLP compared with non-CF PMNs . Erythromycin had no significant effect on migration responses to IL-8 and in vitro exposure of PMNs to erythromycin had no effect . CONCLUSIONS: CF derived PMNs show higher migratory responsiveness to IL-8 but not to fMLP, suggesting that CF PMNs may be "primed" to IL-8 which is significantly increased in CF serum compared with non-CF serum . Treatment with erythromycin had no significant effect on PMN migration in vitro.

Am J Respir Crit Care Med, 2000 Dec, 162(6), 2218 - 20
Reduced nasal nitric oxide in diffuse panbronchiolitis; Nakano H et al.; Diffuse panbronchiolitis (DPB) is a pulmonary disease of unknown origin with inflammation in the respiratory bronchioles, bronchiectasis, and recurrent sinusitis . Patients with DPB suffer from chronic airway infections resulting from mucociliary dysfunction . Whereas a high concentration of nasal nitric oxide (NO) has been documented in healthy subjects, only two diseases are known to reduce nasal NO: primary ciliary dyskinesia syndrome and cystic fibrosis . We hypothesized that patients with DPB have abnormal levels of nasal NO . To test our hypothesis, we measured NO with the chemiluminescence technique . Air was sampled directly from the nose in 15 healthy subjects and eight patients with DPB . Nasal NO was 88% lower in DPB patients than in the age-matched control subjects (69 +/- 70 versus 556 +/- 87 nl/min; p < 0.001) . Treatment with erythromycin for 2 wk did not alter the nasal NO in four control subjects . DPB is the third pulmonary disease in which nasal NO is low . The reduced nasal NO may well be involved in the pathogenesis of DPB, and NO measurements may serve as a noninvasive test in the diagnosis of DPB.

Can J Physiol Pharmacol, 2000 Nov, 78(11), 912 - 9
Differential alteration of cytochrome P450 isoenzymes in two experimental models of cirrhosis; Bastien MC et al.; Liver diseases are associated with a decrease in hepatic drug elimination, but there is evidence that cirrhosis does not result in uniform changes of cytochrome P450 (CYP) isoenzymes . The objective of this study was to determine the content and activity of four CYP isoenzymes in the bile duct ligation and carbon tetrachloride (CCl4)-induced models of cirrhosis . The hepatic content of CYP1A, CYP2C, CYP2E1, and CYP3A was measured by Western blot analysis . CYP activity in vivo was evaluated with breath tests using substrates specific for different isoenzymes: caffeine (CYP1A2), aminopyrine (CYP2C11), nitrosodimethylamine (CYP2E1), and erythromycin (CYP3A) . Bile duct ligation resulted in biliary cirrhosis; CYP1A, CYP2C and CYP3A content was decreased and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas CYP2E1 content and the nitrosodimethylamine breath test were unchanged compared with controls . CCl4 treatment resulted in cirrhosis of varying severity as assessed from the decrease in liver weight and serum albumin . In rats with mild cirrhosis, CYP content was comparable with controls except for a decrease in CYP2C . The activity of CYPs was also unchanged except for an increase in CYP2E1 activity . In rats with more severe cirrhosis, the content of all four CYP isoenzymes and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas the nitrosodimethylamine breath test was unchanged . In both models of cirrhosis, there was a significant correlation between the breath tests results and the severity of cirrhosis as assessed from serum albumin levels . These results indicate that content and the catalytic activity of individual CYP enzymes are differentially altered by cirrhosis in the rat and also suggest that drug probes could be useful to assess hepatic functional reserve.

Curr Treat Options Gastroenterol, 1999 Jun, 2(3), 239 - 250
Chronic Intestinal Pseudo-obstruction; Quigley EM; For many patients, nutritional support and relief of symptoms remain the primary management goal of pseudo-obstruction . Specific pharmacological agents for this disorder are, in general, lacking . Given that the efficacy of many of the individual available agents is far from excellent, several centers have turned to combination therapy . Though there is at present no evidence from controlled studies to support this strategy, it is, at the very least, theoretically attractive as these agents act through a number of separate mechanisms . The combination of a prokinetic and an emetic may prove especially useful . As the pseudo-obstruction syndromes are, individually, rare, and experience with any given prokinetic agent in these disorders limited, it is difficult to develop strict guidelines for their use in this context . It stands to reason that a response to a prokinetic agent would seem unlikely in a patient with an advanced myopathic process; anecdotal evidence suggests, however, that some patients with severe scleroderma may derive some symptomatic improvement . Where oral therapy is tolerated, cisapride would appear the best choice among available agents . When this fails, subcutaneous octreotide may be added or substituted . In the acute situation, intravenous erythromycin may alleviate gastroparesis, but probably exerts little beneficial effect beyond the pylorus; parenteral metoclopramide may be tried, but, here again, convincing evidence of efficacy is lacking . The roles of endoscopy and surgery are largely confined to facilitating nutrition and providing decompression.

Curr Treat Options Gastroenterol, 1999 Feb, 2(1), 13 - 19
Irritable Bowel Syndrome; Wald A; I believe there are four essential elements in the management of patients with irritable bowel syndrome (IBS): to establish a good physician-patient relationship; to educate patients about their condition; to emphasize the excellent prognosis and benign nature of the illness; and to employ therapeutic interventions centering on dietary modifications, pharmacotherapy, and behavioral strategies tailored to the individual . Initially, I establish the diagnosis, exclude organic causes, educate patients about the disease, establish realistic expectations and consistent limits, and involve patients in disease management . I find it critical to determine why the patient is seeking assistance (eg, cancer phobia, disability, interpersonal distress, or exacerbation of symptoms) . Most patients can be treated by their primary care physician . However, specialty consultations may be needed to reinforce management strategies, perform additional diagnostic tests, or institute specialized treatment . Psychological co-morbidities do not cause symptoms but do affect how patients respond to them and influence health care-seeking behavior . I find that these issues are best explored over a series of visits when the physician-patient relationship has been established . It can be helpful to have patients fill out a self-administered test to identify psychological co-morbidities . I often use these tests as a basis for extended inquiries into this area, resulting in the initiation of appropriate therapies . I encourage patients to keep a 2-week diary of food intake and gastrointestinal symptoms . In this way, patients become actively involved in management of their disease, and I may be able to obtain information from the diary that will be valuable in making treatment decisions . I do not believe that diagnostic studies for food intolerances are cost-effective or particularly helpful; however, exclusion diets may be beneficial . I introduce fiber supplements gradually and monitor them for tolerance and palatability . Synthetic fiber is often better-tolerated than natural fiber, but must be individualized . In my experience, excessive fiber supplementation often is counterproductive, as abdominal cramps and bloating may worsen . Antidiarrheal agents are very effective when used correctly, preferably in divided doses . I use them in patients in anticipation of diarrhea and especially in those who fear symptoms when engaged in activities outside the home . I encourage patients to make decisions as to when and how much to use . However, almost always, a morning dose before breakfast is used (loperamide, 2 to 6 mg) and, perhaps again later in the day when symptoms of diarrhea are prominent . I prefer antispasmodics to be used intermittently in response to periods of increased abdominal pain, cramps, and urgency . For patients with daily symptoms, especially after meals, agents such as dicyclomine before meals are useful . For patients with infrequent but severe episodes of unpredictable pain, sublingual hyoscyamine often produces rapid relief and instills confidence . In general, I recommend that oral antispasmodics be used for a limited period of time rather than indefinitely, and generally for periods of time when symptoms are prominent . For chronic visceral pain syndromes, I recommend small doses of tricyclic antidepressants . These agents are especially effective in diarrhea-predominant patients with disturbed sleep patterns but may be unacceptable to patients with constipation . I educate patients that side effects occur early and benefits may not be apparent for 3 to 4 weeks . I consider using SSRIs in low doses in patients with constipation-predominant IBS; cisapride, 10 to 20 mg three times per day, also may be beneficial . When taken with drugs that inhibit cytochrome P450, cisapride has been associated with serious cardiac arrhythmias caused by QT prolongation, including ventricular arrhythmias and torsades de pointes . These drugs include the azole fungicides; erythromycin, clarithromycin, and troleandomycin; some antidepressants; HIV protease inhibitors; and others . In patients with IBS with mild to moderate co-morbid depression, I have found that the use of SSRIs such as paroxetine, fluoxetine, or sertraline may be beneficial . It is important to tell patients that anxiety and disturbed sleep may occur during the first 10 days and benefits may not occur for 3 to 4 weeks . I prescribe a small amount of a short-acting benzodiazepine such as alprazolam, 0.5 mg two times per day, to control these symptoms . For generalized anxiety without depression, buspirone or clonazepam may be useful . I have found that patients who also have associated panic disorder may benefit from a benzodiazepine, tricyclic antidepressant, or an SSRI . However, these patients are best managed in conjunction with a psychiatrist or psychologist . I consider the use of alternative therapies in patients who fail to respond to conventional measures and who are receptive to alternative strategies . These include general relaxation techniques such as biofeedback and hypnosis therapies.

Chem Pharm Bull (Tokyo), 2000 Nov, 48(11), 1835 - 7
Three-dimensional structure-activity relationship analysis between motilin and motilide using conformational analysis and a novel molecular superposing method; Gouda H et al.; Motilide, an erythromycin derivative, has been shown to equal activity to that of motilin as an agonist at the motilin receptor . However, there is little information on the three-dimensional (3D) structure-activity relationship between these two molecules, largely because they have quite different structures . In this study, we applied a rational computational procedure consisting of conformational analysis and a novel superposing method to investigate the 3D structure-activity relationship between motilide and motilin . We propose common 3D structural features between these molecules, which may be important for their similar activity.

Mol Gen Genet, 2000 Oct, 264(3), 227 - 32
Construction and characterization of a Streptomyces rimosus recA mutant: the RecA-deficient strain remains viable; Mikoc A et al.; Although previously reported attempts to construct recA null mutants in Streptomyces spp . have been unsuccessful, we have used the suicide plasmid pErmdeltaRecA to inactivate the recA gene in Streptomyces rimosus by gene disruption . pErmdeltaRecA carries the erythromycin resistance gene ermE and a 451-bp fragment of the S . rimosus recA gene (encoding amino acids 2-151) . An erythromycin-resistant clone with single plasmid integration into the recA gene on the chromosome was analyzed in detail . This clone possesses one inactive copy of recA which lacks the entire promoter region and the ATG start codon, and a second, truncated gene that encodes only first 151 amino acids of the RecA protein . This S . rimiosus rec A mutant can therefore be considered a completely RecA-deficient strain . The mutant strain is highly sensitive to UV light . Introduction of a plasmid carrying the wild type S . rimosus recA gene completely restored the UV resistance of the recA mutant to wild-type levels . recA genes encoding RecA proteins with short deletions at the C-terminus (21 and 51 amino acids) could not fully rescue the UV sensitivity of the S . rimosus recA strain, when introduced in the same way.

Bone Marrow Transplant, 2000 Oct, 26(8), 907 - 10
Improvement in bronchiolitis obliterans organizing pneumonia in a child after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin; Ishii T et al.; We report a 13-year-old boy who developed dyspnea at rest 1 year after the occurrence of cGVHD following an allogeneic bone marrow transplant (BMT) . Pulmonary function data, imaging studies, lung biopsy, and bronchoalveolar lavage were consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP) . Although reports suggest that oral methylprednisolone or methylprednisolone pulse therapies improve BOOP after BMT, we treated our patient with a combination of oral prednisolone (1 mg/kg) and low dose erythromycin (10 mg/kg) to avoid the side-effects of high-dose steroids . With this therapy, our patient showed clinical and radiological improvements within 1 week . The steroids were tapered off 12 months later and erythromycin was given for 14 months . We conclude that therapy consisting of a combination of oral prednisolone and low-dose erythromycin for BOOP after BMT may minimize the dose and duration of steroid use.

Cancer Lett, 2000 Dec 8, 161(1), 35 - 46
Chemoprevention of lung tumorigenesis induced by a mixture of benzo(a)pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate; Prokopczyk B et al.; We evaluated the chemopreventive efficacy of the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) against the development of tumors of the lung and forestomach induced by a mixture of benzo(a)pyrene (B(a)P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), two of the major lung carcinogens present in tobacco smoke . A/J mice (20 mice/group) were given intragastric doses of a mixture of B(a)P (3 micromol/mouse) and NNK (3 micromol/mouse) in cottonseed oil (0.1 ml) once a week for eight consecutive weeks . Mice were fed either AIN-76A control diet or control diet containing p-XSC (10 ppm selenium), either during or after carcinogen administration . Dietary p-XSC significantly reduced lung tumor multiplicity, regardless of whether it was given during or after carcinogen administration . p-XSC was also an effective inhibitor of tumor development in the forestomach . To provide some biochemical insights into the protective role of p-XSC, its effect on selected phase I and II enzyme activities involved in the metabolism of NNK and B(a)P was also examined in vivo in this animal model . Dietary p-XSC significantly inhibited the activities of the phase I enzymes, methoxyresorufin O-dealkylase (MROD) and N-nitrosodimethylamine N-demethylase (NDMAD), in mouse liver, but it had no effect on ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD), and erythromycin N-demethylase (ERYTD) . Total glutathione S-transferase (GST) enzyme activity, as well as GST-pi and GST-mu enzyme activities, were significantly induced by dietary p-XSC in both the lung and liver . Glutathione peroxidase (GPX) activity was also induced by p-XSC in mouse lung, but not in the liver . Dietary p-XSC had no effect on selenium-dependent glutathione peroxidase (GPX(Se)), GST-alpha, and UDP-glucuronosyl transferase (UDPGT) enzyme activities in either the lung or the liver . These studies suggest that the chemopreventive efficacy of p-XSC, when fed during carcinogen administration, may be, in part, due to the inhibition of certain phase I enzymes involved in the metabolic activation of these carcinogens, and the induction of specific phase II enzymes involved in their detoxification . The mechanisms that account for the effect of p-XSC when fed after carcinogen administration remain to be determined.

J Mol Microbiol Biotechnol, 2000 Oct, 2(4), 581 - 6
Insertional inactivation of the prtP gene of Treponema denticola confirms dentilisin's disruption of epithelial junctions; Ellen RP et al.; The purified chymotrypsin-like protease of Treponema denticola, designated dentilisin or PrtP (DDBJ accession no . D83264), can disrupt cell-cell junctions and impair the barrier function of epithelial monolayers in vitro . Serine protease inhibitors block these effects . Yet, the protease is apparently less significant in perturbing intracellular signaling pathways and cytoskeletal rearrangement in fibroblasts . The purpose of this study was to use a PrtP-deficient mutant of T . denticola to confirm that the cytopathic effects of whole bacteria and its outer membrane on epithelial cell junctions were primarily accounted for by the activity of this protease . The prtP gene of ATCC 35405 was inactivated by insertion of an erythromycin-resistance cassette, yielding mutant K1 . In contrast to wildtype ATCC 35405, mutant K1 grew in tight cell aggregates; the cells had a disrupted outer sheath, as determined by electron microscopy . When compared by silver stained SDS-PAGE of sonicated extracts of whole cells, the extract of mutant K1 was missing a band at approximately 90 kDa that was present in the wildtype ATCC 35405 strain . Whole cells and Triton X-100 outer membrane (OM) extracts of K1 and the wildtype strains were compared 1) for SAAPNA degrading activity by a colorimetric assay, 2) for stress fiber disruption in human gingival fibroblasts (HGF) by fluorescence microscopy of TRITC-phalloidin stained cells, and 3) the OM extracts only for perturbation of HEp-2 epithelial monolayers by electrical cell-substrate impedance sensing (ECIS) . Mutant K-1 cells and OM had no SAPPNA degrading activity that is characteristic of dentilisin . K1 cells had HGF stress fiber disrupting activity (86 +/- 4.5% of HGFs affected) equivalent to both 35405 wildtype strains (84 +/- 3.9% and 71 +/- 14.1% of HGF, respectively) . Yet, mutant K1 OM had diminished stress fiber disrupting activity (12.9 +/- 4.6% of HGF) compared with its parent 35405's OM (94.6 +/- 2.9%) . The major cytopathogenic difference between the K1 mutant and wildtype strains was in their OM's effect on epithelial cell junctions . ATCC 35405 OM completely disrupted epithelial resistance in a concentration - dependent manner; mutant K1 OM had negligible effects . These data confirm that inactivation of the prtP gene completely reverses T . denticola's disruption of epithelial junctions, but there are pleiotropic effects of the mutation that may account for its apparently diminished effects on the cytoskeleton of HGF when the cells were challenged with OM extracts.

Rhinology, 2000 Sep, 38(3), 124 - 9
The effects of erythromycin on human peripheral neutrophil apoptosis; Inamura K et al.; Erythromycin is reported to have an anti-inflammatory action, which may account for its clinical effectiveness in treating chronic inflammatory diseases of the respiratory tract such as diffuse panbronchiolitis (DPB) and chronic sinusitis . The evaluate the anti-inflammatory action of erythromycin, we examined apoptosis of isolated neutrophils incubated with and without erythromycin . As a result, erythromycin augmented neutrophil apoptosis in a dose-dependent manner, with a maximal effect at 10 micrograms/ml and above . The percentage of neutrophil apoptosis at 12 h was 79.2 +/- 2.3% in medium with 10 micrograms/ml of erythromycin compared with 51.2 +/- 4.1% in control medium (p < 0.005) . In a manner similar to that of erythromycin, another macrolide antibiotic, roxithromycin, also increased neutrophil apoptosis . However, there was no effect on apoptosis induced by treatment with josamycin (macrolide antibiotic), ampicillin (beta-lactam.) and cefazolin (cephalosporin antibiotic), or gentamycin (aminoglycoside) . These findings suggest that erythromycin shortens neutrophil survival by accelerating neutrophil apoptosis.

Eur J Pharm Biopharm, 2000 Nov, 50(3), 365 - 71
Effect of compression force on the crystal properties of erythromycin acistrate tablets; Riippi M et al.; The crystal properties of compressed and powdered erythromycin acistrate tablets were studied by the X-ray powder diffraction (XRPD) method . Detailed analysis of X-ray powder diffraction line profiles was performed . Diffraction peak intensities and full width at half maximum (FWHM) values of the peaks corresponding to three different crystal lattice directions were determined . Crystallite size was calculated by Scherrer's equation using the data of integral breadth of the peaks . The preferred orientation of the crystallites is also discussed . According to the results, the crystallite size increased on the tablet surface after a small compression force (4 kN) in all crystal lattice directions studied . Even small compression forces caused recrystallization . With higher compression forces (8-18 kN) the crystallite size and the FWHM values remained rather constant . After the compression force of 18 kN the peaks in different crystal lattice directions behaved differently . In the lattice directions of diffraction maxima 2 and 3, the effect was the same with the small (4 kN) and the high compression force (22 kN) . Further recrystallization occurred with 22 kN . However, in the crystal lattice direction of diffraction maximum 1 at the compression force of 8 kN the crystallite broke and crystallinity decreased . These were not seen in the powdered tablet samples . It could be concluded that the effect of compression force on the crystal properties of erythromycin acistrate tablets was seen on the tablet surface but not in the powdered tablets . Compression force also affected the preferred orientation of crystallites on the tablet surface and especially in the lattice direction of diffraction maximum 3 . This was not seen in the powdered tablets.

World J Surg, 2000 Oct, 24(10), 1236 - 41; discussion 1242
Manometric evidence of improved early gastric stasis by erythromycin after pylorus-preserving pancreatoduodenectomy; Matsunaga H et al.; Gastric stasis is a frequent complication of pylorus-preserving pancreatoduodenectomy (PPPD) . We demonstrated that it might be attributable to delayed recovery of phase III activity of the gastric migrating motor complex due to low concentrations of plasma motilin caused by resection of the duodenum . Leucine 13-motilin is effective for treating gastric stasis, but it is not yet available for clinical use . Whether erythromycin would improve early gastric stasis after PPPD was tested clinically and by manometry . A manometric tube assembly and a gastrostomy tube were inserted in the stomach of 10 patients at PPPD for pressure recording from the gastric antrum and jejunum and for gastric juice drainage, respectively . After baseline recording, erythromycin 5 mg/kg was given intravenously on day 14 and saline as a placebo on day 17 every 4 hours four times a day . The daily volume of gastric juice output and the gastric motility index were measured . The mean period until the return of gastric phase III was 31 +/- 1 days . Erythromycin significantly increased the gastric motility index from 7.9 +/- 1.3 mmHg to 15.7 +/- 1.8 mmHg (p = 0.0005), whereas saline did not (7.2 +/- 1.6 mmHg to 6.5 +/- 1.2 mmHg; p = 0.21) . Erythromycin significantly decreased the gastric juice output from 1,080 +/- 190 ml to 738 +/- 199 ml (p < 0.0001), but the saline injections did not (1,064 +/- 174 ml to 1,115 +/- 189 ml; p = 0.35) . Erythromycin, a universally available motilin agonist, is a safe, effective, potent drug for the treatment of early gastric stasis after PPPD.

Int J Clin Pract, 2000 Sep, 54(7), 429 - 31
Benefits of a standardised feeding regimen during a clinical trial in preterm neonates; Patole SK et al.; The feeding regimen was standardised for a trial of erythromycin to reduce the time to reach full feeds (150 ml/kg/day) by 30% in neonates of < or = 32 weeks gestation . No significant improvement was noted in the primary outcome (median time: erythromycin 93.5 vs placebo 104 hours, p = 0.60) . However, necrotising enterocolitis > or = stage II disappeared and the time to full feeds was reduced by over 50% in all neonates during the 18-month trial, and for more than two years after the trial, when the standardised feeding regimen was adopted as routine policy for feeding neonates of < or = 32 weeks (< 28 weeks: 13 vs 4.8 days, p < 0.05; > 28 weeks: 8 vs 3.9 days, p < 0.05) . This was in contrast to an average of six cases of NEC per year with 45% mortality during the previous five years . The benefits of standardised feeding schedules--improved detection/treatment of signs/symptoms of feed intolerance--are emphasised.

Respiration, 2000, 67(5), 546 - 51
Superoxide dismutase in alveolar macrophages from patients with diffuse panbronchiolitis; Morikawa T et al.; BACKGROUND: Diffuse panbronchiolitis (DPB) is characterized by chronic neutrophil-mediated inflammation of the airway mediated by oxygen radical production . DPB can be controlled with low-dose and long-term erythromycin therapy based on its anti-inflammatory effect . OBJECTIVE: In this study, the antioxidant levels were analyzed as an anti-inflammatory effect of erythromycin in the patients . METHODS: We investigated the activity and protein level of an antioxidant enzyme, Cu, Zn-superoxide dismutase (SOD) in alveolar macrophages (AMs) of patients with DPB before and after erythromycin therapy . AMs were obtained from bronchoalveolar lavage fluid . RESULTS: There was no significant difference in the activity of Cu, Zn-SOD between normal subjects and untreated patients . Erythromycin therapy (600 mg/day) significantly increased the activity of the enzyme relative to that before therapy and normal subjects {18.2 units/10(6) cells (9.2-26.2) vs . 4.4 units/10(6) cells (1.1-9.3), p < 0.01 and 10.4 units/10(6) cells (2.4-20.6), p < 0.05, respectively} . Furthermore, the protein level of Cu, Zn-SOD in AMs in treated patients was significantly higher than in the other two groups {69.4 ng/10(6) cells (34.2-147.1) vs . 20.1 ng/ 10(6) cells (16.9-39.8) for untreated patients, p < 0.01 and 43.2 ng/10(6) cells (32.6-68.2) for normal subjects, p < 0.01}, but the levels in the latter groups were not different . CONCLUSION: Our results suggest that one of the anti-inflammatory effects of erythromycin in DPB may be, in part, mediated by enhancement of antioxidant activity in AMs .

Anticancer Res, 2000 Sep-Oct, 20(5A), 2827 - 34
Inhibitory effect of erythromycin on P-glycoprotein-mediated biliary excretion of doxorubicin in rats; Kiso S et al.; The macrolide antibiotic erythromycin has recently been shown to overcome the resistance to anticancer drugs that results from overexpression of P-glycoprotein . The present study, using erythromycin lactobionic acid as a model drug, investigated the inhibitory effects of erythromycin on the efflux of doxorubicin from P388/ADR cells expressing P-glycoprotein and on the biliary excretion mechanism of doxorubicin in rats, which is primarily mediated by P-glycoprotein . Erythromycin lactobionic acid was found to inhibit the efflux of doxorubicin (5 microM) from P388/ADR cells in a concentration-dependent manner . In rats receiving constant-rate infusion of doxorubicin (30 micrograms/min), both the biliary and renal clearance of this drug dramatically decreased and its plasma concentrations increased after an intravenous injection of erythromycin lactobionic acid (100 mg/kg as erythromycin) . These results suggest that erythromycin competitively inhibits P-glycoprotein-mediated biliary and renal excretion of doxorubicin . The effect of erythromycin on the biliary secretion of doxorubicin was also analyzed quantitatively by the competitive inhibition model . The computer-estimated values of Vmax/Km, Km and Ki were 8.79 ml/minute, 0.82 microgram/ml and 0.41 microgram/ml, respectively . The findings of these experiments suggest that the inhibitory effect of erythromycin on the P-glycoprotein-mediated biliary excretion of doxorubicin is competitive and that combination chemotherapy of doxorubicin with erythromycin may induce toxicity as a result of increased plasma concentrations of doxorubicin.

Ned Tijdschr Geneeskd, 2000 Oct 7, 144(41), 1945 - 8
{Treatment of severely delayed gastric emptying}; Samsom M et al.; For the drug treatment of gastroparesis, domperidone, metoclopramide and cisapride may be prescribed as prokinetics . Positive effects on the rate of emptying of the stomach, dyspeptic symptoms and quality of life are best documented for cisapride . Simultaneous use of cisapride with substances that inhibit the metabolism of cisapride or that may lengthen the QT interval, is contraindicated because of the risk of arrhythmias . Erythromycin is a powerful prokinetic, but because of its antibiotic effects it is usually prescribed only for a brief period . For patients who in spite of drug treatment have persistent unacceptable symptoms and keep losing weight, invasive treatment should be considered . The first step is then insertion of a jejunal tube, followed, if necessary, by antrectomy with Billroth-I reconstruction . The next step is subtotal gastrectomy with Roux-Y reconstruction, this may result in abatement of the symptoms, which, however, rarely disappear altogether.

Life Sci, 2000 Sep 22, 67(18), 2189 - 200
Effects of baicalein and wogonin on drug-metabolizing enzymes in C57BL/6J mice; Ueng YF et al.; Effects of baicalein and wogonin, the major flavonoids of Scutellariae radix, on cytochrome P450 (CYP), UDP-glucuronosyl transferase (UGT), and glutathione S-transferase (GST) were studied in C57BL/6J mice . One-week treatment of mice with a liquid diet containing 5 mM baicalein resulted in 29%, 14%, 36%, 28%, and 46% decreases of hepatic benzo(a)pyrene hydroxylation (AHH), benzphetamine N-demethylation (BDM), N-nitrosodimethylamine N-demethylation (NDM), nifedipine oxidation (NFO), and erythromycin N-demethylation (EMDM) activities, respectively . Treatment with a liquid diet containing 5 mM wogonin resulted in 43%, 22%, 21%, 24%, and 35% decreases of hepatic AHH, BDM, NDM, NFO, and EMDM activities, respectively . However, hepatic 7-methoxyresorufin O-demethylation (MROD) activity was increased and decreased by baicalein- and wogonin-treatments, respectively . Similar modulation was observed with caffeine 3-demethylation (CDM) activity . Immunoblot analysis showed that the levels of hepatic CYP2E1 and CYP3A proteins were decreased by both baicalein- and wogonin-treatments . Hepatic CYP1A2 protein level was increased by baicalein but decreased by wogonin . In extrahepatic tissues, renal AHH activity was decreased by wogonin whereas pulmonary AHH, 7-ethoxyresorufin O-deethylation (EROD), and MROD activities were increased by both flavonoids . Both baicalein and wogonin strongly increased CYP1A protein level in mouse lung . Hepatic and renal UGT activities toward p-nitrophenol were suppressed by baicalein- and wogonin-treatments . However, cytosolic GST activity was not affected by flavonoids . These results suggest that ingestion of baicalein or wogonin can modulate drug-metabolizing enzymes and the modulation shows tissue specificity.

Exp Parasitol, 2000 Aug, 95(4), 265 - 70
Tetracycline inhibits development of the infective-stage larvae of filarial nematodes in vitro; Smith HL et al.; In recent years, studies have linked tetracycline treatment of filaria-infected animals with reduced adult worm burdens and decreased levels of microfilaremia . These observations are believed to be attributable to clearance of Wolbachia, intracellular rickettsial-like organisms found within filarial tissues . Although maximal worm reductions were observed when treatment was initiated early in infection, it is not known whether tetracycline inhibits development of infective-stage larvae . To address this issue, we studied the effect of tetracycline on three different species of filarial nematodes, Brugia malayi, Brugia pahangi, and Dirofilaria immitis, in a serumfree in vitro system supporting molting to the fourth larval stage . Tetracycline was capable of inhibiting L3 to L4 molting within a dosage range similar to that reported for susceptible rickettsial organisms . However, Wolbachia DNA could still be detected in nematodes from tetracycline-treated cultures . In addition, three other antibiotics with anti-rickettsial and anti-chlamydial activity (chloramphenicol, erythromycin, and ciprofloxacin) failed to inhibit L3 to L4 molting . Although tetracycline is capable of completely blocking molting of infective-stage larvae, it remains possible that this effect is due to pharmacological activities unrelated to its anti-rickettsial functions .

Drug Metab Dispos, 2000 Nov, 28(11), 1317 - 20
Decreased in vivo metabolism of drugs in chronic renal failure; Leblond FA et al.; Chronic renal failure (CRF) is associated with a decrease in renal excretion of drugs, but its effects on the liver metabolism of xenobiotics are poorly defined . The objectives of this study were to determine the effects of CRF on hepatic cytochrome P450 (CYP450) and its repercussions on in vivo hepatic metabolism of drugs . Two groups of rats were studied: control paired-fed and CRF . CRF was induced by subtotal nephrectomy . Total CYP450 activity and protein expression of several CYP450 isoforms (CYP1A2, CYP2C11, CYP3A1, CYP3A2) were assessed in liver microsomes . In vivo cytochrome P450 activity was evaluated with breath tests using substrates for different isoenzymes: caffeine (CYP1A2), aminopyrine (CYP2C11), and erythromycin (CYP3A2) . Creatinine clearance was reduced by 60% (P < . 01) in rats with CRF . Compared with control paired-fed rats, total CYP450 activity was reduced by 40% in rats with CRF . Protein expression of CYP2C11, CYP3A1, and CYP3A2 was considerably reduced (more than 45%, P <.001) in rats with CRF, whereas the levels of CYP1A2 were unchanged . In rats with CRF, there was a 35% reduction in the aminopyrine (CYP2C11) and the erythromycin (CYP3A2) breath tests compared with control animals (P <.001) . The caffeine (CYP1A2) breath tests remained comparable to controls . Creatinine clearance correlated with the aminopyrine and erythromycin breath tests (r(2) = 0.73 and r(2) = 0.81, respectively, P <.001) . In conclusion, CRF is associated with a decrease in total liver CYP450 activity in rats (mainly in CYP2C11, CYP3A1, and CYP3A2), which leads to a significant decrease in the metabolism of drugs.

J Natl Cancer Inst, 2000 Oct 18, 92(20), 1641 - 50
Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571; Gambacorti-Passerini C et al.; BACKGROUND: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl . Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571 . This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated . We created a mouse model to explore the mechanism of resistance in vivo . METHODS Nude mice were injected with KU812 Bcr-Abl(+) human leukemic cells . After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours) . Cells recovered from relapsing animals were used for in vitro experiments . Statistical tests were two-sided . RESULTS: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed . Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug . However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug . The plasma protein alpha1 acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner . Plasma AGP concentrations were strongly associated with tumor load . Erythromycin competed with STI571 for AGP binding . When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P:<.001) were observed after the combination treatment . CONCLUSION: AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase . Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this drug.

Curr Microbiol, 2000 Mar, 40(3), 164 - 8
Construction of a promoter-rescue plasmid for Butyrivibrio fibrisolvens and its use in characterization of a flagellin promoter; Beard CE et al.; The Butyrivibrio fibrisolvens/Escherichia coli shuttle vector pBHerm has been modified to produce a plasmid (pBHE) that can be used for the identification and characterization of promoters in B . fibrisolvens . pBHE allows the insertion of a test promoter immediately upstream of a promoterless erythromycin resistance gene (ermAM) . The efficacy of the pBHE plasmid in isolating and characterizing promoters was tested by inserting the flagellin gene (flaA) promoter from B . fibrisolvens OR77 . Transcription of the ermAM gene from the flaA promoter was significantly higher than that observed when the ermAM gene was under the control of its own promoter . The flagelling gene of OR77 appears to be transcribed from two different promoters that produce transcripts initiating approximately 130 bp apart . Two mutant flaA promoter constructs, containing mutations in the -10 and -35 regions of either of the two putative promoter regions, showed drastic alterations in both the origin and amounts of the two transcripts produced . Mutations in either promoter affected transcription from both promoters, indicating that both regions contribute to gene expression.

Ther Drug Monit, 2000 Oct, 22(5), 503 - 9
Frequency and clinical outcome of potentially harmful drug metabolic interactions in patients hospitalized on internal and pulmonary medicine wards: focus on warfarin and cisapride; Laine K et al.; Drug metabolic interactions present potential risks in patient care, but their frequency and relative importance as a clinical problem remains unclear . To assess the frequency and clinical outcome of potentially harmful drug metabolic interactions in hospitalized patients, the authors performed a survey of the medication data of patients treated on internal and pulmonary medicine wards in a university hospital . The database was searched for concomitantly administered drug pairs that would, according to Hansten and Horn's drug interaction database, carry a high risk for a clinically harmful metabolic drug interaction . Coadministrations involving warfarin or cisapride were subjected to further analysis regarding clinical outcome . A total of 142 patients were exposed to 150 interactions with potentially harmful clinical outcome, resulting in a frequency of 0.9% (95% CI 0.7% to 1.0%) . Inhibition of warfarin metabolism by metronidazole produced significant overanticoagulation as evidenced by elevated international normalized ratio values, whereas inducers (rifampicin and phenobarbital) of warfarin metabolism significantly reduced the efficacy of warfarin . One case of minor bleeding and one case of clavicular vein thrombosis were detected as possible consequences of disturbed anticoagulation . The coadministration of cisapride and erythromycin significantly prolonged the corrected QT (QTc) interval and was associated with clinical symptoms of cardiac arrhythmias . Coadministration of cisapride with fluconazole or miconazole was not associated with prolongation of the QTc interval or cardiac sequelae . Evaluations of patient materials are needed to assess the clinical relevance of metabolic drug interactions.

Drugs, 2000 Sep, 60(3), 597 - 605
Treatment of Chlamydia trachomatis infections in pregnant women; Miller JM et al.; The intent of this article is to provide an overview of the epidemiology and pharmacotherapy, including cost analyses, of Chlamydia trachomatis infections in pregnant women . Chlamydia is a common sexually transmitted infection . For pregnant women, there are concerns both for the mother (post-partum endometritis, horizontal transmission) and the newborn (conjunctivitis, delayed pneumonia) . Therapeutic options are restricted because of the fetus and include multi-day treatment with erythromycin, amoxicillin, clindamycin or single dose azithromycin . Clinical cure rates with these options are 86, 92, 93 and 95%, respectively . Pharmacoeconomic analyses have been conducted to determine if the initial increase in acquisition cost of azithromycin (approximately 3-fold higher than erythromycin or amoxicillin) is offset by improvement in compliance and drug efficacy . Clindamycin has received little attention because of its expense (4-fold more than azithromycin) . Analyses have been retrospective . As models incorporate more complications of failure to cure, azithromycin increasingly becomes more cost effective and is our recommended treatment.

Am J Ophthalmol, 2000 Sep, 130(3), 340 - 9
Ocular bartonellosis; Cunningham ET et al.; PURPOSE: To review recent advances in the basic and clinical biology of Bartonella-related eye disease . METHOD: A review of the pertinent medical literature was performed . RESULTS: A number of novel Bartonella species have been identified over the past decade . Of these, Bartonella henselae, the etiologic agent in cat scratch disease, is most often associated with ocular complications, which may include Parinaud oculoglandular syndrome, neuroretinitis, and focal retinochoroiditis . Although cat and flea exposure appear to be the main risk factors for contracting cat scratch disease, the diagnosis of ocular bartonellosis relies primarily on the recognition of suggestive clinical signs in conjunction with positive serologic testing . B . henselae-associated ocular complications are usually self-limited but may be treated with doxycycline or erythromycin, with or without rifampin, when the infections are severe or sight-threatening . CONCLUSIONS: B . henselae infection is common and should be considered in patients with Parinaud oculoglandular syndrome, neuroretinitis, or focal retinochoroiditis, particularly when there is a history of cat or flea exposure.

Am J Gastroenterol, 2000 Sep, 95(9), 2233 - 41
The stimulation of antral motility by erythromycin is attenuated by hyperglycemia; Rayner CK et al.; OBJECTIVE: Diabetic gastroparesis is usually treated with prokinetic drugs, of which the most potent, when given intravenously during euglycemia, is erythromycin . Recent studies have demonstrated that the gastrokinetic effects of erythromycin are attenuated by hyperglycemia . The aim of this study was to determine whether the effects of erythromycin on antropyloroduodenal motility, including the organization of antral pressure waves, are modified by hyperglycemia . METHODS: A total of eight healthy male volunteers (median age 24 yr) were studied on 2 days each in randomized order . A manometric assembly, incorporating six antral, two pyloric, and seven duodenal sideholes and a pyloric sleeve sensor, was positioned with the sleeve spanning the pylorus . The blood glucose concentration was stabilized at about 5 mmol/L (euglycemia) or 15 mmol/L (hyperglycemia) . After 30 min (T = 0), an intraduodenal lipid infusion (1.5 kcal/min) was commenced and continued until the end of the study . At T = 20 minutes, erythromycin (200 mg) as the lactobionate was infused intravenously over 20 min, followed by 100 mg over the next 40 min . RESULTS: Intravenous erythromycin increased the amplitude of antral waves during intraduodenal lipid infusion at both blood glucose concentrations (p < 0.01 for euglycemia and p < 0.05 for hyperglycemia) . After erythromycin (T = 20 to T = 80), the frequency (p < 0.05) and amplitude (p < 0.01) of antral waves were less during hyperglycemia than euglycemia . Both propagated (p < 0.0005) and nonpropagated (p < 0.01) antral waves were decreased by hyperglycemia, but the suppression of propagated waves was greater (p < 0.05) . Erythromycin reduced the frequency (p = 0.09) but increased the amplitude (p < 0.05) of phasic pyloric pressures, and decreased basal pyloric pressure (p < 0.0005) . The frequency (p = 0.06) and amplitude (p < 0.05) of phasic pyloric waves during erythromycin infusion were slightly less during hyperglycemia than euglycemia, whereas there was no effect of the blood glucose concentration on basal pyloric pressure . Erythromycin increased the amplitude (p < 0.001) but not the frequency of duodenal waves; the frequency and amplitude of duodenal waves did not differ between the two blood glucose concentrations . CONCLUSIONS: Hyperglycemia attenuates the stimulation of antral pressures and propagated antral sequences by erythromycin, but not the effects of erythromycin on pyloric or duodenal motility.

Drug Saf, 2000 Sep, 23(3), 197 - 213
Comparative tolerability of the HMG-CoA reductase inhibitors; Farmer JA et al.; The availability of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has revolutionised the treatment of lipid abnormalities in patients at risk for the development of coronary atherosclerosis . The relatively widespread experience with HMG-CoA therapy has allowed a clear picture to emerge concerning the relative tolerability of these agents . While HMG-CoA reductase inhibitors have been shown to decrease complications from atherosclerosis and to improve total mortality, concern has been raised as to the long term safety of these agents . They came under close scrutiny in early trials because ocular complications had been seen with older inhibitors of cholesterol synthesis . However, extensive evaluation demonstrated no significant adverse alteration of ophthalmological function by the HMG-CoA reductase inhibitors . Extensive experience with the potential adverse effect of the HMG-CoA reductase inhibitors on hepatic function has accumulated . The effect on hepatic function for the various HMG-CoA reductase inhibitors is roughly dose-related and 1 to 3% of patients experience an increase in hepatic enzyme levels . The majority of liver abnormalities occur within the first 3 months of therapy and require monitoring . Rhabdomyolysis is an uncommon syndrome and occurs in approximately 0.1% of patients who receive HMG-CoA reductase inhibitor monotherapy . However, the incidence is increased when HMG-CoA reductase inhibitors are used in combination with agents that share a common metabolic path . The role of the cytochrome P450 (CYP) enzyme system in drug-drug interactions involving HMG-CoA reductase inhibitors has been extensively studied . Atorvastatin, cerivastatin, lovastatin and simvastatin are predominantly metabolised by the CYP3A4 isozyme . Fluvastatin has several metabolic pathways which involve the CYP enzyme system . Pravastatin is not significantly metabolised by this enzyme and thus has theoretical advantage in combination therapy . The major interactions with HMG-CoA reductase inhibitors in combination therapy involving rhabdomyolysis include fibric acid derivatives, erythromycin, cyclosporin and fluconazole . Additional concern has been raised relative to overzealous lowering of cholesterol which could occur due to the potency of therapy with these agents . Currently, there is no evidence from clinical trials of an increase in cardiovascular or total mortality associated with potent low density lipoprotein reduction . However, a threshold effect had been inferred by retrospective analysis of the Cholesterol and Recurrent Events study utilising pravastatin and the role of aggressive lipid therapy is currently being addressed in several large scale trials.

Acta Anaesthesiol Sin, 2000 Jun, 38(2), 65 - 72
Modulation of cytochrome P450-dependent monooxygenases in streptozotocin-induced diabetic hamster: II . Reverse role of insulin in P450 activity and defluorination; Chen TG et al.; BACKGROUND: Metabolic activities of cytochrome (cyt) P450-dependent monooxygenase could be modulated by diabetic state in experimental diabetic animals . The purpose of this study is to validate the effect of insulin on the modulation of the metabolic activity of cyt P450 and the defluorination ability to inhalational anesthetics in diabetic animals . METHODS: Diabetic state in golden Syrian hamsters was achieved by intraperitoneal injection of streptozotocin 40 mg/kg once a day for 4 days . After stabilization of diabetic state for 6 weeks, a regimen of insulin treatment given subcutaneously was carried out . Metabolic activities of cyt P450 were assessed by the reaction with benzo(a) pyrene, pentoxyresorufin, aniline and erythromycin (specific substrates) . The metabolic activities of cyt 1A1, 2B1, 2E1 and 3A4 respectively in a NADPH-generating system in microsomal preparations of the diabetic hamsters were observed before and after insulin treatment, and were compared with the control group . The ability of defluorination was evaluated by measuring the free fluoride metabolites after incubating the microsomes with enflurane in diabetic and insulin-treated hamsters . Contents of cyt P450 isozymes were measured by electrophoresis and immunoblotting before and after insulin treatment . Pathological features of hepatocytes in diabetic hamsters were evaluated microscopically before and after insulin treatment . RESULTS: The defluorination of enflurane and activity of aniline hydroxylase (cyt 2E1) were successfully induced by diabetic state (P < 0.01) . The pentoxyresorufin O-dealkylase (cyt 2B1) was inhibited nearly 50% in the diabetic hamster liver when compared with that of control (P < 0.01) . While the activities of benzo(a)pyrene hydroxylase (cyt 1A1) and the erythromycin N-demethylase (cyt 3A4) were basically unaffected by diabetes, alterations in content of cyt P450 were parallel to the alterations in enzyme activities . Microscopically, diabetes induced vacuolization with fatty droplets in the hepatocytes . After treatment with insulin injection, the enzyme activities, protein content and pathologic features returned to the baseline similar to the control . CONCLUSIONS: Our data demonstrated that under diabetic state, metabolic activities of cyt P450 and its extent of defluorination would be polymorphically modulated . After administration of insulin, the activities of cyt P450 and defluorination of enflurane returned to baseline as the blood sugar level had been normalized . This could remind the clinicians of the importance of insulin treatment in the potential drug-to-drug interactions in the diabetic patients.

Acta Anaesthesiol Sin, 2000 Mar, 38(1), 15 - 21
Modulation of cytochrome P-450 dependent monooxygenases in streptozotocin-induced diabetic hamster: I . Effects of propofol on defluorination and cytochrome P-450 activities; Chen TL et al.; BACKGROUND: Diabetes mellitus could induce polymorphic alterations of metabolic activities of cytochrome P-450 dependent monooxygenases in chemical-induced diabetic animals . The purpose of this study is to define the functional impact of clinical concentrations of propofol on the metabolic activities of cytochrome P-450 in the diabetic animals . METHODS: In order to validate the effect of propofol on cytochrome P-450 activities, especially the cytochrome P-450 2E1 and its defluorination activity, we applied NADPH-generating system to measure the metabolizing activities of cytochrome P-450 isozymes of streptozotocin-induced diabetic hamsters within the microsomes preincubated with various concentrations of propofol . The extent of defluorination and activity of cytochrome P-450 2E1 were assessed by reacting the propofol-treated microsomes in NADPH-generating system with enflurane and aniline as substrates respectively . Drug metabolizing activities of cytochrome 1A1, 2B1, and 3A4 were evaluated by metabolizing specific substrates, benzo(a)pyrene, pentoxyresorufin and erythromycin, within the microsomes of diabetic hamsters preincubated with various concentrations of propofol . RESULTS: The hepatic and renal defluorination of enflurane was significantly inhibited by 0.05 and 0.10 mM propofol in the microsomes of diabetic hamster (P < 0.05) . The activities of aniline hydroxylase (cytochrome 2E1), pentoxyresorufin O-dealkylase (cytochrome 2B1) and benzo(a)pyrene hydroxylase (cytochrome 1A1) were inhibited by propofol in a concentration-dependent manner from 0.05 to 0.10 mM . However, propofol showed no significant effect to the erythromycin N-demethylase (cytochrome 3A4) at its concentration of 0.05-0.10 mM in the diabetic hamsters . CONCLUSIONS: Our data demonstrated that propofol in therapeutic concentrations of 0.05 and 0.10 mM, could inhibit both liver and kidney defluorination and cytochrome P-450's activities of the diabetic hamsters in vitro of different extent . This should remind clinicians of propofol's potential drug-to-drug interactions in the diabetic patients.

Mol Pharmacol, 2000 Oct, 58(4), 863 - 9
Mdr1 limits CYP3A metabolism in vivo; Lan LB et al.; We determined whether the drug efflux protein P-glycoprotein (Pgp) could influence the extent of CYP3A-mediated metabolism of erythromycin, a widely used model substrate for CYP3A . We compared CYP3A metabolism of erythromycin (a Pgp substrate) using the erythromycin breath test in mice proficient and deficient of mdr1 drug transporters . We first injected mdr1(+/+) mice with {(14)C}N-methyl erythromycin and measured the rate of appearance of (14)CO(2) in the breath as a measure of hepatic CYP3A activity . Animals treated with CYP3A inducers or inhibitor showed accelerated or diminished (14)CO(2) in the breath, respectively . The erythromycin breath test was next administered to mdr1a(-/-) and mdr1a/1b(+/+) and (-/-) mice . These animals had equivalent levels of immunoreactive CYP3A and CYP3A activity as measured by erythromycin N-demethylase activity in liver microsomes . Nevertheless, the rate of (14)CO(2) appearance in the breath showed no relationship with these measurements of CYP3A, but changed proportionally to expression of mdr1 . The average breath test (14)CO(2) area under the curves were 1.9- and 1.5-fold greater in mdr1a/1b(-/-) and mdr1a(-/-) mice, respectively, compared with (+/+) mice, and CER(max) was 2-fold greater in mdr1a/1b(-/-) compared with (+/+) mice . We conclude that Pgp, by limiting intracellular substrate availability can be an important determinant of CYP3A metabolism of numerous medications that are substrates for CYP3A and Pgp.

Clin Cancer Res, 2000 Sep, 6(9), 3480 - 5
Optimizing the erythromycin breath test for use in cancer patients; Rivory LP et al.; The erythromycin breath test (EBT) is a putative in vivo probe for drug metabolism by cytochrome P450 3A4 (CYP3A4) . Because many anticancer drugs are metabolized by this system, we sought to further develop the EBT as a tool for predicting the clearance, in cancer patients, of drugs metabolized by CYP3A4 . Sixteen adult patients with incurable cancer were studied . The EBT was performed on day 1 and breath sampled after the i.v . injection of 4 microCi of 14C-erythromycin . The breath 14CO2 flux (CERt) was estimated at 11 time points over 2 h . On day 2, the EBT was repeated midway through a 10-min infusion of 100 mg of erythromycin lactobionate, and the plasma pharmacokinetics of erythromycin were determined . The infusion of 100 mg of erythromycin did not modify the EBT results significantly . The values of the conventional EBT parameter CER20 min obtained on day 1 were comparable for most subjects (0.03-0.06% dose/min), with the exception of an individual receiving the known CYP3A4 inducers dexamethasone and phenytoin who returned a value of 0.14% dose/min . There was no significant correlation between any of the conventional EBT parameters and erythromycin clearance . However, two parameters reflecting early emergence of breath radioactivity (1/TMAX and CER3 min/CERMAX) correlated significantly with erythromycin clearance (P = 0.005 and 0.006, respectively) . Novel parameters derived from the EBT are significantly correlated with the clearance of erythromycin even in the presence of confounding factors, such as metastatic liver disease, altered protein binding, and comedication . These parameters may enable dose optimization of cytotoxics metabolized by CYP3A4.

Nippon Ronen Igakkai Zasshi, 2000 Jun, 37(6), 464 - 8
{The pathogenesis and therapy of virus infection-induced senile bronchial asthma}; Yamaya M et al.; We investigated the pathogenesis and therapy of virus infection-induced senile bronchial asthma in vitro . To examine the effects of rhinovirus infection on the production of cytokines and intercellular adhesion molecule-1 (ICAM-1), human tracheal epithelial cells and submucosal gland cells were cultured, and infected with human rhinovirus . Rhinovirus upregulated the production of interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha in supernatants of epithelial cells and submucosal-gland cells, and IL-1 alpha and granulocyte macrophage colony-stimulating factor (GM-CSF) in supernatants of submucosal gland cells . Rhinovirus upregulated the expression of ICAM-1 mRNA . Rhinovirus infection also increased epithelial permeability . These events may be important for the spread of airway inflammation after rhinovirus infection . Furthermore, we studied the effects of dexamethasone and erythromycin on the modulation of virus infection and induction of cytokines and ICAM-1 in tracheal epitherial cells . Both of them reduced viral titers of rhinovirus type 14, a major group rhinovirus, and cytokine production of supernatants, and ICAM-1 mRNA expression in the cells . Because it is known that acidic conditions by proton pumps are needed for rhinovirus entry into the cells, we studied the effects of H+ ATPase inhibitor bafilomycin A1 . Bafilomycin A1 reduced the virus titers of both rhinovirus type 2 and 14 in supernatants . These findings in our in vitro study suggest that dexamethasone, erythromycin and bafilomycin A1 may inhibit rhinovirus infection and modulate airway inflammation induced by rhinovirus infection.

Drug Metab Dispos, 2000 Oct, 28(10), 1231 - 7
The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: comparison with cisapride and mosapride citrate; Mushiroda T et al.; The goals of the present study were to identify the enzyme responsible for metabolism of itopride hydrochloride (itopride) and to evaluate the likelihood of drug interaction involving itopride . In human liver microsomes, the involvement of flavin-containing monooxygenase in N-oxygenation, the major metabolic pathway of itopride, was indicated by the following results: inhibition by methimazole and thiourea, heat inactivation, and protection against heat inactivation by NADPH . When the effects of ketoconazole on the metabolism of itopride, cisapride, and mosapride citrate (mosapride) were examined using human liver microsomes, ketoconazole strongly inhibited the formation of the primary metabolites of cisapride and mosapride, but not itopride . Other cytochrome P450 (CYP) 3A4 inhibitors, cimetidine, erythromycin, and clarithromycin, also inhibited the metabolism of cisapride and mosapride . In an in vivo study, itopride (30 mg/kg), cisapride (1.5 mg/kg), or mosapride (3 mg/kg) was orally administered to male rats with or without oral pretreatment with ketoconazole (120 mg/kg) twice daily for 2 days . The ketoconazole pretreatment significantly increased the area under the serum concentration curve and the maximum serum concentration of cisapride and mosapride but had no significant effect on the pharmacokinetics of itopride . In addition, itopride did not inhibit five specific CYP-mediated reactions of human liver microsomes . These results suggest that itopride is unlikely to alter the pharmacokinetics of other concomitantly administered drugs.

J Chir (Paris), 2000 Aug, 137(4), 214 - 20
{Surgical treatment of pancreatic adenocarcinoma: limitations and latest developments}; Dousset B et al.; Duodenopancreatectomy with preservation of the tail for pancreatic adenocarcinoma is not contraindicated by age except in case of comorbidity . Curative excision is contraindicated in case of metastasis to the liver, peritoneum or distal nodes or in case of arterial invasion . Inversely, isolated venous invasion is not incompatible with curative surgery if one can accept the potential overmortality due to the vascular risk . Palliative surgery may be indicated for tumors limited to the pancreas in selected patients as it appears to improve survival and quality of life over derivation surgery . Preoperative biliary drainage using an endoscopic, a percutaneous or a surgical approach increases the rate of surgical complications and mortality and should be avoided, especially when the resectability of the tumor is not formally established . Wide node dissection does not modify prognosis after excision and would not be warranted on the basis of current data . Preserving the pyloris increases the rate of postoperative gastroparesia without bringing the expected nutritional advantages . It is not warranted in this indication . The type of pancreas anastomosis (pancreatogastric or pancreatojejunal) does not modify the incidence of complications or pancreatic fistulae . The rate of pancreatic fistulae and postoperative complications is decreased by preventive administration of octreotide, particularly when the pancreas is healthy . The prevalence of postoperative gastroparesia is decreased by preventive treatment with intravenous erythromycin . Progress will undoubtedly issue from complimentary treatments combining radiotherapy and chemotherapy

Antimicrob Agents Chemother, 2000 Oct, 44(10), 2679 - 83
Sequencing of the rpoB gene in Legionella pneumophila and characterization of mutations associated with rifampin resistance in the Legionellaceae; Nielsen K et al.; Rifampin in combination with erythromycin is a recommended treatment for severe cases of legionellosis . Mutations in the rpoB gene are known to cause rifampin resistance in Escherichia coli and Mycobacterium tuberculosis, and the purpose of the present study was to investigate a possible similar resistance mechanism within the members of the family Legionellaceae . Since the RNA polymerase genes of this genus have never been characterized, the DNA sequence of the Legionella pneumophila rpoB gene was determined by the Vectorette technique for genome walking . A 4,647-bp DNA sequence that contained the open reading frame (ORF) of the rpoB gene (4,104 bp) and an ORF of 384 bp representing part of the rpoC gene was obtained . A 316-bp DNA fragment in the center of the L . pneumophila rpoB gene, corresponding to a previously described site for mutations leading to rifampin resistance in M . tuberculosis, was sequenced from 18 rifampin-resistant Legionella isolates representing four species (L . bozemanii, L . longbeachae, L . micdadei, and L . pneumophila), and the sequences were compared to the sequences of the fragments from the parent (rifampin-sensitive) strains . Six single-base mutations which led to amino acid substitutions at five different positions were identified . A single strain did not contain any mutations in the 316-bp fragment . This study represents the characterization of a hitherto undescribed resistance mechanism within the family Legionellaceae.

Antimicrob Agents Chemother, 2000 Oct, 44(10), 2630 - 7
Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats; Ohtani H et al.; In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats . Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections . Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations . RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges . The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms . ml/microg for CAM, RXM, and AZM, respectively . There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug . The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM . In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM . These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

J Toxicol Sci, 2000 Aug, 25(3), 213 - 22
Sex-related effect of hemin on cytochrome P450 and drug-metabolizing enzymes in rat liver; Kobayashi Y et al.; We examined the effect of hemin on rat hepatic microsomal cytochrome P450 (P450) and its molecular species (P450 2E1, 3A2, 2C11 and 2C12) under the induction of heme oxygenase activity in male and female rats . Hemin produced an inverse relationship between the induction of heme oxygenase activity and the decrease of P450 content in a dose-dependent manner . A time course study revealed that hemin produced a significant decrease in total P450 content in male rats to about 37% that of the controls at 24 hr after its administration . Western and Northern blot analyses revealed that the increase in both heme oxygenase-1 (HO-1) protein and HO-1 mRNA reached a maximum at 24 hr and returned to control levels within 120 hr in both sexes . With respect to P450-dependent monooxygenase activities, we found that there was a significant decrease of aniline p-hydroxylase activity to about 30% of the control animals, but not in erythromycin N-demethylase activity at various time intervals . Immunoblot analysis revealed that P450 2E1 in male rat liver was dramatically decreased at 24 hr to about 20% of the controls, but not P450 3A2 . Parallel to the decrease of androstenedione 16 alpha-hydroxylase activity, there was a marked decrease of P450 2C11 or 2C12 in male or female rats, respectively, at 72 hr after the treatment; however, hemin did not decrease androstenedione 16 alpha-hydroxylase activity in phenobarbital-pretreated rat liver . These findings suggest that hemin predominantly affects constitutively expressed isozymes rather than inducible P450 species in rat liver.

Toxicol Appl Pharmacol, 2000 Sep 15, 167(3), 237 - 45
Cytochrome P450-dependent monooxygenase activities and their inducibility by classic P450 inducers in the liver, kidney, and nasal mucosa of male adult ring-necked pheasants; Giorgi M et al.; In this study, several P450-dependent monoxygenase activities in the liver, kidney, and nasal mucosa of ring-necked pheasants were examined . In addition, the presence and inducibility of P450 isoenzymes in the hepatic and renal tissues of pheasants were examined by using typical substrates and inducers of P450s along with polyclonal antibodies raised against mammalian isoforms . Anti-rat P450 1A1 recognized in microsomes of both pheasant liver and kidney a protein that was markedly induced by beta-naphthoflavone and accompanied by an increase of various monooxygenases, in particular, methoxyresorufin-O-demethylase (MROD) activity . Anti-rat P450 2E1 revealed in microsomes of the pheasant liver but not in kidney an immunoreactive protein that was slightly induced by acetone but not accompanied by an increase of para-nitrophenol hydroxylase activity . On the other hand, acetone treatment caused an induction of other hepatic monoxygenases including MROD, erythromycin N-demethylase, and 6beta-testosterone hydroxylase . These two latter activities, known to be markers for 3A isoenzymes in rodents, were also enhanced in pheasant liver by phenobarbital but not by dexamethasone . The treatment with these two inducers also lacked to point out hepatic and renal proteins immunorelated to P450 3A or 2B subfamily, suggesting that these isoforms may be not expressed in pheasant . On the other hand, anti-rat P450 2C11 recognized two immunorelated proteins in the liver of both control and treated pheasants . The treatment with clofibrate, a mammalian inducer of 4A subfamily, induced both in liver and kidney of pheasant: i) a protein that cross-reacted with anti rat P450 4A1 and ii) the (omega) and (omega-1) lauric acid hydroxylase activities, known to be associated in mammals to this P450 subfamily . In the nasal mucosa of pheasant, a protein immunorelated to P450 2A and some monooxygenase activities (i.e., 7-ethoxycoumarin O-deethylase) linked, in mammals, to this isoform have been found; by contrast a protein immunoreactive with anti P450 2G1 was not found . In conclusion, the immunochemical properties and monooxygenase activities of constitutive and inducible P450s in pheasants were different not only from those of mammals but also from those of chickens . The findings of the present work also suggest that the P450 induction profiles might provide a potential biomarker of pheasant exposure to chemicals or environmental pollutants in the wild-field or in the stock-farm .

Anaesth Intensive Care, 2000 Aug, 28(4), 375 - 85
Potential use of pharmacological markers to quantitatively assess liver function during liver transplantation surgery; Gao L et al.; Early functioning of the transplanted liver is of crucial importance to the recipient . This function may be assessed by measuring the disposition of substances that are mainly eliminated via the liver . None of the agents currently used is ideal for this purpose . Measurement of mono-ethyleneglycinexylidide (MEGX) formation from lignocaine is useful and has been widely used in liver transplantation to assess liver graft function . MEGX formation can be affected by the use of drugs that influence liver perfusion or interfere with the CYP450 enzyme system . Indocyanine green clearance is a convenient method but both blood flow and hepatocellular function affect the test results . Tests of caffeine clearance, galactose elimination capacity and antipyrine clearance all require time-consuming, technically cumbersome and expensive serial blood sampling . The aminopyrine breath test is non-invasive, but gastric emptying and the patient's physical state affect results . The potential hazard of exposure to radioactive compounds limits the wide clinical use of both aminopyrine and erythromycin breath tests . Monitoring the rate of recovery from neuromuscular blockade induced by vecuronium and rocuronium can provide valuable information on liver function.

Med J Malaysia, 1997 Dec, 52(4), 390 - 8
Evaluation of the sensitivity in vitro of Plasmodium falciparum and in vivo of Plasmodium chabaudi Malaria to various drugs and their combinations; Rahman NN; K1 strain of Plasmdoium falciparum is resistant in vitro to chloroquine, pyrimethamine and sulfadoxine . Response of this strain to combinations of antimalarial drugs in the in vitro hypoxanthine incorporation test was coupled with that of a line of strain NF54 relatively sensitive to chloroquine and fully sensitive to other antimalarials . Pyrimethamine and sulfadoxine showed potentiative synergism against NF54 and less marked against K1 . Erythromycin and chloroquine showed potentiation, but less marked against NF54 . Quinine and clindamycin had an additive effect against NF54 but potentiated against K1 . Combinations of chloroquine with quinine or amodiaquine or of amodiaquine with clindamycin or erythromycin showed mild antagonistic or additive effects . In vivo studies in mice, using the 4-day suppressive test, the AS(3CQ) clone of Plasmodium chabaudi was resistant to pyrimethamine and chloroquine but sensitive to sulfadoxine . Similar combinations as above were carried out and their responses were compared between the resistant and sensitive strains . For both strains, the combinations of chloroquine-erythromycin, pyrimethamine-sulfadoxine, quinine-clindamycin showed potentiation; antagonistic effects were observed in chloroquine-amodiaquine combinations whereas when amodiaquine combined with erythromycin the effect was additive . Amodiaquine-clindamycin and chloroquine-quinine combinations have an antagonistic effect against the sensitive strain but additive against the resistant strain.

Anal Biochem, 2000 Sep 10, 284(2), 342 - 7
High-performance liquid chromatography determination of N- and O-demethylase activities of chemicals in human liver microsomes: application of postcolumn fluorescence derivatization using Nash reagent; Kobayashi K et al.; Formaldehyde is liberated in the process of cytochrome P450 (CYP) mediated demethylation of a wide variety of compounds containing the CH(3)N or CH(3)O functionality . A highly sensitive method using a high-performance liquid chromatography (HPLC) system with postcolumn derivatization was developed to measure the liberated formaldehyde as N- and O-demethylase activity of drugs in human liver microsomes . Following the chromatographic separation of formaldehyde on a C18 column, the formaldehyde was reacted with the Nash reagent in the postcolumn reactor at 100 degrees C and detected by the fluorescence method . The results showed that the present method has excellent precision and accuracy . The intra- and interassay variances of this method were less than 10% . The newly developed HPLC method was found to be about 80-fold more sensitive than the colorimetric method in detection of formaldehyde . The N-demethylase activity of sertraline in rat liver microsomes determined by the present method did not differ from those detected by previous methods quantifying produced desmethyl metabolite . The present method has been successfully applied to determine the N-demethylase activities of several drugs, including aminopyrine, erythromycin, fluoxetine, S-mephenytoin, and sertraline, in human liver microsomes . This assay should be useful for generic analysis of N- and O-demethylase activities of xenobiotic and endobiotic chemicals by CYP enzymes .

J Bacteriol, 2000 Sep, 182(18), 5052 - 8
Regulation of transcription of the mph(A) gene for macrolide 2'-phosphotransferase I in Escherichia coli: characterization of the regulatory gene mphR(A); Noguchi N et al.; The synthesis of macrolide 2'-phosphotransferase I {Mph(A)}, which inactivates erythromycin, is inducible by erythromycin . The expression of high-level resistance to erythromycin requires the mph(A) and mrx genes, which encode Mph(A) and an unidentified protein, respectively . We have studied the mphR(A) gene, which regulates the inducible expression of mph(A) . An analysis of the synthesis of Mph(A) in minicells and results of a complementation test indicated that mphR(A) is located downstream from mrx and that its product, MphR(A), represses the production of Mph(A) . DNA sequencing indicated that the mph(A), mrx, and mphR(A) genes exist as a cluster that begins with mph(A) and that the deduced amino acid sequence of MphR(A) can adopt an alpha-helix-turn-alpha-helix structure . To study the regulation of gene expression by MphR(A), we performed Northern blotting and primer extension . A transcript of 2 . 9 kb that corresponded to the transcript of mph(A) through mphR(A) was detected, and its level was elevated upon exposure of cells to erythromycin . Gel mobility shift assays and DNase I footprinting indicated that MphR(A) binds specifically to the promoter region of mph(A), and the amount of DNA shifted as a results of the binding of MphR(A) decreased as the concentration of erythromycin was increased . These results indicate that transcription of the mph(A)-mrx-mphR(A) operon is negatively regulated by the binding of a repressor protein, MphR(A), to the promoter of the mph(A) gene and is activated upon inhibition of binding of MphR(A) to the promoter in the presence of erythromycin.

Yonsei Med J, 2000 Jun, 41(3), 340 - 4
A comparative efficacy and safety study of clarithromycin, roxithromycin and erythromycin stearate in mild pneumonia; Hatipoglu ON et al.; The efficacy and safety of clarithromycin, roxithromycin and erythromycin stearate in mild pneumonia were compared in an open randomized trial . Eighty-six male patients, doing their obligatory military service, ranging between 19 and 24 years of age (mean 20), were randomly treated: 29 with clarithromycin 500 mg 12-hourly, 30 with roxithromycin 150 mg 12-hourly, and 27 with erythromycin stearate 500 mg 6-hourly, each course being administered for 10 days . Seventy-eight patients were able to be evaluated for efficacy, 28 receiving clarithromycin, 28 roxithromycin, and 22 erythromycin stearate . There were no significant differences among the groups in terms of clinical success rates (clinical cure or improvement: 89% for clarithromycin, 82% for roxithromycin, and 73% for erythromycin stearate, p = 0.32) . However, we found that there were significant differences among the groups in terms of clinical cure rates (75% for clarithromycin, 64% for roxithromycin, and 41% for erythromycin stearate, p = 0.04) . Adverse events, mostly gastrointestinal, caused discontinuation of treatment in 3.4% of the patients in the clarithromycin group, in 6.6% of the patients in the roxithromycin group, and in 18.5% of the patients in the erythromycin stearate group . The results indicate that there were no statistically significant differences among the three treatment groups in terms of clinical success rates, but that clarithromycin and roxithromycin were better tolerated.

Mil Med, 2000 Aug, 165(8), 636 - 7
Stevens-Johnson syndrome after erythromycin therapy while deployed at sea; Williams DA; Stevens-Johnson syndrome is a cutaneous reaction pattern that represents the progression of symptoms of erythema multiforme . These reactions can range from mild (EM minor) to severe (EM major) and even life-threatening (Stevens-Johnson syndrome or toxic epidermal necrolysis) . The difference between Stevens-Johnson syndrome and toxic epidermal necrolysis is the percentage of body surface area involved; toxic epidermal necrolysis involves widespread skin necrosis and bullous formation with epidermal detachment resembling scalded skin . The three most common triggers for Stevens-Johnson syndrome are herpes simplex infection, Mycoplasma infection, and drug reactions . This is a case of Stevens-Johnson syndrome occurring after erythromycin treatment aboard an aircraft carrier while deployed at sea in the Persian Gulf.

J Biol Chem, 2000 Nov 17, 275(46), 35999 - 6006
An A245T mutation conveys on cytochrome P450eryF the ability to oxidize alternative substrates; Xiang H et al.; Cytochrome P450(eryF) (CYP107A1), which hydroxylates deoxyerythronolide B in erythromycin biosynthesis, lacks the otherwise highly conserved threonine that is thought to promote O-O bond scission . The role of this threonine is satisfied in P450(eryF) by a substrate hydroxyl group, making deoxyerythronolide B the only acceptable substrate . As shown here, replacement of Ala(245) by a threonine enables the oxidation of alternative substrates using either H(2)O(2) or O(2)/spinach ferredoxin/ferredoxin reductase as the source of oxidizing equivalents . Testosterone is oxidized to 1-, 11alpha-, 12-, and 16alpha-hydroxytestosterone . A kinetic solvent isotope effect of 2.2 indicates that the A245T mutation facilitates dioxygen bond cleavage . This gain-of-function evidence confirms the role of the conserved threonine in P450 catalysis . Furthermore, a Hill coefficient of 1.3 and dependence of the product distribution on the testosterone concentration suggest that two testosterone molecules bind in the active site, in accord with a published structure of the P450(eryF)-androstenedione complex . P450(eryF) is thus a structurally defined model for the catalytic turnover of multiply bound substrates proposed to occur with CYP3A4 . In view of its large active site and defined structure, catalytically active P450(eryF) mutants are also attractive templates for the engineering of novel P450 activities.

Clin Ther, 2000 Jul, 22(7), 872 - 8
Effect of macrolides as part of initial empiric therapy on medical outcomes for hospitalized patients with community-acquired pneumonia; Burgess DS et al.; OBJECTIVE: The goal of this study was to compare the outcomes of hospitalized patients receiving a nonpseudomonal third-generation cephalosporin with or without a macrolide for the treatment of community-acquired pneumonia (CAP) . BACKGROUND: The initial treatment of CAP is usually based on empirically selected antibiotic therapy . The need for coverage of atypical pathogens in hospitalized patients is widely debated, and regional variations may exist . METHODS: All patients admitted to a community hospital or to a university hospital for 1 year who were aged > or =18 years and had a principal discharge diagnosis of pneumonia with no organism specified according to the International Classification of Diseases, Ninth Revision, Clinical Modification were evaluated . Each patient's medical chart was reviewed by a clinical pharmacist at each facility . The following information was collected for each patient using a standardized form: demographic characteristics, coexisting illnesses, length of hospital and intensive care unit stays, antibiotic regimens, length of parenteral and oral therapy, laboratory and radiographic findings (ie, blood urea nitrogen, glucose, hematocrit, sodium, PO2, pH, and pleural effusion), physical examination results, and mortality . Patients treated with a nonpseudomonal third-generation cephalosporin with or without a macrolide were included in this analysis . Categoric variables were compared using the chi-square test or the Fisher exact test, and continuous variables were compared using the Mann-Whitney U test . A P value < 0.05 was considered statistically significant . RESULTS: A total of 213 patients met the entry criteria and were treated with a nonpseudomonal third-generation cephalosporin with (116 patients) or without (97 patients) a macrolide . The mean (+/- SD) age of the patients was 62.2+/-19.6 years; 47% were male . The most common comorbid conditions were chronic obstructive pulmonary disease, diabetes mellitus, congestive heart failure, and cerebrovascular accident (CVA) . Of the 116 patients who received a macrolide, the majority (66%) received erythromycin . Other macrolides used were clarithromycin (19%) and oral azithromycin (15%) . There were no statistical differences between patients who did and did not receive a macrolide in terms of comorbid illnesses, length of hospital stay (5.2+/-2.8 vs 5.2+/-3.4 days, respectively), length of intravenous antibiotic therapy (4.4+/-2.5 vs 4.1+/-2.3 days, respectively), or mortality (0.9% vs 3.1%, respectively; P = 0.333) . The only difference between the groups was in age . Those patients who received a macrolide were significantly younger than those who received only a nonpseudomonal third-generation cephalosporin (57.4+/-19.2 years vs 67.9+/-18.5 years; P < 0.001) . However, when age and severity of illness were taken into account, no difference existed between the patients who received a nonpseudomonal third-generation cephalosporin alone or in combination with a macrolide . CONCLUSIONS: We concluded that the addition of a macrolide to a nonpseudomonal third-generation cephalosporin as initial therapy for the treatment of CAP may not be necessary . A randomized, prospective clinical trial comparing a nonpseudomonal third-generation cephalosporin alone and in combination with a macrolide is warranted.

Jpn Circ J, 1999 May, 63(5), 421 - 2
Clarithromycin associated with torsades de pointes; Kamochi H et al.; Two cases of QT prolongation and torsades de pointes (TdP) are presented . The patients had been taking clarithromycin (400 mg/day) for respiratory disease . Although erythromycin is reportedly associated with TdP, this is the first report of clarithromycin associated with TdP in the absence of other drugs already known to produce QT prolongation.

Pharmacotherapy, 2000 Aug, 20(8), 898 - 907
Variability in activity of hepatic CYP3A4 in patients infected with HIV; Slain D et al.; STUDY OBJECTIVES: To evaluate hepatic cytochrome P450 (CYP) 3A4 activity in patients infected with the human immunodeficiency virus (HIV) using the erythromycin breath test (ERMBT), and to examine the relationship of the ERMBT to plasma concentrations of indinavir and nelfinavir . DESIGN: Prospective observational study . SETTING: University infectious diseases clinic . SUBJECTS: Thirty-nine HIV-positive patients and 47 healthy controls . INTERVENTION: After the ERMBT in patients and controls, 25 patients received indinavir or nelfinavir . MEASUREMENTS AND MAIN RESULTS: Compared with controls, ERMBT variability was significantly greater in HIV-positive patients, including a subset of 19 patients receiving no concurrent drugs reported to alter CYP3A4 activity . Correlation between the ERMBT and first-dose plasma indinavir concentrations nearly reached statistical significance (p=0.07) . CONCLUSION: Variability in hepatic activity of CYP3A4 in HIV-positive patients may be greater than in controls and may explain some between-subject variability in plasma concentrations of indinavir . However, clearance mechanisms for protease inhibitors are complex, and if it is important to assess systemic exposure, the ERMBT is not a substitute for direct measurement of plasma concentrations.

Immunopharmacology, 2000 Jul 20, 48(2), 185 - 97
Effect of poloxamer CRL-1072 on drug uptake and nitric-oxide-mediated killing of Mycobacterium avium by macrophages; Jagannath C et al.; Mycobacterium avium-intracellulare complex (MAI) are common pathogens of opportunistic infections that are naturally resistant to most antibiotics and develop acquired resistance rapidly . An experimental drug, poloxamer CRL-1072, was found to have two unusual properties: it synergistically enhanced the activity of several antibiotics against MAI even though it had little activity as a single agent and it had greater activity against MAI in macrophage culture or in mice than in broth culture . Studies were undertaken to investigate the mechanisms of these effects . CRL-1072 was taken up by MAI and enhanced the uptake of fluorescent-labeled streptomycin and erythromycin in broth culture . The labeled antibiotics had reduced activity so the relevance for naive antibiotics must be inferred . In culture with human U937 monocytoid cells, CRL-1072 became localized in phagosomes and promoted uptake of streptomycin . Finally, CRL-1072 was found to induce production of mRNA for inducible nitric oxide synthase (iNOS) and nitric oxide (NO) by U937 cells . The antimycobacterial effect in macrophages was reversed by the iNOS inhibitor N-monomethyl L-arginine (NMMA), suggesting that CRL-1072 promotes killing of MAI by inducing NO . These effects were induced by noncytotoxic concentrations of CRL-1072 . These data suggest that the antimycobacterial mechanisms of CRL-1072 include enhancing the delivery of antibiotic to targets within MAI and enhancement of the ability of macrophages to kill ingested organisms.

P N G Med J, 1998 Jun, 41(2), 77 - 82
Multiple liver abscesses: an unusual case which demonstrates the importance of ultrasonography in the detection of liver pathology; Spicer PE et al.; A 48-year-old caucasian male was admitted to hospital with right-sided chest pain, pyrexia and cough . He had no history of dysentery . He was treated with erythromycin and cotrimoxazole for right lower lobe pneumonia but failed to respond . Tender hepatomegaly developed and ultrasound scan demonstrated multiple abscesses in the liver . Entamoeba histolytica was identified in his faeces . He was treated with intravenous metronidazole, chloramphenicol and gentamicin and then oral tinidazole, after which improvement was rapid . He was later transferred to Australia . Subsequent abdominal CAT scan and aspiration of abscesses confirmed the diagnosis of multiple amoebic liver abscesses with secondary bacterial infection . Final treatment was with oral ciprofloxacin and metronidazole for four weeks . Ultrasonography is a noninvasive technique which is invaluable in the diagnosis of abdominal and especially liver pathology . This technique should be available in larger centres in tropical countries . Anyone living in or visiting the tropics should be aware of possible exotic diseases presenting in unusual ways.

Analyst, 2000 Jun, 125(6), 1077 - 81
High-performance liquid chromatographic assay of erythromycin from biological matrix using electrochemical or ultraviolet detection; Dreassi E et al.; Two chromatographic methods were developed for the determination of erythromycin A (EA) residues in animal tissues (muscle, liver, kidney and fat of cattle, pigs and poultry) and cow's milk . In addition to a more traditional method using electrochemical detection, we developed an original alternative method based on UV detection at 236 nm, by pretreating to create a chromophore in the molecule . An internal standard was used with both methods to check the variability of the analytical system . Analysis times and performance were compared . The recovery of EA from various matrices was greater than 95% . For both methods the quantification limit for EA was 0.25 microgram ml-1 for plasma, 0.025 microgram g-1 for milk and 0.125 microgram g-1 for the other biological matrices . The methods can be used to check for EA residues in these matrices; in fact, the statutory maximum residue limits (MRLs) of EA are 0.4 microgram g-1 in muscle, kidney, liver and fat of beef cattle, sheep, pigs and poultry, and 0.04 microgram g-1 in cow's and sheep's milk.

Can J Anaesth, 2000 Jul, 47(7), 680 - 6
Propofol inhibits renal cytochrome P450 activity and enflurane defluorination in vitro in hamsters; Chen TL et al.; PURPOSE: To determine the effect of propofol on renal cytochrome P450 activity and defluorination of enflurane . METHODS: Renal microsomes were prepared by homogenization and differential centrifugation from pooled hamster kidneys . Defluorination of enflurane was assessed by measuring free fluoride metabolites after reacting enflurane with renal microsomes incubated with various concentrations, 0.05 - 1.0 mmol x L(-1) propofol in the NADPH-generating system . Drug metabolizing activities of renal cytochrome P450 mono-oxygenase enzymes were evaluated within microsomes preincubated with propofol and reacted with the specific marker substrates, aniline, benzo(a)pyrene, erythromycin and pentoxyresorufin, for cytochrome P450 2E1, 1A1, 3A4 and 2B1, respectively . RESULTS: Renal defluorination of enflurane was inhibited by clinical concentrations, 0.05 mmol x L(-1) of propofol (P < 0.05) . Dose-dependent inhibition of defluorination, aniline and benzo(a)pyrene hydroxylase within kidney microsomes was related to propofol concentration . Propofol demonstrated a profound inhibition of renal pentoxyresorufin dealkylase activity even at low concentrations, 0.05 mmol x L(-1) (P < 0.01) . Propofol did not exhibit inhibition of erythromycin N-demethylation of kidney microsomes except at high concentration, 1.0 mmol x L(-1) . Spectral analyses of key coenzymes of renal cytochrome P450 monooxygenase, cytochrome b5 and cytochrome c reductase, demonstrated an inhibition when incubated with high concentrations of propofol (P < 0.05) . CONCLUSION: In an in vitro study in an NADPH-generating system of hamster kidney microsomes, propofol, in clinical concentrations, exhibited a broad-spectrum of inhibition to renal monooxygenase activities and enflurane defluorination.

Klin Padiatr, 2000 May-Jun, 212(3), 129 - 30
{Myositis caused by a mycoplasma infection}; Brunner J et al.; Mycoplasma pneumonia infection can be associated with neurological manifestations such as meningoencephalitis, cerebellitis, aseptic meningoitis, polyradiculopathy, transverse myelitis, cranial nerve palsies and myositis {4, 5} . We report a case of a white female 11 years, 2 months old child, who presented with a 3 day history of pain in the left leg . The electromyograpy showed pathological signs . We found a serological titer of IgM antibodies for Mycoplasma pneumoniae . By treatment with erythromycin the complaints improved quickly . CONCLUSION: A myositis can be caused with an infection with Mycoplasma pneumoniae . The differential diagnosis is essential.

J Investig Allergol Clin Immunol, 2000 May-Jun, 10(3), 178 - 9
Localized pustulosis induced by betalactams; Novalbos A et al.; Localized forms of pustular drug eruptions related to antibiotics are uncommon and their mechanism is still unknown . We describe herein a patient who developed numerous pin-head pustules without erythema in the peribuccal area after ingestion of ceftibuten and amoxicillin . The relationship with these drugs was confirmed by single-blind oral challenges . The following tests were performed: prick and intradermal tests with benzylpenicilloyl polylysine, minor determinant mixture, benzylpenicillin and amoxicillin; patch tests were also carried out with benzylpenicillin, amoxicillin, cloxacillin, cefuroxime, ceftriaxone, cefazolin, ceftibuten and cefaclor . All cutaneous tests were negative . Controlled single-blind challenge tests were performed with amoxicillin, cefadroxil, ceftibuten, cefuroxime, cefaclor, erythromycin and ciprofloxacin . All betalactam antibiotics tested gave a positive reaction, with good tolerance of other antibiotics; this would appear to indicate a specific mechanism of hypersensitivity and not an unspecific reaction to wide spectrum antibiotics.

Crit Care Med, 2000 Jul, 28(7), 2334 - 7
Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding; Chapman MJ et al.; OBJECTIVE: To evaluate the effect of intravenous erythromycin on gastric emptying and the success of enteral feeding in mechanically ventilated, critically ill patients with large volume gastric aspirates . DESIGN: Prospective, double-blind, randomized, and placebo-controlled trial . SETTING: General intensive care unit in a university hospital . PATIENTS: Twenty critically ill, mechanically ventilated patients intolerant of nasogastric feeding (indicated by a residual gastric volume of > or =250 mL during feed administration at > or =40 mL/hr) . INTERVENTIONS: After a gastric aspirate of > or =250 mL, which was discarded, the enteral feeding was continued at the previous rate for 3 hrs . Intravenous erythromycin (200 mg) or placebo was then administered over 20 mins . The residual gastric contents were again aspirated and the volume was recorded 1 hr after the infusion began . MEASUREMENTS AND MAIN RESULTS: Gastric emptying was calculated as volume of feed infused into the stomach over 4 hrs minus the residual volume aspirated . Mean gastric emptying was 139+/-37 (+/-SEM) mL after erythromycin and -2+/-46 mL after placebo (p = .027) . Nasogastric feeding was successful in nine of ten patients treated with erythromycin and five of ten who received placebo 1 hr after infusion (chi-square p = .05) . CONCLUSION: In critically ill patients who have large volumes of gastric aspirates indicating a failure to tolerate nasogastric feeding, a single small dose of intravenous erythromycin allows continuation of feed in the short term.

Am J Obstet Gynecol, 2000 Jul, 183(1), 131 - 5
An appraisal of treatment guidelines for antepartum community-acquired pneumonia; Yost NP et al.; OBJECTIVE: The optimal strategy for the initial evaluation and management, including criteria for hospitalization, of pregnant women with pneumonia has not been defined . Our purpose was to evaluate a treatment protocol for antepartum pneumonia and to identify criteria for selection of women for potential outpatient treatment . STUDY DESIGN: A protocol based on British and American Thoracic Society guidelines was introduced and included prompt hospitalization and empiric initiation of erythromycin therapy . Maternal and neonatal outcomes were analyzed to assess the efficacy of the protocol . A second analysis involved the retrospective application of published guidelines to ascertain for which women outpatient management might have been appropriate . RESULTS: There were no maternal deaths among the 133 women studied, and in 14 (10%) women there was a misdiagnosis at admission . Erythromycin monotherapy was judged adequate in all but one of the 99 women so treated . Using a modified version of the American Thoracic Society guidelines, we project that only 25% of the women hospitalized with pneumonia could have been managed safely as outpatients . CONCLUSION: Most pregnant women with pneumonia respond well to monotherapy with erythromycin . Outpatient management may be a reasonable option for selected women.

Rapid Commun Mass Spectrom, 2000, 14(15), 1391 - 7
Pulsed helium introduction into a quadrupole ion trap for reduced collisional quenching during infrared multiphoton dissociation of electrosprayed ions
Boue SM, Stephenson JL Jr, Yost RA.
Previous infrared multiphoton dissociation (IRMPD) experiments utilizing a quadrupole ion trap mass spectrometer yielded limited photodissociation efficiencies . Helium buffer gas continuously infused into the analyzer region at pressures of typically 1 x 10(-3) Torr to improve ion trap performance can collisionally quench photoexcited ions during the IRMPD process . Photodissociation experiments have indicated that uncorrected pressures below 2 x 10(-5) Torr are necessary to avoid collisional deactivation of photoexcited ions . This paper describes IRMPD in the quadrupole ion trap at reduced pressures utilizing a dual-pulsed introduction of helium buffer gas incorporated into the ion trap scan function . The pulsed introduction of helium buffer gas before ion injection allows the efficient trapping of ions injected from an electrospray source and the removal of helium before laser irradiation . A second pulse of helium directly before ion detection improves the intensity of the ion signal . The use of this dual-pulsed inlet of helium for improved IRMPD is demonstrated with the carbohydrate antibiotics neomycin and erythromycin .

J Biol Chem, 2000 Nov 3, 275(44), 34415 - 23
Accumulation of mitochondrial P450MT2, NH(2)-terminal truncated cytochrome P4501A1 in rat brain during chronic treatment with beta-naphthoflavone . A role in the metabolism of neuroactive drugs; Boopathi E et al.; The biochemical and molecular characteristics of cytochrome P4501A1 targeted to rat brain mitochondria was studied to determine the generality of the targeting mechanism previously described for mitochondrial cytochrome P450MT2 (P450MT2) from rat liver . In rat brain and C6 glioma cells chronically exposed to beta-naphoflavone (BNF), P450MT2 content reached 50 and 95% of the total cellular pool, respectively . P450MT2 from 10 days of BNF-treated rat brain was purified to over 85% purity using hydrophobic chromatography followed by adrenodoxin affinity binding . Purified brain P450MT2 consisted of two distinct molecular species with NH(2) termini identical to liver mitochondrial forms . These results confirm the specificity of endoprotease-processing sites . The purified P450MT2 showed a preference for adrenodoxin + adrenodoxin reductase electron donor system and exhibited high erythromycin N-demethylation activity . Brain mitoplasts from 10-day BNF-treated rats and also purified P450MT2 exhibited high N-demethylation activities for a number of neuroactive drugs, including trycyclic anti-depressants, anti-convulsants, and opiates . At 10 days of BNF treatment, the mitochondrial metabolism of these neuroactive drugs represented about 85% of the total tissue activity . These results provide new insights on the role of P450MT2 in modulating the pharmacological potencies of different neuroactive drugs in chronically exposed individuals.

Pharmacotherapy, 2000 Jul, 20(7), 830 - 6
Quality of pharmacotherapy consultations provided by drug information centers in the United States; Calis KA et al.; We evaluated the performance of 116 U.S . drug information centers in responding to specific questions about drugs . The primary measures were correctness of responses and extent of probing for patient data . Questions addressed the effect of ranitidine on blood alcohol concentrations, the potential interaction between didanosine and dapsone, prevention of nonsteroidal antiinflammatory drug (NSAID)-induced peptic ulcers, and use of erythromycin for diabetic gastroparesis . The percentages of centers providing correct overall responses were 70% for the ranitidine question, 90% for the didanosine-dapsone question, 8% for the NSAID question, and 20% for the erythromycin question . For the three patient-specific questions, the percentages of centers eliciting vital patient data were 27% for the didanosine-dapsone question, 86% for the NSAID question, and 5% for the erythromycin question . In providing pharmacotherapy consultations, drug information centers generally failed to obtain pertinent patient data, thereby risking incorrect responses and inappropriate recommendations.

Aliment Pharmacol Ther, 2000 Jul, 14(7), 955 - 60
Motilides accelerate regional gastrointestinal transit in the dog; Chiba T et al.; BACKGROUND: Motilides have prokinetic effects on the upper gut during fasting, increasing the strength of antral contractions and stimulating gastroduodenal phase 3 sequences . Effects on the distal gut, and postprandially, are less well documented . AIM: To evaluate dose-response effects of motilin and erythromycin on gastric emptying, small bowel and colonic transit in the dog using a validated scintigraphic technique . METHODS: For gastric emptying and small bowel transit, 99mTc labelled beads were added to a meal of dog chow (450 kcal) . Regional colonic transit was measured by 111In labelled beads placed in a capsule which dissolved and released radiation into the proximal colon . Scintiscans were taken at regular intervals and indices of whole-gut transit were calculated . Drugs were given by slow intravenous administration . RESULTS: In the doses used, motilin accelerated regional colonic transit but did not hasten gastric emptying or small bowel transit . Single or repeated doses of motilin had similar effects on colonic transit . Erythromycin accelerated gastric emptying, small bowel transit and regional colonic transit . CONCLUSIONS: Motilin receptors are apparently present in the canine small bowel and colon . Postprandially, motilides accelerate transit in the distal gut.

J Reprod Med, 2000 Jun, 45(6), 465 - 8
Erythromycin for chlamydiasis in pregnant women . Assessing adherence to a standard multiday, multidose course; Wehbeh H et al.; OBJECTIVE: To assess patient adherence among pregnant women infected with Chlamydia trachomatis given a self-administered, 10-day course of erythromycin prescribed as 500-mg tablets to be taken four times a day for the full 10-day period of treatment . STUDY DESIGN: Study participants (n = 30) were given the standard, 10-day supply of 500-mg tablets of erythromycin and instructed to take one tablet four times daily for 10 days . Patients were blinded to the fact that the Medication Event Monitoring System was being used and that their adherence to this course of drug therapy was being monitored . RESULTS: A 100% cure rate was achieved . The average percentage of therapeutic coverage actually achieved by the study participants declined with the length of erythromycin therapy . Further, as the duration of treatment increased, the longest interval between two successive doses of erythromycin also increased . CONCLUSION: This study demonstrated the importance of assessing both the quantitative and temporal aspects of self-administered oral medication when assessing patient adherence . Moreover, since the length of the course of antibiotic therapy was shown to affect patient adherence, coupled with the 100% cure rate we observed, future research geared toward maximizing adherence while minimizing duration of treatment seems warranted.

Pharmacogenetics, 2000 Jul, 10(5), 373 - 88
Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method; Ozdemir V et al.; The CYP3A4 enzyme contributes to the disposition of more than 60 therapeutically important drugs and displays marked person-to-person variability of the catalytic function . However, the extent of genetic contribution to variability in CYP3A4 activity remains elusive . Recently, we showed that a comparison of between- (SDb2) and within-person (SDW2) variances provides an estimate of the genetic component of variability in drug disposition . The aim of the present analysis was to assess the genetic control of CYP3A4 activity in vivo . A computerized literature search was conducted covering 1966 to September 1999 to identify studies reporting repeated administration of CYP3A4 substrates . The genetic contribution (rGC) to disposition of each CYP3A4 substrate was obtained by the formula (SDb2-SDW2)/SDb2 . The rGC values approaching 1.0, point to overwhelming genetic control, whereas those close to zero suggest that environmental factors dominate . A total of 16 studies with 10 different CYP3A4 substrates were identified (n = 161 subjects) . The rGC for hepatic CYP3A4 activity as measured by midazolam plasma clearance or the erythromycin breath test was 0.96 (0.92-0.98) (95% Cl) and 0.89 (0.65-0.98), respectively (P < 0.05) . The point estimates of rGC for composite (hepatic + intestinal) CYP3A4 activity measured after oral administration of cyclosporine, ethinylestradiol, ethylmorphine, nifedipine and nitrendipine, ranged from 0.66-0.98 (median: 0.83) (P < 0.05) . Cyclosporine data suggested a higher genetic control of CYP3A4 at night than during the day . These data indicate that further molecular genetic investigations are warranted to identify genetic variants at CYP3A4 or elsewhere in the genome which contribute to regulation of CYP3A4 activity.

Pharmacol Toxicol, 2000 Jun, 86(6), 250 - 6
Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes; Beckmann-Knopp S et al.; Silibinin, the main constituent of silymarin, a flavonoid drug from silybum marianum used in liver disease, was tested for inhibition of human cytochrome P-450 enzymes . Metabolic activities were determined in liver microsomes from two donors using selective substrates . With each substrate, incubations were carried out with and without silibinin (concentrations 3.7-300 microM) at 37 degrees in 0.1 M KH2PO4 buffer containing up to 3% DMSO . Metabolite concentrations were determined by HPLC or direct spectroscopy . First, silibinin IC50 values were determined for each substrate at respective K(M) concentrations . Silibinin had little effect (IC50>200 microM) on the metabolism of erythromycin (CYP3A4), chlorzoxazone (CYP2E1), S(+)-mephenytoin (CYP2C19), caffeine (CYP1A2) or coumarin (CYP2A6) . A moderate effect was observed for high affinity dextromethorphan metabolism (CYP2D6) in one of the microsomes samples tested only (IC50=173 microM) . Clear inhibition was found for denitronifedipine oxidation (CYP3A4; IC50=29 microM and 46 microM) and S(-)-warfarin 7-hydroxylation (CYP2C9; IC50=43 microM and 45 microM) . When additional substrate concentrations were tested to assess enzyme kinetics, silibinin was a potent competitive inhibitor of dextromethorphan metabolism at the low affinity site, which is not CYP2D6 (Ki.c=2.3 microM and 2.4 microM) . Inhibition was competitive for S(-)-warfarin 7-hydroxylation (Ki,c=18 microM and 19 microM) and mainly non-competitive for denitronifedipine oxidation (Ki,n=9 microM and 12 microM) . With therapeutic silibinin peak plasma concentrations of 0.6 microM and biliary concentrations up to 200 microM, metabolic interactions with xenobiotics metabolised by CYP3A4 or CYP2C9 cannot be excluded.

Clin Ther, 1999 Nov, 21(11), 1951 - 72
Drug utilization reviews of oral quinolone, cephalosporin, and macrolide use in nonacute care: a systematic review; Spooner CH et al.; Drug utilization review (DUR) is a tool for monitoring the appropriateness of physicians' prescribing patterns . The present systematic overview was undertaken to determine the extent of appropriate use of oral quinolones, cephalosporins, and macrolides in nonacute-care settings in North America reported in published DUR studies . Potentially relevant DURs conducted since 1987 were retrieved from an electronic search of 6 databases (augmented by manual searches of bibliographies of appropriate articles) and from personal communications with local experts . Independent reviewers applied objective criteria to select the DURs for inclusion . Quality assessments were performed by 4 independent reviewers using the Edmonton Quality Assessment Tool for Drug Utilization Reviews, an instrument developed to assess the potential for systematic bias in a DUR . Data from the studies included were abstracted independently by 2 reviewers using a standard data-collection form . Twelve of 587 (2.0%) articles met the inclusion criteria . Eight studies targeted the appropriateness of prescriptions for ciprofloxacin (appropriateness range, 5% to 95%), 3 included cephalosporins (range, 0% to 100%), and 2 examined erythromycin (40%) . There were 2 primary reasons for a rating of inappropriate: (1) the prescription was not first-line therapy, or (2) there was insufficient documentation in the patient record . The designation inappropriate did not mean that the drug did not benefit the patient . Of the 4 intervention-based DURs, 1 study showed a significant improvement in appropriate use . Because of heterogeneity in study design, delivery of interventions, and outcome assessment, a pooled estimate of effect was not derived . Four studies estimated the cost of inappropriate prescribing to the institutional study site, which ranged from $20,500 to $173,359 annually; however, these estimates cannot be generalized because of various limitations . When the 12 studies were assessed for methodologic quality, 1 study was rated as high, 7 as moderate, and 4 as low . Levels of prescribing appropriateness reported in the DUR literature should be interpreted cautiously . The DUR studies included in this review varied greatly in the methodologic rigor applied to sample selection, standardized data collection, application of standardized screening criteria, and validated data analysis.

Indian J Pediatr, 2000 May, 67(5), 388 - 9
Chromobacterium violaceum diarrhea; Ballal M et al.; This is the first case of Chromobacterium violaceum diarrhoea from coastal Karnataka reported in a 2 year 10 months old girl . Stool culture yielded Chromobacterium violaceum and was sensitive to ampicillin, gentamicin, chloramphenicol, erythromycin and septran . Patient completely recovered with ampicillin and gentamicin.

Anaesthesist, 2000 May, 49(5), 455 - 9
{Protection of the mucosal barrier by nutritional strategies . What are the therapeutic options?}; Lubke HJ; The dysfunction of intestinal barrier allows the translocation of both endotoxin and whole bacterial organisms . It plays an important role in the development of multiple organ failure (MOF) . The mucosa ia one component of this barrier . Trauma, atrophy and the "systemic inflammatory response syndrome" increase gastrointestinal permeability . These abnormalities may contribute to the pathophysiology of sepsis . Malnutrition per se compromises the gut's barrier function . Maintenance of gastrointestinal blood flow may be facilitated by (glutamine-enriched?) enteral diets . The most important conclusions of the majority of controlled trials support the concept of the very early enteral nutrition (within 24 hours after trauma): the outcome of seriously ill patients is improved, the rate of complications and infections is reduced . Gastrointestinal motility disorders may interfere with the initiation and tolerance of early enteral nutrition . They may be managed by prokinetic agents (cisapride, erythromycin) or by bypassing the stomach with a nasoenteric tube.

J Protein Chem, 2000 Jan, 19(1), 23 - 32
Synthetic peptide mimics of a predicted topographical interaction surface: the cytochrome P450 2B1 recognition domain for NADPH-cytochrome P450 reductase; Omata Y et al.; In order to identify the cytochrome P450-binding domain for NADPH-cytochrome P450 reductase, synthetic peptide mimics of predicted surface regions of rat cytochrome P450 2B 1 were constructed and evaluated for inhibition of the P450-reductase interaction . A peptide corresponding to residues 116-134, which includes the C helix, completely inhibited reductase-mediated benzphetamine demethylation by purified P450 2B1 . Replacement of Arg-125 by Glu yielded a noninhibitory peptide, suggesting that this residue significantly contributes to the reductase-P450 interaction . Additional P450 peptides were prepared which correspond to combinations of regions distant in primary sequence, but predicted to be spatially proximate . A peptide derived from segments of the C and L helices was a more potent inhibitor than peptides derived from either segment alone . This topographically designed peptide not only inhibited P450 2B1 in its purified form, but also when membrane-bound in rat liver microsomes . The peptide also inhibited microsomal aryl hydrocarbon hydroxylase, aniline hydroxylase, and erythromycin demethylase activities derived from other P450s . These results indicate that the C and L helices contribute to a reductase-binding site common to multiple P450s, and present a peptide mimic for this region that is useful for inhibition of P450-mediated microsomal activities.

Drug Saf, 2000 Jun, 22(6), 441 - 57
HMG-CoA reductase inhibitors and myotoxicity; Ucar M et al.; The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors specifically inhibit HMG-CoA reductase in the liver, thereby inhibiting the biosynthesis of cholesterol . These drugs significantly reduce plasma cholesterol level and long term treatment reduces morbidity and mortality associated with coronary heart disease . The tolerability of these drugs during long term administration is an important issue . Adverse reactions involving skeletal muscle are not uncommon, and sometimes serious adverse reactions involving skeletal muscle such as myopathy and rhabdomyolysis may occur, requiring discontinuation of the drug . Occasionally, arthralgia, alone or in association with myalgia, has been reported . In this article we review scientific data provided via Medline, adverse drug reaction case reports from the Swedish Drug Information System (SWEDIS) and the World Health Organization's International Drug Information System (INTDIS) database, focusing on HMG-CoA reductase inhibitor-related musculoskeletal system events . Cytochrome P450 (CYP) 3A4 is the main isoenzyme involved in the metabolic transformation of HMG-CoA reductase inhibitors . Individuals with both low hepatic and low gastrointestinal tract levels of CYP3A4 expression may be at in increased risk of myotoxicity due to potentially higher HMG-CoA reductase inhibitor plasma concentrations . The reported incidence of myotoxic reactions in patients treated with this drug class varies from 1 to 7% and varies between different agents . The risk of these serious adverse reactions is dose-dependent and may increase when HMG-CoA reductase inhibitors are prescribed concomitantly with drugs that inhibit their metabolism, such as itraconazole, cyclosporin, erythromycin and nefazodone . Electrolyte disturbances, infections, major trauma, hypoxia as well as drugs of abuse may increase the risk of myotoxicity . It is important that the potentially serious adverse reactions are recognised and correctly diagnosed so that the HMG-CoA reductase inhibitor may at once be withdrawn to prevent further muscular damage.

Pharm Res, 2000 Apr, 17(4), 419 - 26
Prediction of in vivo interaction between triazolam and erythromycin based on in vitro studies using human liver microsomes and recombinant human CYP3A4; Kanamitsu S et al.; PURPOSE: To quantitatively predict the in vivo interaction between triazolam and erythromycin, which involves mechanism-based inhibition of CYP3A4, from in vitro studies using human liver microsomes (HLM) and recombinant human CYP3A4 (REC) . METHODS: HLM or REC was preincubated with erythromycin in the presence of NADPH and then triazolam was added . alpha- and 4-hydroxy (OH) triazolam were quantified after a 3 min incubation and the kinetic parameters for enzyme inactivation (k(inact) and K('app)) were obtained . Drug-drug interaction in vivo was predicted based on a physiologically-based pharmacokinetic (PBPK) model, using triazolam and erythromycin pharmacokinetic parameters obtained from the literature and kinetic parameters for the enzyme inactivation obtained in the in vitro studies . RESULTS: Whichever enzyme was used, triazolam metabolism was not inhibited without preincubation, even if the erythromycin concentration was increased . The degree of inhibition depended on preincubation time and erythromycin concentration . The values obtained for k(inact) and K('app) were 0.062 min(-1) and 15.9 microM (alpha-OH, HLM), 0.055 min(-1) and 17.4 microM (4-OH, HLM), 0.173 min(-1) and 19.1 microM (alpha-OH, REC), and 0.097 min(-1) and 18.9 microM (4-OH, REC) . Based on the kinetic parameters obtained using HLM and REC, the AUCpo of triazolam was predicted to increase 2.0- and 2.6-fold, respectively, following oral administration of erythromycin (333 mg t.i.d . for 3 days), which agreed well with the reported data . CONCLUSIONS: In vivo interaction between triazolam and erythromycin was successfully predicted from in vitro data based on a PBPK model involving a mechanism-based inhibition of CYP3A4.

J Pharmacol Exp Ther, 2000 Jun, 293(3), 1106 - 11
Effect of novel motilide ABT-229 versus erythromycin and cisapride on gastric emptying in dogs; Cowles VE et al.; ABT-229 (8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B-6,9-hemiacetal), a synthetic derivative of erythromycin (ERY) with no antibiotic activity, has been shown to bind to motilin receptors and stimulate contractile activity of the antrum and small intestine . The objective of this study was to determine the effect of ABT-229 on canine gastric emptying (GE) and contractile activity of the antrum and duodenum in response to a solid meal . Six beagles were used to determine GE of a solid meal and contractile activity in response to either vehicle, ABT-229 (0.17, 0.83, 2.5, or 5.0 microg/kg/min), ERY (33.3 microg/kg/min), or cisapride (CIS) (10 microg/kg/min) . Lag (t(lag)), half-emptying (t(1/2)), and complete emptying (t(full)) times were determined . Contractile data were analyzed for motility index and gastroduodenal coordination . Compared with vehicle, ABT-229 dose dependently accelerated GE, t(lag) was decreased at the two highest doses, t(1/2) was decreased compared with vehicle at the three highest doses, and t(full) was decreased at all doses compared with vehicle . ERY also decreased t(1/2) and t(full), whereas CIS decreased all GE parameters . The slopes of the linear phase of GE curves for all drugs and doses were greater than those for vehicle . ABT-229 dose dependently increased the motility index as well as gastroduodenal coordination . ABT-229 (two highest doses) and CIS accelerated GE of a solid meal by decreasing the lag phase and increasing the rate of GE, whereas ERY only increased the rate of GE . The data suggest that ABT-229 is 7- to 40-fold more potent than ERY in accelerating GE.

Eur Arch Otorhinolaryngol, 2000, 257(4), 199 - 204
Effects of macrolides on interleukin-8 secretion from human nasal epithelial cells; Fujita K et al.; Low-dose, long-term macrolide treatment has recently been reported to be very effective in patients with chronic airway diseases . We examined the in vivo and in vitro effects of 14-membered macrolide antibiotics erythromycin (EM) and clarithromycin (CAM) on interleukin (IL)-8 secretion from human nasal epithelial cells . Fifteen patients with chronic sinusitis received macrolide treatment (CAM 400 mg/day) for 1 to 3 months . The number of infiltrated neutrophils and IL-8 concentrations in the nasal discharges of these patients decreased significantly at 1 to 2 months after the treatment . In vitro effects of EM and CAM on IL-8 secretion were examined in nasal epithelial cells cultured at the air-liquid interface . After 14-day culture in the air-liquid interface, macrolide antibiotics were added in medium for 24 h . EM and CAM at concentrations of 10(-4) M did not affect spontaneous secretions or IL-1 beta-induced secretions of IL-8 either apically or basolaterally . When cells were preincubated with 10(-4) M CAM for 7 days, the IL-1 beta-induced secretion of IL-8 decreased significantly . However, no difference was observed between the effects of 10(-4) M CAM and 10(-4) M josamycin, a 16-membered macrolide . These results suggest that macrolide treatment inhibits neutrophil infiltration and IL-8 secretion in nasal epithelium in vivo and that these clinical effects depend on a mechanism other than the direct action of macrolide on nasal epithelial cells.

Cancer Res, 2000 Jun 15, 60(12), 3232 - 8
In vivo antitumor activity and host toxicity of methoxymorpholinyl doxorubicin: role of cytochrome P450 3A; Quintieri L et al.; Methoxymorpholinyl doxorubicin (MMDX; PNU 152243) is a promising doxorubicin derivative currently undergoing clinical evaluation . Previous in vitro studies suggested that the compound undergoes hepatic biotransformation by cytochrome P450 (CYP) 3A into a more cytotoxic metabolite(s) . The present study examined the role of CYP3A-mediated metabolism in the in vivo antitumor activity and host toxicity of MMDX in the mouse model and investigated the potential for increasing the therapeutic effectiveness of the drug by inducing its hepatic CYP-catalyzed activation . We found that MMDX cytotoxicity for cultured M5076 tumor cells was potentiated 22-fold by preincubating the drug with NADPH-supplemented liver microsomes from untreated C57BL/6 female mice . A greater (50-fold) potentiation of MMDX cytotoxicity was observed after its preincubation with liver microsomes isolated from animals pretreated with the prototypical CYP3A inducer pregnenolone-16alpha-carbonitrile . In contrast, in vivo administration of the selective CYP3A inhibitor troleandomycin (TAO) reduced both potentiation of MMDX cytotoxicity and the rate of CYP3A-catalyzed N-demethylation of erythromycin by isolated liver microsomes (55.5 and 49% reduction, respectively) . In vivo antitumor activity experiments revealed that TAO completely suppressed the ability of 90 microg/kg MMDX i.v., a dose close to the LD10, to delay growth of s.c . M5076 tumors in C57BL/6 mice and to prolong survival of DBA/2 mice with disseminated L1210 leukemia . Moreover, TAO administration markedly inhibited the therapeutic efficacy of 90 microg/kg MMDX i.v . in mice bearing experimental M5076 liver metastases; a complete loss of MMDX activity was observed in liver metastases-bearing animals receiving 40 microg/kg MMDX i.v . plus TAO . However, pregnenolone-16alpha-carbonitrile pretreatment failed to enhance MMDX activity in mice bearing either s.c . M5076 tumors or experimental M5076 liver metastases . Additional experiments carried out in healthy C57BL/6 mice showed that TAO markedly inhibited MMDX-induced myelosuppression and protected the animals against lethal doses of MMDX . Taken together, these findings demonstrate that an active metabolite(s) of MMDX synthesized via CYP3A contributes significantly to its in vivo antitumor activity and host toxicity.

J Pharm Sci, 2000 Jul, 89(7), 958 - 66
Structure determination from conventional powder diffraction data: application to hydrates, hydrochloride salts, and metastable polymorphs; Stephenson GA; Recent advances in crystallographic computing have made it possible to solve by powder diffraction methods structures that have not been possible to solve by single-crystal methods . Although there is vast improvement in the quality of data obtained from high-intensity synchrotron radiation, we found that surprisingly reliable results can be obtained from conventional laboratory sources . In this article we examine the application of Monte Carlo/simulated annealing methods for the determination of structures ranging in complexity from 9 to 15 degrees of freedom . We re-determine the structures of papaverine hydrochloride and erythromycin A dihydrate by the powder diffraction method and compare the structures to those determined by single-crystal diffraction methods . The structure of a metastable polymorphic form of acetohexamide, form B, is solved and examined spectroscopically . Its structure has not previously been solved by single-crystal techniques because of the small size of its crystals.

Therapie, 2000 Jan-Feb, 55(1), 185 - 93
Cardiac K+ channels and drug-acquired long QT syndrome; Drici MD et al.; The hallmark of long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram and a propensity to the occurrence of syncopes resulting from polymorphic ventricular tachycardia, called torsades de pointes . They may degenerate to ventricular fibrillation, possibly causing sudden death . Congenital LQTS, which implicates at least six chromosomal loci, LQT1 to LQT6, three of them corresponding to mutations concerning the coding of K+ channel proteins, give useful information about the mechanism underlying the arrhythmia . One of the potassium channel genes implicated in congenital LQTS is HERG, which encodes the IKr current channel protein . This current has provided a relevant insight into the occurrence of drug-acquired LQTS, since all drugs associated with torsades, such as erythromycin, terfenadine, haloperidol, or cisapride, also block IKr.

Br J Dermatol, 2000 Jun, 142(6), 1219 - 20
Red facial pseudochromhidrosis; Thami GP et al.; We describe a 9-year-old girl with pseudochromhidrosis simulating apocrine chromhidrosis . Treatment with topical and systemic erythromycin resulted in complete clearance of the reddish discoloration of the face . No relapse or recurrence was observed over a 3-month period.

Nihon Kokyuki Gakkai Zasshi, 2000 Mar, 38(3), 195 - 200
{Rheumatoid arthritis-associated bronchiolitis successfully treated with erythromycin}; Matsui S et al.; A 52-year-old man with a 4-year history of rheumatoid arthritis, and who had an episode of suspected BOOP in early 1994, was admitted to our hospital because of cough and fever . A chest X-ray film on admission showed small patchy infiltrates, and a computed tomographic (CT) scan showed centrilobular nodules and patchy infiltrates with thickened broncho-vascular bundles in both lungs . Transbronchial and thoracoscopic lung biopsies disclosed the coexistence of interstitial pneumonia with BOOP pattern, follicular bronchiolitis, and diffuse panbronchiolitis-like purulent and obliterative bronchiolitis . Due to findings of chronic sinusitis, the patient was treated with erythromycin for 8 weeks, and the abnormal CT shadows regressed . This was an interesting case of various pulmonary lesions associated with rheumatoid arthritis, and successfully treated with erythromycin.

J Infect Dis, 2000 Jun, 181 Suppl 3, S563 - 5
Past use of erythromycin, tetracycline, or doxycycline is not associated with risk of first myocardial infarction; Jackson LA et al.; A population-based case-control study of patients enrolled at Group Health Cooperative of Puget Sound was conducted to evaluate whether past use of antibiotics active against Chlamydia pneumoniae is associated with a decrease in the risk of first myocardial infarction (MI) . Cases with incident fatal and nonfatal MI from mid-1986 through 1995 (n=1796) were compared with randomly sampled controls frequency-matched to cases for age, sex, and year (n=4882) . Use of erythromycin, tetracycline, or doxycycline during the previous 5 years was not associated with an alteration in the risk of first MI . In an adjusted logistic regression model, the odds ratios and 95% confidence intervals for categories of cumulative duration of therapy with any of the three agents combined for 0, 1-14, 15-28, and >/=29 days were 1.0 (reference), 0.93 (0.81-1.07), 0.99 (0.81-1.20), and 1.03 (0.84-1.26), respectively . These results suggest little or no association between past use of erythromycin or tetracycline antibiotics and the risk of first MI among this population.

Life Sci, 2000 Apr 21, 66(22), 2193 - 212
Role of cytochrome P450 3A in the metabolism of mefloquine in human and animal hepatocytes; Fontaine F et al.; We studied mefloquine metabolism in cells and microsomes isolated from human and animal (monkey, dog, rat) livers . In both hepatocytes and microsomes, mefloquine underwent conversion to two major metabolites, carboxymefloquine and hydroxymefloquine . In human cells and microsomes these metabolites only were formed, as already demonstrated in vivo, while in other species several unidentified metabolites were also detected . After a 48 hr incubation with human and rat hepatocytes, metabolites accounted for 55-65% of the initial drug concentration, whereas in monkey and dog hepatocytes, mefloquine was entirely metabolized after 15 and 39 hrs, respectively . The consumption of mefloquine was less extensive in microsomes, and unchanged drug represented 60% (monkey) to 85-100% (human, dog, rat) of the total radioactivity after 5 hr incubations . The involvement of the cytochrome P450 3A subfamily in mefloquine biotransformation was suggested by several lines of evidence . Firstly, mefloquine metabolism was strongly increased in hepatic microsomes from dexamethasone-pretreated rats, and also in human and rat hepatocytes after prior treatment with a cytochrome P450 3A inducer . Secondly, mefloquine biotransformation in rifampycin-induced human hepatocytes was inhibited in a concentration-dependent manner by the cytochrome P450 3A inhibitor ketoconazole and thirdly, a strong correlation was found between erythromycin-N-demethylase activity (mediated by cytochrome P450 3A) and mefloquine metabolism in human microsomes (r=0.81, P < 0.05, N=13) . Collectively, these findings concerning the role of cytochrome P450 3A in mefloquine metabolism may have important in vivo consequences especially with regard to the choice of agents used in multidrug antimalarial regimens.

Drug Saf, 2000 May, 22(5), 389 - 404
A risk-benefit assessment of drugs used for neonatal chronic lung disease; Sweet DG et al.; Improvements in neonatal intensive care have resulted in more extremely low birthweight babies surviving who are at risk of developing chronic lung disease . The preterm lung is vulnerable as it is both structurally immature and deficient in surfactant and antioxidant defences . Mechanical ventilation and high inspired oxygen concentrations are often necessary for preterm babies to survive but they can cause pulmonary inflammation which leads to lung damage . Abnormal healing in the presence of ongoing inflammation leads to airways remodelling which can result in protracted respiratory problems in these babies . A commonly used definition for chronic lung disease is the requirement for supplemental oxygen beyond 36 weeks' postconception . Many drugs that are commonly used for chronic lung disease have not been subjected to proper randomised controlled trials but are widely used on the basis of small studies showing short term benefits . They can be broadly divided into 2 groups . First, there are preventative drugs that are administered early to reduce oxygen toxicity and pulmonary inflammation . Secondly, there are those administered in established chronic lung disease, designed to reduce respiratory morbidity . Pulmonary inflammation in the neonate is reduced by systemic corticosteroids . Corticosteroid therapy within the first 2 weeks of life enables earlier extubation of preterm babies with subsequent reduced chronic lung disease and improved neonatal survival when given between 7 and 14 days . However, there is an increased risk of gastrointestinal haemorrhage, metabolic derangement, ventricular hypertrophy and potential effects on long term growth and brain development . Diuretics and inhaled bronchodilators improve pulmonary compliance and reduce oxygen requirements in established chronic lung disease but probably have little effect in reducing the incidence . In babies with established chronic lung disease, home oxygen therapy enables earlier discharge and prophylaxis against respiratory syncytial virus can reduce morbidity from bronchiolitis . All of the above therapies have adverse effects that need to be considered before initiating treatment . Recently, new drugs have become available which may be beneficial . These include inhaled nitric oxide for reduction of ventilation-perfusion mismatching, recombinant human superoxide dismutase for protection against oxidative stress and alpha-1 proteinase inhibitor which may reduce airways remodelling . At present these therapies are undergoing clinical trials . Exogenous surfactant is beneficial in respiratory distress syndrome and may reduce the risk of chronic lung disease but there have been no randomised controlled trials of its use in established chronic lung disease . Drugs which have been tried unsuccessfully include erythromycin, ambroxol and mast cell stabilisers.

Intern Med, 2000 May, 39(5), 404 - 6
An autopsy case of diffuse panbronchiolitis associated with lung cancer; Ishioka S et al.; The prognosis of diffuse panbronchiolitis (DPB) has been remarkably improved after the development of low-dose erythromycin therapy, possibly due to anti-inflammatory rather than anti-infective mechanisms . Interestingly, DPB associated with lung cancer is quite rare . Here, we report an autopsy case of DPB who developed lung cancer after a long successful therapy with low-dose erythromycin.

Indian J Pediatr, 1995 Mar-Apr, 62(2), 201 - 5
Acute chest syndrome in children with sickle cell disease; Srair HA et al.; Acute chest syndrome (ACS) is an acute pulmonic process in patients with sickle cell disease . We prospectively studied 50 patients with ACS admitted to the Pediatric Medical Ward during one year period (Jan . 1993 through Dec . 1993) . Twenty eight of them were males and twenty two were females giving a male: female ratio of 1.2:1 . The age ranged between one and 12 years . Twelve (24%) of the patients had chest pain on presentation . Twenty seven (54%) patients had significant temperature (> 38 degrees C) . The x-ray findings showed that the right lung was involved in 30 patients, the left in 10 patients and both lungs in 10 patients . Three patients had pleural effusion that required chest tube insertion . Laboratory profiles showed that the erythrocyte sedimentation rate ranged between 15 and 90 mm/h, and their hemoglobin ranged between 4.2 gm and 12 gm/dl . Seven (14%) patients had significantly positive mycoplasma pneumoniae titer . None of the blood cultures was positive . All of our patient received antibiotic, usually either Cefuroxime or Ceftriaxone with Erythromycin in addition to other supportive measures such as blood transfusion, oxygen therapy and hydration therapy.

Rapid Commun Mass Spectrom, 2000, 14(10), 878 - 84
Investigation of unknown related substances in commercial erythromycin samples with liquid chromatography/mass spectrometry; Govaerts C et al.; A selective reversed phase liquid chromatography/mass spectrometry (LC/MS(n)) method is described for the identification of erythromycin impurities and related substances in commercial erythromycin samples . Mass spectral data are acquired on a LCQ ion trap mass spectrometer equipped with an electrospray interface operated in positive ion mode . The LCQ is ideally suited for identification of impurities and related substances because it provides on-line LC/MS(n) capability . Compared with UV detection, this hyphenated LC/MS(n) technique provides as a main advantage efficient identification of novel substances without time-consuming isolation and purification procedures . Using this method four novel related substances were identified in commercial samples .

Pol J Pharmacol, 1999 Sep-Oct, 51(5), 435 - 42
Effects of selective cytochrome P-450 inhibitors on the metabolism of thioridazine . In vitro studies; Daniel WA et al.; The aim of the present study was to determine optimum conditions for the study of thioridazine metabolism in rat liver microsomes and to investigate the influence of specific cytochrome P-450 inhibitors on 2- and 5-sulfoxidation, and N-demethylation of thioridazine . Basing on the developed method, the thioridazine metabolism in liver microsomes was studied at linear dependence of the product formation on time, and protein and substrate concentrations (incubation time was 15 min, concentration of microsomal protein was 0.5 mg/ml, substrate concentrations were 25, 50 and 75 nmol/ml) . Dixon analysis of tioridazine metabolism carried out in the control liver microsomes, in the absence and presence of specific cytochrome P-450 inhibitors, showed that quinine (CYP2D1 inhibitor), metyrapone (CYP2B1/B2 inhibitor) and alpha-naphthoflavone (CYP1A2 inhibitor) affected while erythromycin (CYP3A inhibitor) and sulfaphenazole (CYP2C9 inhibitor) did not affect the neuroleptic biotransformation . Thus, quinine and metyrapone inhibited competitively thioridazine N-demethylation and mono-2-sulfoxidation . As reflected by Ki values, N-demethylation was inhibited to a higher degree (Ki = 16.5 and 43 microM, respectively) than mono-2-sulfoxidation (Ki = 25 and 137 microM, respectively) . On the other hand, alpha-naphthoflavone inhibited competitively not only N-demethylation and mono-2-sulfoxidation, but also 5-sulfoxidation of thioridazine . The calculated Ki values showed that the highest potency of alpha-naphthoflavone to inhibit thioridazine metabolism was observed for N-demethylation and it descended in the following order: N-demethylation (Ki = 13.8 microM) > mono-2-sulfoxidation (Ki = 34 microM) > 5-sulfoxidation (Ki = 70.4 microM) . In conclusion, it can be assumed that N-demethylation and mono-2-sulfoxidation are catalyzed by the isoenzymes 2D1, 2B and 1A2 while 5-sulfoxidation only by 1A2; isoenzymes belonging to the subfamilies 2C and 3A seem not to be involved in the metabolism of thioridazine . The obtained results are discussed in the view of species and structure differences in the enzymatic catalysis of phenothiazines' metabolism as well as in relation to their pharmacological and clinical significance.

Trop Med Int Health, 2000 Apr, 5(4), 275 - 9
Targeting of Wolbachia endobacteria in Litomosoides sigmodontis: comparison of tetracyclines with chloramphenicol, macrolides and ciprofloxacin; Hoerauf A et al.; Endobacteria of the genus Wolbachia in filarial nematodes are related to Rickettsiaceae and can be depleted by tetracycline antibiotics . This depletion blocks female worm development as well as early embryogenesis, in contrast to the currently used microfilaricidal ivermectin which blocks only the last stage of embryogenesis . Since targeting Wolbachia is becoming an area of research for the treatment of human filariases, it was investigated if antibiotics other than tetracyclines are able to deplete Wolbachia from filariae . BALB/c mice infected with the rodent filaria Litomosoides sigmodontis were treated with erythromycin, chloramphenicol or ciprofloxacin . All drugs were well resorbed and resulted in serum levels clearly above breakpoint levels for bacteria susceptible to the respective antibiotic . However, contrary to tetracycline, none of these antibiotics depleted Wolbachia or altered worm development and fertility, as evidenced by immunohistology, immunoelectron microscopy and semiquantitative PCR.

Trop Med Int Health, 2000 Apr, 5(4), 275 - 9
Targeting of wolbachia endobacteria in litomosoides sigmodontis: comparison of tetracyclines with chloramphenicol, macrolides and ciprofloxacin
Hoerauf A.
Endobacteria of the genus Wolbachia in filarial nematodes are related to Rickettsiaceae and can be depleted by tetracycline antibiotics . This depletion blocks female worm development as well as early embryogenesis, in contrast to the currently used microfilaricidal ivermectin which blocks only the last stage of embryogenesis . Since targeting Wolbachia is becoming an area of research for the treatment of human filariases, it was investigated if antibiotics other than tetracyclines are able to deplete Wolbachia from filariae . BALB/c mice infected with the rodent filaria Litomosoides sigmodontis were treated with erythromycin, chloramphenicol or ciprofloxacin . All drugs were well resorbed and resulted in serum levels clearly above breakpoint levels for bacteria susceptible to the respective antibiotic . However, contrary to tetracycline, none of these antibiotics depleted Wolbachia or altered worm development and fertility, as evidenced by immunohistology, immunoelectron microscopy and semiquantitative PCR.

J Tongji Med Univ, 1998, 18(4), 216 - 20
The expression of PDGF-B chain mRNA in lung tissue from rats repeatedly infected with mycoplasma pneumoniae; Liu J et al.; In order to investigate the role played by platelet derived growth factor-BB (PDGF-BB) in the pathogenesis of pulmonary interstitial fibrosis in rats repeatedly infected with mycoplasma pneumoniae (MP), a rat MP infection model was developed by infecting rats with MP for 9 times during a period of 24 weeks with a technique of ultrasonic nebulizing inhalation . Then in situ hybridization was performed with PDGF-B chain cDNA probe and the results were quantitatively analyzed to measure the changes in PDGF-B chain mRNA expression in the lung tissue . The results showed that: (1) MP polymerase chain reaction (PCR) tests showed positive results in the bronchoalveolar lavage fluid (BALF) from all of the MP-infected rats (n = 4) while they were all negative in BALF from the control animals (n = 4, P < 0.05) and in BALF from those rats both infected with MP and, at the same time, treated with erythromycin (n = 4, P < 0.05) . Bacterial cultures of the bronchial and lung tissue were negative in all three groups . The observation under a transmission electron microscope indicated that the interalveolar septa were widened with increased amount of collagen in the MP-infected rats while there were no obvious abnormalities in the other two groups . (2) Strong positive expression of PDGF-B chain mRNA was found in the plasma of monocytes and macrophages located in the locally widened interalveolar septa and alveolar spaces in the lung tissue from the MP-infected animals with the integral optical densities being 37.42 +/- 9.05 (n = 4) which was significantly higher than the values of control group (0.42 +/- 0.08, n = 4, P < 0.01) and of the group with MP-infection plus erythromycin treatment (1.62 +/- 0.40, n = 4, P < 0.01) . These results suggest that PDGF-BB may be involved in the process of the development of pulmonary interstitial fibrosis caused by the repeated MP-infection . It may be an important growth factor for mediating the roles of monocytes and macrophages to promote the aggregation and proliferation of fibroblasts which can then secrete collagen in large quantity in the pulmonary interstitium.

Gastroenterol Clin Biol, 2000 Mar, 24(3), 361 - 3
{Small bowel pseudo-obstruction revealing an early scleroderma . Long-term efficacy of octreotide and erythromycin}; Lecomte T et al.; Skin abnormalities are the most common manifestations in patients with systemic sclerosis but many other organs can be involved . We report here the case of a 61 year-old-man in whom small bowel involvement was the initial presentation of limited systemic sclerosis . The clinical features consisted of recurrent small bowel obstruction without any organic lesion . The patient responded well to erythromycin (125 mg thrice a day before meals) and octreotide (50 microg subcutaneously at bedtime) with complete symptom relief . This permitted recovery of nutritional autonomy for two years . This observation shows that, in patients with intestinal pseudo-obstruction, systemic sclerosis should be considered . The long-term administration of octreotide and erythromycin can be effective in treating small bowel dysmotility in such patients.

Am J Physiol Gastrointest Liver Physiol, 2000 May, 278(5), G744 - 52
Enteric locus of action of prokinetics: ABT-229, motilin, and erythromycin; Sarna SK et al.; We investigated the in vivo and in vitro locus of actions of prokinetics: motilin, erythromycin, and ABT-229 . The test substances were infused close intra-arterially in short segments of the jejunum in the intact conscious state . Each prokinetic acted on a presynaptic neuron and utilized at least one nicotinic synapse to stimulate circular muscle contractions . The final neurotransmitter at the neuroeffector junction was ACh . Motilin and erythromycin, but not ABT-229, also released nitric oxide . Each prokinetic utilized somewhat different subtypes of muscarinic, serotonergic, tachykininergic, and histaminergic receptors, except for the M(3) receptor, which was common to all of them . In contrast, none of the prokinetics stimulated contractions in mucosa-free or mucosa-attached muscle strips, or rings, even though methacholine or electrical field stimulation induced phasic contractions in all of them . The prokinetics also did not release ACh in longitudinal muscle-myenteric plexus preparations . Each prokinetic, however, decreased the length of enzymatically dispersed single cells . In conclusion, each prokinetic may act on a different subset of presynaptic neurons that converge on the postsynaptic cholinergic and nonadrenergic noncholinergic motoneurons . The presynaptic neurons may be impaired in the muscle bath environment.

Cochrane Database Syst Rev . 2000;(2):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 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 . One study is 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 . 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 . (ABSTRACT TRUNCATED)

Dig Dis Sci, 2000 May, 45(5), 937 - 45
Erythromycin enhances solid-phase gastric emptying in induced-hyperglycemia in patients with truncal vagotomy and pyloroplasty; Petrakis IE et al.; Erythromycin has been found to be a gastrointestinal prokinetic agent while acute hyperglycemia has been associated with delayed gastric emptying in healthy controls and diabetics . The aim of this study was to investigate whether hyperglycemia, per se, alters gastric motility, during erythromycin-induced acceleration of gastric emptying of solids in patients with truncal vagotomy and pyloroplasty (TVP) and the role of vagus nerves . Eight TVP patients and six controls underwent scintigraphic measurement of gastric emptying of a solid meal, during placebo in normoglycemia (5-8.9 mmol/liter glucose) or 200 mg intravenous erythromycin lactobionate in normo- or hyperglycemia (16-19 mmol/liter glucose) induced by intravenous glucose infusion, on separate days in random order . In the TVP patients during normoglycemia, the erythromycin compared to placebo accelerated the meal gastric half-emptying time (T1/2), (37.12 +/- 6.87 vs 91.88 +/- 11.53, P < 0.001) and decreased the lag-phase duration (P < 0.001) and the percentage of meal retained in the stomach at 120 min (P < 0.001) . Erythromycin in hyperglycemia compared to normoglycemia increased T1/2 (61.25 +/- 10.67 vs 37.12 +/- 6.87, P < 0.001), prolonged lag-phase duration (P < 0.001), and the percentage of isotope retained in the stomach at 120 min (P < 0.001) . The T1/2, the lag phase duration, and the meal retained in the stomach at 120 min, after giving placebo was significantly increased, compared to erythromycin administration in hyperglycemia (P < 0.001) . Significant differences among patients and controls were found during gastric emptying after giving placebo and after erythromycin in hyperglycemia (P = 0.04 and P = 0.007, respectively), while nonsignificant differences were found after giving erythromycin in normoglycemia . We conclude that the effect of erythromycin-induced acceleration on gastric emptying is related to the plasma glucose level . Hyperglycemia reduces the erythromycin-induced acceleration of gastric emptying of solids in both controls and TVP patients . A significant increase in the delay of gastric emptying was achieved in TVP patients compared to controls after giving erythromycin in hyperglycemia and after placebo . Despite the inhibitory effect of induced hyperglycemia on gastric emptying, erythromycin is still able to accelerate the emptying rate and could prove to be a useful prokinetic agent under hyperglycemic conditions . Hyperglycemia may indicate a cholinergic-antagonist pathway that delays the erythromycin-induced acceleration of gastric emptying of solids and is more evident in vagotomized patients than controls, who retain the functional integrity of the vagus nerves.

Eur J Pharmacol, 2000 Apr 28, 395(2), 165 - 72
EM574, an erythromycin derivative, improves delayed gastric emptying of semi-solid meals in conscious dogs; Sato F et al.; The gastroprokinetic effects of de(N-methyl)-N-isopropyl-8, 9-anhydroerythromycin A 6,9-hemiacetal (EM574), a non-peptide motilin receptor agonist, were investigated in conscious dogs in a normal state and with experimentally-induced gastroparesis . Gastric emptying of semi-solid meals was assessed indirectly from acetaminophen absorption with simultaneous recording of gastric antral motility . In the normal state, post-prandial intraduodenal administration of EM574 (0.03 mg/kg) {corrected} stimulated antral motility and significantly enhanced gastric emptying as potently as did intravenous porcine motilin (0.003 mg/kg/h) . Intraduodenal cisapride at 1 mg/kg denal cisapride at 1 mg/kg elicited antral contractions and tended to accelerate gastric emptying but at 3 mg/kg, gastric emptying was not enhanced despite a further increase in the motor index . In dogs with gastroparesis induced by intraduodenal oleic acid or intravenous dopamine, EM574 (0.03 mg/kg) increased antral motility and reversed the delayed gastric emptying completely . Cisapride (1 mg/kg) partially ameliorated the impaired emptying under these conditions . In atropinized dogs, no acceleration of gastric emptying by EM574 was observed . These results indicate that EM574 potently accelerates gastric emptying of caloric meals in dogs in a normal state and with experimentally-induced gastroparesis, and also suggest that the effect is mediated through stimulation of a cholinergic neural pathway.

Mol Microbiol, 2000 Apr, 36(2), 391 - 401
A defined system for hybrid macrolide biosynthesis in Saccharopolyspora erythraea; Gaisser S et al.; The biological activity of polyketide antibiotics is often strongly dependent on the presence and type of deoxysugar residues attached to the aglycone core . A system is described here, based on the erythromycin-producing strain of Saccharopolyspora erythraea, for detection of hybrid glycoside formation, and this system has been used to demonstrate that an amino sugar characteristic of 14-membered macrolides (D-desosamine) can be efficiently attached to a 16-membered aglycone substrate . First, the S . erythraea mutant strain DM was created by deletion of both eryBV and eryCIII genes encoding the respective ery glycosyltransferase genes . The glycosyltransferase OleG2 from Streptomyces antibioticus, which transfers L-oleandrose, has recently been shown to transfer rhamnose to the oxygen at C-3 of erythronolide B and 6-deoxyerythronolide B . In full accordance with this finding, when oleG2 was expressed in S . erythraea DM, 3-O-rhamnosyl-erythronolide B and 3-O-rhamnosyl-6-deoxyerythronolide B were produced . Having thus validated the expression system, endogenous aglycone production was prevented by deletion of the polyketide synthase (eryA) genes from S . erythraea DM, creating the triple mutant SGT2 . To examine the ability of the mycaminosyltransferase TylM2 from Streptomyces fradiae to utilise a different amino sugar, tylM2 was integrated into S . erythraea SGT2, and the resulting strain was fed with the 16-membered aglycone tylactone, the normal TylM2 substrate . A new hybrid glycoside was isolated in good yield and characterized as 5-O-desosaminyl-tylactone, indicating that TylM2 may be a useful glycosyltransferase for combinatorial biosynthesis . 5-O-glucosyl-tylactone was also obtained, showing that endogenous activated sugars and glycosyltransferases compete for aglycone in these cells.

J Thorac Cardiovasc Surg, 2000 May, 119(5), 998 - 1007
Potential role of vacuolar H-adenosine triphosphatase in neointimal formation in cultured human saphenous vein; Otani H et al.; OBJECTIVE: Vacuolar H(+)-adenosine triphosphatase plays a pivotal role in pH regulation and molecular transport across the vacuolar membranes and is involved in cell proliferation and transformation . In the present study, possible involvement of vacuolar H(+)-adenosine triphosphatase in neointimal formation was investigated in an organ culture model of human saphenous vein . Methods and results: Cultured saphenous vein segments developed neointimal formation and marked thickening of the media within 14 days . Neointimal formation and medial thickening were completely inhibited by 10 nmol/L bafilomycin A(1), a selective inhibitor of vacuolar H(+)-adenosine triphosphatase, although structurally related macrolide antibiotics FK-506 and erythromycin were without an effect . The neointimal cells were positive for alpha-smooth muscle actin and vimentin but negative for desmin, indicative of myofibroblasts . The emergence of myofibroblasts was inhibited, and endothelial cells were preserved in the saphenous vein segments treated with bafilomycin A(1) . Uptake of bromodeoxyuridine, a proliferation marker, by myofibroblasts was abrogated in the saphenous vein segments treated with 10 nmol/L bafilomycin A(1) . Detection of apoptotic cells by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling concomitant with identification of desmin-expressing smooth muscle cells demonstrated that neointimal myofibroblasts, but not medial smooth muscle cells, that expressed desmin underwent apoptosis by treatment with bafilomycin A(1) . CONCLUSIONS: These results suggest that vacuolar H(+)-adenosine triphosphatase may be involved in myofibroblast growth that contributes to neointimal formation and medial thickening in cultured human saphenous vein . Increased sensitivity of myofibroblasts, but not endothelial cells, and differentiated smooth muscle cells to bafilomycin A(1) may have potential therapeutic implications in the treatment for vein graft disease.

Acta Anaesthesiol Scand, 2000 May, 44(5), 560 - 3
The effect of paracetamol (acetaminophen) on fentanyl metabolism in vitro; Feierman DE; BACKGROUND: Fentanyl is a synthetic opioid widely used in anesthesia and analgesia . In experimental animals and in humans it has been shown that most fentanyl biotransformation occurs in the liver, where this opioid is converted primarily to its N-dealkylated derivative, norfentanyl . Recent studies have shown that fentanyl is metabolized to norfentanyl via cytochrome P-450 3A4 (CYP3A4) . CYP3A4 is responsible for the metabolism of numerous other therapeutic agents, including those administered concurrently with fentanyl (e.g., nifedipine, lidocaine, erythromycin and cyclosporine) . Paracetamol is also metabolized by the CYP3A family, with a Km that is nearly equal to therapeutic blood concentrations . Since paracetamol is widely used, its potential interaction with fentanyl metabolism would be of great interest . METHODS: In the present study, rat and human liver microsomes were used to assess the ability of paracetamol to inhibit fentanyl metabolism . RESULTS: In both sets of microsomes, paracetamol produced a concentration-dependent inhibition of fentanyl oxidation to norfentanyl . Kinetic analysis of the data showed that 0.5-5 mM paracetamol inhibited fentanyl metabolism in a noncompetitive fashion . A Dixon plot revealed that the Ki for paracetamol inhibition of fentanyl metabolism is approximately 3.2 mM and 2.8 mM for human and rat liver microsomes, respectively . CONCLUSIONS: Since these concentrations of paracetamol are approximately one order of magnitude greater than therapeutic concentrations, it would appear that potentially important and possibly harmful fentanyl-paracetamol drug interactions do not occur with therapeutic concentrations of paracetamol.

Clin Cancer Res, 2000 Apr, 6(4), 1255 - 8
The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance; Hirth J et al.; Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors . Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects . Docetaxel undergoes metabolism by cytochrome CYP3A4 . Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL . Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2) . Hepatic CYP3A4 activity in each patient was measured by the {14C-N-methyl}erythromycin breath test (ERMBT) . Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis . Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population . CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2) . The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein . The natural log of ERMBT accounted for 67% of the interpatient variation in CL . Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL . The greatest toxicity was seen in patients with the lowest ERMBT . Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL . Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel . Those with high activity may be receiving a suboptimal dose . By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.

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