Am J Vet Res, 2000 Apr, 61(4), 420 - 4 Prokinetic effects of erythromycin on the ileum, cecum, and pelvic flexure of horses during the postoperative period; Roussel AJ et al.; OBJECTIVE: To evaluate the effect of erythromycin on motility of the ileum, cecum, and pelvic flexure of horses during the postoperative and post-recovery periods . ANIMALS: 8 healthy adult horses . PROCEDURE: Horses were anesthetized and bipolar electrodes were implanted in smooth muscle of the ileum, cecum, and pelvic flexure . Approximately 4, 16, and 24 hours (postoperative recording sessions) and at least 8 days (post-recovery recording session) after surgery, myoelectric activity was recorded before and after administration of erythromycin (0.5 mg/kg) . RESULTS: Following erythromycin administration, myoelectric activity was increased in the ileum during all postoperative recording sessions but not during the post-recovery recording session . Myoelectric activity was increased in the cecum following erythromycin administration only during the post-recovery recording session . Myoelectric activity was increased in the pelvic flexure following erythromycin administration during all recording sessions . During several recording sessions, there were short periods during which myoelectric activity was significantly decreased following erythromycin administration . CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that erythromycin has an effect on myoelectric activity of the ileum, cecum, and pelvic flexure in horses; however, prokinetic effects of erythromycin administered during the postoperative period were not always the same as effects obtained when the drug was administered after horses had recovered from the effects of surgical implantation of recording devices . Therefore, caution must be exercised when extrapolating results of prokinetic studies in healthy animals to animals with abnormal gastrointestinal tract motility. Am J Vet Res, 2000 Apr, 61(4), 413 - 9 In vitro effects of erythromycin, lidocaine, and metoclopramide on smooth muscle from the pyloric antrum, proximal portion of the duodenum, and middle portion of the jejunum of horses; Nieto JE et al.; OBJECTIVE: To evaluate effects of erythromycin, lidocaine, and metoclopramide on smooth muscle of the pyloric antrum (PA), proximal portion of the duodenum (PD), and middle portion of the jejunum (MJ) of horses . Sample Population-Strips of smooth muscle from 7 horses . PROCEDURE: Isolated muscle strips were suspended in a bath and attached to isometric force transducers . Once stable spontaneous contractions were observed, agents were added . Isometric stress responses were compared with the amplitude of spontaneous contractions . RESULTS: A single dose of erythromycin to the PA increased contractile amplitude (CA) for the longitudinal smooth muscle (mean +/- SEM, 76+/-16 g/cm2) but decreased CA for circular smooth muscle (-79+/-23 g/cm2) . The inhibitory effect was decreased by tetrodotoxin, N(G)-nitro-L-arginine methyl ester, and a vasoactive intestinal peptide antagonist . Erythromycin increased CA for the MJ, which was maximal at 10(-4)M (171+/-36 g/cm2) . Lidocaine increased CA for the PD, which was maximal at 10(-4) M (60+/-5 g/cm2) . Metoclopramide increased the CA, which was maximal at 10(-4) M for the PA (75+/-26 g/cm2), PD (279+/-33 g/cm2), and MJ (456+/-59 g/cm2) . CONCLUSIONS: Regional differences in responses to erythromycin, lidocaine, and metoclopramide were evident in the gastrointestinal tract of horses . Metoclopramide increased CA in all tissues used, whereas erythromycin inhibited CA in circular smooth muscle but stimulated CA in longitudinal smooth muscle from the PA . Inhibition is caused by stimulation of inhibitory nerves and is mediated, in part, by nitric oxide and vasoactive intestinal peptide. Ann Pharmacother, 2000 Apr, 34(4), 495 - 513 Macrolide drug interactions: an update; Pai MP et al.; OBJECTIVE: To describe the current drug interaction profiles for the commonly used macrolides in the US and Europe, and to comment on the clinical impact of these interactions . DATA SOURCES: A MEDLINE search (1975-1998) was performed to identify all pertinent studies, review articles, and case reports . When appropriate information was not available in the literature, data were obtained from the product manufacturers . STUDY SELECTION: All available data were reviewed to provide an unbiased account of possible drug interactions . DATA EXTRACTION: Data for some of the interactions were not available from the literature, but were available from abstracts or company-supplied materials . Although the data were not always explicit, the best attempt was made to deliver pertinent information that clinical practitioners would need to formulate practice opinions . When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied . DATA SYNTHESIS: Several clinically significant drug interactions have been identified since the approval of erythromycin . These interactions usually were related to the inhibition of the cytochrome P450 enzyme systems, which are responsible for the metabolism of many drugs . The decreased metabolism by the macrolides has in some instances resulted in potentially severe adverse events . The development and marketing of newer macrolides are hoped to improve the drug interaction profile associated with this class . However, this has produced variable success . Some of the newer macrolides demonstrated an interaction profile similar to that of erythromycin; others have improved profiles . The most success in avoiding drug interactions related to the inhibition of cytochrome P450 has been through the development of the azalide subclass, of which azithromycin is the first and only to be marketed . Azithromycin has not been demonstrated to inhibit the cytochrome P450 system in studies using a human liver microsome model, and to date has produced none of the classic drug interactions characteristic of the macrolides . CONCLUSIONS: Most of the available data regarding macrolide drug interactions are from studies in healthy volunteers and case reports . These data suggest that clarithromycin appears to have an interaction profile similar to that of erythromycin . Given this similarity, it is important to consider the interaction profile of clarithromycin when using erythromycin . This is especially necessary as funds for further studies of a medication available in generic form (e.g., erythromycin) are limited . Azithromycin has produced few clinically significant interactions with any agent cleared through the cytochrome P450 enzyme system . Although the available data are promising, the final test should come from studies conducted in patients who are taking potentially interacting compounds on a chronic basis. Antimicrob Agents Chemother, 2000 May, 44(5), 1391 - 3 In vitro activities of telithromycin (HMR 3647) against Rickettsia rickettsii, Rickettsia conorii, Rickettsia africae, Rickettsia typhi, Rickettsia prowazekii, Coxiella burnetii, Bartonella henselae, Bartonella quintana, Bartonella bacilliformis, and Ehrlichia chaffeensis; Rolain JM et al.; In vitro activities of telithromycin compared to those of erythromycin against Rickettsia spp., Bartonella spp., Coxiella burnetii, and Ehrlichia chaffeensis were determined . Telithromycin was more active than erythromycin against Rickettsia, Bartonella, and Coxiella burnetii, with MICs of 0.5 microg/ml, 0.003 to 0.015 microg/ml, and 1 microg/ml, respectively, but was inactive against Ehrlichia chaffeensis. Antimicrob Agents Chemother, 2000 May, 44(5), 1381 - 2 In vitro activity of telithromycin (HMR3647), a new ketolide, against clinical isolates of Mycoplasma pneumoniae in Japan; Yamaguchi T et al.; The in vitro activity of telithromycin (HMR3647), a new ketolide, against Mycoplasma pneumoniae was determined by the broth microdilution test using 41 clinical isolates obtained in Japan, as compared with those of five macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin, and josamycin), minocycline, and levofloxacin . Telithromycin was less potent than azithromycin, but it was more active than four other macrolides, minocycline, and levofloxacin; its MICs at which 50 and 90% of the isolates tested were inhibited were both 0.00097 microg/ml, justifying clinical studies to determine its efficacy for treatment of M . pneumoniae. Gene, 2000 Apr 4, 246(1-2), 123 - 31 Identification of two polyketide synthase gene clusters on the linear plasmid pSLA2-L in Streptomyces rochei; Suwa M et al.; The 200kb linear plasmid pSLA2-L was suggested to be involved in the production of two macrolide antibiotics, lankamycin (Lm) and lankacidin (Lc), in Streptomyces rochei 7434AN4 . Hybridization experiments with the polyketide synthase (PKS) genes for erythromycin and actinorhodin identified two eryAI-homologous regions and an actI-homologous region on pSLA2-L . The nucleotide sequence of a 3.6kb SacI fragment carrying one of the eryAI-homologs revealed that it codes for part of a large protein with four domains for ketoreductase, acyl carrier protein, ketosynthase, and acyltransferase . Gene disruption confirmed that the two eryAI-homologs are parts of a large type-I PKS gene cluster for Lm . A 4.8kb DNA carrying the actI-homologous region contains four open reading frames (ORF1-ORF4) as well as an additional ORF, i.e . ORF5, which might code for a thioesterase . Deletion of the ORF2-ORF4 region showed that it is not involved in the synthesis of Lm or Lc . Thus, it was confirmed that pSLA2-L contains two PKS gene clusters for Lm and an unknown type-II polyketide. J Diabetes Complications, 1999 Sep-Dec, 13(5-6), 314 - 5 Should cisapride be avoided in patients with diabetic gastroparesis? Evans AJ, Krentz AJ. The gastrointestinal motility stimulants, cisapride and erythromycin, have been used in the management of diabetic gastroparesis . However, drug interactions may result in prolongation of the electrocardiographic QT interval with the risk of ventricular arrhythmias . These drugs should, therefore, not be used in combination . We report two cases that illustrate inappropriate use of these agents . Moreover, patients with recurrent severe hypoglycemia or renal impairment may be at increased risk from cisapride-related cardiotoxicity . Thus, even as monotherapy, cisapride may pose dangers for high-risk diabetic patients. Peptides, 2000 Feb, 21(2), 283 - 7 Neural and muscular receptors for motilin in the rabbit colon; Miller P et al.; Motilin receptors were classically recognized in the gastroduodenal area, where they help to regulate interdigestive motility . More recently, motilin receptors were identified in the colon where their biologic significance remains unclear . We aimed here to characterize the motilin receptors of the rabbit colon . Distal colon and duodenum were obtained from sacrificed rabbits . Tissues homogenized by Polytron were submitted to differential centrifugation to obtain neural synaptosomes or smooth muscle plasma membranes enriched solutions . Motilin binding to these membranes was determined by the displacement of (125)I MOT by the native peptide MOT 1-22, or by peptide analogues MOT 1-12 {CH(2)NH}(10-11) or GM-109 and by erythromycin derivative GM-611 . Motilin binding capacity was maximum in colon nerves (49.5 +/- 6.5 fmol/mg protein vs . 19.9 +/- 2.5 in colon muscles or 9.4 +/- 2.8 and 6.6 +/- 1.2 in duodenal muscles and antral nerves respectively); all tissues expressed similar affinity for MOT 1-22, and the motilin agonist GM-611 bound equally to neural or muscle tissues from the rabbit colon; the synthetic antagonist MOT 1-12 {CH(2)NH}(10-11) showed greater affinity for colon nerves than for colon muscles (plC50: 7.23 +/- 0.07 vs . 6.75 +/- 0.03) . Similar results were obtained with the peptide antagonist GM-109; receptor affinity toward MOT 1-12 {CH(2)NH(10-11)} was always five times superior in neural tissues, whether they came from the colon or the antrum, than in muscle tissues, whether they were obtained from colon or from duodenum . Motilin receptors are found in very high concentration in nerves and in muscles from rabbit colon; specific motilin receptor subtypes are identified in nerves (N) and muscles (M) of the rabbit colon; N and M receptor subtypes seem independent of the organ location. J Clin Pharmacol, 2000 Apr, 40(4), 347 - 53 Prokinetic effects of erythromycin after antimotion sickness drugs; Stewart JJ et al.; Motion sickness and the antimotion sickness drugs scopolamine (SCP) and promethazine (PMZ) inhibit gastric emptying (GE) . This study was conducted to determine if erythromycin would exert its well-known prokinetic effects in normal and motion-sick subjects given antimotion sickness drugs . Fifteen fasted volunteers (11 males, 4 females) participated in the study . In control tests, 8 subjects were given intramuscular (i.m.) saline (SAL, 0.5 ml), SCP (0.1 mg), or PMZ (25 mg) . GE of liquid (300 ml) containing 1 mCi of Tc 99m diethylenetriaminepentaacetic acid (DTPA) was measured by sequential gastric scintigraphy 30 minutes after i.m . treatments . In other tests, GE was measured in 8 subjects after each i.m . treatment, followed 10 minutes later by 200 mg of erythromycin ethylsuccinate (ESS) suspension given orally . In a third group of tests, 7 subjects received an i.m . treatment, oral EES 10 minutes later, and were then brought to an advanced level of motion sickness short of vomiting . To induce motion sickness, blindfolded subjects made timed head movements while seated in a rotating chair . GE was measured immediately after rotation . GE half-life, rate constant, area under the curve (AUC), and lag time were calculated using conventional mathematical methods for analyzing exponential rate processes . GE parameters calculated for normal and motion-sick subjects given antimotion sickness drugs and EES were compared with those from subjects given i.m . treatments (control) only . In normal subjects, EES significantly (p < 0.05) increased the GE rate constant for all i.m . treatments and reduced the AUC for SAL, SCP, and PMZ by 49% (p < 0.05), 44% (p < 0.05), and 69% (p < 0.01), respectively . In motion-sick subjects, lag time was significantly (p < 0.05) increased, and the rate constant and AUC values were unchanged from control for all i.m . treatments . The authors conclude that oral EES reverses the gastrostatic actions of the antimotion sickness drugs but does not affect the inhibition of gastric emptying associated with motion sickness . The results suggest that motion sickness and antimotion sickness drugs reduce GE through different mechanisms. Mol Microbiol, 2000 Apr, 36(1), 183 - 93 Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA; Douthwaite S et al.; The macrolide antibiotic erythromycin and its 6-O-methyl derivative (clarithromycin) bind to bacterial ribosomes primarily through interactions with nucleotides in domains II and V of 23S rRNA . The domain II interaction occurs between nucleotide A752 and the macrolide 3-cladinose moiety . Removal of the cladinose, and substitution of a 3-keto group (forming the ketolide RU 56006), results in loss of the A752 interaction and an approximately 100-fold drop in drug binding affinity . Within domain V, the key determinant of drug binding is nucleotide A2058 and substitution of G at this position is the major cause of drug resistance in some clinical pathogens . The 2058G mutation disrupts the drug-domain V contact and leads to a further > 25 000-fold decrease in the binding of RU 56006 . Drug binding to resistant ribosomes can be improved over 3000-fold by forming an alternative and more effective contact to A752 via alkyl-aryl groups linked to a carbamate at the drug 11/12 position (in the ketolide antibiotics HMR 3647 and HMR 3004) . The data indicate that simultaneous drug interactions with domains II and V strengthen binding and that the domain II contact is of particular importance to achieve binding to the ribosomes of resistant pathogens in which the domain V interaction is perturbed. Int J Syst Evol Microbiol, 2000 Mar, 50 Pt 2, 575 - 81 Mycobacterium septicum sp . nov., a new rapidly growing species associated with catheter-related bacteraemia; Schinsky MF et al.; Rapidly growing mycobacteria are capable of causing several clinical diseases in both immunosuppressed and immunocompetent individuals . A previously unidentified, rapidly growing mycobacterium was determined to be the causative agent of central line sepsis in a child with underlying metastatic hepatoblastoma . Four isolates of this mycobacterium, three from blood and one from the central venous catheter tip, were studied . Phenotypic characterization, HPLC and genetic analysis revealed that while this organism most closely resembled members of the Mycobacterium fortuitum complex and Mycobacterium senegalense, it differed from all previously described species . Phenotypic tests useful in differentiating this species from similar rapidly growing mycobacteria included: growth at 42 degrees C, hydrolysis of acetamide, utilization of citrate, production of arylsulfatase (3-d), acidification of D-mannitol and i-myo-inositol, and susceptibility to erythromycin, vancomycin and tobramycin . The name Mycobacterium septicum is proposed for this new species . The type strain has been deposited in Deutsche Sammlung von Mikroorganismen und Zellkulturen as DSM 44393T and in the American Type Culture Collection as strain ATCC 700731T. Biochemistry, 2000 Apr 18, 39(15), 4406 - 14 Amino acid 305 determines catalytic center accessibility in CYP3A4; Fowler SM et al.; Site-directed mutagenesis has been used to replace alanine 305 with phenylalanine (A305F) and serine (A305S) in the active site of cytochrome P450 3A4 (CYP3A4) . Enzyme kinetics for diazepam, erythromycin, nifedipine, and testosterone metabolism have been determined for both mutants and wild-type CYP3A4 . The A305F mutation abolished diazepam oxidase activity and reduced the S(50) and V(max) for erythromycin N-demethylase activity from 17 to 10 microM and from 3.2 to 1.2 pmol product/min/pmol P450, respectively . The V(max) for testosterone 6beta-hydroxylase activity was also significantly reduced, from 2.3 to 0.6 pmol product/min/pmol P450, whereas the S(50) increased from 33 to 125 microM . The nifedipine oxidase activity was diminished to a lesser extent, down from 6.5 to 4.9 pmol product/min/pmol P450, whereas the S(50) increased from 9 to 42 microM . The K(i) for ketoconazole, a CYP3A4 selective inhibitor, was increased more than 10-fold from 0.050 to 0.55 microM, from 0.052 to 0.73 microM, and from 0.043 to 2.2 microM by the A305F mutation when measured against erythromycin, nifedipine, and testosterone metabolism activities, respectively . Similarly, the inhibition constants of the broader specificity inhibitors; clotrimazole, econazole, and miconazole were increased 3- to 15-fold by the A305F mutation . In contrast, the A305S mutation increased testosterone 6beta-hydroxylase (V(max) = 2.9 pmol product/min/pmol P450) and erythromycin N-demethylase (V(max) = 5.1 pmol product/min/pmol P450) activities, but reduced nifedipine oxidase activity (V(max) = 4.6 pmol product/min/pmol P450) . K(i) values for ketoconazole and other azole inhibitors were unchanged by the A305S mutation . It is proposed that in CYP3A4, the mutagenesis of alanine 305 to a phenylalanine increases the steric hindrance of the catalytic center, thereby greatly reducing azole inhibitor binding affinity, but maintaining monoogygenase activity. Rev Med Chir Soc Med Nat Iasi, 1997 Jul-Dec, 101(3-4), 166 - 9 {Dermatologic preparations with erythromycin--the correlation of the pharmaceutical form-therapeutic effect}; Cojocaru I et al.; Erythromycin associated with progesterone and A vitamin has been included in three dermatological pharmaceutical forms: a lotion, a L/H emulsion and a L/H nonionogenic ointment . Aspect of these preparations has been noticed for a 90 days period . pH and electrical conductance were also determined during this interval . All the formulations mentioned above revealed insignificant variations of these parameters proving an appreciable physico-chemical stability . Clinical investigative studies in juvenile acne, showed efficiency, particularly for the emulsion form. Dig Dis, 1999, 17(4), 241 - 7 Induced-hyperglycemia attenuates erythromycin-induced acceleration of hypertonic liquid-phase gastric emptying in type-I diabetic patients; Petrakis IE et al.; BACKGROUND: Erythromycin has been found to be a gastrointestinal prokinetic agent of hypertonic liquids, while acute hyperglycemia has been associated with delayed gastric emptying in diabetic patients . AIM: To investigate whether hyperglycemia, per se, reduces gastric motility during erythromycin-induced acceleration on gastric emptying of hypertonic liquids in diabetic patients . METHODS: In 12 type-I diabetic patients following a hypertonic radiolabeled liquid meal, gastric emptying was measured scintigraphically during normoglycemia (5-8.9 mmol/l glucose) or hyperglycemia induced by intravenous (16-19 mmol/l) glucose infusion . The tests were performed on 4 separate days in random order after administering either placebo or 200 mg i.v . erythromycin . RESULTS: In the hyperglycemic state compared to normoglycemia, the gastric emptying of the hypertonic liquid was reduced after placebo or erythromycin administration . The lag-phase duration (17.8+/-5.5 and 7.8+/-4.5 vs . 10.8+/-3.4 and 3.7+/-2.5 min, respectively, p<0.001), the overall gastric emptying time of the half meal (52.8+/-13 and 24.9+/-5.5 vs . 42.5+/-10.5 min and 16.6+/-6 min, respectively, p<0.001) and the retained percentage of liquid meal in the stomach at 60 and 100 min postprandially (p<0.001) were significantly increased . CONCLUSIONS: The erythromycin-induced acceleration on gastric emptying of hypertonic liquids in diabetic patients is related to the plasma glucose level . The induced hyperglycemia reduces the erythromycin-induced acceleration of liquid-phase gastric emptying, decreasing the overall gastric emptying rate . In spite of the inhibitory effect of induced hyperglycemia on the gastric emptying of hypertonic liquids, erythromycin is still able to accelerate the emptying rate and could prove to be a useful prokinetic agent under hyperglycemic conditions. J Spinal Cord Med, 1999 Winter, 22(4), 236 - 8 Refractory spinal cord injury induced gastroparesis: resolution with erythromycin lactobionate, a case report; Clanton LJ Jr et al.; Erythromycin lactobionate (ERY), a macrolide antibiotic, has been the focus of investigation as a new gastrointestinal prokinetic agent . In individuals who are able-bodied (AB), ERY has shown promise in various forms of gastroparesis (GP) . Recent evidence suggests that medications used to stimulate intestinal motility in individuals who are AB have had similar results in those individuals with spinal cord injury (SCI) . Medications that have been used in the past for GP in SCI include metaclopramide, neostigmine, and bethanechol . In this observation, a patient with T-6 paraplegia, who developed GP secondary to acute SCI, is presented . During his hospital stay, the patient was treated with gastric decompression, bowel rest, H2 blockers, intravenous metaclopramide, and eventually required parenteral nutritional support . ERY was started and symptoms abated . At this point, the nasogastric tube was removed and oral feeding was successfully started . This case report is the first to describe a patient with refractory SCI-induced GP who responded to intravenous ERY . Further study in this area is warranted. Am J Physiol Lung Cell Mol Physiol, 2000 Apr, 278(4), L726 - 36 Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells; Zhao DM et al.; ATP induced a biphasic increase in the intracellular Ca(2+)concentration ({Ca(2+)}(i)), an initial spike, and a subsequent plateau in A549 cells . Erythromycin (EM) suppressed the ATP-induced {Ca(2+)}(i) spike but only in the presence of extracellular calcium (Ca(2+)(o)) . It was ineffective against ATP- and UTP-induced inositol 1,4,5-trisphosphate {Ins(1,4,5)P(3)} formation and UTP-induced {Ca(2+)}(i) spike, implying that EM perturbs Ca(2+) influx from the extracellular space rather than Ca(2+)release from intracellular Ca(2+) stores via the G protein-phospholipase C-Ins(1,4,5)P(3) pathway . A verapamil-sensitive, KCl-induced increase in {Ca(2+)}(i) and the Ca(2+) influx activated by Ca(2+) store depletion were insensitive to EM . 3'-O-(4-benzoylbenzoyl)-ATP evoked an Ca(2+)(o)-dependent {Ca(2+)}(i) response even in the presence of verapamil or the absence of extracellular Na(+), and this response was almost completely abolished by EM pretreatment . RT-PCR analyses revealed that P2X(4) as well as P2Y(2), P2Y(4), and P2Y(6) are coexpressed in this cell line . These results suggest that in A549 cells 1) the coexpressed P2X(4) and P2Y(2)/P2Y(4) subtypes contribute to the ATP-induced {Ca(2+)}(i) spike and 2) EM selectively inhibits Ca(2+) influx through the P2X channel . This action of EM may underlie its clinical efficacy in the treatment of airway inflammation. Am J Physiol Lung Cell Mol Physiol, 2000 Apr, 278(4), L675 - 82 Human neutrophil elastase releases two pools of mucinlike glycoconjugate from tracheal submucosal gland cells; Dwyer TM et al.; Neutrophil elastase can contribute to the pathogenesis of increased airway reactivity and excess mucus secretion in many pulmonary diseases . Ten nanomolar human neutrophil elastase (HNE) effectively empties airway serous cells, raising the question of why HNE is not equally effective at emptying mucous cells of their stored mucin because total release of mucin granules is not seen in postmortem examination of even the most severe disease . To better resolve the mucus secretagogue action of HNE, we measured secretion of mucinlike glycoconjugates (MGCs) released from freshly isolated swine tracheal submucosal gland cells in fractions of the superfusate acquired every 2 min . Six to fifty nanomolar HNE released a fixed quantity of MGCs at an increasing rate with increasing concentrations of enzyme, an action consistent with the release of cell surface mucinlike molecules . The polycation poly-L-lysine (1 microg/ml) released a similar transient of MGCs . A steady-state doubling of MGC rate of release was seen as long as 100 nM HNE was present, but this stimulus represented less than a 1% release of stored MGCs/min and was consistent with release of mucin vesicles from cell stores . Both actions of HNE were inhibited by the specific inhibitors L-680833 and DMP-777 but not by 30 microM erythromycin . Therefore, HNE release of MGCs from tracheal submucosal glands is limited by both the fixed quantity of the MGCs in the transient pool and by the small steady-state response to the higher concentrations of enzyme. J Chromatogr A, 2000 Mar 3, 872(1-2), 85 - 90 Liquid chromatography-electrospray time-of-flight mass spectrometry for on-line accurate mass determination and identification of cyclodepsipeptides in a crude extract of the fungus Metarrhizium anisopliae; Potterat O et al.; Electrospray ionisation time-of-flight mass spectrometry (ESI-TOF-MS) has been used for the detection and identification of destruxins (cyclodepsipeptides) in a crude extract of the fungus Metarrhizium anisopliae . HPLC-MS analyses were performed with a post-column addition of erythromycin as a reference compound (lock mass procedure) . Seven destruxin derivatives could be identified on-line from their accurate masses (deviation from calculated values <5.5 ppm) through elemental composition calculations . As a highly sensitive and accurate method, ESI-TOF-MS proved to be very powerful for the analysis and dereplication of natural products in complex mixtures. Dig Dis Sci, 2000 Mar, 45(3), 525 - 8 Effect of meal and intravenous erythromycin on manometric and electrogastrographic measurements of gastric motor and electrical activity; Faure C et al.; Electrogastrography (EGG) measures, on the skin surface, the myoelectrical activity attributable to gastric smooth muscle cells . The physiological significance of signal amplitude and variation has not been clearly established . The increased signal amplitude after eating a meal may be related to increased contractile activity or to gastric distension . This study investigates the effect of increased gastric motor activity, unaccompanied by gastric distension, on the EGG recording and compares it to the effect of a meal . Nine children (3 months to 15 years old), were assessed by antroduodenal manometry for chronic intestinal pseudoobstruction (N = 5), chronic vomiting (N = 2), and abdominal distension (N = 2) . Synchronized EGG recording was performed simultaneously . During the study, four children were given a meal and five were given intravenous erythromycin 3 mg/kg over 1 hr . The ratio of the antral motor index (MI = number of waves x sum of amplitudes) determined 1 hr before a meal (or erythromycin) to that determined 1 hr after a meal (or during intravenous erythromycin) was calculated . The ratio of the running total spectrum power of the electrical signal at the same times was also calculated . Antral MI increased after a meal {MI ratio (mean +/- SE) 5.33 +/- 2.2} and after intravenous erythromycin (MI ratio: 9.36 +/- 2.6) . The amplitude of the electrical activity also increased after the meal {power ratio (mean +/- SE) 3.01 +/- 0.65} and after intravenous erythromycin (power ratio: 1.23 +/- 0.39), but the increase was greater after the meal (P < 0.05 vs intravenous erythromycin) . No correlation was found between antral MI ratio and running total spectrum power ratio . In conclusion, the increased amplitude of the gastric electrical activity recorded by the EGG after a meal seems to be only partly due to the increase in antral motor activity . The increase in power is also related to gastric distension. Diagn Microbiol Infect Dis, 2000 Jan, 36(1), 49 - 52 In vitro activity of quinupristin/dalfopristin (Synercid, RP 59500) against Legionella spp; Edelstein PH et al.; The activities of quinupristin/dalfopristin (Synercid), erythromycin and azithromycin against 22 Legionella spp . isolates were measured by a microbroth dilution method . The MICs that inhibited 90% of strains tested were 0.5, 0.35, and 0.5 microg/mL for quinupristin/dalfopristin, erythromycin, and azithromycin, respectively . Quinupristin/dalfopristin was only partially active against intracellular L . pneumophila at high (2 microg/mL), but not low (1 microg/mL) concentration . Activity of the drug in a guinea pig model of Legionnaires' disease could not be accurately determined because of drug toxicity for the guinea pig, although there was evidence that the drug has in vivo activity. Bioorg Med Chem Lett, 2000 Mar 6, 10(5), 433 - 7 Design and synthesis of mimics of S-adenosyl-L-homocysteine as potential inhibitors of erythromycin methyltransferases; Hanessian S et al.; A series of indanotriazine C-ribosides were prepared as SAH mimics, and tested for their ability to inhibit erythromycin resistance methylases Erm AM and Erm C' . A carbocyclic analogue derived from quinic acid was also synthesized and tested. J Toxicol Sci, 2000 Feb, 25(1), 57 - 61 Induction of hepatic CYP2B1/2 by a teratogenic compound cis-1-{-4-(p-menthane-8-yloxy)phenyl}piperadine (YM9429) in rats; Numazawa S et al.; A teratogenic compound cis-1-{-4-(p-menthane-8-yloxy)phenyl}piperadine (YM9429) selectively induces skeletal malformations characterized by cleft palate in rat fetuses . In the present study, we investigated the effect of YM9429 on hepatic cytochrome P-450s and their activities in rats . Oral administrations of YM9429 at a dose of 250, 500 or 750 mg/kg daily for 3 days induced cytochrome P-450 contents in a dose-dependent manner . Concomitant induction of enzyme activities of benzphetamine N-demethylase, erythromycin N-demethylase and, to a lesser extent, aminopyrine N-demethylase was observed . Immunoblot analysis revealed that YM9429 up-regulated hepatic levels of CYP2B1/2 and CYP3A1/2 proteins . A single dose of YM9429 at 250 mg/kg induced CYP2B1/2 protein levels significantly . These results suggest that YM9429 is a strong inducer of cytochrome P-450 with characteristics resembling those of phenobarbital. Intern Med, 2000 Feb, 39(2), 150 - 3 Tubulointerstitial nephritis associated with Legionnaires' disease; Nishitarumizu K et al.; A 47-year-old man was admitted to our hospital for community-acquired pneumonia complicated with acute renal failure . Legionella pneumophila serogroup type 1 was grown in BCYE (buffered charcoal yeast extract) agar for sputum culture . Although his respiratory illness responded to intravenous erythromycin therapy, renal failure worsened and necessitated hemodialysis . Renal biopsy showed profound tubulointerstitial nephritis . After initiation of steroid therapy his renal function improved and he was discharged thereafter . These findings suggest that in Legionnaires' disease with acute renal failure, tubulointerstitial nephritis should also be considered and steroid therapy may be an effective modality for the renal complication. Dis Colon Rectum, 2000 Mar, 43(3), 333 - 7 Prokinetic effect of erythromycin after colorectal surgery: randomized, placebo-controlled, double-blind study; Smith AJ et al.; PURPOSE: Nausea and vomiting three to seven days after an elective operation on the colon and rectum remain a persistent clinical problem . Erythromycin, a safe, inexpensive drug that stimulates intestinal motilin receptors, has previously been shown to accelerate gastric emptying significantly after upper gastrointestinal surgery . We aimed to evaluate the effect of postoperative intravenous erythromycin on postoperative ileus in patients undergoing elective surgery for primary colorectal cancer . METHODS: Between May 1998 and April 1999, 150 patients undergoing primary resection of colon or rectal cancer were enrolled in this prospective, randomized, placebo-controlled trial . One hundred thirty-four patients completed the study . Patients were excluded if they had extensive metastatic disease, were taking medications known to interact with erythromycin, or if they required an ileostomy . Patients received either 200 mg of intravenous erythromycin or placebo every six hours . Clinical endpoints were recorded and continuous end-points are presented as mean +/- standard deviation . RESULTS: There were no significant complications related to erythromycin . The erythromycin (n = 65) and placebo (n = 69) groups were comparable regarding demographic and operative factors . The erythromycin group had a slightly shorter length of time to passage of flatus (4.1 +/- 1.3 vs . 4.4 +/- 1.1 days; P = 0.03) . There was no significant difference between erythromycin and placebo in time to first solid food (5.6 +/- 1.9 vs . 5.4 +/- 1.8 days), time to first bowel movement (5.2 +/- 1.9 vs . 5.4 +/- 1.3 days), or time to discharge from hospital (7.5 +/- 2.0 vs . 7.6 +/- 2.8 days) . There was no difference in the rate of clinically significant nausea (26 vs . 26 percent; P = 0.99), vomiting (17 vs . 16 percent; P = 0.88), or nasogastric tube placement (9 vs . 7 percent; P = 0.68) . CONCLUSIONS: Erythromycin does not seem to alter clinically important outcomes related to postoperative ileus in patients undergoing resection for colorectal cancer. Drugs, 2000 Feb, 59(2), 301 - 21 Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria; Simpson K et al.; Fexofenadine, the active metabolite of terfenadine, is a selective histamine H1 receptor antagonist that does not cross the blood brain barrier and appears to display some anti-inflammatory properties . Fexofenadine is rapidly absorbed (onset of relief < or = 2 hours) and has a long duration of action, making it suitable for once daily administration . Clinical trials (< or = 2 weeks' duration) have shown fexofenadine 60 mg twice daily and 120 mg once daily to be as effective as loratadine 10 mg once daily, and fexofenadine 120 mg once daily to be as effective as cetirizine 10 mg once daily in the overall reduction of symptoms of seasonal allergic rhinitis . When given in combination, fexofenadine and extended release pseudoephedrine had complementary activity . Fexofenadine was effective in relieving the symptoms of sneezing, rhinorrhoea, itchy nose palate or throat, and itchy, watery, red eyes in patients with seasonal allergic rhinitis . There were often small improvements in nasal congestion that were further improved by pseudoephedrine . Fexofenadine produced greater improvements in quality of life than loratadine to an extent considered to be clinically meaningful, and enhanced patients' quality of life when added to pseudoephedrine treatment . Although no comparative data with other H1 antagonists exist, fexofenadine 180 mg once daily was effective in reducing the symptoms of chronic idiopathic urticaria for up to 6 weeks . Fexofenadine was well tolerated in clinical trials in adults and adolescents and the adverse event profile was similar to placebo in all studies . The most frequently reported adverse event during fexofenadine treatment was headache, which occurred with a similar incidence to that seen in placebo recipients . Fexofenadine does not inhibit cardiac K+ channels and is not associated with prolongation of the corrected QT interval . When given alone or in combination with erythromycin or ketoconazole, it was not associated with any adverse cardiac events in clinical trials . As it does not cross the blood brain barrier, fexofenadine is free of the sedative effects associated with first generation antihistamines, even at dosages of up to 240 mg/day . CONCLUSIONS: fexofenadine is clinically effective in the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria for which it is a suitable option for first-line therapy . Comparative data suggest that fexofenadine is as effective as loratadine or cetirizine in the treatment of seasonal allergic rhinitis . In those with excessive nasal congestion the combination of fexofenadine plus pseudoephedrine may be useful . In clinical trials fexofenadine is not associated with adverse cardiac or cognitive/psychomotor effects. Drug Metab Dispos, 2000 Apr, 28(4), 383 - 5 Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A; Gantenbein M et al.; Bupivacaine is used to provide prolonged anesthesia and postoperative analgesia . The human cytochrome P450 (CYP) involved in bupivacaine degradation into pipecolylxylidine (PPX), its major metabolite, has, to our knowledge, never been described . Microsome samples were prepared from six human livers and incubated in the presence of bupivacaine . The concentrations of PPX in the microsomal suspensions were assessed, and K(m) and V(max) values were calculated . Bupivacaine incubations were then performed with specific CYP substrates and inhibitors . For each sample of hepatic microsomes, the correlation between the rate of PPX formation and the corresponding erythromycin N-demethylase activity was analyzed . Finally, an immunoinhibition study using an anti-rabbit CYP3A6 antibody and assays with cDNA-expressed human CYP were conducted . The apparent K(m) and V(max) values of bupivacaine were, respectively, 125 microM and 4.78 nmol/min/mg of microsomal protein . The strongest inhibition of bupivacaine metabolism was obtained for troleandomycin (-95% at 50 microM), a specific CYP3A inhibitor . The correlation between PPX formation and erythromycin N-demethylase activity showed an R value of 0.99 whereas anti-rabbit CYP3A6 antibody inhibited the degradation of bupivacaine into PPX by 99% . Finally, CYP1A2 and CYP2E1 cDNA-expressed forms of human CYP did not allow PPX formation, CYP2C19 and CYP2D6 produced only small amounts whereas CYP3A4 most efficiently metabolized bupivacaine into PPX . These results demonstrated that bupivacaine degradation into PPX was mediated in humans by CYP3A. Antimicrob Agents Chemother, 2000 Apr, 44(4), 978 - 84 Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers; Brophy DF et al.; The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarithromycin . To determine if an interaction exists when these two drugs are coadministered, the pharmacokinetics of amprenavir and clarithromycin were investigated in healthy adult male volunteers . This was a Phase I, open-label, randomized, balanced, multiple-dose, three-period crossover study . Fourteen subjects received the following three regimens: amprenavir, 1,200 mg twice daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 days (seven doses of each drug) . Twelve subjects completed all treatments and the follow-up period . The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit . Coadministration of clarithromycin and amprenavir significantly increased the mean amprenavir AUC(ss), C(max,ss), and C(min,ss) by 18, 15, and 39%, respectively . Amprenavir had no significant effect on the AUC(ss) of clarithromycin, but the median T(max,ss)for clarithromycin increased by 2.0 h, renal clearance increased by 34%, and the AUC(ss) for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with amprenavir . Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered . The baseline ERMBT value did not correlate with clearance of amprenavir or clarithromycin . A pharmacokinetic interaction occurs when amprenavir and clarithromycin are coadministered, but the effects are not likely to be clinically important, and coadministration does not require a dosage adjustment for either drug. J Chromatogr A, 2000 Feb 18, 870(1-2), 227 - 35 Separation of erythromycin and related substances on base-deactivated reversed-phase silica gel columns; Chepkwony HK et al.; An official liquid chromatographic method for the analysis of erythromycin and related substances, which is based on a polymer reversed-phase, is described in the European Pharmacopoeia and in the United States Pharmacopeia . The pH of the mobile phase used in this system is 9.0 . Recent advanced technology has led to the introduction of a new generation of silica-based reversed-phase column packings, which are claimed to be much more stable towards bases . They are useful for the analysis of basic compounds . Studies to verify the separation of erythromycin and related substances on Hypersil BDS C18, Luna C18(2), Inertsil ODS-2 and Supelcosil ABZ+ have been performed and the results are presented . It is shown that these base-deactivated phases give a better sensitivity and selectivity towards erythromycins than the polymer phase, provided that an adapted mobile phase is used . This is the first liquid chromatographic method described for the separation of erythromycin D from erythromycin A. Presse Med, 2000 Feb 19, 29(6), 294 - 8 {Allergy to macrolides . 21 cases}; Demoly P et al.; OBJECTIVE: Allergic drug reactions to macrolides are extremely rare and there is little information in the literature concerning relevant diagnostic tests . PATIENTS AND METHODS: Twenty-one patients were recently seen for assumed allergies (principally urticaria) to diverse macrolides . Skin tests (prick and intradermal tests) were performed with injectable forms of spiramycin and erythromycin . Seventeen out of 21 patients were provoked under strict hospital surveillance . RESULTS: Only 3 patients had a positive provocation test and were thus truly allergic (to spiromycin) . They had positive skin tests to both macrolides tested . CONCLUSION: Most hypersensitivity reactions to macrolides are therefore diagnosed with provocation tests. J Chromatogr B Biomed Sci Appl, 2000 Feb 11, 738(2), 405 - 11 Determination of erythromycin, clarithromycin, roxithromycin, and azithromycin in plasma by high-performance liquid chromatography with amperometric detection; Taninaka C et al.; In this study, a high-performance liquid chromatographic method was developed for the quantitative determination of erythromycin (EM), roxithromycin (RXM), and azithromycin (AZM) in rat plasma with amperometric detection under a standardized common condition using clarithromycin (CAM) as an internal standard . This method was also proved to be applicable for the determination of CAM by employing RXM as an internal standard . Each drug was extracted from 150 microl of plasma sample spiked with internal standard under an alkaline condition with tert.-butyl methyl ether . The detector cell potential for the oxidation of the drugs was set at +950 mV . The linearity of the calibration curves were preserved over the concentration ranges of 0.1-10 microg/ml for EM and RXM, and 0.03-3.0 microg/ml for CAM and AZM . Coefficients of variation and relative error were less than 9% and +/-7%, respectively . The analytical method presented here was proved to be useful for the investigation of the pharmacokinetic characteristics of EM, CAM, RXM, and AZM in rats. Rapid Commun Mass Spectrom, 2000, 14(6), 468 - 75 Analysis of a commercial preparation of erythromycin estolates by tandem mass spectrometry and high performance liquid chromatography/electrospray ionization tandem mass spectrometry using an ion trap mass spectrometer; Lai CC et al.; Because of the lack of a UV chromophore and their much smaller abundances in comparison with the major component, the minor components in erythromycin estolate preparations are difficult to analyze by high performance liquid chromatography ultraviolet (HPLC-UV) . Tentative assignment of the major and minor components can be achieved with the combination of full scan and ZoomScan using an ion trap mass spectrometer . Tandem mass spectrometry (MS/MS) provided an effective method to quickly identify most components without chromatographic separation, and all the related compounds, except the isobaric pair ECE and PdMeEA, could be identified in this way . The best result was obtained by using liquid chromatography/tandem mass spectrometry (LC/MS/MS) operated in selected reaction monitoring mode . The major compound, the estolate of erythromycin A (EAE), and seven other minor components, could be separated and identified, with semiquantitative estimates of relative concentrations . J Oral Pathol Med, 2000 Feb, 29(2), 91 - 6 Bacillary angiomatosis affecting the oral cavity . Report of two cases and review; Lopez de Blanc S et al.; Bacillary angiomatosis (BA) is an infectious disease characterized by proliferative vascular lesions; it mainly affects HIV-positive patients . Multiple cutaneous nodular lesions together with fever, chills, malaise, anorexia, vomiting and headache are the most important clinical manifestations . It may also involve the heart, liver, spleen, bones, lung, muscles, lymph nodes, central nervous system and other organs . Erythromycin, 500 mg four times a day, is the drug of choice . The importance of this lesion lies in its clinical and histological similarity with other diseases . Cutaneous and oral lesions of BA clinically resemble Kaposi's sarcoma (KS) . Histopathologically, BA may be confused with angiosarcoma, pyogenic granuloma and epithelioid hemangioma . We report two HIV-positive men with BA lesions in the oral mucosa . Diagnosis was confirmed by biopsy and Warthin-Starry silver staining. Eur J Drug Metab Pharmacokinet, 1999 Jul-Sep, 24(3), 272 - 8 A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition; Zhao XJ et al.; Our previous study showed that several drugs inhibited quinine 3-hydroxylation, a cytochrome P450 (CYP) 3A4-mediated reaction, in vitro . In this extended study, 13 drugs were selected and tested by human liver microsomes in order to further determine their respective inhibition constant (Ki) and type of inhibition . According to the apparent Ki values, the inhibitory rank order of these tested drugs was as follows: ketoconazole > doxycycline > omeprazole > tetracycline > troleandomycin (with pre-incubation) > primaquine > troleandomycin (without pre-incubation) > nifedipine > erythromycin > verapamil > oleandomycin > diltiazem > cimetidine > hydralazine . Among these drugs, doxycycline, tetracycline, ketoconazole, nifedipine and hydralazine were judged as mixed inhibitors; whereas, the remaining other drugs tested were judged as competitive inhibitors . When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, troleandomycin and erythromycin are likely to be inhibitors of quinine metabolism in patients when these drugs are co-administrated with quinine. Gene, 2000 Mar 7, 245(1), 203 - 11 Genetic architecture of the polyketide synthases for methymycin and pikromycin series macrolides; Xue Y et al.; The methymycin and pikromycin series of antibiotics are structurally related macrolides produced by several Streptomyces species, including Streptomyces venezuelae ATCC 15439, which produces both 12-membered ring macrolides methymycin, neomethymycin, and 14-membered ring macrolides pikromycin and narbomycin . Cloning and sequencing of the biosynthetic gene clusters for these macrolides from three selected Streptomyces strains revealed a common genetic architecture of their polyketide synthases (PKSs) . Unlike PKS clusters of other 14-membered ring macrolides such as erythromycin and oleandomycin, each of the pikromycin series producers harbors a six module PKS cluster, in which modules 5 and 6 are encoded on two separate proteins instead of one bimodular protein, as well as a thioesterase II gene immediately downstream of the main PKS gene . The results shed new light on the evolution of modular PKSs and provide further evidence on the regulation of methymycin and pikromycin production in S . venezuelae ATCC 15439. Chest, 2000 Mar, 117(3), 662 - 71 Acute exacerbation of COPD: factors associated with poor treatment outcome; Dewan NA et al.; OBJECTIVES: To determine the effect of age, severity of lung disease, severity and frequency of exacerbation, steroid use, choice of an antibiotic, and the presence of comorbidity on the outcome of treatment for an acute exacerbation of COPD . DESIGN: A retrospective chart analysis over 24 months . SETTING: A university Veterans Affairs medical center . PATIENTS: Outpatients with COPD who were treated with an antibiotic over a period of 24 months for an acute exacerbation of COPD . METHODS: Severity of an acute exacerbation of COPD was defined using the criteria of Anthonisen et al: increased dyspnea, increased sputum volume, and increased sputum purulence . Severity of lung disease was stratified based on FEV(1) percent predicted using American Thoracic Society guidelines (stage I, FEV(1) > or = 50%; stage II, FEV(1) 35 to 49%; stage III, FEV(1) < 35%) . Treatment outcome was judged successful when the patient had no return visit in 4 weeks for a respiratory problem . Failure was defined as a return visit for persistent respiratory symptoms that required a change of an antibiotic in < 4 weeks . RESULTS: One-hundred seven patients with COPD (mean age +/- SD, 66.9 +/- 9.5 years) experienced 232 exacerbations over 24 months . First-line antibiotics (trimethoprim-sulfamethoxazole, ampicillin/amoxicillin, and erythromycin) were used to treat 78% of all exacerbations . Treatment failure was noted in 12.1% of first exacerbations and 14 . 7% of all exacerbations, with more than half the failures requiring hospitalization . Host factors that were independently associated with treatment failure included the following: FEV(1) < 35% (46.4% vs 22.4%; p = 0.047), use of home oxygen (60.7% vs 15.6%; p < 0 . 0001), frequency of exacerbation (3.8 +/- 2.0 vs 1.6 +/- 0.91; p < 0 . 001), history of previous pneumonia (64.3% vs 35.1 p < 0.007), history of sinusitis (28.6% vs 8.8%; p < 0.009) and use of maintenance steroids (32.1% vs 15.2% p = 0.052) . Using stepwise logistic regression analysis to identify the top independent variables, the use of home oxygen (p = 0.0002) and frequency of exacerbation (p < 0.0001) correctly classified failures in 83.3% of the patients . Surprisingly, age, the choice of an antibiotic, and the presence of any one or more comorbidity did not affect the treatment outcome . CONCLUSION: The results of our study suggest that patient host factors and not antibiotic choice may determine treatment outcome . Prospective studies in appropriately stratified patients are needed to validate these findings. J Clin Pharmacol, 2000 Mar, 40(3), 219 - 30 Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans; Krecic-Shepard ME et al.; Pharmacokinetic studies of i.v . and oral racemic verapamil and 14C-erythromycin breath tests (ERBT) were performed in 84 healthy men (n = 42) and women (n = 42) . Verapamil was measured by HPLC, concentration versus time data were analyzed by noncompartmental models, protein binding was measured by equilibrium dialysis, and statistical analyses were performed by ANOVA . Clearance of i.v . and p.o . verapamil was 13.7 +/- 4.3 and 58.4 +/- 35 ml/min/kg (mean +/- SD) in women compared to 12.6 +/- 3.4 and 82.6 +/- 70 ml/min/kg in men (p = 0.076) . Bioavailability was higher in women (0.25 +/- 0.09) compared to men (0.20 +/- 0.09, p = 0.019) with a significant Gender x Formulation interaction (p = 0.04) . ERBT were higher in women (p < 0.0001) . Verapamil (i.v . and p.o.) decreased blood pressure in all subjects with greater heart rate increases after p.o . verapamil in women compared to men (p = 0.041) . The findings suggest that sex-specific differences in drug metabolism may occur in both the gut and the liver and involve multiple metabolic pathways and that pharmacokinetic differences will alter pharmacodynamic responses. Crit Care Med, 2000 Feb, 28(2), 438 - 44 Sequential single doses of cisapride, erythromycin, and metoclopramide in critically ill patients intolerant to enteral nutrition: a randomized, placebo-controlled, crossover study; MacLaren R et al.; OBJECTIVE: To evaluate the comparative efficacy of enteral cisapride, metoclopramide, erythromycin, and placebo for promoting gastric emptying in critically ill patients with intolerance to gastric enteral nutrition (EN) . DESIGN: A randomized, crossover study . SETTING: Adult medical intensive care unit at a university-affiliated private hospital and trauma intensive care unit at a university teaching hospital . PATIENTS: Ten adult, critically ill, mechanically ventilated patients not tolerating a fiber-containing EN product defined as a single aspirated gastric residual volume >150 mL or two aspirated gastric residual volumes >120 mL during a 12-hr period . INTERVENTIONS: Patients received 10 mg of cisapride, 200 mg of erythromycin ethylsuccinate, 10 mg of metoclopramide, and placebo as 20 mL of sterile water every 12 hrs over 48 hrs . Acetaminophen solution (1000 mg) was administered concurrently . Gastric residual volumes were assessed, and plasma acetaminophen concentrations were serially determined by TDx between 0 and 12 hrs to evaluate gastric emptying . MEASUREMENTS AND MAIN RESULTS: Gastric residual volumes during the study were not significantly different between agents . No differences in area under the concentration vs . time curve or elimination rate constant were identified between agents . Metoclopramide and cisapride had a significantly shorter mean residence time of absorption than erythromycin (6.3+/-4.5 {SEM} mins and 10.9+/-5.8 vs . 30.1+/-4.5 mins, respectively {p<.05}) . Metoclopramide (9.7+/-15.3 mins) had a significantly shorter time to peak concentration compared with erythromycin and placebo (60.7+/-8.1 and 50.9+/-13.5 mins, respectively {p<.05}) . The time to onset of absorption was significantly shorter for metoclopramide vs . cisapride (5.7+/-4.5 vs . 22.9+/-5.7 mins {p<.05}) . CONCLUSION: In critically ill patients intolerant to EN, single enteral doses of metoclopramide or cisapride are effective for promoting gastric emptying in critically ill patients with gastric motility dysfunction . Additionally, metoclopramide may provide a quicker onset than cisapride. Int J Pharm, 2000 Mar 20, 197(1-2), 153 - 60 Investigation of the chemical stability of an erythromycin-tretinoin lotion by the use of an optimization system; Brisaert M et al.; A combination of 2% erythromycin and 0.05% tretinoin in an alcohol-isopropanol lotion was prepared . Two parameters were investigated for their influence on the stability of erythromycin and/or tretinoin, namely pH and the concentration of butylhydroxytoluene (BHT) as antioxidant . To investigate these two parameters, an optimization technique was used with two factors (pH and concentration of BHT) at two levels . Accelerated stability analysis was performed at 45 degrees C in the dark to exclude isomerization of tretinoin . To analyse erythromycin and tretinoin in the combination preparation, a TLC method, previously developed in the laboratory, was used . The degradation of erythromycin seemed to be much faster than the tretinoin degradation . Optimal stability is shown in the pH range of 8.2-8.6 for erythromycin and 7.2-8.2 for tretinoin while the concentration of BHT had no significant influence. J Pharmacol Exp Ther, 2000 Mar, 292(3), 1118 - 26 Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats: implication of concentrative uptake of inhibitors into liver; Yamano K et al.; To evaluate the degree of drug-drug interaction concerning metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio (R) of midazolam (MDZ) by erythromycin (EM), diltiazem (DLZ), or verapamil (VER) in rats . MDZ was administered through the portal vein at the steady state of plasma concentration of these inhibitors . The R values in the area under the plasma concentration curve of MDZ in the presence of EM, DLZ, and VER were 2.02, 1.64, and 1.30, respectively . The liver to plasma unbound concentration ratios of EM, DLZ, and VER at the steady state after infusion were 20.8, 1.02, and 3.01, respectively, suggesting concentrative uptake of EM and VER into the liver . The predicted R value in the presence of EM calculated by use of plasma unbound concentration was 1.03, whereas the value calculated with liver unbound concentration was 1.61, which was very close to the observed value . These findings indicated the need to consider the concentrative uptake of inhibitors into the liver for the quantitative prediction of metabolic inhibition . However, the predicted values in the presence of DLZ or VER calculated by use of liver unbound concentration were still underestimated . This result may be due to the metabolic inhibition by the metabolites of both inhibitors . Therefore, when predicting the degree of metabolic inhibition quantitatively, the inhibitory effect by coadministered drugs and the disposition of these metabolites in the liver must also be considered. J Pharmacol Exp Ther, 2000 Mar, 292(3), 921 - 8 c-Myc antisense limits rat liver regeneration and indicates role for c-Myc in regulating cytochrome P-450 3A activity; Arora V et al.; Expression of c-myc protein is associated with cell proliferation . The present study uses antisense oligomers to inhibit c-myc expression in the regenerating rat liver after 70% partial hepatectomy (PH) . Antisense phosphorodiamidate morpholino oligomers (novel DNA analogs) were administered i.p . immediately after surgery to block expression of c-myc within the first 24 h after PH . A 20-mer PMO complimentary to the c-myc mRNA at the translation start site was an effective sequence (AVI-4126, 5'-ACGTTGAGGGGCATCGTCGC-3') . A single i.p . dose of 0.5 mg/kg AVI-4126 caused reduction of the regenerating liver c-myc protein in a sequence-specific and dose-dependent manner . Inhibition of c-myc expression resulted in reduction of proliferating cell nuclear antigen and arrested cells in the G(0)/G(1) phase of the cell cycle . The ratio of G(2):G(0) cell populations in the regenerating liver 24 h after PH dropped from 29.1 in saline vehicle-treated rats to 18.0 in rats treated with 2.5 mg/kg AVI-4126 . The expression of cell cycle checkpoint protein p53 was inhibited with increasing doses of AVI-4126, but expression of p21(waf-1) was unaffected . The activity of cytochrome P-450 3A2 (CYP3A2) was evaluated by immunoblot analysis and erythromycin N-demethylation . AVI-4126 did not alter CYP3A activity in nonhepatectamized animals but showed a dose-dependent decrease in PH rats . We conclude that AVI-4126, antisense oligomer to c-myc, can reduce cell proliferation in the regenerating rat liver . Furthermore, inhibition of c-myc may indirectly influence the expression of CYP3A. Fertil Steril, 2000 Feb, 73(2), 387 - 94 Comparative effects of quinacrine and erythromycin in adult female rats: a nonsurgical sterilization study; Fail PA et al.; OBJECTIVE: To compare the efficacies of erythromycin and quinacrine for nonsurgical sterilization in rats . Quinacrine used for nonsurgical sterilization in women is mutagenic, and most clinical regimens have had a higher failure rate than surgical sterilization . DESIGN: This acute mammal study included five groups of rats assigned randomly and evaluated at two times after treatment . ANIMAL(S): Adult female Sprague-Dawley rats . INTERVENTION(S): Five groups of female Sprague-Dawley rats (20 per group) were given 70 or 280 mg/kg of erythromycin lactobionate, 350 mg/kg of quinacrine hydrochloride, or vehicle control administered transcervically . Rats were mated 21 days later . Additional groups (n = 4 per group) were treated and killed 21 days later without mating . MAIN OUTCOME MEASURE(S): Fourteen days after mating, numbers of ovarian corpora lutea, total uterine implants, and embryos were evaluated . For unmated animals, uterine sections were examined for fibrosis and lumen closure . RESULT(S): Neither drug altered numbers of corpora lutea . Erythromycin decreased pregnancy rate and number of implantations (increased preimplantation loss) in a dose-related fashion . Quinacrine increased resorptions . Uterine pathology was more extensive and frequent in erythromycin-treated animals, with extent and severity increasing from 21 to 35+ days . CONCLUSION(S): Erythromycin was more effective than quinacrine in preventing pregnancy. Hua Xi Yi Ke Da Xue Xue Bao, 1997 Dec, 28(4), 437 - 9 {The value of erythromycin pleurodesis in the treatment of malignant pleural effusions}; Tang X et al.; Malignant pleural effusion is a frequent complication of patients with advanced malignant tumors . For many patients suffering from malignant pleural effusion that increases rapidly and may be life threatening, it is important to control the effusions . To investigate the value of erythromycin as a pleural sclerosant, a dose of 1 g erythromycin in 30 ml of 5% glucose was injected into the pleural cavity of 26 patients with malignant pleural effusion . The results were assessed by Miller's standards . After treatment, numerous adhesions were present in 15 cases; Pleural effusion reduced in 7 patients, and no effect was noted in 4 patients . The total response rate was 84.6%, and there were no severe side-effects . The erythromycin-induced pleurodesis is probably the result of induced chemical inflammation in the locality . This study suggests that erythromycin is a useful pleural sclerosant. J Cardiovasc Pharmacol Ther, 1998 Jan, 3(1), 29 - 36 Comparative Study of the Effects of Erythromycin and Roxithromycin on Action Potential Duration and Potassium Currents in Canine Purkinje Fibers and Rabbit Myocardium; West PD et al.; BACKGROUND: Erythromycin and roxithromycin are macrolide antibiotics in common clinical use . Erythromycin occasionally produces life-threatening arrhythmias (torsades de pointes) by blocking the outward potassium current responsible for repolarization of the cardiac action potential . METHODS AND RESULTS: We used standard cellular electrophysiological and whole-cell patch-clamping techniques to compare the relative efficacy of erythromycin and roxithromycin in prolonging cardiac action potential in canine Purkinje fibers and in blocking individual outward potassium currents in isolated rabbit ventricular myocytes . We demonstrated significant prolongation of action potential duration in canine Purkinje fibers by erythromycin but not roxithromycin at a concentration of 100 microM . The delayed rectifier, the outward potassium current thought to be most sensitive to modulation by drugs, was significantly depressed by both agents at concentrations of >/=30 microM in isolated rabbit ventricular myocytes . Both drugs had similar potencies (26% and 21% reduction by 30 microM erythromycin and roxithromycin, respectively, and 50% and 36% reduction by 100 microM erythromycin and roxithromycin) . Neither agent significantly blocked other potassium currents (including the transient outward current) . CONCLUSIONS: Taking into account normally observed peak blood concentrations of these agents in clinical use and the fact that roxithromycin is not normally administered intravenously, we conclude that the risk of proarrhythmia during normal clinical use of oral roxithromycin is extremely remote. Clin Pharmacokinet, 2000 Jan, 38(1), 41 - 57 Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition; Dresser GK et al.; Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance . Pharmacokinetic interactions often occur as a result of a change in drug metabolism . Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes . The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition . Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein . Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice . Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide . Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors . Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil . Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors . Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor . Beneficial drug interactions can occur . Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant . Certain HIV protease inhibitors, e.g . saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir . The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related . Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response . Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index . In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age . Interactions may occur under single dose conditions or only at steady state . The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes . Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen . Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction. Chem Biol, 2000 Feb, 7(2), 77 - 84 Formation of functional heterologous complexes using subunits from the picromycin, erythromycin and oleandomycin polyketide synthases; Tang L et al.; BACKGROUND: Recently developed tools for the genetic manipulation of modular polyketide synthases (PKSs) have advanced the development of combinatorial biosynthesis technologies for drug discovery . Although many of the current techniques involve engineering individual domains or modules of the PKS, few experiments have addressed the ability to combine entire protein subunits from different modular PKSs to create hybrid polyketide pathways . We investigated this possibility by in vivo assembly of heterologous PKS complexes using natural and altered subunits from related macrolide PKSs . RESULTS: The pikAI and pikAII genes encoding subunits 1 and 2 (modules 1-4) of the picromycin PKS (PikPKS) and the eryAIII gene encoding subunit 3 (modules 5-6) of the 6-deoxyerythronolide B synthase (DEBS) were cloned in two compatible Streptomyces expression vectors . A strain of Streptomyces lividans co-transformed with the two vectors produced the hybrid macrolactone 3-hydroxynarbonolide . Co-expression of the same pik genes with the gene for subunit 3 of the oleandomycin PKS (OlePKS) was also successful . A series of hybrid polyketide pathways was then constructed by combining PikPKS subunits 1 and 2 with modified DEBS3 subunits containing engineered domains in modules 5 or 6 . We also report the effect of junction location in a set of DEBS-PikPKS fusions . CONCLUSIONS: We show that natural as well as engineered protein subunits from heterologous modular PKSs can be functionally assembled to create hybrid polyketide pathways . This work represents a new strategy that complements earlier domain engineering approaches for combinatorial biosynthesis in which complete modules or PKS protein subunits, in addition to individual enzymatic domains, are used as building blocks for PKS engineering. Kurume Med J, 1999, 46(3-4), 185 - 9 Bronchial amyloidosis successfully treated with low-dose long-term erythromycin therapy; Nakahara S et al.; A 69-year-old man was admitted for evaluation of an abnormal chest X-ray . A diagnosis of primary bronchial amyloidosis was made on the basis of the chest X-ray, CT scans and bronchial biopsy specimens . The patient was treated with low-dose long-term erythromycin therapy (600 mg/day) . After four months of therapy, chest CT scans, bronchoscopic findings and bronchial biopsy specimens revealed significant improvement of inflammatory changes . Low-dose erythromycin therapy may be helpful in terms of its anti-inflammatory effects for patients with bronchial amyloidosis. Bioorg Med Chem, 1999 Dec, 7(12), 2749 - 52 A new convenient transformation of erythromycin A into clarithromycin; Allevi P et al.; Erythromycin A was transformed into clarithromycin by the sequence of reactions: selective thexyldimethylsilylation of the 9-oxime, trimethylsilylation of the 2',4''-hydroxy groups, methylation of the resulting 2',4''-{O-bis(trimethylsilyl)}-9-{O-(dimethylthexylsilyl)oxime} and acidic regeneration of the protected functionalities. J Infect Dis, 2000 Feb, 181 Suppl 1, S110 - 5 Clinical characteristics and management of 676 hospitalized diphtheria cases, Kyrgyz Republic, 1995; Kadirova R et al.; The Kyrgyz Republic experienced a widespread resurgence of diphtheria during 1994-1998 . To describe the clinical characteristics and management of diphtheria patients hospitalized in 1995, a retrospective chart review was conducted . Physician-diagnosed cases of diphtheria were classified according to the system recommended by the World Health Organization and UNICEF . Among 676 patients hospitalized with respiratory diphtheria, 163 (24%) were carriers, 186 (28%) had tonsillar forms, 78 (12%) had combined types or delayed diagnosis, and 201 (30%) had severe forms of diphtheria . The highest age-specific incidence rates occurred among persons 15-34 years old, and 70% of cases were among those >/=15 years of age . Myocarditis occurred among 151 patients (22%), and 19 patients died (case fatality ratio: 3%) . Diphtheria antitoxin was administered to 507 patients (75%), and all patients received antibiotics (penicillin or erythromycin) . Respiratory diphtheria remains a potentially fatal disease, commonly presenting with a typical membranous pharyngitis . Early diagnosis and treatment of cases with diphtheria antitoxin and antibiotics are the cornerstones of effective treatment. J Biol Chem, 2000 Feb 4, 275(5), 3065 - 74 Characterization of two polyketide methyltransferases involved in the biosynthesis of the antitumor drug mithramycin by Streptomyces argillaceus; Lozano MJ et al.; A DNA chromosomal region of Streptomyces argillaceus ATCC 12596, the producer organism of the antitumor polyketide drug mithramycin, was cloned . Sequence analysis of this DNA region, located between four mithramycin glycosyltransferase genes, showed the presence of two genes (mtmMI and mtmMII) whose deduced products resembled S-adenosylmethionine-dependent methyltransferases . By independent insertional inactivation of both genes nonproducing mutants were generated that accumulated different mithramycin biosynthetic intermediates . The M3DeltaMI mutant (mtmMI-minus mutant) accumulated 4-demethylpremithramycinone (4-DPMC) which lacks the methyl groups at carbons 4 and 9 . The M3DeltaM2 (mtmMII-minus mutant) accumulated 9-demethylpremithramycin A3 (9-DPMA3), premithramycin A1 (PMA1), and 7-demethylmithramycin, all of them containing the O-methyl group at C-4 and C-1', respectively, but lacking the methyl group at the aromatic position . Both genes were expressed in Streptomyces lividans TK21 under the control of the erythromycin resistance promoter (ermEp) of Saccharopolyspora erythraea . Cell-free extracts of these clones were precipitated with ammonium sulfate (90% saturation) and assayed for methylation activity using different mithramycin intermediates as substrates . Extracts of strains MJM1 (expressing the mtmMI gene) and MJM2 (expressing the mtmMII gene) catalyzed efficient transfer of tritium from {(3)H}S-adenosylmethionine into 4-DPMC and 9-DPMA3, respectively, being unable to methylate other intermediates at a detectable level . These results demonstrate that the mtmMI and mtmMII genes code for two S-adenosylmethionine-dependent methyltransferases responsible for the 4-O-methylation and 9-C-methylation steps of the biosynthetic precursors 4-DPMC and 9-DPMA3, respectively, of the antitumor drug mithramycin . A pathway is proposed for the last steps in the biosynthesis of mithramycin involving these methylation events. Aliment Pharmacol Ther, 2000 Feb, 14(2), 233 - 40 Low-dose intravenous erythromycin: effects on postprandial and fasting motility of the small bowel; Medhus AW et al.; BACKGROUND: Erythromycin is a motilin agonist and its effects on gastrointestinal motility are dependent on both dose and whether it is administered during the postprandial or fasting state . AIM: To study the motility response of the small bowel to a low dose of intravenous erythromycin after meal intake and during fasting . METHODS: Eighteen healthy subjects with mean age of 25 years were studied by small bowel manometry . Erythromycin was administered intravenously (0.75 mg per kg body weight) during 20 min in the postprandial (n=9) and the fasting state (n=9), and the motility response was recorded . RESULTS: Erythromycin significantly reduced the frequency of propagated contractions (P < 0.001) and the amplitude of contractions (P < 0.02) in the small bowel during established postprandial motility . During the fasting state, erythromycin invariably initiated a phase III-like activity, which was similar to the spontaneous nocturnal phase III and migrated significantly more slowly than the diurnal phase III (P < 0.01) . CONCLUSIONS: A low dose of erythromycin administered intravenously during the postprandial state significantly inhibits small bowel motility, whereas administration during the fasting state initiates a phase III resembling the nocturnal rather than the diurnal phase III . These effects of erythromycin may indicate interference with vagal pathways . Due to its inhibitory effects, the clinical use of erythromycin in patients with hypomotility should be reconsidered, and the potential usefulness of these effects in patients with exaggerated intestinal motility deserves further attention. Am J Physiol Gastrointest Liver Physiol, 2000 Jan, 278(1), G18 - 23 Motilin receptors in the human antrum; Miller P et al.; Motilin is an intestinal peptide that stimulates contraction of gut smooth muscle . The motilin receptor has not been cloned yet, but motilin-receptor agonists appear to be potent prokinetic agents for the treatment of dysmotility disorders . The aim of this study was to determine neural or muscular localization of motilin receptors in human upper gastrointestinal tract and to investigate their pharmacological characteristics . The binding of (125)I-labeled motilin to tissue membranes prepared from human stomach and duodenum was studied; rabbit tissues were used for comparison . Solutions enriched in neural synaptosomes or in smooth muscle plasma membranes were obtained . Various motilin analogs were used to displace the motilin radioligand from the various tissue membranes . The highest concentration of human motilin receptors was found in the antrum, predominantly in the neural preparation . Human motilin receptors were sensitive to the NH(2)-terminal portion of the motilin molecule, but comparison with rabbit showed that both species had specific affinities for various motilin analogs {i.e., Mot-(1-9), Mot-(1-12), Mot-(1-12) (CH(2)NH)(10-11), and erythromycin} . Motilin receptors obtained from synaptosomes or muscular plasma membranes of human antrum expressed different affinity for two motilin-receptor agonists, Mot-(1-12) and Mot-(1-12) (CH(2)NH)(10-11), suggesting that they correspond to specific receptor subtypes . We conclude that human motilin receptors are located predominantly in nerves of the antral wall, are functionally (and probably structurally) different from those found in other species such as the rabbit, and express specific functional (and probably structural) characteristics dependent on their localization on antral nerves or muscles, suggesting the existence of specific receptor subtypes, potentially of significant physiological or pharmacological relevance. J Am Acad Dermatol, 2000 Feb, 42(2 Pt 1), 299 - 301 Bacillary angiomatosis by Bartonella quintana in an HIV-infected patient; Santos R et al.; Bacillary angiomatosis and bacillary peliosis are opportunistic infections caused by Bartonella henselae and Bartonella quintana, which occur in patients with late-stage infection . We report a case of bacillary angiomatosis in an HIV-infected patient with skin, bone, and probably liver involvement, The identification of the agent (B quintana ) was done by polymerase chain reaction in the skin specimen . The patient had complete regression of all lesions after a 6-month regimen of oral erythromycin. J Am Acad Dermatol, 2000 Feb, 42(2 Pt 1), 241 - 4 Erythromycin in pityriasis rosea: A double-blind, placebo-controlled clinical trial; Sharma PK et al.; BACKGROUND: The study stemmed from an incidental observation of improvement in 2 patients with pityriasis rosea while receiving erythromycin . OBJECTIVE: The purpose of the study was to evaluate the efficacy of erythromycin in patients with pityriasis rosea . METHODS: A double-blind, placebo-controlled clinical study was performed in an outpatient setting in a major hospital . Ninety patients over a period of 2 years were alternatively assigned to treatment group or placebo group . Patients in the treatment group received erythromycin in divided doses for 14 days . The response was categorized as complete response, partial response, or no response . All patients were followed up for 6 weeks . RESULTS: Both groups were comparable with regard to age at presentation, sex, and average duration of disease at the time of reporting to the clinic . Upper respiratory tract infection before the appearance of skin lesions was reported in 68.8% of all patients . Complete response was observed in 33 patients (73.33%) in the treatment group and none in the placebo group (P <.0001) . CONCLUSION: Oral erythromycin was effective in treating patients with pityriasis rosea. Rapid Commun Mass Spectrom, 2000, 14(3), 156 - 60 Analysis of erythromycin by liquid chromatography/mass spectrometry using involatile mobile phases with a novel atmospheric pressure ionization source; Bajic S et al.; A critical limitation of electrospray ionization (ESI) liquid chromatography/mass spectrometry (LC/MS) sources is the susceptibility to blockage of interface orifices due to the deposition of involatile components from the sample and/or mobile phase . These components, including salts, buffers, and ion-pairing agents, can be essential to the performance of the chosen analytical method . We report here the performance enhancements provided by a novel atmospheric pressure ionization (API) source in the analysis of erythromycin A (ERY) using mobile phases that contain involatile components . The enhanced robustness of the new source is derived from the use of a continuous flow of aqueous solvent at the sampling cone orifice that maintains unobstructed ion transmission . The ESI mass spectral responses measured for ERY, using an LC separation that incorporates 10 mM sodium phosphate with and without 10 mM octane sulfonate, were monitored by repeated injections over 13-15 h total analysis time . Minimal effects on ESI mass spectral responses (integrated peak area) or chromatographic performance (peak shape, retention time) were observed during these studies . In the absence of the aqueous cleaning flow, complete loss of mass spectral responses and total blocking of the sampling cone was observed in less than 30 min . Responses for ERY spiked into chicken and beef liver, and catfish muscle at or below the regulatory level of interest (100 ppb), were quantified by internal standard calibration using this procedure . These results demonstrate the ability of a novel API-MS ion source to perform analyses that require the use of involatile mobile phase additives . Curr Pharm Des, 2000 Jan, 6(2), 181 - 223 Highlights of semi-synthetic developments from erythromycin A; Wu YJ; Earlier semi-synthetic studies of erythromycin A culminated in the discovery of two successful second generation macrolide antibiotics, azithromycin and clarithromycin, for the treatment of community-acquired bacterial infections . More recent structural modifications of erythromycin A have resulted in the discovery of novel ketolide antibiotics and new motilide prokinetic agents . This review is an account of the semi-synthetic developments from erythromycin A by chemical transformations. Rev Pneumol Clin, 1999 Oct, 55(5), 338 - 43 {Drugs for respiratory tropism and pregnancy}; Rouveix B et al.; The pharmokinetics of drugs used to treat lung disease in pregnant women undergo changes due to the physiological variations induced by pregnancy . Dosage must therefore be adapted; increased doses are often required for the treatment of severe lung infections . Most drugs used for lung disease have a teratogenic potential and thus carry a risk for the fetus . Drugs used for asthma usually present little risk for the fetus . Administration by inhalation is particularly well adapted as it limits systemic diffusion . Excessively high doses can however lead to neonatal toxicity . Penicillins, cephalosporins and erythromycin have been shown to be well tolerated and are the choice antibiotics . Aminoglycosides require careful monitoring due to the risk of renal and auditory toxicity . Fluoroquinolones, sulfamides and tetracyclines should be avoided . Available data on recent compounds such as the new macrolides (azithromycin, clarithromycin) are too limited for recommending their use during pregnancy . In case of resistant tuberculosis, it is sometimes necessary to prescribe a second choice anti-tuberculosis drug with known or suspected fetal toxicity. MMWR Morb Mortal Wkly Rep, 1999 Dec 17, 48(49), 1117 - 20 Hypertrophic pyloric stenosis in infants following pertussis prophylaxis with erythromycin--Knoxville, Tennessee, 1999; Efficient purification and kinetic characterization of a bimodular derivative of the erythromycin polyketide synthase; Cambridge Centre for Molecular Recognition, Department of Organic Chemistry, University of Cambridge, UKModular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), are giant multienzymes that biosynthesize a number of clinically important natural products . The modular nature of PKSs suggests the possibility of a combinatorial approach to the synthesis of novel bioactive polyketides, but the efficacy of such a strategy depends critically on gaining fundamental insight into PKS structure and function, most directly through experiments with purified PKS proteins . Several recent investigations into important aspects of the activity of these enzymes have used only partially purified proteins (often 3-4% of total protein), reflecting how difficult it is to purify these multienzymes in amounts adequate for kinetic and structural analysis . We report here the steady-state kinetic analysis of a typical bimodular PKS, 6-deoxyerythronolide B synthase 1-thioesterase (DEBS 1-TE), purified from recombinant Saccharopolyspora erythraea JCB101 by a new, high-yielding procedure consisting of three steps: ammonium sulfate precipitation, hydrophobic interaction chromatography and size-exclusion chromatography . The method provides 13-fold purification with a recovery of 11% of the applied PKS activity . The essentially homogeneous synthase exhibits an intrinsic methylmalonyl-CoA hydrolase activity, which competes with polyketide chain extension . The most reliable value for the kcat for synthesis of (3S,5R)-dihydroxy-(2R,4R)-dimethyl-n-heptanoic acid-delta-lactone is 0.84 min-1, and the apparent Km for (2RS)-methylmalonyl-CoA is 17 microM . This kcat is approximately 10-fold lower than the value reported previously for a differently engineered version of the truncated PKS, DEBS 1+TE . The difference likely reflects the fact that the DEBS 1-TE contains a hybrid acyl carrier protein (ACP) domain in its second module, which lowers its catalytic efficiency. Arch Pediatr Adolesc Med, 2000 Jan, 154(1), 62 - 4 Steroid rosacea in prepubertal children; Weston WL et al.; OBJECTIVE: To examine clinical associations, family history of rosacea, and response to treatment in prepubertal children with steroid rosacea . DESIGN: Retrospective case-series evaluation of children younger than 13 years with steroid rosacea seen over an 8-year period (1991-1998) . SETTING: Ambulatory care university hospital . PATIENTS: Referral patients from pediatricians serving a population of 3.4 million . INTERVENTIONS: Abrupt cessation of topical corticosteroid use and initiation of treatment with oral erythromycin stearate for 4 weeks . MAIN OUTCOME MEASURES: Age at onset, class of topical corticosteroid used, family history of rosacea, location of lesions, treatment, and weeks to clearing . RESULTS: We evaluated 106 (46 boys and 60 girls) who developed steroid rosacea . Preceding steroids used were predominantly (54% of children) class 7 agents including 1% hydrocortisone and over-the-counter hydrocortisone preparations . Only 3% of children had used superpotent (class 1) topical corticosteroids . The mean age at onset was 7.04 years (range, 6 months to 13 years) . Twenty-nine children were younger than 3 years . A family history of rosacea was found for 20% of the children . After abruptly stopping topical steroid use and starting treatment with oral erythromycin, 86% of children had complete clearing within 4 weeks and 100% by 8 weeks . Clearing within 3 weeks was observed in 22% of children . CONCLUSIONS: Abrupt discontinuation of topical corticosteroids and institution of oral antibiotics resulted in clearing within 4 weeks . This finding does not support the concept that prepubertal children with steroid rosacea need to continue low-strength steroids in a gradual withdrawal strategy . This conclusion is supported by the finding that 54% developed the steroid rosacea while being treated with the lowest-strength (class 7) topical corticosteroids . Even over-the-counter hydrocortisone preparations induced steroid rosacea in susceptible children . Susceptibility may be genetic as 20% of children had a first-degree relative with rosacea. Exp Parasitol, 2000 Jan, 94(1), 8 - 14 Azithromycin: antimalarial profile against blood- and sporozoite-induced infections in mice and monkeys; Puri SK et al.; The spectrum of antimalarial activity of the new macrolide antibiotic azithromycin was evaluated against blood- and sporozoite-induced infections with a chloroquine-resistant strain of Plasmodium yoelii nigeriensis (N-67) in Swiss mice and with simian parasite Plasmodium cynomolgi B in rhesus monkeys . Against experimental rodent malaria, a 70 mg/kg/day dose showed curative blood-schizontocidal activity in a four-dose regimen administered orally from day 0 to day 3 or from day 2 to day 5 to mice harboring established infection . The curative response was also obtained with a 40 mg/kg/day dose administered in an extended seven-dose (days 0-6) regimen . Azithromycin was also effective in the causal prophylactic test, since a 50 mg/kg dose from day -1 to day +2 protected mice against P . y . nigeriensis (N-67) sporozoite challenge . In comparison, erythromycin did not show either of the above activities up to a 405 mg/kg/day dose in identical regimens . Comparison of the ED(90) values showed that azithromycin was 31-fold more effective than erythromycin as a blood schizontocide . In the simian model, trophozoite-induced infections of P . cynomolgi B were cured with 25 mg/kg/day azithromycin administered for 7 days . In the causal prophylactic test, the prepatent period was significantly extended in monkeys challenged with P . cynomolgi B sporozoites, presumably because of the growth inhibition of preerythrocytic schizonts in hepatocytes . Azithromycin did not exhibit any hypnozoitocidal (dormant exoerythrocytic stages) activity at 25 mg/kg/day in a seven-dose regimen . Dig Dis Sci, 1999 Dec, 44(12), 2439 - 42 Effect of intravenous clarithromycin on interdigestive gastroduodenal motility of patients with functional dyspepsia and Helicobacter pylori gastritis; Bortolotti M et al.; Gastroduodenal motility of 16 patients complaining of functional dyspepsia and Helicobacter pylori gastritis was recorded by means of a low-compliance manometric system with four recording ports in the stomach and four in the duodenum . Clarithromycin (CLA) 250 mg (group A: 8 patients) or normal saline solution (group B: 8 patients) was infused intravenously randomly and in double-blind manner 30 min after the end of the first recorded activity front (AF) of the migrating motor complex or, in the absence of AFs, after 200 min of recording, continuing the recording until an AF was observed during the subsequent 200 min . CLA administration was followed by a typical gastroduodenal AF in a significantly higher number of patients than saline administration . In addition, the time-lag between the drug administration and the appearance of AFs was 22 min +/-7.4 (mean +/- SD), significantly shorter than after saline (109+/-56 min) and the CLA-related duodenal AFs showed a duration of 7.4 min +/-1.6 in group A, significantly longer than that of the spontaneous AFs (3.5 min +/-1), while in group B AF duration after saline was not significantly different from that of the spontaneous ones . In conclusion, clarithromycin is able to stimulate cyclic interdigestive gastroduodenal motility . This prokinetic property of clarithromycin is not unexpected because it is a macrolide like erythromycin, the prokinetic activity of which is well known, and could be utilized for therapeutic uses. South Med J, 1999 Dec, 92(12), 1178 - 82 Effect of erythromycin on myocardial repolarization in patients with community-acquired pneumonia; Kdesh A et al.; BACKGROUND: Erythromycin has been associated with prolongation of myocardial repolarization and torsades de pointes (TdP) . METHODS: To determine the frequency, dose-response, and risk factors for erythromycin-associated prolongation of myocardial repolarization, we observed data of patients admitted to our hospital with pneumonia who were treated with erythromycin . RESULTS: In 35 women and 28 men enrolled in this study, the QTc increased from 434 +/- 4 milliseconds at baseline to 464 +/- 5 milliseconds after receiving a cumulative dose of 3.2 +/- 0.2 g of erythromycin . Neither age, sex, presence of preexistent congestive heart failure/coronary artery disease, electrolyte values, nor cumulative dose of erythromycin was associated with QTc prolongation . In 27 patients who received intravenous erythromycin for 3 days, the QTc increased from 427 +/- 5 milliseconds before to 461 +/- 8 milliseconds at 24 hours but did not increase further by day 3 (457 +/- 10 milliseconds) . No patient in this cohort had TdP . CONCLUSIONS: Erythromycin therapy is associated with prolongation of myocardial repolarization that manifests after the first few doses in a majority of patients. Biochem Biophys Res Commun, 2000 Jan 7, 267(1), 124 - 8 Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells; Desaki M et al.; Erythromycin (EM), and related 14-member macrolide antibiotics, has attracted attention for its effectiveness in airway diseases including diffuse panbronchiolitis and sinobronchial syndrome . However, its molecular mechanisms remain unknown . We evaluated the effects of EM on activation of several transcription factors, including nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) in human bronchial epithelial cell line BET-1A, which are known to regulate the expression of many proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) . BET-1A cells were cultured with hormonally defined Ham's F12 medium, and were stimulated by phorbol myristate acetate (PMA) . EM suppressed mRNA expression as well as the release of IL-8 at therapeutic and noncytotoxic concentrations (% inhibition of IL-8 protein release: 42.2 +/- 5.5%, at 10(-6) M) . Furthermore, electrophoretic mobility shift assays revealed that EM inhibited the activations of NF-kappaB and AP-1 induced by PMA in BET-1A cells . These data indicate that EM has inhibitory effects not only on the mRNA expression and release of IL-8, but also on the activation of transcription factors NF-kappaB and AP-1 . Our findings support the concept that the recruitment of neutrophils in airway diseases may be regulated by NF-kappaB and AP-1 . Eur J Clin Invest, 2000 Jan, 30(1), 66 - 71 Effects of erythromycin on human colonic circular muscle in idiopathic chronic constipation; Chieppa DM et al.; BACKGROUND: Erythromycin has been shown to have profound prokinetic effects on the gastrointestinal tract of humans and animals, probably through its action on endogenous motilin receptors . The purpose of this study was to determine both the direct and indirect effects ('off contraction') of erythromycin and motilin on ex vivo circular muscle strips of the distal colon from patients with or without idiopathic chronic constipation (ICC) . MATERIALS AND METHODS: Cumulative concentrations of erythromycin (1-20 microM) and motilin (0.05-1 microM) were tested in both control and ICC preparations in order to evaluate the direct drugs effect . A range doses of both erythromycin (0.5-10 microM) and motilin (0.05-0.5 microM) were tested on their ability to affect the off-contraction that follows the typical inhibitory response evoked by low frequencies of Electrical Field Stimulation (EFS) (1-5 Hz, 20 V, 1 msec pulse trains lasting 1 min) . RESULTS: The direct effect of both erythromycin and motilin was a slight increase (less than 10% of the maximal ACh-induced contraction) in the basal tension, with no dose-response relationship . The off-contraction, evoked by EFS, was not affected by drugs pretreament in control preparations . Conversely, in ICC preparations both drugs significantly increased the off-contraction (about 30%) . CONCLUSIONS: Erythromycin causes mainly an indirect contractile effect in circular muscle strips from ICC patients . This effect may be related to the activation of inhibitory neuronal motilin receptors . This activation might potentiate NANC relaxation, proportionally increasing the circumferential reflex contraction that follows the EFS-induced relaxation. Eur J Pharm Biopharm, 2000 Jan, 49(1), 73 - 8 Dose uniformity and redispersibility of pharmaceutical suspensions 2: assessment of three commercial erythromycin ethyl succinate oral liquids; Deicke A et al.; The content of active ingredient of single doses of a suspension depends to a large extent upon the redispersibility of the product . Mathematical and technical aspects of a procedure to test this property have been discussed in a preceding article . Here, the method is applied to three commercial erythromycin ethylsuccinate suspensions obtained from community pharmacies in Germany . Three specimens of each product were tested in parallel . For approximately two weeks, samples were taken t.i.d . at 9 am, 1 pm and 5 pm after shaking the bottles on a prototype testing apparatus with an intensity of 134m(2)/s(3) per cycle corresponding to the 25th percentile of a group of 79 subjects, whose shaking habits had been assessed previously . In order to minimize volumetric errors, 2.5ml samples were drawn using a syringe . They were assayed by HPLC with electrochemical detection using oleandomycin as an internal standard . While one of the products performed satisfactorily and one showed moderate shortcomings, the dose uniformity of two specimens of the third product was clearly deficient . The problem seems to be associated with poor wetting behaviour of the solids. Reprod Toxicol, 1999 Nov-Dec, 13(6), 531 - 6 A population-based case-control teratologic study of oral erythromycin treatment during pregnancy; Czeizel AE et al.; The objective of the study was to evaluate the human teratogenic potential of oral erythromycin treatment during pregnancy in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996 . Of 38,151 pregnant women who had newborn infants without any congenital abnormalities (population control group), 172 (0.5%) had received erythromycin, while of 22,865 pregnant women who had newborns or fetuses with congenital abnormalities, 113 (0.5%) had been treated with erythromycin (crude OR with 95% Cl = 1.1, 0.9-1.4) . The case-control pair analysis did not indicate a teratogenic potential of erythromycin during the second through third months of gestation, i.e., in the critical period for most major congenital abnormalities . The frequency of maternal erythromycin treatments during the second-third months of pregnancy was also not higher in different congenital abnormality groups compared with the rate of the total control group as referent . Thus, treatment with oral erythromycin during pregnancy did not present detectable teratogenic risk to the fetus. Plasmid, 2000 Jan, 43(1), 1 - 11 The importance of homologous recombination in the generation of large deletions in hybrid plasmids in Amycolatopsis mediterranei; Tuteja D et al.; The cloning vector pRL60 was developed previously as a tool for genetic manipulations in Amycolatopsis mediterranei, which produces the commercially and medicinally important antibiotic rifamycin . Here, a method based on intraplasmid recombinations is described for the construction of smaller plasmids in A . mediterranei, which also helped in delimiting the origin of replication (pA-rep) of the parent plasmid . The strategy involved the cloning of a selectable marker, erythromycin resistance gene (ermE), onto plasmids pULAM2 and pULVK2A (derivatives of pRL1), followed by selection of the hybrid or concatemeric plasmids pRL50 and pRL80 (with large homologous repeats) in Escherichia coli GM2163 . These hybrid plasmids were then transferred to A . mediterranei DSM 40773 by electroporation, with selection in the presence of different antibiotics . During the process of transformation and selection in A . mediterranei, pRL50 and pRL80 underwent intraplasmid recombinations, yielding derivatives that retained a common region essential for maintenance and replication, as well as the selected resistance genes . This approach produced several smaller plasmids designated pRL51, pRL52, pRL53, pRL60, pRL81, and pRL82 . These plasmids, isolated from A . mediterranei DSM 40773, could be transferred to different Amycolatopsis strains at transformation efficiencies ranging from 0.7 x 10(2) to 4 x 10(4) transformants/microg DNA . The electroporation parameters under which maximum transformation efficiencies were obtained varied from strain to strain . Since the isolation of plasmid DNA from Amycolatopsis strains were extremely difficult, a convenient and rapid method of direct transfer of plasmid DNA, i.e., electroduction, was also developed in which the above-described shuttle plasmids were transferred directly from A . mediterranei to E . coli . In addition, the sequence of the minimal (pA-rep, approximately 1.0 kb) of plasmid pRL51 was determined . The nucleotide base sequence of the pA-rep region did not have any clear similarity to the DNA or amino acid sequences in various databases, suggesting that it is unique . Lancet, 1999 Dec 18-25, 354(9196), 2101 - 5 Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromcyin: a case review and cohort study; Honein MA et al.; BACKGROUND: In February, 1999, a local US health department identified a cluster of pertussis cases among neonates born at a community hospital and recommended oral erythromycin for post-exposure prophylaxis for about 200 neonates born at that hospital between Feb 1 and Feb 24, 1999 . We investigated a cluster of seven cases of infantile hypertrophic pyloric stenosis (IHPS) that occurred the following month among the neonates who had received erythromycin . METHODS: We obtained a masked, independent review of the IHPS ultrasonography diagnoses, calculated the monthly IHPS incidence, and compared index and historical (1998-99) IHPS cases with respect to several characteristics including erythromycin exposure . We used a retrospective cohort of infants born in January and February, 1999, to investigate further erythromycin exposure and development of IHPS . FINDINGS: An independent review confirmed the ultrasonographic diagnoses of all seven index IHPS cases . All index cases versus none of the historical IHPS cases had been given erythromycin for pertussis prophylaxis . The IHPS rate for infants born in the hospital in February, 1999, was 32.3 per 1000 liveborn infants, representing nearly a seven-fold increase over 1997-98 (relative risk 6.8 {95% CI 3.0-15.7}) . Among infants born in January and February, 1999, erythromycin was associated with IHPS (absolute risk 4.5%, relative risk infinity {1.7-infinity}) . INTERPRETATION: Neonates receiving oral erythromycin may have an increased risk of IHPS . The risks and benefits of erythromycin for neonatal pertussis prophylaxis should be re-evaluated, and caution should be used in defining risk groups for prophylaxis. Pharmacol Toxicol, 1999 Nov, 85(5), 201 - 5 Fluvoxamine is a more potent inhibitor of lidocaine metabolism than ketoconazole and erythromycin in vitro; Wang JS et al.; CYP3A4 is generally believed to be the major CYP enzyme involved in the biotransformation of lidocaine in man; however, recent in vivo studies suggest that this may not be the case . We have examined the effects of the CYP3A4 inhibitors erythromycin and ketoconazole and the CYP1A2 inhibitor fluvoxamine on the N-deethylation, i.e . formation of monoethylglycinexylidide (MEGX), and 3-hydroxylation of lidocaine by human liver microsomes . The experiments were carried out at lidocaine concentrations of 5 microM (clinically relevant concentration) and 800 microM . The formation of both MEGX and 3-hydroxylidocaine was best described by a two-enzyme model . At 5 microM of lidocaine, fluvoxamine was a potent inhibitor of the formation of MEGX (IC50 1.2 microM) . Ketoconazole and erythromycin also showed an inhibitory effect on MEGX formation, but ketoconazole (IC50 8.5 microM) was a much more potent inhibitor than erythromycin (IC50 200 microM) . At 800 microM of lidocaine, fluvoxamine (IC50 20.7 microM) and ketoconazole (IC50 20.4 microM) displayed a modest inhibitory effect on MEGX formation, whereas erythromycin was a weak inhibitor (IC50 >250 microM) . The 3-hydroxylation of lidocaine was potently inhibited by fluvoxamine at both lidocaine concentrations (IC50 0.16 microM at 5 microM and 1.8 microM at 800 microM) . Erythromycin and ketoconazole showed a clear inhibitory effect on the 3-hydroxylation of lidocaine at 5 microM of lidocaine (IC50 9.9 microM and 13.9 microM, respectively), but did not show a consistent effect at 800 microM of lidocaine (IC50 >250 microM and 75.0 microM, respectively) . Although further studies are needed to elucidate the role of distinct CYP enzymes in the biotransformation of lidocaine in humans, the findings of this study suggest that while both CYP1A2 and CYP3A4 are involved in the metabolism of lidocaine by human liver microsomes, CYP1A2 is the more important isoform at clinically relevant lidocaine concentrations. Pharmacotherapy, 1999 Dec, 19(12), 1378 - 84 Pharmacokinetic interaction between ketoconazole and amprenavir after single doses in healthy men; Polk RE et al.; STUDY OBJECTIVE: To determine the effects of coadministration of amprenavir and ketoconazole on the pharmacokinetics of both drugs, and to assess the utility of the erythromycin breath test (ERMBT) to predict and explain these effects . DESIGN: Open-label, randomized, balanced, single-dose, three-period crossover study . SETTING: University research center . SUBJECTS: Twelve healthy men . INTERVENTION: Subjects received amprenavir 1200 mg, ketoconazole 400 mg, and amprenavir 1200 mg plus ketoconazole 400 mg . Each treatment was separated by 14 days . MEASUREMENTS AND MAIN RESULTS: Serial plasma samples for amprenavir and ketoconazole concentrations were measured by high-performance liquid chromatography . Coadministration of the drugs increased amprenavir area under the curve extrapolated to infinity (AUCinfinity) by 31% and reduced its maximum concentration (Cmax) by 16% . Amprenavir increased the AUCinfinity of ketoconazole by 44% and increased the drug's half-life and Cmax by 23% and 19%, respectively . Both agents resulted in substantial inhibition of ERMBT . CONCLUSION: Coadministration of ketoconazole and amprenavir results in a statistically significant increase in AUC for both agents, but the changes are not likely to be clinically important. Adv Exp Med Biol, 1999, 455, 343 - 8 Azathioprine in dermatological practice . An overview with special emphasis on its use in non-bullous inflammatory dermatoses; Scerri L; Azathioprine is employed for its immunosuppressive properties, as a steroid-sparing agent or as monotherapy . Its most traditional clinical indications are connective tissue diseases, vasculitis, post-transplant, and immunobullous dermatoses . The main disadvantages of azathioprine therapy are a delayed onset of action (6-8 weeks), and rare profound bone marrow toxicity . Susceptibility to bone marrow toxicity is due to a genetically determined metabolic defect (1 in 300) . Patients at risk of such toxicity may be identified by a Thiopurine methyltransferase enzyme assay . We have undertaken a retrospective study, looking at the use of azathioprine as monotherapy for non-bullous inflammatory dermatoses . We studied a total of 24 patients (10 male, 14 female) . The dermatoses comprised: atopic eczema (10), pompholyx (6), plaque psoriasis (6), and chronic actinic dermatitis (2) . All patients had severe refractory disease warranting systemic second line therapy . The mean age was 49.4 years (range 17-86 years) . The starting dose of azathioprine was 100-150 mg/day, and the maintenance dose 50-100 mg/day . The mean duration of treatment was 33.5 months(range 1-132 months) . Eighteen patients (75%) showed a good to excellent sustained clinical response to azathioprine . This response rate was evenly represented in the 4 dermatoses studied . The adverse reactions encountered were raised MCV (6), leucopenia (2), raised hepatic enzymes (6),