Mechanism of action of 6, 7, 8, 9, 10, 12-hexahydro-azepino-[2, 1-b] quinazolin-12-one-(RLX)--a novel bronchodilator

The present study presents a mode of action profile of RLX (6, 7, 8, 9, 10, 12-hexahydro-azepino-[2, 1-b]-quinazoline-12-one) a bronchodilator obtained by the chemical modification in the molecule of alkaloid vasicine (Ex: Adhatoda vesica). The effect of RLX (p.o.) was observed on: (a) mast cell degranulation, (b) release of histamine and prostaglandin E (PGE), (c) 45Ca uptake and (d) activities of cAMP phosphodiesterase (PDEase) and lipoxygenase enzymes in mesenteries/peritoneal mast cells/lung tissue homogenates in rats under systemic anaphylaxis. RLX (10 and 20 mg/kg) inhibited antigen-induced mast cell degranulation and released of histamine from target tissues. An increased outflow of PGE (lungs) and an inhibited 45Ca uptake (peritoneal mast cells) were noted. Lung PDEase and lipoxygenase activities were decreased. These results suggested that RLX could be acting like disodium cromoglycate and aminophyline with additional attributes its oral efficacy and long duration of action.     

Characterization and regulation of catabolic genes

Although a wide range of microorganisms have been discovered that are able to degrade highly stable, toxic xenobiotics, still many pollutants persist in the environment. Recent advances in the field of r-DNA technology has provided solutions to these problems. One important factor limiting the bioremediation of sites contaminated with certain hazardous wastes is the slow rate of degradation. This slow rate limits the practicality of using bacteria in remediating contaminated sites. It is possible to extend the range of substrates that an organism can utilize. It is even possible to endow an organism with the ability to degrade a predetermined range of xenobiotics. Because biotechnological processes are based on natural activities of microorganisms and constitute variations in classic domestic waste treatment processes, they are publicly more accepted. This is an area where genetic engineering can make a marked improvement by manipulating catabolic genes of microorganisms. Advances in r-DNA technology have opened up new avenues to move toward the goal of genetically engineered microorganisms to function as "designer biocatalysts" in which certain desirable biodegradation pathways or enzymes from different organisms are brought together in a single host with the aim of performing specific detoxification. In the last 2 decades much progress has been made in this direction, and as a result catabolic genes have been cloned and characterized for organochlorines, polychlorinated biphenyls, chlorobenzoates, naphthalene etc. The aim of this review is to provide an insight in the recent advances made on characterization and expression of catabolic genes that encode the degradation/detoxification of these persistent and toxic xenobiotic compounds.     

Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer

Background: Drug resistance mechanisms can reduce response rateand duration in men with castration-resistant prostate cancer(CRPC) receiving docetaxel-based therapy. Patupilone (epothiloneB), a microtubule-targeting agent, may be unaffected by someresistance mechanisms. Therefore, a phase II study assessedthe patupilone safety and activity in CRPC patients with andwithout previous chemotherapy. Methods: CRPC patients received patupilone 2.5 mg/m² weeklyfor 3 weeks of a 4-week cycle. Patients were required to havemeasurable disease or prostate-specific antigen (PSA) progression(levels > 20 ng/ml). Results: All 45 enrolled patients (median age, 69 years) weresafety and response assessable. Sixty-four percent had previouschemotherapy (55% had previous taxane therapy). Patients receiveda median of three patupilone cycles. Patupilone was generallywell tolerated. Ten (22%) patients experienced grade 3 diarrhea,six (13%) grade 3 fatigue, and one (2%) grade 3 neuropathy withno neutropenia or thrombocytopenia incidence. Six (13%) patientshad 50% decline in PSA (three had previous taxane therapy).No patient with measurable disease had a response. Median overallsurvival was 13.4 months. Conclusions: The safety profile of weekly patupilone in CRPCpatients compares favorably with that of other microtubule inhibitors.At the dose and schedule tested, patupilone demonstrated minimalactivity in CRPC. Key words: clinical trial, epothilone B, prostatic neoplasms, tubulin modulators Received for publication April 4, 2008. Revision received August 27, 2008. Accepted for publication September 9, 2008.     

Antimycobacterial serratamolides and diacyl peptoglucosamine derivatives from Serratia sp

The cyclodepsipeptide serratamolide A ( 1) and five closely related compounds together with three new glucosamine derivatives were isolated by bioactivity-guided chromatography from the XAD adsorber resin extract of a Serratia sp. The structures of the compounds were elucidated by 2D NMR and MS analyses. In addition to the known serratamolide A ( 1) with two C 10 alkyl chains, its derivatives always contained one C 10 chain combined with either C 12:1, C 12, C 11, C 9, or C 8 chains. The glucosamine derivatives contained a common core consisting of an N-butyl-alpha-glucopyranosylamide, which was acylated at the C-1 oxygen with valine. The differences between the derivatives arise from the nature of the acyl groups attached to the N-terminus of valine, which were identified as the linear fatty acid moieties C 16:1, C 15, or C 14. Each compound was present in two isomeric forms arising from racemization of the valine moiety. All compounds showed antibiotic activity against Mycobacterium diernhoferi and other rapidly growing mycobacteria.     

Canadian Cardiovascular Society Cardiovascular Screening of Competitive Athletes: The Utility of the Screening Electrocardiogram to Predict Sudden Cardiac Death

Prevention of sudden cardiac arrest/death (SCA/D) among athletes is a universal goal, although the optimal strategy for its achievement is controversial, with the inclusion of the 12-lead electrocardiogram (ECG) at the center of the debate. The ECG exhibits superior sensitivity over history and physical examination to detect conditions associated with SCA/D. However, the identification of disease does not necessarily lead to a significant reduction in SCA/D. The “Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Statement on the Cardiovascular Screening of Competitive Athletes” recommended against the routine performance of an ECG for the initial cardiovascular screening of competitive athletes. The incidence of SCA/D among athletes (<35 years of age), the risk of SCA/D during sport participation among individuals with abnormalities found on screening ECG, the efficacy of the ECG to identify conditions associated with SCA/D, and the positive predictive value of an abnormal ECG to predict SCA/D are critically examined. This review presents the evidence informing the panel’s recommendation.