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Antitubercular Drugs (antitubercular + drug)
Selected AbstractsSynergism of microwave irradiation and enzyme catalysis in synthesis of isoniazidJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 11 2007Ganapati D Yadav Abstract Isoniazid is a useful antitubercular drug widely employed in combination therapy with rifampicin. The synthesis of isoniazid from ethyl isonicotinate and hydrazine hydrate was studied in non-aqueous media via lipase-catalyzed hydrazinolysis under both conventional heating and microwave irradiation by using different supported lipases. Among three different commercial lipases used, namely Novozym 435 (Candida antarctica lipase), Lipozyme RM IM (Rhizomucor miehei lipase) and Lipozyme TL IM (Thermomyces lanuginosus lipase), Novozym 435 was found to be the most effective, with conversion of 54% for equimolar concentrations at 50 °C in 4 h. The rate of reaction as well as final conversion increased synergistically under microwave irradiation in comparison with conventional heating, which showed 36.4% conversion, even after 24 h, for the control experiment. Effects of various process parameters such as speed of agitation, catalyst loading, substrate concentration, product concentration and temperature were studied. A kinetic model is also described. Copyright © 2007 Society of Chemical Industry [source] GSTT1 and GSTM1 gene deletions are not associated with hepatotoxicity caused by antitubercular drugsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2010S. Chatterjee MD Summary Background and objective:, Susceptibility to antitubercular drug (ATD)-induced hepatotoxicity may be genetically mediated, with variant alleles of genes such as N -acetyltransferase (NAT2) and CYP2E1 reported as risk factors. Two studies of Asian populations have reported that GSTM1*0/*0 (null) genotype was a likely predictor of hepatotoxicity, whereas another of a Caucasian population implicated GSTT1*0/*0. We undertook a prospective case,control study to investigate whether GSTM*0/*0 and GSTT1*0/*0 were risk factors for ATD-induced hepatotoxicity. Methods:, Pulmonary tuberculosis patients on isoniazid, rifampicin and pyrazinamide who developed hepatotoxicity using defined criteria were prospectively identified. These cases were then matched with at least one control subject on the same drugs but without hepatotoxicity. Genotyping for GSTM1 and GSTT1 was performed by multiplex PCR on genomic DNA. The odds ratios for the frequency of specific GSTM1 and GSTT1 homozygotes in the case and control subjects were calculated to test for association between the genotypes and hepatotoxicity. Results and discussion:, Hundred and fifty-one subjects (51 cases, 100 controls) were enrolled. Odds ratio for GSTM1 null genotype was 1·00 (95% CI 0·51,1·97) and GSTT1 null was 2·02 (95% CI 0·39,10·39), respectively, showing that these genotypes are not associated with hepatotoxicity. Conclusion:,GSTM1 *0/*0 or GSTT1 *0/*0 or both null genotypes, do not appear to be associated with ATD-induced hepatotoxicity in our Indian population. [source] Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drugBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2005Lee Jia 1SQ109 is a novel [1,2]-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening. The present study aimed at characterizing its pharmacodynamics and pharmacokinetics. 2The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis -infected murine macrophages) and in vivo (M. tuberculosis -infected C57BL/6 mice) and compared to isoniazid (INH) and EMB. SQ109 showed potency and efficacy in inhibiting intracellular M. tuberculosis that was similar to INH, but superior to EMB. In vivo oral administration of SQ109 (0.1,25 mg kg,1 day,1) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg,1 day,1, but was less potent than INH at 25 mg kg,1 day,1. Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg,1 day,1) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC. 3Pharmacokinetic profiles of SQ109 in mice following a single administration showed its Cmax as 1038 (intravenous (i.v.)) and 135 ng ml,1 (p.o.), with an oral Tmax of 0.31 h. The elimination t1/2 of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.). The oral bioavailability was 4%. However, SQ109 displayed a large volume of distribution into various tissues. The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma. The next ranked tissues were spleen and kidney. SQ109 levels in most tissues after a single administration were significantly higher than that in blood. High tissue concentrations of SQ109 persisted for the observation period (10 h). 4This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties. British Journal of Pharmacology (2005) 144, 80,87. doi:10.1038/sj.bjp.0705984 [source] Extensively drug-resistant tuberculosis: current challenges and threatsFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 2 2008Amita Jain Abstract Extensively drug-resistant tuberculosis (XDR-TB) is defined as tuberculosis caused by a Mycobacterium tuberculosis strain that is resistant to at least rifampicin and isoniazid among the first-line antitubercular drugs (multidrug-resistant tuberculosis; MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second-line drugs, namely amikacin, kanamycin and/or capreomycin. Recent studies have described XDR-TB strains from all continents. Worldwide prevalence of XDR-TB is estimated to be c. 6.6% in all the studied countries among multidrug-resistant M. tuberculosis strains. The emergence of XDR-TB strains is a reflection of poor tuberculosis management, and controlling its emergence constitutes an urgent global health reality and a challenge to tuberculosis control activities in all parts of the world, especially in developing countries and those lacking resources and as well as in countries with increasing prevalence of HIV/AIDS. [source] Potentiation of isoniazid-induced liver toxicity by rifampicin in a combinational therapy of antitubercular drugs (rifampicin, isoniazid and pyrazinamide) in Wistar rats: A toxicity profile studyHEPATOLOGY RESEARCH, Issue 10 2007Sheikh Abdullah Tasduq Aim:, Biochemical characterization of long-term toxic manifestations of anti-tubercular (anti-TB) drugs , rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) , individually and in two combinations: (i) RIF + INH, and (ii) RIF + INH + PZA in Wistar rats. Methods:, Animals received anti-TB drugs , alone or in combination , once daily p.o. for up to 90 days (doses, in mg/kg: RIF, 250; INH, 50; PZA, 100). Assays for alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin (serum) and lipid peroxidation (LPO), glutathione (GSH), glutathione peroxidase (GPx), catalase, Na+K+-ATPase and CYP 2E1 (liver) were performed to assess liver toxicity. Clinical biochemistry was done by commercial kits. Determinations were made at 0, 15, 30 and 90 days of treatment schedule. Results:, Anti-TB drugs-treated animals showed abnormal rises or falls (>1.5,2 fold) in the serum/liver parameters. Mild hyperlipidemia, hypercholesterolemia and hyperuricemia were the other pathologies. Of all the treated groups, INHalone or in combination with other drugs produced a progressive enhancement of toxicity over 15,90 days. The in vivo results were further supported by in vitro results (MTT assay, GSH and LPO) in primary cultures of rat hepatocyte. Results indicated that anti-TB drugs in combination: (i) caused membrane damage resulting in leakage of ALT, ALP and bilirubin; (ii) caused imbalance in endogenous enzymatic oxidant,antioxidant defense via increased lipid peroxidation and in glutathione homeostasis; and (iii) enhanced the CYP 2E1-mediated bioactivation mechanism. Conclusion:, Toxicity manifestations seemed to be heptocytic injury targeted at hepatocytes, bile ducts or sinusoidal cells related to hepatitis and primary biliary cholestasis. [source] GSTT1 and GSTM1 gene deletions are not associated with hepatotoxicity caused by antitubercular drugsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2010S. Chatterjee MD Summary Background and objective:, Susceptibility to antitubercular drug (ATD)-induced hepatotoxicity may be genetically mediated, with variant alleles of genes such as N -acetyltransferase (NAT2) and CYP2E1 reported as risk factors. Two studies of Asian populations have reported that GSTM1*0/*0 (null) genotype was a likely predictor of hepatotoxicity, whereas another of a Caucasian population implicated GSTT1*0/*0. We undertook a prospective case,control study to investigate whether GSTM*0/*0 and GSTT1*0/*0 were risk factors for ATD-induced hepatotoxicity. Methods:, Pulmonary tuberculosis patients on isoniazid, rifampicin and pyrazinamide who developed hepatotoxicity using defined criteria were prospectively identified. These cases were then matched with at least one control subject on the same drugs but without hepatotoxicity. Genotyping for GSTM1 and GSTT1 was performed by multiplex PCR on genomic DNA. The odds ratios for the frequency of specific GSTM1 and GSTT1 homozygotes in the case and control subjects were calculated to test for association between the genotypes and hepatotoxicity. Results and discussion:, Hundred and fifty-one subjects (51 cases, 100 controls) were enrolled. Odds ratio for GSTM1 null genotype was 1·00 (95% CI 0·51,1·97) and GSTT1 null was 2·02 (95% CI 0·39,10·39), respectively, showing that these genotypes are not associated with hepatotoxicity. Conclusion:,GSTM1 *0/*0 or GSTT1 *0/*0 or both null genotypes, do not appear to be associated with ATD-induced hepatotoxicity in our Indian population. [source] Antitubercular potential of plants: A brief account of some important moleculesMEDICINAL RESEARCH REVIEWS, Issue 4 2010Arvind S. Negi Abstract Mycobacterium tuberculosis is the most lethal pathogen causing tuberculosis in human. After the discovery of antitubercular drugs pyrazinamide, rifampicin, isoniazid, streptomycin, and ethambutol (PRISE), the disease was controlled for a limited period. However, over the course of their usage, the pathogen acquired resistance and evolved into multi-drug resistant, single-drug resistant, and extensive drug resistant forms. A good number of plant secondary metabolites are reported to have antitubercular activity comparable to the existing antitubercular drugs or sometimes even better in potency. A well-defined strategy is required to exploit these phytomolecules as antitubercular drugs. This review gives concise up-to-date information regarding the chemistry and pharmacology of plant-based leads and some insight into their structure,activity relationship. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 4, 603,645, 2010 [source] Molecular epidemiology of tuberculosis in the Tula area, Central Russia, before the introduction of the Directly Observed Therapy StrategyCLINICAL MICROBIOLOGY AND INFECTION, Issue 9 2010S. Dubiley Clin Microbiol Infect 2010; 16: 1421,1426 Abstract Tuberculosis remains a major public health concern in Russia and worldwide. Given the great geographical, ethnic, and socio-economic heterogeneities between Russian regions, epidemiological data cannot be generalized from a regional to a country-wide level. We present data on the epidemiology of tuberculosis in Central Russia. We report a high level of resistance to major antitubercular drugs in both new and previously treated patients in the region. The level of drug resistance in new cases was almost twice as high as the estimated average national level. The Mycobacterium tuberculosis strains that circulated in the region were predominantly represented by LAM-RUS and Beijing genotypes. These two lineages were strongly associated with drug resistance and clustering. Using molecular epidemiology techniques, we showed a high interpenetration by M. tuberculosis strains between the prison and civilian populations. A limited number of identical strains were responsible for the majority of drug-resistant tuberculosis cases in both settings. [source] | |||||||||||||