Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly devel...Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly developed high-performance liquid chromatography method. All related substances were characterized rapidly but some impurities were found to be intermediates. Proposed structures were further confirmed by characterization using NMR, FT-IR, and HRMS techniques. Based on the spectroscopic data;unknown related sub-stances were characterized as 1-(Methylsulfonyl)-4-[4-(trifluoromethoxy) phenoxy]piperidine;4-{4-[4-(Tri-fluoromethoxy)-phenoxy]piperidin-1-yl}phenol and 4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenyl methane sulfonate;4-Bromophenyl methane sulfonate, Ethyl 3,6-dihydro-1(2H)-pyridine carboxylate, (2S)-3-(4-Bromophenoxy)-2-hydroxy-2-methylpropyl methane sulfonate, (2S)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diyldimethane-sulfonate, (2S)-2-Methyl-3-(4-{4-[4-(trifluoromethoxy) phenoxy]-piperidin-1-yl} phenoxy)-propane-1,2-diyldimethane sulfonate, (S)-3-(4-Bromophenoxy)-2-methyl-propane-1,2-diol and corresponding Enantiomer, (2R)-2-[(4-Bromo-phenoxy)methyl]-2-methyloxirane and (2R)-2-[(4-bromophenoxy)methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole. A possible mechanism for the formation of these related substances is also proposed.展开更多
Rifampicin-resistant tuberculosis (RR-TB) is a global public health problem caused by mycobacterium tuberculosis resistant to Rifampicin. Drug-induced peripheral neuropathy and neurotoxicity are well-known adverse eff...Rifampicin-resistant tuberculosis (RR-TB) is a global public health problem caused by mycobacterium tuberculosis resistant to Rifampicin. Drug-induced peripheral neuropathy and neurotoxicity are well-known adverse effects of treatment regimens that cause significant morbidity. Pyridoxine is often added to treatment regimens for the prevention and/or treatment of these side effects. The basis and effectiveness of this practice are unclear. We conducted a systematic review to evaluate the effectiveness of pyridoxine in preventing and/or treating neuropathy and neurotoxicity associated with RR-TB treatment. We included studies with patients with RR-TB who experienced neuropathy or neurotoxicity attributed to RR-TB regimens and were given pyridoxine. Our findings showed contradicting evidence on the use of pyridoxine for preventing or treating neurotoxicity due to cycloserine in the treatment of RR-TB. Moreover, pyridoxine did not have a protective effect against neuropathy and/or neurotoxicity caused by other RR-TB regimens that do not contain isoniazid. In conclusion, we found that withdrawing or withholding medications such as linezolid, cycloserine, thioamides, fluoroquinolones, and ethambutol, implicated in causing neuropathy or neurotoxicity was more effective than using pyridoxine to stop the progression of symptoms, and in some instances, led to their reversal over time.展开更多
Background:Multidrug drug resistant Tuberculosis(MDR-TB)and extensively drug resistant Tuberculosis(XDR-TB)have emerged as significant public health threats worldwide.This systematic review and meta-analysis aimed to ...Background:Multidrug drug resistant Tuberculosis(MDR-TB)and extensively drug resistant Tuberculosis(XDR-TB)have emerged as significant public health threats worldwide.This systematic review and meta-analysis aimed to investigate the effects of community-based treatment to traditional hospitalization in improving treatment success rates among MDR-TB and XDR-TB patients in the 27 MDR-TB High burden countries(HBC).Methods:We searched PubMed,Cochrane,Lancet,Web of Science,International Journal of Tuberculosis and Lung Disease,and Centre for Reviews and Dissemination(CRD)for studies on community-based treatment and traditional hospitalization and MDR-TB and XDR-TB from the 27 MDR-TB HBC.Data on treatment success and failure rates were extracted from retrospective and prospective cohort studies,and a case control study.Sensitivity analysis,subgroup analyses,and meta-regression analysis were used to explore bias and potential sources of heterogeneity.Results:The final sample included 16 studies involving 3344 patients from nine countries;Bangladesh,China,Ethiopia,Kenya,India,South Africa,Philippines,Russia,and Uzbekistan.Based on a random-effects model,we observed a higher treatment success rate in community-based treatment(Point estimate=0.68,95%CI:0.59 to 0.76,p<0.01)compared to traditional hospitalization(Point estimate=0.57,95%CI:0.44 to 0.69,p<0.01).A lower treatment failure rate was observed in community-based treatment 7%(Point estimate=0.07,95%CI:0.03 to 0.10;p<0.01)compared to traditional hospitalization(Point estimate=0.188,95%CI:0.10 to 0.28;p<0.01).In the subgroup analysis,studies without HIV co-infected patients,directly observed therapy short course-plus(DOTS-Plus)implemented throughout therapy,treatment duration>18 months,and regimen with drugs>5 reported higher treatment success rate.In the meta-regression model,age of patients,adverse events,treatment duration,and lost to follow up explains some of the heterogeneity of treatment effects between studies.Conclusion:Community-based management improved treatment outcomes.A mix of interventions with DOTSPlus throughout therapy and treatment duration>18 months as well as strategies in place for lost to follow up and adverse events should be considered in MDR-TB and XDR-TB interventions,as they influenced positively,treatment success.展开更多
Background Diagnosis and appropriate treatment of multidrug-resistant tuberculosis （MDR-TB） remain major challenges. We sought to elucidate that persons who share a household with drug resistance tuberculosis patien...Background Diagnosis and appropriate treatment of multidrug-resistant tuberculosis （MDR-TB） remain major challenges. We sought to elucidate that persons who share a household with drug resistance tuberculosis patients are at high risk for primary drug resistance tuberculosis and how to prevent these outbreaks. Methods We used 12-locus mycobactedal interspersed repetitive unit and 7-locus variable-number tandem repeat to identify household transmission of extensively drug resistant and multiple drug resistant Mycobacterium tuberculosis in three families admitted in Shanghai Pulmonary Hospital affiliated with Tongji University. Drug susceptibility tests were done by the modified proportion method in the MGIT 960 system in the same time. Clinical data were also obtained from the subjects＇ medical records. Results All of the six strains were defined as Beijing genotype by the deletion-targeted multiplex PCR （DTM-PCR） identification on the genomic deletion RD105. Strains from family-1 had the same minisatellite interspersed repetitive unit （MIRU） pattern （232225172531） and the same MIRU pattern （3677235）. Strains from family-2 had the same MIRU pattern （2212261553323） and the same MIRU pattern （3685134）. Strains from family-3 did not have the same MIRU pattern and they differed at only one locus （223326173533, 223325173533）, and did not have the same VNTR pattern with two locus differed （3667233, 3677234）. Conclusions Household transmission exists in the three families. A clear chain of tuberculosis transmission within family exists. Tuberculosis susceptibility should be considered when there is more than one tuberculosis patients in a familv. Household tuberculosis transmission could be prevented with adequate treatment of source Patients.展开更多
Objective To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. Methods Biapenem/clavulanate(BP/CL) was evaluated for in vitro activity against Myc...Objective To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. Methods Biapenem/clavulanate(BP/CL) was evaluated for in vitro activity against Mycobacterium tuberculosis(Mtb) multidrug-resistant(MDR) isolates, extensively drug-resistant(XDR) isolates, and the H37 RV strain. BP/CL activity against the H37 Rv strain was assessed in liquid cultures, in macrophages, and in mice. Results BP/CL exhibited activity against MDR and XDR Mtb isolates in liquid cultures. BP/CL treatment significantly reduced the number of colony forming units(CFU) of Mtb within macrophages compared with control untreated infected macrophages. Notably, BP/CL synergized in pairwise combinations with protionamide, aminosalicylate, and capreomycin to achieve a fractional inhibitory concentration for each pairing of 0.375 in vitro. In a mouse tuberculosis infection model, the efficacy of a cocktail of levofloxacin + pyrazinamide + protionamide + aminosalicylate against Mtb increased when the cocktail was combined with BP/CL, achieving efficacy similar to that of the positive control treatment(isoniazid + rifampin + pyrazinamide) after 2 months of treatment. Conclusion BP/CL may provide a new option to clinically treat MDR tuberculosis.展开更多
文摘Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly developed high-performance liquid chromatography method. All related substances were characterized rapidly but some impurities were found to be intermediates. Proposed structures were further confirmed by characterization using NMR, FT-IR, and HRMS techniques. Based on the spectroscopic data;unknown related sub-stances were characterized as 1-(Methylsulfonyl)-4-[4-(trifluoromethoxy) phenoxy]piperidine;4-{4-[4-(Tri-fluoromethoxy)-phenoxy]piperidin-1-yl}phenol and 4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenyl methane sulfonate;4-Bromophenyl methane sulfonate, Ethyl 3,6-dihydro-1(2H)-pyridine carboxylate, (2S)-3-(4-Bromophenoxy)-2-hydroxy-2-methylpropyl methane sulfonate, (2S)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diyldimethane-sulfonate, (2S)-2-Methyl-3-(4-{4-[4-(trifluoromethoxy) phenoxy]-piperidin-1-yl} phenoxy)-propane-1,2-diyldimethane sulfonate, (S)-3-(4-Bromophenoxy)-2-methyl-propane-1,2-diol and corresponding Enantiomer, (2R)-2-[(4-Bromo-phenoxy)methyl]-2-methyloxirane and (2R)-2-[(4-bromophenoxy)methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole. A possible mechanism for the formation of these related substances is also proposed.
文摘Rifampicin-resistant tuberculosis (RR-TB) is a global public health problem caused by mycobacterium tuberculosis resistant to Rifampicin. Drug-induced peripheral neuropathy and neurotoxicity are well-known adverse effects of treatment regimens that cause significant morbidity. Pyridoxine is often added to treatment regimens for the prevention and/or treatment of these side effects. The basis and effectiveness of this practice are unclear. We conducted a systematic review to evaluate the effectiveness of pyridoxine in preventing and/or treating neuropathy and neurotoxicity associated with RR-TB treatment. We included studies with patients with RR-TB who experienced neuropathy or neurotoxicity attributed to RR-TB regimens and were given pyridoxine. Our findings showed contradicting evidence on the use of pyridoxine for preventing or treating neurotoxicity due to cycloserine in the treatment of RR-TB. Moreover, pyridoxine did not have a protective effect against neuropathy and/or neurotoxicity caused by other RR-TB regimens that do not contain isoniazid. In conclusion, we found that withdrawing or withholding medications such as linezolid, cycloserine, thioamides, fluoroquinolones, and ethambutol, implicated in causing neuropathy or neurotoxicity was more effective than using pyridoxine to stop the progression of symptoms, and in some instances, led to their reversal over time.
文摘Background:Multidrug drug resistant Tuberculosis(MDR-TB)and extensively drug resistant Tuberculosis(XDR-TB)have emerged as significant public health threats worldwide.This systematic review and meta-analysis aimed to investigate the effects of community-based treatment to traditional hospitalization in improving treatment success rates among MDR-TB and XDR-TB patients in the 27 MDR-TB High burden countries(HBC).Methods:We searched PubMed,Cochrane,Lancet,Web of Science,International Journal of Tuberculosis and Lung Disease,and Centre for Reviews and Dissemination(CRD)for studies on community-based treatment and traditional hospitalization and MDR-TB and XDR-TB from the 27 MDR-TB HBC.Data on treatment success and failure rates were extracted from retrospective and prospective cohort studies,and a case control study.Sensitivity analysis,subgroup analyses,and meta-regression analysis were used to explore bias and potential sources of heterogeneity.Results:The final sample included 16 studies involving 3344 patients from nine countries;Bangladesh,China,Ethiopia,Kenya,India,South Africa,Philippines,Russia,and Uzbekistan.Based on a random-effects model,we observed a higher treatment success rate in community-based treatment(Point estimate=0.68,95%CI:0.59 to 0.76,p<0.01)compared to traditional hospitalization(Point estimate=0.57,95%CI:0.44 to 0.69,p<0.01).A lower treatment failure rate was observed in community-based treatment 7%(Point estimate=0.07,95%CI:0.03 to 0.10;p<0.01)compared to traditional hospitalization(Point estimate=0.188,95%CI:0.10 to 0.28;p<0.01).In the subgroup analysis,studies without HIV co-infected patients,directly observed therapy short course-plus(DOTS-Plus)implemented throughout therapy,treatment duration>18 months,and regimen with drugs>5 reported higher treatment success rate.In the meta-regression model,age of patients,adverse events,treatment duration,and lost to follow up explains some of the heterogeneity of treatment effects between studies.Conclusion:Community-based management improved treatment outcomes.A mix of interventions with DOTSPlus throughout therapy and treatment duration>18 months as well as strategies in place for lost to follow up and adverse events should be considered in MDR-TB and XDR-TB interventions,as they influenced positively,treatment success.
文摘Background Diagnosis and appropriate treatment of multidrug-resistant tuberculosis （MDR-TB） remain major challenges. We sought to elucidate that persons who share a household with drug resistance tuberculosis patients are at high risk for primary drug resistance tuberculosis and how to prevent these outbreaks. Methods We used 12-locus mycobactedal interspersed repetitive unit and 7-locus variable-number tandem repeat to identify household transmission of extensively drug resistant and multiple drug resistant Mycobacterium tuberculosis in three families admitted in Shanghai Pulmonary Hospital affiliated with Tongji University. Drug susceptibility tests were done by the modified proportion method in the MGIT 960 system in the same time. Clinical data were also obtained from the subjects＇ medical records. Results All of the six strains were defined as Beijing genotype by the deletion-targeted multiplex PCR （DTM-PCR） identification on the genomic deletion RD105. Strains from family-1 had the same minisatellite interspersed repetitive unit （MIRU） pattern （232225172531） and the same MIRU pattern （3677235）. Strains from family-2 had the same MIRU pattern （2212261553323） and the same MIRU pattern （3685134）. Strains from family-3 did not have the same MIRU pattern and they differed at only one locus （223326173533, 223325173533）, and did not have the same VNTR pattern with two locus differed （3667233, 3677234）. Conclusions Household transmission exists in the three families. A clear chain of tuberculosis transmission within family exists. Tuberculosis susceptibility should be considered when there is more than one tuberculosis patients in a familv. Household tuberculosis transmission could be prevented with adequate treatment of source Patients.
基金supported by the Beijing Medical Award Foundation [YJHYXKYJJ-104]
文摘Objective To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. Methods Biapenem/clavulanate(BP/CL) was evaluated for in vitro activity against Mycobacterium tuberculosis(Mtb) multidrug-resistant(MDR) isolates, extensively drug-resistant(XDR) isolates, and the H37 RV strain. BP/CL activity against the H37 Rv strain was assessed in liquid cultures, in macrophages, and in mice. Results BP/CL exhibited activity against MDR and XDR Mtb isolates in liquid cultures. BP/CL treatment significantly reduced the number of colony forming units(CFU) of Mtb within macrophages compared with control untreated infected macrophages. Notably, BP/CL synergized in pairwise combinations with protionamide, aminosalicylate, and capreomycin to achieve a fractional inhibitory concentration for each pairing of 0.375 in vitro. In a mouse tuberculosis infection model, the efficacy of a cocktail of levofloxacin + pyrazinamide + protionamide + aminosalicylate against Mtb increased when the cocktail was combined with BP/CL, achieving efficacy similar to that of the positive control treatment(isoniazid + rifampin + pyrazinamide) after 2 months of treatment. Conclusion BP/CL may provide a new option to clinically treat MDR tuberculosis.
