The Part One Evaluation Of Drug Regimens Containing Clofazimine For Tuberculosis In Chronic Relapsing Mouse Model The Part Two The Relationship Between N-acetyltransferase2Genotypes And The Concentration Of Isoniazid In Human Plasma The Part Three Occurre

Objective To establish the treatment and relapse model in chronic mousetuberculosis infection and evaluate the sterilizing activity and the relapse of thecombination of clofazimine with rifampicin and (or) pyrazimamide. MethodThrough simulate the way, mode and treatment of human infected mycobacteriumtuberculosis, to establish the treatment and relapse model in chronic mousetuberculosis. The treatment programs contain the combination of two or three drugsincluding cofazimine and the standard regimen. They are5CRZ,5CZ,5RH,5RZ andthe2HRZ/3HR. The lung and spleen CFU counts and the proportion of relapse wereused to compare the sterilizing activity and relapse with each combination. ResultsCompared with the the standard regimen2HRZ/3HR, the5CRZ group showed bettertreatment effect: treatment with5CRZ for2weeks, the lung CFU was lower than2HRZ/3HR, and the difference showed statistically significant（2HRZ/3HR vs.5CRZ，P＝0.000）. For1month, the lung mean CFU count reduced by over3.73log10and the culture of the spleen tissue was negative, and for2month, both the lung andspleen all achieve aseptic. Followed by the5CRZ, the effect of bactericidal activity ofthe5CZ was similar with the2HRZ/3HR. The relapse results showed that thetreatment prevented relapse in all mice receiving5CRZ and5CZ.The highest relapserate occurred in5RH group(84.62%,11/13）,followed by the5RZ(40%,6/15）.4monthof treatment, the relapse rate of5RZ and5RH has decreased,3relapse in theformer(3/15,20%，P＝0.055) and7in the latter(7/15,46,67%，P＝0.427), but thedifference was not statistically significant. At5month, relapse only occurred in5RZgroup. Conclusion The results reveal the regimens including CLF showed thebest effect no matter what the bactericidal or the sterilizing activity. The first-lineregimen including CLF showed better sterilizing activity and ability to prevent relapse compared with the standared regimen. It proved that the CLF regimens with thepotential to shorten the duration of treatment have important significance to reduceand prevent the drug-resistant TB. Objective To study the correlation between N-acetyltransferase2(NAT2) genotypesand the concentration of isoniazid (INH) in the plasma, and provide a theoretical basisfor the individualized medication of tuberculosis (TB) patients by NAT2genotyping.Methods The NAT2genotypes of121TB patients were analyzed by polymerase chainreaction-restriction fragment length polymorphism (PCR-RFLP); INH concentrationin the plasma was detected by the liquid chromatography-tandem mass spectrometry(LC/MS-MS) at2hours after treatment. The differences between the groups weretested by using single factor analysis of variance, and then the differences of everytwo groups were tested by using Tamhaneˊs T2, P＜0.05was considered statisticallysignificant. Results Of121TB patients,55were NAT2rapid acetylation (RA) type,and their average concentration of INH in plasma was（1.86±1.28）μg/ml;17wereslow acetylation(SA) type (homozygous mutant),and their average concentration was（5.86±2.10）μg/ml;49were intermediate acetylation (IA) type (heterozygous mutant),and the concentration was（3.49±2.60）μg/ml.INH concentration of hospitalized TBpatients in plasma was（3.08±2.42）μg/ml.INH concentrations among the threegroups have statistically significant differences.(RA with IA,P＝0.001，with SA，P＝0.000; IA with SA，P＝0.002，P＜0.05). Conclusion There were significantdifferences among the TB patients with different NAT2genotypes. NAT2genotypinghas important guiding significance for the INH treatment in the TB patients. Objective To analyze the prevalence of low serum drug concentrations in tuberculosispatients and investigate the possible determinants of the low serum drugconcentrations for isoniazid, rifampicin and pyrazinamide. Method The2h serumconcentrations after drugs ingestion of the196tuberculosis patients were detected byusing Liquid chromatography-tandem mass spectrometry (LC-MS/MS). TheN-acetyltransferase2(NAT2) genotypes of55isoniazid patients were analyzed bypolymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The association between the factors and the serum concentrations was analyzed byunivariate linear and multivariate linear regression. The serum concentrationdifference between the dose/kg of weight≥50kg and the dose/kg of weight＜50kg,and the difference among three NAT2genotypes were tested byindependent-samples t test analysis. Results In168isoniazid patients,92rifampicinpatients, and125pyrazinamide patients, the prevalence of the low serumconcentrations were33.93%,64.13%and46.4%, respectively, and the meanconcentrations were4.22±2.33μg/ml，6.22±4.69μg/ml and22.93±11.08μg/ml,respectively.6patients were found have low serum concentrations of all three agentssimultaneously. Univariate and multivariate linear regression analysis showed that thedose/kg of body weight and the N-acetyltransferase2genotype were significantlyassociated with the serum concentration of isoniazid, while the serum concentration ofrifampicin was only related with the dose/kg of weight. In univariate linear regression,the dose/kg of weight and the sex both were associated with the concentration ofpyrazinamide, but the sex factor was not established in the multivariate linearregression. The mean values of2h isoniazid and pyrazinamide concentrations were significantly higher in patients with a body weight of＜50kg than in patients with abody weight of≥50kg by independent-samples t test，and the serum concentrations ofthree kinds NAT2genotypes also showed statistically significant differences(rapidacetylation RA; intermediate acetylation IA; slow acetylation SA; P＜0.05).Conclusion The phenomenon of low serum concentrations was found in TB patientswith isoniazid, rifampicin and pyrazinamide. In our study, we proved that the dose/kgof weight were directly associated with the serum concentrations. So it is necessary toadjust the drug doses to optimize the therapy by therapeutic drug monitoring (TDM).