In-vitro activity of rifabutin against rifampicin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations

The relationship between resistance to rifampicin and rifabutin and genetic alterations in the rpoB gene of 41 rifampicin-resistant isolates of Mycobacterium tuberculosis was evaluated. Although 35 isolates with rifampicin MICs > or = 32 mg/L were also rifabutin-resistant, six isolates with rifampicin MICs of 2-16 mg/L were susceptible to rifabutin (MIC < or = 0.5 mg/L). Mutations Asp516Val, Asp516Tyr, Leu533Pro and the double mutation Met515Ile and Leu533Pro influenced susceptibility to rifampicin, but not to rifabutin. All mutations at codons 531 and 526, except one isolate with a His526Cys mutation, correlated with resistance to both compounds.     

A MODEL BASED ASSESSMENT OF REDISTRIBUTION DEPENDENT ELIMINATION AND BIOAVAILABILITY OF RIFABUTIN

The autoinduction characteristic of rifabutin (RIF) following multiple oral dosing was investigated via pharmacokinetic modeling. A two-compartment model with first-order absorption was fit to plasma RIF data obtained from a study conducted in healthy normal volunteers following both a single and multiple oral doses. Parameter estimates showed an elimination rate constant (k₁₀) of about 0·12--0·14 h⁻¹ which was independent of the single or multiple-dosing condition. The lower-than-expected drug accumulation following multiple dosing seems to suggest that prolonged dosing perturbs the linear kinetic system. However, this analysis has shown no significant changes (p>0·05) in the rate constants describing RIF absorption, tissue distribution/redistribution, and elimination. The mean rate of drug redistribution from the tissue compartment (k₂₁; 0·04--0·06 h⁻¹) was twofold to threefold lower than k₁₀, and, with a large steady-state distribution volume (V_ss/F after a single dose, 1630 L), RIF elimination appears to be dependent on drug redistribution. This hypothesis was further supported by a significant correlation (p<0·01) BETWEEN RIF TISSUE REDISTRIBUTION (k₂₁) and terminal disposition phase rate (λ_z) constants. The redistribution dependent elimination of RIF also helps explain the stability of the terminal half-life under both single and multiple-dosing paradigms. Urinary excretion of RIF and its 25-O-deacetyl metabolite totalled less than 7% of the oral dose following single dosing, and decreased to about 4% after multiple dosing. For individual patients, the decrease in urinary recovery of the 25-O-deacetyl metabolite was directly proportional to the decrease in urinary RIF recovery. In addition, both estimates of the model intercepts (A and B) were lower following multiple dosing. Further analyses revealed a linear relationship between A and B intercepts, and also between the urinary RIF recovery and the B intercept. These relationships, in conjunction with the lack of significant increase in the rate of elimination, indicate that induction of presystemic extrahepatic metabolism and/or decrease in the extent of oral absorption may be the primary causes for the lower-than-expected systemic RIF plasma levels after multiple oral dosing.     

利福布汀的代谢研究

 目的通过亚细胞、器官和整体动物3种水平的代谢实验,研究了利福布汀(rifabutin,RBT)自身代谢以及RBT被连续给药后对自身代谢及肝细胞色素P450酶系的影响,为临床的合理用药提供有益的指导。方法36只Wistar大鼠随机分为6组,每组6只。3种水平的实验研究各有空白对照组和RBT给药组(口服灌胃300 mg·kg^-1·d^-1×7 d)。亚细胞代谢研究利用制备的肝微粒体,体外温孵CYP1A2,CYP2D6,CYP2C9,CYP2E1及CYP3A等几种重要亚酶的特异性底物,通过比较其代谢产物的生成速率来评价RBT对这些亚酶的影响;器官代谢研究采用大鼠原位肝脏灌流方法,整体实验动物代谢研究通过颈静脉插管手术,器官与整体代谢都是比较其代谢参数的差异。结果连续口服7 d RBT之后,酶蛋白水平和总体CYP450活力分别为空白对照组的84.60%和410.0%。CYP3A及CYP2D6亚酶活性分别为空白对照组的184.0%及155.7%。器官和整体动物水平都表明RBT连续给药组显著加快了自身药物的代谢,t_1/2分别为空白对照组的58.96%和71.00%,并且器官水平显示AUC也仅为空白对照组的49.06%。结论RBT代谢存在自身诱导,连续服用RBT之后,不仅自身的代谢将会被改变,那些经CYP3A及CYPD2D6代谢的合用药物的代谢也将被改变。     

Drug-Induced Uveitis

Uveitis has been reported in association with a variety of topical, intraocular, periocular, and systemic medications. To establish causality of adverse events by drugs, in 1981, Naranjo and associates proposed seven criteria, which are related to the frequency and documentation of the event; circumstances of occurrence, recovery, and recurrence; and coexistence of other factors or medications. Rarely does a drug meet all seven criteria. The authors review reports of drug-associated uveitis, applying the seven criteria and examining possible mechanisms. Only systemically administered biphosphonates and, perhaps, topical metipranolol meet all seven criteria. Systemic sulfonamides, rifabutin, and topical glucocorticoids fulfill at least five criteria. (Surv Ophthalmol 42:557-570, 1998.     

Evidence-based recommendations for successful Helicobacter pylori treatment

An effective Helicobacter pylori therapy reliably provides high cure rates in infections with susceptible strains. It is possible to predict the efficacy of any regimen if one knows the prevalence of antibiotic resistance for a regimen or for a specific patient. We show how to predict the outcome for current regimens and discuss the factors that undermine different regimens (i.e., their Achilles heel). In general, in Western countries, clarithromycin-containing triple and sequential therapy should be considered obsolete as empiric therapies. Preferred regimens are 14-day concomitant or bismuth-containing quadruple therapy. We provide details of how to identify a regimen for a patient or region that will reliably cure 90% or more as well as those that will reliably fail.     

Comparative study on altered hepatic metabolism of CYP3A substrates in rats with glycerol-induced acute renal failure

To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol-induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis-Menten parameters, K(m) and V(max) , were examined in the incubation study, the K(m) values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The V(max) values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased K(m) values accompanied the decreased V(max) values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the K(m) value was observed in ARF rats, but it did not accompany the decrease in the V(max) value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti-CYP3A1 and anti-CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats.     

布鲁菌利福霉素耐药与rpoB基因突变的相关性研究

目的采用现代分子生物学技术,应用MSW理论观测布鲁菌耐药问题,探讨布鲁菌在利福霉素选择压力下出现的突变特征。方法富集10^10cfu／mL布鲁菌,采用琼脂稀释法测定利福平和利福布丁对布鲁菌的最低抑菌浓度及防突变浓度。PCR扩增不同药物浓度筛选出的耐药突变株的rpoB基因并测序。结果利福平和利福布丁对布鲁菌的防突变浓度分别为460mg／L和512mg／L,细菌耐药选择指数为115和728。筛选出的耐药突变株中均检测出rpoB基因突变。结论调整药物剂量可防止对利福霉素耐药的布鲁菌突变株的富集。布鲁菌的利福霉素耐药株中H536Y突变体最为稳定。     

利福布丁对耐多药结核病的疗效观察

目的:探讨利福布丁治疗耐多药结核病的临床疗效.方法:选取来我院门诊及住院治疗的耐多药肺结核病患者作为观察对象,并随机分为两组,治疗方案分为3个月强化治疗,6个月巩固治疗,9个月继续治疗,对照组强化期给予利福平+帕司烟肼+左氧氟沙星+乙胺丁醇+丙硫异烟胺+丁胺卡那霉素,巩固期减去丁胺卡那霉素,继续治疗期减去乙胺丁醇,观察组使用利福布丁替换利福平,比较两组患者治疗效果.结果:两组患者治疗后症状、疗效较治疗前均有所好转,其中观察组患者改善更为明显,较对照组有统计学差异.经过18个月治疗后,观察组痰菌阴转率及病灶吸收率显著高于对照组.治疗后,观察组不良反应发生情况明显少于对照组患者.结论:在联合用药治疗耐多药结核病患者时,联合使用利福布丁方案疗效优于联用利福平组,值得进一步深究.