利福平胸腔注入治疗结核性胸膜炎的疗效分析

目的观察胸腔内注入利福平、异烟肼和地塞米松治疗结核性胸腔积液的疗效。方法将安阳市结核病防治所收治的初治中等量结核性胸腔积液患者98例，随机分为观察组48例和对照组50例，2组除均按照同样的抗结核方案治疗外。观察组抽胸腔积液后注入利福平、异烟肼和地塞米松，对照组抽胸腔积液以后只注入异烟肼和地塞米松，比较2组的疗效。结果治疗胸膜炎疗效观察组好于对照组（x^2=25．52，v=2，P〈0．01）。主要表现在观察组胸腔穿刺次数较对照组减少，胸腔积液完全吸收时间较对照组显著变短，胸膜增厚、粘连与对照组比较其差异有统计学意义（x^2=12．02，P〈0．01），临床症状与对照组比较其差异有统计学意义（x^2=6．94，P〈0．01）。结论胸腔内注入利福平、异烟肼和地塞米松治疗结核性胸腔积液优于常规胸腔内只注入异烟肼和地塞米松的疗效。     

In vitro evaluation of food effect on the bioavailability of rifampicin from antituberculosis fixed dose combination formulations

Rifampicin is one of the major first line anti-tuberculosis drugs used in the therapy of tuberculosis. In literature, there are conflicting reports regarding effect of food on the bioavailability of rifampicin. In vitro, effect of food on the bioavailability can be studied by simulating in vivo conditions in dissolution fluid hence, to understand the variable effect of food on rifampicin release, dissolution studies were done by simulating in vivo conditions after meal intake. In this study, we assessed the effect of hydrodynamic stress in presence of food and meal composition on two rifampicin containing fixed dose combination formulations by carrying out dissolution at different agitation rates (simulation of fasted and fed state) as well as in the presence of different percentage of oil (fatty food). Agitation intensity as well as presence of oil did not had any influence on rifampicin release from formulation A. This formulation had shown excellent release characteristics at all the conditions studied. Whereas, formulation B showed agitation rate dependent release and also release was affected in presence of oil. Hence, it is concluded that food may not have any effect on the release of rifampicin from the formulation and subsequently on its bioavailability if the formulation has excellent release profile (>85% release in 10 min). Further, effect of food on the rifampicin release was a function of dosage form characteristics such as disintegration time and dissolution rate, which will subsequently affect the release behavior of a formulation in presence of food.     

Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine

Objective Rifampicin greatly reduces the plasma concentrations of many drugs. Our aim was to characterise the inducibility of cytochrome P450 (CYP) 1A2 by rifampicin, using tizanidine and caffeine as probe drugs for presystemic and systemic CYP1A2-mediated metabolism.Methods In a randomised, 2-phase crossover study, ten healthy volunteers were given a 5-day pretreatment with 600 mg rifampicin or placebo once daily. On day 6, a single 4-mg dose of tizanidine was administered orally. Plasma and urine concentrations of parent tizanidine and several of its metabolites (M-3, M-4, M-5, M-9, M-10) and pharmacodynamic variables were measured up to 24 h. A caffeine test was performed in both phases.Results Rifampicin moderately reduced the peak plasma concentration (by 51%; P=0.002) and area under the plasma concentration-time curve [AUC(0–∞)] (by 54%; P=0.009) of parent tizanidine, and had no effect on its half-life. The tizanidine/M-3 and tizanidine/M-4 AUC(0–∞) ratios were slightly (by 30%; P=0.014; and by 38%; P=0.007) decreased by rifampicin. Also, the excretion of metabolites M-3, M-4 and M-5 into urine was reduced (P<0.005), but that of M-10 was increased (P=0.008) by rifampicin. Rifampicin reduced the tizanidine/M-10 ratio (by 55%; P=0.047) but had no significant effect on the other tizanidine/metabolite ratios in urine. The caffeine/paraxanthine ratio was reduced by 23% (P=0.081) by rifampicin. The effect of rifampicin on the caffeine/paraxanthine ratio correlated significantly with the effect of rifampicin on, for example, the AUC(0–∞) of tizanidine and the tizanidine/M-3 AUC(0–∞) ratio. The pharmacodynamic effects of tizanidine were reduced by rifampicin.Conclusions Rifampicin moderately decreases the plasma concentrations of tizanidine. The strong inducing effects of rifampicin on other CYP enzymes, e.g. CYP3A4, may have contributed to the findings, and the inducibility of CYP1A2-mediated presystemic (tizanidine) and systemic (tizanidine, caffeine) metabolism by rifampicin is weak at the most. Compared to CYP3A4 substrate drugs, substrates of CYP1A2 are much less susceptible to drug interactions caused by enzyme inducers of the rifampicin type.     

A case of severe repeated immunological reactions to intermittent rifampicin treatment

Summary A case is reported in which a 36-year-old patient twice suffered a rapidly-developing severe reaction to intermittent rifampicin therapy. The symptoms were upper abdominal and back pain, nausea and shivering. Acute renal failure, thrombocytopenia, jaundice and haemolytic anaemia also developed. Aetiologically this was due to an immunopathological effect. This case was unusual in that all the previously observed reactions to rifampicin of an immunological aetiology occurred together, resulting in a marked leucocytosis with the presence of immature cells. It appears that the immediate administration of high-dose corticosteroids can favourably influence this condition. We consider that despite its greater risks daily treatment with rifampicin is to be preferred to discontinuous therapy because of its better tuberculostatic effect.     

Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance

Summary Eleven patients with hepatic cirrhosis or cholestasis were treated with rifampicin for 7 to 132 days. Ten patients received hexobarbital (7.32 mg/kg) and five received tolbutamide (20 mg/kg) by i.v. infusion prior to and after rifampicin treatment; plasma concentrations of the two test compounds were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 624 to 262 min and that of tolbutamide from 292 to 160 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased more than two-fold and that of tolbutamide almost two-fold. The results suggest that rifampicin is able to stimulate hepatic drug metabolism in patients with liver disease. It was apparent in general that the induction did not lead to improvement of hepatocellular function during disease as judged by laboratory findings.     

Pharmacokinetics of oral and intravenous rifampicin during chronic administration

Summary We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic first-pass effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.Abbreviations AUC area under the serum concentration-time curve - Cl clearance - RMP rifampicin - t 1/2 half-life - Vd_area volume of distribution Dedicated to Professor Dr. Hans J. Dengler on the occasion of his 60th birthday     

Validation of a RP-LC method for the simultaneous determination of isoniazid,pyrazinamide and rifampicin in a pharmaceutical formulation

A simple and accurate liquid chromatographic method was developed and validated for estimation of isoniazid (ISN), pyrazinamide (PYR) and rifampicin (RIF) in combined dosage forms. Drugs were chromatographed on a reverse phase C18 column using a mobile phase gradient and monitored at the corresponding maximum of each compounds. Peaks were identified with retention time as compared with standards and confirmed with characteristic spectra using diode-array detector. Solution concentrations were measured on a weight basis to avoid the use of an internal standard. The method does not require any specific sample preparation except the use of a guard column. The method is linear (r²>0.999), precise (RSD%: 0.50% for ISN, 0.12% for PYR and 0.98% for RIF), accurate (overall average recovery yields: 98.55% for ISN, 98.51 for PYR and 98.56% for RIF) and selective. Due to its simplicity and accuracy the method is suitable for routine quality control analysis of antitubercolosis combination dosage form.     

基于伏立康唑血药浓度监测的药物相互作用研究

目的 临床药师通过治疗药物监测(TDM)手段，研究利福平和伏立康唑之间的药物相互作用。方法 基于利福平和伏立康唑联用，及停用利福平后使用伏立康唑这两类患者的伏立康唑血药浓度监测情况，揭示利福平和伏立康唑间的药物相互作用强度与持续时间。结果 18例利福平和伏立康唑联用患者，94.44%患者的伏立康唑血药浓度低于有效治疗浓度范围下限(1.0mg/L)，其中72.22%患者低于定量下限0.16mg/L；19例停用利福平后再使用伏立康唑的标本中，停药6d内伏立康唑血药浓度小于1.0mg/L共12例，占总例数的63.16%，占停药6d内例数的91.67%；停药7d及以上伏立康唑血药浓度大于1mg/L的5例，占总例数的26.32%，占停药7d及以上例数的83.33%。结论 利福平会严重降低伏立康唑血药浓度，在停用利福平第7d起伏立康唑血药浓度很可能才上升有效浓度范围，因此临床上应避免伏立康唑与利福平联用。临床药师借助TDM成功干预了有临床意义的药物相互作用，TDM是临床药师参与药物治疗的有效技术手段。     

The protective effect of lycopene against oxidative kidney damage associated with combined use of isoniazid and rifampicin in rats

It is known that the combined use of antibiotics, such as isoniazid and rifampicin, in the treatment of tuberculosis causes oxidative kidney damage. The aim of this study was to biochemically and histopathologically investigate the effect of lycopene on oxidative kidney damage due to the administration of isoniazid and rifampicin in albino Wistar male rats. Lycopene at a dose of 5 mg/kg was orally administered to lycopene+isoniazid+rifampicin (LIR) rats, and normal sunflower oil (0.5 mL) was orally administered to isoniazid+rifampicin (IR) and healthy control (HG) rats as vehicle by gavage. One hour after the administration of lycopene and vehicle, 50 mg/kg isoniazid and rifampicin were given orally to the LIR and IR groups. This procedure was performed once a day for 28 days. Rats were sacrificed by a high dose of anesthesia at the end of this period, and oxidant-antioxidant parameters were measured in the removed kidney tissues. Creatinine and blood urea nitrogen (BUN) levels were measured in blood samples, and kidney tissues were also evaluated histopathologically. The combined administration of isoniazid and rifampicin changed the oxidant-antioxidant balance in favor of oxidants, and it increased blood urea nitrogen and creatinine levels, which are indicators of kidney function. Co-administration of isoniazid and rifampicin also caused oxidative kidney damage. Lycopene biochemically and histopathologically decreased oxidative kidney damage induced by isoniazid and rifampicin administration. These results suggested that lycopene may be beneficial in the treatment of nephrotoxicity due to isoniazid and rifampicin administration.