Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.     

Changes in the pharmacokinetics of plasma total and free prednisolone during daily and intermittent regimens

To determine the pharmacokinetic changes of prednisolone associated with differing therapy regimens, we studied 15 patients with various diseases who were treated with daily doses of prednisolone and were then placed on an intermittent regimen, [administration for 4 consecutive days (on-day period), followed by 3 days cessation (off-day period)]. The mean duration of the study and the mean total dosage were 1.6 months and 2.4 g in the daily period, respectively, and 4.7 months and 3.5 g in the intermittent period, respectively. Blood was drawn for 6 h after iv administration of 20 mg prednisolone (average, 0.36 mg/kg). Plasma total and free prednisolone concentrations were measured by RIA. On-day and off-day tests were performed during the same week. The mean MCR of both total and free prednisolone decreased significantly in the daily and on-day periods compared with the pretreatment values. The decreased MCR during the on-day period was restored to the pretreatment level during the off-day period. A similar trend was observed in the changes in half-life, prolongation in the daily and on-day periods compared with the pretreatment value, and restoration to the pretreatment level during the off-day period. These alterations were not associated with the total duration or the total dosage of prednisolone administered. The results indicate that the pharmacokinetic parameters of prednisolone may periodically change during the intermittent regimen, and that off-day and on-day parameters are similar to those before therapy and during the daily period, respectively.     

On the pharmacokinetics of rifampicin during treatment with intermittent administration. II. Influence of age and sex and of the patients.

Pharmacokinetic investigations in 75 patients receiving their first treatment for infectious lung tuberculosis gave the following results: RMP and its products of biotransformation are excreted via the urine in smaller amounts in patients above 55 years than in younger patients. In the older age group the induction phase - as measured by the urinary excretion of RMP - is also more marked than in younger patients. Both the serum RMP-concentration and the urinary excretion of RMP are significantly higher in women than in men. The sex specific differences in pharacokinetics seem to be of clinical importance. Because of the higher serum RMP-concentration it is possible to reduce the RMP-dosage 10% in female patients, even with intermittent administration, and to diminish the risk of dose-dependent side effects.     

Salivary levels of isoniazid and rifampicin in tuberculous patients

Concentrations of isoniazid and rifampicin were determined in time-matched samples of saliva and serum from 30 tuberculous patients (18 with pulmonary tuberculosis and 12 with intestinal tuberculosis), comprising 18 slow and 12 rapid acetylators of isoniazid, following administration of isoniazid 300 mg and rifampicin 12 mg/kg. The diffusion of isoniazid into saliva was quite rapid and the salivary concentrations were similar to those in serum, suggesting that saliva could be used in place of serum for all pharmacokinetic studies with isoniazid. The salivary concentrations of rifampicin were much lower than those in serum, the mean peak concentrations being 0.9 and 8.5 microgram/ml, respectively. Further, there was evidence of a significant delay in the diffusion of rifampicin from serum to saliva.     

Measurement of rifampicin concentrations in tuberculous pleural effusion before and after combination treatment with oral and local rifampicin

<正>Objective To investigate the changes of rifampin concentrations in pleural effusion before and after combination treatment with oral and pleural administration of rifampicin by electro-phonophoresis (EP). Methods A self-control study was performed in 32 cases of tuberculous pleurisy treated in the Second Department of Respiratory Medicine of Affiliated Hospital of Zunyi Medical     

The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide.

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.     

Relapses in paucibacillary patients after treatment with three short-term regimens containing rifampin

Three multidrug regimens all containing rifampin and dapsone have been tried for the treatment of 278 cases of paucibacillary leprosy. Regimen I was the one recommended by the WHO Study Group. Regimen II was the same as Regimen I with depsone alone continued for a further 6 months. Regimen III was the same as Regimen II but rifampin was given daily for the first 7 days. The patients were comparable with regard to disease classification, lepromin status, bacteriological status, and number of lesions. As reported earlier, the disease inactivity rates by 1 year of treatment were much greater with Regimens II and III than with Regimen I (94% and 97% vs 76%). Early reaction was seen in 6% of those in Regimen III and in none in Regimens I and II. Late reaction was observed in 9% of those in Regimen I and none in Regimens II and III. During 3 1/2 years of follow up, 13% of the cases in Regimen I, 1% in Regimen II, and 2% in Regimen III relapsed. Since the patients in the three regimens were otherwise comparable, it is concluded that the high inactivity rate, low relapse rate (1%-2%), and no early or late reaction as observed in Regimen II patients were because of adequate treatment.     

不同方案治疗单耐异烟肼或利福平肺结核患者的预后分析

目的 对单耐异烟肼(H)及单耐利福平(R)肺结核患者采用不同方案治疗后发生耐多药结核病(MDR-TB)的情况进行分析,以指导临床合理用药。方法 搜集2010年1月至2014年12月河南省濮阳市耐药监测项目发现的单耐H肺结核患者332例、单耐R肺结核患者114例为研究对象。随机(抽签法,单耐H、单耐R的患者分别随机分组)分为标准化疗方案组(采用初、复治标准化疗方案,简称“标化组”,共计222例)和含左氧氟沙星化疗方案组(依据药物敏感性试验结果采用含左氧氟沙星化疗方案,简称“左氧组”,共计224例)。观察两组患者治疗后发生MDR-TB的情况。采用SPSS 20.0统计软件包进行统计分析,组间比较采用χ ²检验,P<0.05为差异有统计学意义。 结果 标化组患者中MDR-TB发生率(11.7%,26/222)明显高于左氧组患者(4.9%,11/224)(χ ²=6.779,P=0.009)。在初治患者中,标化组患者中MDR-TB发生率(4.4%,8/180)稍高于左氧组患者(2.2%,4/185),但两者比较差异无统计学意义(χ ²=1.495,P=0.222);在复治患者中,标化组患者中MDR-TB发生率(42.9%,18/42)高于左氧组患者(17.9%,7/39)(χ ²=5.880,P=0.015)。单耐R的患者中,标化组患者中MDR-TB发生率(37.5%,21/56)明显高于左氧组患者(17.2%,10/58)(χ ²=5.906,P=0.015)。复治单耐R患者中,标化组患者中MDR-TB发生率(56.5%,13/23)明显高于左氧组患者(27.3%,6/22)(χ ²=3.493,P=0.047)。 结论 单耐H和单耐R的初治患者,采用标准化疗方案不增加MDR-TB的发生率,单耐R较单耐H的肺结核患者容易发展为MDR-TB,尤其单耐R的复治肺结核患者更易发展为MDR-TB。     

A comparative study of daily followed by twice- or once-weekly regimens of ethambutol and rifampicin in the retreatment of patients with pulmonary tuberculosis: Second report

Three hundred and twenty-nine patients with isoniazid-resistant cultures, 66% with radiographically far advanced disease and 86 % with cavities, have been treated with rifampicin and ethambutol and followed-up for 2 years after the end of treatment.The drugs were given daily for 12 weeks (600 mg rifampicin and 25 mg/kg ethambutol), thereafter once- or twice-weekly (600 or 1200 mg rifampicin and 50 mg/kg ethambutol) for a total of 12, 18 or 24 months (in the 600 mg group for 12 months only).With both 600 and 1200 mg rifampicin dosage the bacteriological results at the end of a year were similar (5 % bacteriologically unfavourable in each group).Prolonging treatment to 18 or 24 months with the 1200 mg rifampicin dose had no effect on the bacteriological results.During the 2 years follow-up period after treatment stopped 6 patients had a bacteriological relapse. Of the 74 with a favourable status after 1 year in the 600 mg rifampicin group 5 (6.7 %) relapsed, but only 1 (0.6 %) of 168 in the 1200 mg groups treated for 12,18 or 24 months (the duration of treatment did not appear to be related to relapse).Side-effects were reported more frequently with once-weekly dosage. They were more frequent with 1200 mg rifampicin than with 600 mg and with the former dose more frequent in the groups treated for longer than 1 year. With 12 months treatment with 600 mg rifampicin only 1 % of patients had to have the regimen changed; with 1200 mg it was 9 % and with this dose for 24 months 20 %.With the lower dosage of rifampicin there were fewer failures due to toxicity but more failures due to relapse. Of 82 patients in the 600 mg regimen there were 12 unfavourable results (4 bacteriological failures, 5 relapses and 1 change of treatment for toxicity). Of 78 patients in the 1200 mg regimen there were 13 % unfavourable results (3 bacteriological failures, no relapses and 7 changes of treatment for toxicity).     

Interaction of rifampicin treatment with pharmacokinetics and metabolism of ethinyloestradiol in man

[6,7-3H]Ethinyloestradiol (50 microng) was administered intravenously to volunteers and the free extractable ethinyloestradiol in the plasma was measured. The compound showed a biphasic plasma decline. The half-life of the second phase was 7.5+/-1.7 (SD) hours. Administration of rifampicin (600 mg for 6 days) shifted the half-life of ethinyloestradiol to 3.3+/-0.9 h while the apparent volume of distribution for the second phase of elimination was not changed. When [2,4,6,7-3H]ethinyloestradiol (100 microng) was administered orally, some of the tritium was released by oxidative metabolism from the steroid and transformed to tritiated water (HTO) which equilibrated with whole body water. This portion, normally 7.17+/-1.66% of the tritium dose, was increased by previous administration of rifampicin to 10.62+/-2.27%. The initial rate of oxication of [2,4,6,7-3H]ethinyloestradiol was increased more than twofold by rifampicin treatment. The results are consistent with previous findings that rifampicin induces the oestrogen-2-hydroxylase in the endoplasmic reticulum of human liver, and explain the reduced effectiveness of ethinyloestradiol in oral contraceptives, if the patients are treated with rifampicin.