Isoniazid acetylation rates (phenotypes) of patients being treated for tuberculosis

Isoniazid therapy could be used more rationally if patients'' isoniazid acetylation rates were known. To explore the clinical usefulness of a recently described simple method for acetylator phenotyping, acetylated and free isoniazid were measured semiquantitatively in morning urine specimens from sanatorium in-patients being treated with the drug. The distribution of acetylisoniazid: isoniazid ratios was bimodal. The ratios thus identify rapid and slow acetylators of isoniazid, without disturbing their routine or their therapy. Ratios measured in samples from control subjects who had received a single dose of isoniazid did not discriminate between these phenotypes, and urine from diabetic patients gave false reactions.     

Rate of inactivation of isoniazid in South Indian patients with pulmonary tuberculosis: 1. Microbiological assay of isoniazid in serum following a standard intramuscular dose

Since isoniazid is metabolized in man to several derivatives with little or no specific activity against the tubercle bacillus, its rate of inactivation in the body may have an important bearing on its efficacy as an antituberculosis drug. The inactivation rate, though constant in any one person, is known to vary from individual to individual and from race to race. A series of studies on the rate of inactivation of isoniazid in Indian patients with pulmonary tuberculosis has recently been undertaken at the Tuberculosis Chemotherapy Centre, Madras. The present paper describes the first of these studies, in which the concentration of isoniazid in the serum of patients admitted to a controlled comparison of four domiciliary chemotherapeutic regimens was determined by microbiological assay four-and-a-half hours after administration of a standard dose of isoniazid (3 mg/kg body-weight). Patients with serum levels of 0.58 μg/ml or more were classified as slow inactivators of isoniazid and those with levels below 0.58 μg/ml as rapid inactivators. By this definition, 195 (61%) of the 321 patients studied were found to be slow inactivators and 126 (39%) rapid inactivators. A relationship was shown between sex and the rate of inactivation, there being a significantly higher proportion of rapid inactivators among the females than among the males. The observed estimates of the error of the microbiological assay procedure are discussed and possible ways of reducing the error suggested.     

Rate of inactivation of isoniazid in South Indian patients with pulmonary tuberculosis: 2. Clinical implications in the treatment of pulmonary tuberculosis with isoniazid either alone or in combination with PAS

A series of studies on the rate of inactivation of isoniazid in Indian patients with pulmonary tuberculosis undergoing domiciliary chemotherapy with isoniazid, alone or in combination with p-aminosalicylic acid, has recently been undertaken by the Tuberculosis Chemotherapy Centre, Madras. In the first study, the serum isoniazid levels of the patients were determined four-and-a-half hours after intramuscular administration of a standard dose of 3 mg/kg body-weight of isoniazid and, according to whether the serum level was 0.58 μg/ml or above, or less than 0.58 μg/ml, the patient was classified as a slow or as a rapid inactivator. The present paper describes the second of these studies, in which the response to treatment of the slow and the rapid inactivators was compared. The results of this investigation suggested that there might be an association between response to treatment and rate of inactivation of isoniazid, since the slow inactivators were more often culture-negative during treatment and showed a higher proportion of individuals with bacteriologically quiescent disease at 12 months and a lower proportion with radiographic deterioration at six months than the rapid inactivators, while the slow inactivators who deteriorated radiographically or clinically to an extent warranting a change of treatment during the two years did so later than the corresponding rapid inactivators. There was slight evidence that the slow and the rapid inactivators differed in the speed of conversion to bacteriological negativity of those patients whose disease was bacteriologically quiescent at 12 months, but no evidence that they differed in the degree of positivity of sputum specimens that were positive on culture at six, nine or 12 months, or in the frequency with which the patients showed moderate or greater radiographic improvement at six months.     

The emergence of isoniazid-resistant cultures in patients with pulmonary tuberculosis during treatment with isoniazid alone or isoniazid plus PAS

Previous reports from the Tuberculosis Chemotherapy Centre, Madras, have described a comparison of four regimens (three of isoniazid alone and one of isoniazid plus PAS) in the treatment of pulmonary tuberculosis and an investigation of the serum isoniazid levels in the patients concerned. The present report studies the emergence of isoniazid-resistant organisms in these patients during treatment. All patients with an unsatisfactory response to treatment yielded resistant cultures, showing that the isoniazid dosage was never too low to inhibit sensitive organisms. From the degree of resistance of the first resistant cultures and of the six-month cultures from the patients treated with isoniazid alone it was concluded that resistance emerged in two stages. In the first stage, very earlyin treatment, highly resistant mutant bacilli grew freely whatever the isoniazid dosage, but mutants of lower resistance were prevented from growing to an extent dependent on the peak isoniazid concentration in the serum. Consequently, when the isoniazid dosage was increased the proportion of patients with resistant organisms decreased, since fewer low-resistance strains were able to develop. In the second stage, organisms with relatively low resistance continued to multiply, though still partially inhibited by isoniazid, and became more resistant, particularly in slow inactivators. The first-stage events determined the results of treatment since, once resistance had emerged, its extent was unrelated to the patient''s eventual progress. These findings emphasize the importance of early intensive chemotherapy and adjustment of the isoniazid dosage according to peak serum concentrations rather than concentrations measured three or six hours after the dose. Concomitant administration of PAS prevented emergence of isoniazid resistance in many patients and in others delayed its emergence and reduced its degree, possibly because growth in the second stage was slow.     

Effect of pyridoxine on vitamin B6 concentrations and glutamic-oxaloacetic transaminase activity in whole blood of tuberculous patients receiving high-dosage isoniazid

An earlier report from the Tuberculosis Chemotherapy Centre, Madras, showed that, in tuberculous patients receiving high-dosage isoniazid (12.5-15.6 mg/kg body-weight), the concomitant administration of 6 mg of pyridoxine prevented peripheral neuropathy. In that study, biochemical determinations of B₆ concentrations and GOT activity in whole blood had been routinely undertaken on all patients on admission to treatment, and at 6, 12, 24 and 52 weeks thereafter; in addition, extra determinations were undertaken for patients who developed peripheral neuropathy. The present paper reports the findings of these investigations, which are: (a) peripheral neuropathy developed predominantly among slow inactivators of isoniazid, and was associated with a substantial reduction in GOT activity but no apparent change in B₆ concentration; (b) the reduction in GOT activity appeared to be due to deficiency of both the coenzyme (pyridoxal phosphate) and the apoenzyme; (c) the concomitant administration of pyridoxine (6 mg or 48 mg) with high-dosage isoniazid to 3 patients with peripheral neuropathy, 1 of whom had convulsions also, resulted in increased B₆ concentrations and GOT activity, and no further convulsions; and (d) the concomitant administration of pyridoxine 6 mg daily, as a prophylactic, resulted in a significant increase in B₆ concentrations and GOT activity and prevention of the neuropathy.     

Therapeutic Drug Monitoring for Slow Response to Tuberculosis Treatment in a State Control Program, Virginia, USA

Therapeutic drug monitoring may be useful in tuberculosis management, but programmatic implementation is understudied. We performed a retrospective cohort study to determine prevalence of lower than expected levels of isoniazid, rifampin, ethambutol, and pyrazinamide measured at time of estimated peak serum concentration. Patients were tested for serum concentration at 2 hours after medication administration. When patients were tested, 22 had concentrations lower than expected range for rifampin, 23 of 39 patients had low levels of isoniazid, and 8 of 26 patients had low levels of ethambutol; all 20 patients tested for pyrazinamide were within expected range. Over 26 months, 42 patients met criteria for slow response. Diabetes was associated with slow response (p<0.001), and persons with diabetes were more likely than persons without diabetes to have low rifampin levels (p = 0.03). Dosage adjustment of rifampin was more likely to elevate serum concentration to the target range than adjustment of isoniazid given in daily doses (p = 0.01).     

2014-2017年三亚市涂阳肺结核患者耐药监测结果分析

目的 通过耐药监测了解三亚市涂阳肺结核患者的耐药状况,为三亚市结核病防治提供参考依据。方法 收集三亚市2014年1月-2017年12月期间新登记活动肺结核患者中获得的602例涂阳肺结核患者的临床分离株,进行菌型鉴定,并采用WHO《结核病药物耐药性监测指南》推荐的比例法对分离菌株进行6种抗结核药物[利福平(RFP)、异烟肼(INH)、链霉素(Sm)、乙胺丁醇(EMB)、氧氟沙星(Ofx)、卡那霉素(Km)]的药物敏感性试验。对各种药物的初始耐药率、获得性耐药率、耐多药率、耐药顺位的差异进行分析。结果 分离的602株菌株经菌型鉴定,共有结核分枝杆菌592株,总体耐药率为22.97%(136/592),总耐多药率为5.57 %(33/592)。获得性耐药率41.67%(40/96)高于初始耐药率19.35%(96/496),差异有统计学意义(x2=22.27, P＜ 0.01)。6种药物耐药率顺位由高到低依次为Sm 12.67%(75/592)、INH 9.46%(56/592)、RFP 8.95%(53/592)、Ofx 5.57%(33/592)、EMB 2.20%(13/592)、Km 2.03%(12/592)。6种药物共出现22种不同耐药谱。不同性别、年龄组的耐药率差异无统计学意义。结论 三亚市结核病患者总体耐药水平相对较低,仍需继续加强对本市结核病患者的耐药性监测。     

The virulence in the guinea-pig of tubercle bacilli isolated before treatment from South Indian patients with pulmonary tuberculosis: 3. Virulence related to pretreatment status of disease and to response to chemotherapy

This is the last of a series of three reports from the Tuberculosis Chemotherapy Centre Madras, on a study undertaken with the object of finding out whether differences in the virulence in the guinea-pig of tubercle bacilli isolated from South Indian tuberculous patients before the start of chemotherapy are related to the severity of the patients'' disease on admission to treatment and to the subsequent response to chemotherapy. The 281 patients in this study were drawn from the patients admitted to a 1-year comparison of four domiciliary chemotherapeutic regimens: (a) 3.9-5.5 mg/kg isoniazid plus 0.2-0.3 g/kg sodium PAS daily, divided into two doses (PH series); (b) 7.8-9.6 mg/kg isoniazid alone daily in one dose (HI-1 series); (c) 7.8-9.6 mg/kg isoniazid alone daily, divided into two doses (HI-2 series); (d) 3.9-5.5 mg/kg isoniazid alone daily, divided into two doses (H series).     

140例肺结核耐药分析

目的观察肺结核耐药情况,为临床制定化疗方案提供科学依据。方法回顾性分析2011年1月至2015年7月于江山市医院就诊的肺结核患者资料病例,并对6种抗结核药物的耐药性进行测试。结果本次研究共纳入有药敏结果的患者626例,其中初治584例,复治42例;165例患者耐药,总耐药率为26.4%,单耐药率为15.7%,多耐药率为5.3%,耐多药为5.4%。初治患者总耐药率为24.5%,单耐药率为15.9%,多耐药率为5.1%,耐多药为3.4%。复治患者的总耐药率为52.4%,单耐药率为11.9%,多耐药率为7.1%,耐多药率为33.3%。初治患者和复治患者耐药率分别是异烟肼(INH)13.7%、42.9%;利福平(RFP)4.3%、33.3%;乙胺丁醇(EMB)2.7%、7.1%;链霉素(SM)13.4%、33.3%;氧氟沙星6.2%、19.0%;卡那霉素(KM)2.9%、11.9%。结论江山市肺结核复治患者的耐药率高,尤其是耐多药率高。初治患者对异烟肼、链霉素的耐药性较高,初、复治患者均对乙胺丁醇耐药率低。应根据本地区耐药性检测情况合理使用抗结核药物,提高疗效,并加强综合管理。     

矽宁的药物代谢动力学研究

利用燐光分析法研究了矽宁在动物体内的药代动力学及其吸收、分布和排泄的特点∈蠊辔覆煌亮课?血药浓度-时间的动力学过程均符合一级吸收二室开放模型;吸收速度较快且完全,分布广泛,在组织中有一定的蓄积性;经小鼠、大鼠的尿、粪便及胆汁中以原形物排出很少。     

A 6-Month Study on the Toxicity of High Doses of Policosanol Orally Administered to Sprague-Dawley Rats

Policosanol is a cholesterol-lowering drug purified from sugar cane. Previous toxicological studies have not demonstrated any policosanol-related toxicity, even with long-term oral administration at 500 mg/kg, a dose 1,724 times larger than the maximal therapeutic dose (20 mg/day) recommended to date. The present study was undertaken to investigate the oral toxicity of policosanol administered for 6 months in doses up to 5,000 mg/kg to Sprague-Dawley rats. Animals were randomly distributed in five groups (15 animals per dose per sex): a control and four groups given oral policosanol (50, 500, 2,500, or 5,000 mg/kg). Eight treated rats (6 males, 2 females) died during the study, five of them (4 males, 1 female) from among those receiving the highest dose (5,000 mg/kg). According to necropsy, all deaths were related to gavage manipulation of higher doses. Although the differences were not significant, body weight gain and food consumption in the groups receiving 2,500 or 5,000 mg/kg tended to be lower than in the control group. Nevertheless, no drug-related toxicity symptoms were detected. Analysis of blood biochemistry, hematology, organ weight ratios, and histopathological findings did not show significant differences compared with controls, nor any tendency with the dose. Therefore, the present study did not show any new evidence of oral toxicity of policosanol, and the findings observed were a consequence of long-term administration by gastric gavage of the highly concentrated suspensions needed to reach the higher doses. It is concluded that policosanol chronically administered by the oral route is safe and that no drug-related toxicity was demonstrated.     

The prevention and treatment of isoniazid toxicity in the therapy of pulmonary tuberculosis: 2. An assessment of the prophylactic effect of pyridoxine in low dosage*

A recent report from the Tuberculosis Chemotherapy Centre, Madras, showed that a vitamin-B-complex preparation containing a small amount of pyridoxine (as well as aneurine hydrochloride, riboflavine, nicotinamide, panthenol and cyanocobalamin) was effective in the treatment of peripheral neuropathy caused by daily high-dosage (12.5-15.2 mg/kg body-weight) isoniazid therapy of pulmonary tuberculosis. The present report gives results which show that the B-complex preparation is fully effective in preventing peripheral neuropathy in patients receiving the same high dosage of isoniazid, and that this is due to the small pyridoxine content of only 6 mg daily, and not to any of its other constituents. The low cost of this small dose of pyridoxine makes high-dosage isoniazid therapy, given in combination with other drugs or alone, a possible proposition in developing countries.     

Prevention of opportunistic infections in immunosuppressed patients in the tropical top end of the Northern Territory.

The population of the Top End of the Northern Territory has a high incidence of several infections of particular significance in the immunosuppressed. The following protocol for evaluation and treatment of patients prior to immunosuppression was developed in order to reduce the incidence of serious opportunistic infections. The infections discussed are Strongyloides stercoralis, tuberculosis, scabies, chronic hepatitis B, melioidosis and other bacterial infections. We recommend that all patients planned to receive more than 0.5 mg/kg/day of prednisolone for >14 days, or any more potent immunosuppressive drug, be evaluated and treated according to this protocol. Details of the rationale, evidence base, and proposed investigations and therapy for such patients are discussed.     

广西某医院近十年HIV阴性者结核分枝杆菌耐药检测结果分析

目的探讨广西HIV阴性结核病患者耐药特征和近十年耐药变化趋势,为其防控提供参考。方法对2010年1月—2019年12月广西某医院HIV阴性疑似结核病患者临床标本进行分枝杆菌培养和分离鉴定,对结核分枝杆菌进行常用一线和部分二线抗结核药物敏感性试验。结果全部标本分枝杆菌培养阳性率为24.13%(3872/16049)。十年间共对3202株结核分枝杆菌进行耐药检测,总耐药率为22.86%,不同年份间耐药率差异无统计学意义(P>0.05)。单耐药率为异烟肼9.96%~20.44%、利福平6.25%~19.57%,此2种药物不同年份间耐药率差异有统计学意义(P值均<0.01),其中异烟肼、利福平耐药率呈逐年下降趋势。多耐药率不同年份间差异无统计学意义;耐多药率不同年份间差异有统计学意义(P<0.01),并呈逐年下降趋势。耐药顺位由高至低分别为异烟肼、利福平、链霉素、氧氟沙星、乙胺丁醇、卡那霉素、对氨基水杨酸钠。结论近年来广西HIV阴性者结核分枝杆菌耐药率和多耐药率、耐多药率、异烟肼和利福平的耐药率等有下降的趋势,显示近年耐药结核病防控工作取得了一定成效。     

膀胱癌病人乙酰基转移酶表型的研究

应用ＤＤＳ作为实验药物，采用高效液相色谱法，研究了目前尚存话的有２－萘胺职业接触史的１１名膀胱癌病人、２５名普通膀胱癌病人及２３名接触对照的ＮＡＴ酶表型。结果表明。无论有无２－萘胺职业接触史，膀胱癌病人中慢型乙酰化者所占比例（５２．２％和４５．５％）均高于对照组（１３．０％），且差异有显著性（Ｐ＜０．０５），比值比０Ｒ分别为５．５６（９５％可信限＝１．０２～３０．３）和７．２５（９５％可信限＝１．７０～３０．３），提示慢型乙酰化者若暴露于２－萘胺更易患膀胱肿瘤，乙酰化慢表型是膀胱癌的一个遗传易感因素。     

重症患者不同负荷剂量替考拉宁早期谷浓度的监测

目的了解给予不同负荷剂量替考拉宁的重症感染患者治疗3 d后的血清药物谷浓度(Cmin)及目标Cmin达标情况,旨在探讨理想的负荷剂量。方法选取2016年2月1日—2017年2月28日入住某院重症医学科重症感染患者,按不同药物负荷剂量(替考拉宁标准剂量6 mg/kg;高剂量10 mg/kg)和不同尿肌酐清除率(Ccr:以50 mL/min为标准线)水平分为4个亚组:标准剂量正常肌酐清除率组(G_(SD1)组)、标准剂量低肌酐清除率组(G_(SD2)组)、高剂量正常肌酐清除率组(G_(HD1)组)、高剂量低肌酐清除率组(G_(HD2)组),比较替考拉宁血清Cmin、目标Cmin达标情况以及不良反应情况。结果共入选患者49例,标准剂量组17例,其第4 d用药前Cmin为(5.98±2.67)mg/L;高剂量组32例,Cmin为(9.05±4.25)mg/L;高剂量组Cmin高于标准剂量组,差异有统计学意义(t=3.10,P=0.003)。G_(SD1)、G_(SD2)、G_(HD1)、G_(HD2)组Cmin分别为(5.78±2.72)、(6.34±2.78)、(8.21±3.77)、(12.07±4.81)mg/L,4组间Cmin比较,差异有统计学意义(F=4.766,P=0.006),G_(HD2)组高于G_(HD1)组、G_(SD2)组和G_(SD1)组;Cmin达标率分别为9.09%(1/11)、16.67%(1/6)、28.00%(7/25)、71.43%(5/7),差异有统计学意义(χ~2=8.766,P=0.033)。各组治疗期间均未发现明显药物相关性皮疹、肝肾功能损害。结论不论患者Ccr正常与否,给予标准负荷剂量的替考拉宁早期均不能达到目标Cmin;低Ccr者给予高负荷剂量替考拉宁早期可达目标Cmin;而正常Ccr者,则需进一步提高负荷剂量。     

Low-dose quinine for treatment of Plasmodium falciparum malaria in Guinea-Bissau

The recommended dose of 10 mg quinine/kg bodyweight 3 times a day for 7 days for treatment of malaria is so high that many patients experience cinchonism. We have earlier obtained good results with 7 days' treatment with 20 mg Quinimax/kg bodyweight divided into 2 daily doses. In order to identify the lowest effective dose, children with symptomatic malaria were treated with quinine twice a day for 7 days. They were assigned to 1 of 3 groups treated daily with 10 mg/kg, 15 mg/kg, or 20 mg/kg bodyweight, respectively; 42, 46, and 34 children, respectively, received treatment and completed 5 weeks of follow-up. The cumulative percentages of all children with parasitaemia during follow-up on day 28 or before were 33%, 13% and 12%, respectively. Treatment with 10 mg quinine salt/kg daily for 7 days gave a significantly higher rate of recrudescence than did treatment with 15 or 20 mg/kg daily. Thus at least 15 mg of quinine salt/kg bodyweight daily should be recommended for treatment of symptomatic Plasmodium falciparum malaria in Guinea-Bissau.     

Chronotherapy of malaria: improved efficacy of timed chloroquine treatment of patients with Plasmodium falciparum infections.

The effect of routine treatment with chloroquine (10 mg/kg on days 1 and 2 and 5 mg/kg on day 3) on parasitaemia and parasitaemic profile of patients infected with Plasmodium falciparum was studied. As with P. vinckei petteri, the mid-term trophozoites of P. falciparum were the most susceptible stages to chloroquine treatment. It is suggested that, in order to diminish the frequency of drug administration and to lower the risks of chemoresistance developing, treatment should be diversified, using the drug which is most effective on the parasite stages present in the peripheral blood.     

衢州市2010年371株结核分支杆菌耐药状况分析

目的：了解衢州市2010年结核分枝杆菌的耐药状况,为结核病的临床诊治和控制提供参考依据。方法：采用WHO推荐的药敏比例法对371株临床分离的结核分支杆菌进行药物敏感性试验。结果：总耐药率为24%,耐多药率为6.7%;对异烟肼与链霉素的耐药率较高,分别为15.4%、11.9%。结论：衢州市结核杆菌的耐药趋势仍然严峻,相关卫生部门应引起重视。     

Pneumocystis carinii as a cause of pneumonia in HIV-infected patients in Lusaka, Zambia.

4 cases of Pneumocystis carinii pneumonia in HIV-infected patients studied at the University of Zambia Medical School, Lusaka, were verified by bronchoalveolar lavage. Pneumocystis is common in North American AIDS patients, but has been considered rare in Africa. One reason may be that facilities for diagnosis, bronchoscopy with bronchoalveolar lavage, are not usually available. 44 consecutive HIV seropositive patients who were unresponsive to a 10-day course of antibiotics, and whose sputum was negative for acid fast bacteria, underwent bronchoalveolar lavage from February 1990 to December 1990. HIV status was assayed with Welcozyme ELISA kits, and P. carinii was detected with toluidine blue O stain. The 1st case of confirmed P. carinii pneumonia was a 35-year old man who had a productive cough for 4 weeks, fever, and dyspnea. He was treated with co-trimoxazole and was symptom-free in 3 weeks, but developed severe Stevens-Johnson reaction. His cultures were positive for M. tuberculosis at week 8. He was lost to follow-up. The 2nd case was a 26-year old man with a 6-month history of cough and white sputum, treated without effect with antituberculous medication. He improved over 3 weeks with co-trimoxazole, but died of respiratory failure 2 months later. The 3rd case was a 30-year old woman being treated for pulmonary tuberculosis, who became progressively dyspneic 7 months later. She developed a generalized maculo-papular rash after taking co-trimoxazole, so was given dapsone 100 mg/day, prednisone 1 mg/kg/day, and trimethoprim 15 mg/kg for 1 week. She improve in 3 weeks. The 4th case was a 30-year old man with a 4-week history of dry cough and dyspnea and recent high fever. He was given co-trimoxazole, but developed generalized purpura after 5 days. His treatment was changed to Dapsone 100 mg/day, prednisone 1 mg/kg/day, and antituberculous medication. He improved after 3 weeks, and is being maintained on Fansidar 1 tablet/week. These cases are remarkable because 2 of them also had pulmonary tuberculosis, which is often the presumed diagnosis of pneumonia in African AIDS patients. Furthermore, 3 developed serious drug reactions to co-trimoxazole, also considered an uncommon occurrence.