Isoniazid acetylation phenotyping in Saudi Arabs

AIMS: The present study is designed to investigate the acetylator status in Saudi Arabs. METHODS: Isoniazid (INH) acetylation phenotyping was studied in 136 Saudi Arabs in Riyadh, Saudi Arabia, using a single plasma sample taken 3 h post-INH oral dose of 200 mg. Metabolic ratio (MR) of plasma acetyl-INH (Ac-INH) to INH was used to determine the acetylation phenotype. RESULTS: The MR had a bimodal distribution with an antimode of 1.0. The frequency distribution of slow acetylators (MR < 1.0) was 94.9% (n = 129). Using Hardy-Weinberg Law, the gene frequency (q) of the recessive allele determining slow acetylator phenotype was found to be 0.97. CONCLUSION: INH phenotyping suggests a high frequency of slow acetylators among Saudi Arabs. There was no association between the MR of plasma Ac-INH/INH and age or gender.     

Orthotopic liver transplantation for subacute hepatic failure following partial treatment of isoniazid-resistant tuberculosis

Abstract: The management of patients with pre-existing tuberculosis (TB) undergoing liver transplantation is challenging. Cautious immunosuppression is required to prevent reactivation of disease, and second-line anti-tuberculous treatment may be necessary to prevent graft hepatotoxicity. Furthermore, liver transplantation in the context of isoniazid-resistant TB has seldom been reported. We report on a 44-year-old man with recent isoniazid-resistant extra-pulmonary TB who developed subacute hepatic failure requiring emergency liver transplantation and treatment with second-line anti-tuberculous therapy. We demonstrate that patients who have pre-existing TB can be successfully treated with alternative anti-tuberculous medication while under immunosuppression post transplantation. Pre-existing TB, including resistant strains, should not be an absolute contraindication to liver transplantation.     

耐多药肺结核对异烟肼和利福平复敏的治疗疗效分析

目的探讨复敏后的耐多药肺结核INH、RFP联合治疗的疗效。方法 50例经痰结核菌培养确定的耐多药肺结核对INH、RFP均复敏的患者随机分为两组,治疗组采用3HRZAKPT/18HRPT化疗方案治疗;对照组采用3VZPTAKCTM/18VPTCTM化疗方案治疗。比较治疗3个月、6个月、12个月、18个月、21个月的痰菌阴转率（涂片与培养）,X线胸片变化及药物不良反应。结果治疗组疗程满3个月痰菌涂片与培养阴转率（32%,28%）分别与对照组（16%,12%）无明显差异（P〉0.05）;两组满疗程痰菌涂片阴转率（48%,40%）、培养阴转率（44%,40%）,X线病灶吸收率（68%,64%）和空洞闭合率（24%,28%）均无明显差异（P〉0.05）;两组均无严重不良反应。结论 INH、RFP对复敏后的耐多药肺结核,近期临床疗效不比对照组第三线化疗方案[1]的疗效差,而且治疗费用低,值得临床推广。     

Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients

AIM

This study was designed to characterize the population pharmacokinetics of isoniazid in South African pulmonary tuberculosis patients.

METHODS

Concentration–time measurements obtained from 235 patients receiving oral doses of isoniazid as part of routine tuberculosis chemotherapy in two clinical studies were pooled and subjected to nonlinear mixed-effects analysis.

RESULTS

A two-compartmental model, including first-order absorption and elimination with allometric scaling, was found to describe the observed dose-exposure relationship for oral isoniazid adequately. A mixture model was used to characterize dual rates of isoniazid elimination. Estimates of apparent clearance in slow and fast eliminators were 9.70 and 21.6 l h⁻¹, respectively. The proportion of fast eliminators in the population was estimated to be 13.2%. Central volume of distribution was estimated to be 10% smaller in female patients and clearance was found to be 17% lower in patients with HIV. Variability in absorption rate (90%) was completely interoccasional in nature, whereas in relative bioavailability, interoccasional variability (8.4%) was lower than interindividual variability (26%). Oral doses, given once daily according to dosing policies at the time, were sufficient to reach therapeutic concentrations in the majority of the studied population, regardless of eliminator phenotype. Simulations suggested that current treatment guidelines (5 mg kg⁻¹) may be suboptimal in fast eliminators with low body weight.

CONCLUSIONS

A population pharmacokinetic model was developed to characterize the highly variable pharmacokinetics of isoniazid in a South African pulmonary tuberculosis patient population. Current treatment guidelines may lead to underexposure in rapid isoniazid eliminators.     

异烟肼缓释固体分散体的制备及其体外评价

目的制备异烟肼缓释固体分散体,考察其分散状态和体外溶出速率。方法以水不溶性聚合物乙基纤维素为载体,用溶剂法制备异烟肼缓释固体分散体。采用X射线衍射法、差示扫描量热法和红外光谱法鉴别药物在固体分散体中的存在状态,并对其体外释放情况进行研究。结果 X射线衍射法表明异烟肼在固体分散体中有一部分是以分子状态分散,而另一部分可能以微晶体状态分散;差示扫描量热法表明所制备的缓释固体分散体中不存在药物结晶;红外光谱法结果表明异烟肼与乙基纤维素未发生化学反应;溶出度试验结果表明其具有良好的缓释效果。结论采用溶剂法制备的异烟肼缓释固体分散体可以使药物达到高度分散状态,制备的异烟肼缓释固体分散体具有较好的缓释效果。     

异烟肼人体血药浓度测定及药代动力学研究

目的建立测定人血浆中异烟肼质量浓度的反相高效液相色谱法并研究异烟肼的药代动力学。方法采用YWG-C18色谱柱(200mm×4.6 mm,5μm),以0.02 mol/L磷酸二氢钾-甲醇(61∶39)为流动相,检测波长为340 nm,进样量20μL。结果异烟肼的血浆质量浓度在0.2～12.0 mg/L范围内与峰面积线性关系良好(r=0.999 6);日内、日间精密度RSD均小于4.0%;平均回收率为97.67%,RSD=2.31%(n=9)。结论反相高效液相色谱法适用于异烟肼药代动力学研究和临床血药浓度监测。     

RP—HPLC法测定异烟肼片中异烟肼含量

目的：建立异烟肼片HPLC含量测定方法。方法：色谱柱Agilent ZORBAX SB—C18（5um,4．6×250mm）,以甲醇-水-冰醋酸（44：55：1）为流动相;检测波长263nm,流速1．0ml／min。结果：异烟肼在0．032—0．160ug范围内呈现良好的线性关系（r=0．99995n=5）：平均回收率为：97．07％,RSD=0．9％。结论：本法分离良好,结果准确。     

Cost-effectiveness of interferon-gamma release assay screening for latent tuberculosis infection treatment in Germany

OBJECTIVES: To assess the cost-effectiveness of the new QuantiFERON-TB Gold In-Tube (QFT-G) [Cellestis; Carnegie, VIC, Australia] assay for screening and treating of persons who have had close contact with tuberculosis (TB) patients and are suspected of having latent tuberculosis infection (LTBI) [hereafter called close-contacts] in Germany. METHODS: The health and economic outcomes of isoniazid treatment of 20-year-old close-contacts were compared in a Markov model over a period of 20 years, using two different cutoff values for the tuberculin skin test (TST), the QFT-G assay alone, or the QFT-G assay as a confirmatory test for the TST results. RESULTS: QFT-G assay-based treatment led to cost savings of $542.9 and 3.8 life-days gained per LTBI case. TST-based treatment at a 10-mm induration size cutoff gained $177.4 and 2.0 life-days gained per test-positive contact. When the cutoff induration size for the TST was reduced to 5 mm, the incremental cost-effectiveness ratio fell below the willingness-to-pay threshold ($30,170 per life-years gained) but resulted in unnecessary treatment of 77% of contacts owing to false-positive TST results. Combination with the 5-mm induration size TST cutoff value compared to the results of the QFT-G assay alone reduced the total costs per 1,000 contacts by 1.8% to $222,869. The number treated to prevent 1 TB case was 22 for the two QFT-G assay-based procedures, 40 for the TST at a cutoff induration size of 10 mm, and 96 for the TST at a cutoff induration size of 5 mm. When the sensitivity rates of the TST and the QFT-G assay were compounded, the QFT-G assay strategy alone was slightly less costly (0.6%) than the two-step approach. CONCLUSIONS: Using the QFT-G assay, but especially combining the QFT-G assay following the TST screening of close-contacts at a cutoff induration size of 5 mm before LTBI treatment is highly cost-effective in reducing the disease burden of TB.     

Coma caused by isoniazid poisoning in a patient treated with pyridoxine and hemodialysis

Isoniazid is widely used to treat tuberculosis. In populations with a high prevalence rate of tuberculosis, acute ingestion of isoniazid has been reported as a potential cause of coma. In this study, we present the diagnosis and treatment of isoniazid poisoning in a case with acute coma as the major clinical presentation.A 32-year-old male who ingested 12 g isoniazid (2 hours prior to medical attention) was brought to the emergency department while in a coma and experiencing frequent seizures. Initial treatment with large doses of pyridoxine (for 6 hours) failed to awaken this patient. The patient was then given hemodialysis and pyridoxine; after 3 days he awoke from coma, with no further reported seizures.Isoniazid poisoning should be suspected in patients whose major symptoms are coma and seizure, especially those who have access to isoniazid. Monitoring the blood level of isoniazid will establish the diagnosis and help clinical management. A combination of hemodialysis and pyridoxine is effective in treating isoniazid poisoning.