Effects of co-administration of Unani pharmacopoeia formulations Qurs Tabasheer Sartani and Arq Hara Bhara with CAT-I antitubercular drugs in rats.

OBJECTIVES: Tuberculosis continues to be a major public health problem globally, despite incredible advancements in healthcare system. In Unani system of medicine, Qurs Tabasheer Sarthani (QTS) and Arq Hara Bhara (AHB) have been traditionally used for tuberculosis like conditions. The study was aimed to investigate the effects of co-administration of QTS and AHB with category I first line antitubercular drugs (CAT-I) on the indices of liver and kidney function in rats. METHODS: QTS and AHB were prepared individually and mixed to achieve final compound Unani pharmacopoeia formulation (UPF). The human equivalent doses for rats were calculated and administered with and without CAT-I. The effects of the formulations on serum indices of kidney and liver function, hematological markers and plasma CAT-I drug levels were estimated at 14th, 60th & 180th days of treatment. RESULTS: The administration of UPF, CAT-I and UPF + CAT-I altered the levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) and haematological markers. These alterations were within permissible range and randomly distributed among groups during various time points. Administration of CAT-I alone resulted in moderate histopathological changes which were completely abrogated in CAT-I + UPF co-administered animals. The co-administration of UPF with CAT-I improved the plasma peak rifampicin (RIF) levels, without altering the liver and kidney functions. CONCLUSIONS: The co-administration of UPF with ATT improved liver and kidney functions and increased the plasma levels of RIF. These beneficial findings provide a scope to evaluate the pharmacokinetic studies in humans.

Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes.

BACKGROUND: The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood. METHODS: We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models. RESULTS: Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-µg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-µg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]). CONCLUSIONS: Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.

Factors Influencing Tuberculosis Treatment Outcome in Adult Patients Treated with Thrice-Weekly Regimens in India.

The Indian Revised National Tuberculosis (TB) Control Programme uses thrice-weekly treatment with standard drug dosages. The role of plasma drug levels and other factors in determining TB treatment outcomes is not well understood. We aimed to determine the factors influencing the concentrations of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) at 2 h postdosing in adult TB patients and to study the factors impacting TB treatment outcome. We recruited 1,912 adult TB patients (newly treated and retreated patients) with pulmonary/extrapulmonary TB receiving antitubercular treatment (ATT) in the RNTCP in Chennai, India. At steady state, the concentrations of RMP, INH, and PZA were determined at 2 h postdosing after supervised drug administration. A total of 1,648 patients had a favorable outcome, while 264 (14%) had an unfavorable outcome. A total of 91%, 16%, and 17% of the patients had suboptimal concentrations of RMP (<8 µg/ml), INH (<3 µg/ml), and PZA (<20 µg/ml), respectively. Factors associated with treatment outcome were low RMP concentrations (adjusted odds ratio [aOR], 0.94; 95% confidence interval [CI], 0.89 to 0.99; P = 0.036), category II ATT (aOR, 2.39; 95% CI, 1.56 to 3.65; P < 0.001), low body weight (aOR, 0.96; 95% CI, 0.94 to 0.98; P < 0.001), alcohol use (aOR, 2.17; 95% CI, 1.42 to 3.31; P < 0.001), male gender (aOR, 1.92; 95% CI, 1.02 to 3.62; P = 0.043), and baseline INH resistance (aOR, 5.74; 95% CI, 3.12 to 10.59; P < 0.001), which significantly increased the likelihood of an unfavorable outcome in multivariate logistic regression analysis. Further studies are needed to optimize anti-TB drug dosages and improve cure rates. Drug susceptibility testing at the baseline and attention to undernutrition and alcohol dependence are other important interventions.

Factors influencing plasma nevirapine levels: a study in HIV-infected children on generic antiretroviral treatment in India.

BACKGROUND: Nevirapine is an important component of paediatric combination HIV therapy. Adequate drug exposure is necessary in order to achieve long-lasting viral suppression. OBJECTIVES: To study the influence of age, drug dose and formulation type, nutritional status and CYP2B6 516G>T polymorphism on blood concentrations of nevirapine in children treated with generic antiretroviral drugs. METHODS: A multicentre study was conducted at four sites in India. HIV-infected children receiving generic nevirapine-based fixed-dose combinations were recruited. Trough and 2 h nevirapine plasma concentrations were determined by HPLC. Characterization of the CYP2B6 gene polymorphism was performed using direct sequencing. Clinical and nutritional status was recorded. Groups were compared using the Mann-Whitney U-test and multivariable logistic regression analysis was performed to identify factors contributing to low drug levels. RESULTS: Ninety-four children of median age 78 months were studied; 60% were undernourished or stunted. Stunted children had a significantly lower 2 h nevirapine concentration compared with non-stunted children (P < 0.05); there were no significant differences in trough concentrations between different nutritional groups. Nevirapine levels were significantly higher in children with TT compared with GG and GT CYP2B6 genotypes (P < 0.01). Children ≤ 3 years had a 3.2 (95% confidence interval 1.07-9.45) times higher risk of having sub-therapeutic nevirapine concentrations. CONCLUSIONS: Nevirapine blood concentrations are affected by many factors, most notably age ≤ 3 years; a combination of young age, stunting and CYP2B6 GG or GT genotype could potentially result in sub-therapeutic nevirapine concentrations. Dosing recommendations for children should be reviewed in the light of these findings.