The potential use of urinary excretion data for assessing the relative bioavailability of rifampicin in fixed dose combination anti-tuberculosis formulations.

Setting: The perceived need for simple, non-invasive methods of assessing the relative bioavailability of rifampicin in fixed-dose combination (FDC) anti-tuberculosis formulations.

Objective: To compare the performance of methods based on urinary excretion data with those utilising plasma concentration-time profiles to assess the relative bioavailability of rifampicin in combined and single-drug formulations.

Design: A two-period randomised crossover bioequivalence study in healthy male volunteers with a 1 week washout period between treatments.

Urine test for the assessment of smoking status.

A simple, quick and inexpensive test for smoking status would be useful in a variety of settings. The non-polar barbituric acid derivative 1,3-dibutyl-2-thiobarbituric acid (DBTB) is described as a novel derivatisation reagent for nicotine and its metabolites in the König reaction to assess smoking status. The relative performance of qualitative methods for assessing smoking status using DBTB and the previously employed derivatisation reagent 1,3-diethyl-2-thiobarbituric acid (DETB), as well as quantitatively-based methods for determining 'total nicotine metabolites' (TNMs) using these two reagents, were evaluated against a cotinine-based radioimmunoassay (RIA) as the 'gold standard'.

The colorimetric analysis of anti-tuberculosis fixed-dose combination tablets and capsules.

Setting: The perceived need to demonstrate whether or not the actual amounts of rifampicin, isoniazid and pyrazinamide in fixed-dose combination tablets or capsules correspond to their stated drug contents.

Objective: To adapt specific, robust and simple colorimetric methods that have been previously applied to measuring plasma and urinary rifampicin, isoniazid, pyrazinamide and ethambutol concentrations to estimate tablet and capsule drug contents.

Design: The methods were applied to the analysis of 14 commercially manufactured fixed-dose combinations: two capsule and three tablet formulations containing rifampicin and isoniazid; seven tablet formulations containing rifampicin, isoniazid and pyrazinamide; and two tablet formulations containing rifampicin, isoniazid, pyrazinamide and ethambutol.

The development of a standardised screening protocol for the in vivo assessment of rifampicin bioavailability.

Setting: The prerequisite for in vivo bioavailability testing of rifampicin in fixed-dose combination (FDC) formulations is widely accepted. However, many smaller drug regulatory authorities and drug manufacturers have difficulty implementing costly and cumbersome testing procedures.

Objective: To test whether a simplified blood sampling schedule can be used for the determination of drug bioequivalence in randomised, single dose, crossover studies of FDCs and appropriate reference formulations.

The evaluation of rifampicin bioavailabilities of fixed-dose combinations of anti-tuberculosis drugs: procedures for ensuring laboratory proficiency.

Setting: The perceived need to demonstrate whether or not the rifampicin bioavailability of commercially manufactured fixed-dose combinations is satisfactory.

Objective: To establish an international laboratory network to assess rifampicin bioavailability.

Design: Convenient assay kits were devised to evaluate the ability of laboratories in China, India, Italy, South Africa, Thailand and the USA to determine plasma and urinary concentrations of rifampicin and desacetyl-rifampicin.

Rifampicin bioavailability: a review of its pharmacology and the chemotherapeutic necessity for ensuring optimal absorption.

The World Health Organization encourages the use of fixed dose combinations (FDCs) of rifampicin (RMP) and isoniazid together with pyrazinamide or pyrazinamide plus ethambutol for the treatment of tuberculosis. The main advantages of such FDCs are the simplification of procurement and prescribing practices and the protection they afford against the potential selection of RMP-resistant strains of Mycobacterium tuberculosis. There is convincing evidence, however, that the rifampicin absorption from FDCs manufactured under suboptimal conditions may be significantly impaired, and this appears to be especially problematic with combined formulations of rifampicin, isoniazid and pyrazinamide.

Assessment of simple colorimetric procedures to determine smoking status of diabetic subjects.

The performance of a simple colorimetric assay for urinary nicotine metabolites to assess smoking status in diabetic subjects (n = 251) was investigated. Several variations of the colorimetric assay and a qualitative extraction procedure were evaluated in comparison with a cotinine immunoassay as the "gold standard." Among these, the best overall performance was achieved with the qualitative test (sensitivity 95%; specificity 100%).

Smoking during pregnancy: the dose dependence of birthweight deficits.

Objective: To assess whether a simple urine based estimate of relative daily nicotine intake could predict smoking related birthweight deficits more accurately than self-reported cigarette consumption.

Design: Active smokers were identified by a simple qualitative colorimetric urine test procedure and their relative nicotine intakes assessed by determining the ratios of the urinary concentrations of nicotine plus its metabolites to creatinine using automated colorimetric methods.

Setting: A large teaching hospital.

Urinary nicotine metabolite excretion and lung cancer risk in a female cohort.

A nested lung cancer case-control study was carried out using 397 12 h urine samples originally collected from a cohort of over 26,000 women aged 40-64 at entry who were then followed for up to 15 years. The urine samples from active smokers were first identified using a simple qualitative method and their total nicotine metabolites/creatinine ratios then determined by automated colorimetric methods. The results obtained demonstrated the capacity of nicotine metabolite estimations in a single 12 h sample of urine to predict the subsequent risk of lung cancer.

Comparison of Chinese and Western rifapentines and improvement of bioavailability by prior taking of various meals.

Bioavailability was measured by rifapentine (RPE) serum concentrations and by the urinary ratio between RPE and creatinine, in specimens obtained 4-50 h after 600 mg RPE preceded by food. The bioavailabilities of RPEs manufactured in China and by a Western manufacturer were similar after a standard English breakfast, and serum concentrations were also similar to those obtained in an earlier Italian study following a complex meal. Although absorption of RPE was unsatisfactory after lipid-rich biscuits or shortbread, absorption after egges and toast was excellent and was nearly as good after a fast-food sandwich.

Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis.

Tuberculous meningitis is a very serious form of tuberculosis. In the absence of randomized controlled trials of alternative treatment regimens, its management depends on employing potent drugs that penetrate well into the cerebrospinal fluid (CSF). The penetration of isoniazid, rifampin, and streptomycin into the CSF of 27 Chinese patients was studied using fluorimetric and microbiologic procedures.

Respiratory effects of lowering tar and nicotine levels of cigarettes smoked by young male middle tar smokers. II. Results of a randomised controlled trial.

Study Objective: The aim was to investigate the effect on respiratory health of male middle tar smokers changing the tar and nicotine levels of the cigarettes they smoke for a six month period.

Design: This was a randomised controlled trial. Middle tar smokers were randomly allocated to smoke one of three different types of cigarette (low tar, middle nicotine; middle tar, middle nicotine; and low tar, low nicotine) in place of their usual cigarette for a six month period.

The use of RNA/DNA ratio measurements to assess rifampicin-induced growth inhibition of Escherichia coli.

Growth rates and cellular levels of RNA, DNA and protein were studied in Escherichia coli during and following exposure to rifampicin, and in the transition from stationary to exponential phase growth in drug-free medium. At rifampicin concentrations of up to twice the MIC, significant changes in growth rates were only apparent after several generations. At higher rifampicin concentrations growth was terminated much more rapidly.

Isoniazid-related hepatotoxicity: a study of the effect of rifampicin administration on the metabolism of acetylisoniazid in man.

It has been proposed that isoniazid-induced hepatotoxicity may be increased by concomitant rifampicin treatment and that this could be mediated by inducing the metabolism of the isoniazid metabolite monoacetylhydrazine to potent acylating agents capable of causing liver necrosis. To investigate this postulated mechanism we studied the kinetics of the metabolism of acetylisoniazid in a slow and a rapid acetylator prior to and after rifampicin administration. Pretreatment with rifampicin did not modify the metabolism of acetylisoniazid to any noteworthy extent nor did it increase the metabolism by non-acetylation routes of the monoacetylhydrazine liberated in vivo from acetylisoniazid.