Academic journal article Bulletin of the World Health Organization

Initial Evaluation of Low-Dose Phenobarbital as an Indicator of Compliance with Antimalarial Drug Treatment

Academic journal article Bulletin of the World Health Organization

Initial Evaluation of Low-Dose Phenobarbital as an Indicator of Compliance with Antimalarial Drug Treatment

Article excerpt

Introduction

During the last 12 years new methods of measuring patient compliance with drug therapy have been introduced. Comparisons of these methods with patient interviews and tablet counts, which have traditionally been employed in clinical trials, suggest that the older methods greatly underestimated the extent of poor compliance. Such is the extent to which the traditional methods are inadequate that an editorial in the Lancet (1) suggested that they be abandoned and that electronic medication monitors or a pharmacological indicator, such as low-dose phenobarbital, or both, be used instead to measure compliance during clinical trials.

Low-dose phenobarbital was introduced as a pharmacological indicator of compliance in 1987 (2). Since then, it has been employed to evaluate compliance with a number of quite diverse treatments and been compared with other methods of evaluating compliance (1, 4-7). However, virtually all of these applications and evaluations have been directed towards the measurement of compliance with treatments lasting over several weeks or even longer. This paper reports an evaluation of this indicator for measuring compliance with short (5 or 7 days) courses of antibiotics or antimalarials.

Methods

Subjects and study protocol. A total of 50 patients with acute, uncomplicated Plasmodium falciparum malaria who attended a clinic for treatment at the Mae Sod Hospital in Thailand were recruited into the study as unpaid volunteers. The subjects were male or female, aged 13-49 years, and weighed 39.5-69 kg. Patients who were pregnant or had evidence of severe infection with falciparum malaria were excluded. The 50 patients were divided into five groups, as follows.

Group 1: 10 patients, aged 16-36 years (mean, 23.9 [+ or -] 6.8 years) and weighing 45-69 kg (mean weight 54.1 [+ or -] 7.1 kg), received 4 mg phenobarbital daily for 5 days, which was taken in conjunction with artesunate (300mg on day 1 and 100mg daily for the next 4 days).(a)

Group 2: 5 patients, aged 15-30 years (mean, 19 [+ or -] 6.3 years) and weighing 41-53 kg (mean, 46.4 [+ or -] 5 kg), received the same regimen as patients in group 1.(a)

Group 3: 10 patients, aged 13-25 years (mean, 19.8 [+ or -] 4 years) and weighing 42-57 kg (mean, 51.7 [+ or -] 5.4 kg), received 4 mg phenobarbital daily for 3 days, as well as artesunate (300mg on day 1 and 100mg daily for the next 4 days).

Group 4: 15 patients, aged 13-48 years (mean, 27 [+ or -] 11 years) and weighing 40-42kg (mean, 50.9 [+ or -] 7.6 kg), received three separate doses of 2 mg phenobarbital daily (total, 6 mg daily) for 7 days, together with quinine + tetracycline (quinine: 600mg x 3 times per day + tetracycline: 250mg x 4 times per day for 7 days).

Group 5: 10 patients, aged 16-49 years (mean, 28.8 [+ or -] 12.1 years) and weighing 41-63kg (mean, 51.5 [+ or -] 6.9kg), received 6mg phenobarbital daily (3 separate doses of 2mg each) for 3 days, together with quinine + tetracycline using the same regimen as group 4.

Blood (1 ml) was drawn by venepuncture into heparinized tubes from patients in groups 1-3 before the consumption of the daily dose of phenobarbital/ artesunate mixture, and daily before the next dose from patients in groups 4 and 5 receiving the quinine/ tetracycline regimen. After centrifugation at 25 [degrees] C for 15 min and 1500g the plasma was separated and transferred to clean plastic 100 [micro]l tubes and stored at -70 [degrees] C before trans-shipment to Leeds, England, for analysis of phenobarbital. Samples were air-freighted on dry ice (-70 [degrees] C) and remained frozen during shipment. On receipt in Leeds, samples were stored at -20 [degrees] C until analysis.

Analytical methods. Phenobarbital and cyclobarbital (internal standard) were obtained from May & Baker Ltd, Dagenham, England. Methanol, acetronitrile, hexane and ethyl acetate (all HPLC grade) were obtained from Rathburn Chemicals Ltd, Walkerburn, Scotland. …

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