Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists.

Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. However, in developing countries like Senegal, these products are used without clear indications on their prescription, their dispensation or their use. This work focuses on the prescription of these medicines with a view to make recommendations for their rational use. Benzodiazepine prescription was studied with psychiatrists or neurologists and generalists in 2003. Specialist doctors work in two Dakar university hospitals and generalists in the 11 health centres in Dakar. We did a survey by direct interview with 29 of 35 specialists and 23 of 25 generalists. All doctors were interviewed in their office. The questionnaire focused on benzodiazepine indications, their pharmacological properties, benzodiazepines prescribed in first intention against a given disease and the level of training in benzodiazepines by doctors. Comparisons between specialists and generalists were made by chi-square test. Benzodiazepines were essentially used for anxiety, insomnia and epilepsy. With these diseases, the most benzodiazepines prescribed are prazepam against anxiety and insomnia and diazepam against epilepsy. About 10% of doctors do not know that there is a limitation for the period of benzodiazepine use. The principal reasons of drugs choice are knowledge of the drugs, habit and low side effects of drugs. All generalists (100%) said that their training on benzodiazepines is poor vs. 62.1% of specialists, and doctors suggest seminars, journals adhesions and conferences to complete their training in this field. There are not many differences between specialists and generalists except the fact that specialists prefer prazepam in first intention in the insomnia treatment where generalists choose bromazepam. In addition, our survey showed that specialists' training in benzodiazepines is better than that of generalists. Overall, benzodiazepine prescription poses problems particularly in training, and national authorities must take urgent measures for rational use of these drugs.

Pharmacokinetic profiles of prazepam and 14C-prazepam in rat.

Pharmacokinetics of Prazepam and 14C-Prazepam were studied in rat. Prazepam was measured in blood and plasma by a gas-liquid chromatography assay with an electron capture detector. Its major metabolite, Desmethyldiazepam, was also determined in blood in the same way. Total radioactivity was measured in plasma by scintillation spectrometry. Pharmacokinetic analysis were carried out by two ways; according to compartmental pharmacokinetic models and by statistic moments.

Comparison of performance of healthy volunteers given prazepam alone or combined with ethanol. Relation to drug plasma concentrations.

The interaction between a single dose of 20 mg of prazepam and 0.5 g/kg body weight ethanol was investigated in 12 healthy male volunteers by nine objective performance tests, eight visual analogue self-rating scales and measurement of prazepam and ethanol plasma concentrations, using a double-blind three-way crossover design. The volunteers were each given three treatments (prazepam+ethanol, placebo+ethanol and prazepam alone), separated by a 2-week interval. They completed the performance tests before treatment and 1.5 and 4 h thereafter, and the self-rating scales before treatment, 1.5, 4 and 8 thereafter. To determine prazepam and ethanol plasma levels, venous blood samples were drawn before drug intake and 0.25, 0.5, 1, 1.5, 3, 4, 5 and 8 h thereafter. In two of the performance tests: auditory reaction time and digit symbol substitution, the combination of prazepam and ethanol was shown to impair performance more than either drug taken alone 1.5 h after their administration. A similar result was found for the drowsiness scored in the self-ratings. The time needed to complete the two-symbol cancellation test was longer when the subjects received prazepam either alone or combined with ethanol. Simultaneous ingestion of prazepam and ethanol did not alter the bioavailability of either drug.

Comparison of the effect of two prazepam formulations on psychomotor and cognitive function in healthy volunteers.

A double-blind crossover design was used to evaluate the effect of two different formulations of prazepam, on motor and cognitive functions and subjective symptoms. Ten healthy male volunteers received 20 mg of prazepam both in tablet and liquid (as drops) formulation, separated by a 1 week interval. All subjects completed a battery of 9 performance tests 2.25 h and 4.75 h after drug intake (corresponding to the times of peak plasma concentration). They also rated themselves on eight visual analogue scales before, 2 h, 4.5 h and 8 h following drug intake. A significant difference between liquid drops and tablets was demonstrated in 4 of the 9 performance tests and 2 of the 8 items of the self rating scales. These results suggest that a single dose of prazepam administered in liquid drop form exhibits greater sedative properties than the same dose administered as tablets in healthy volunteers, probably as a result of more rapid absorption.

Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo.

Thirty-nine healthy volunteers received single oral doses of either alprazolam (1 mg), lorazepam (2 mg), prazepam (20 mg), or placebo in a randomized, double-blind, parallel group study. Plasma drug concentrations, subjective self-ratings, and the digit symbol substitution test (DSST) were evaluated during 24 hours after dosage. Alprazolam was absorbed rapidly and produced correspondingly rapid sedation and impaired DSST performance. These effects also resolved rapidly, being similar to placebo by 4 to 6 hours after dosage. Sedative and DSST-impairing effects of lorazepam were of slower onset but longer duration than those of alprazolam. After oral prazepam, appearance of desmethyldiazepam in plasma was slow, with minimal sedative and DSST-impairing effects. Twenty-four hours after dosage, both alprazolam and lorazepam significantly impaired recall of a list of 16 words learned previously 3 hours after dosage. Thus benzodiazepines with approximately equivalent clinical anxiolytic properties may have different sedative, performance-impairing, and amnesic profiles after single doses in healthy volunteers; these differences are explained at least in part by pharmacokinetic variations.

Comparison of sublingual and oral prazepam in normal subjects. II. Pharmacokinetic and pharmacodynamic data.

The pharmacokinetic profiles of oral and sublingual administrations of prazepam 20 mg to 5 normal volunteers were compared in order to explain the clinical observation that sublingual prazepam appears to exhibit sedative properties when compared to the same dose of oral prazepam. Blood samples for pharmacokinetic evaluation were collected just before drug intake and 7.5, 15, 22.5, 30, 45, 60, 90 min, 2, 3, 5, 6, 7, 8, 9, 10 and 24 h after drug intake. The study was performed in double-blind and crossover conditions. Serum levels of prazepam and its major metabolite N-desmethyl-diazepam were measured by HPLC. No prazepam was detected at a concentration higher than 20 ng/ml (limit of detection) whereas N-desmethyl-diazepam reached concentrations around 140 ng/ml. To correlate this observation with the clinical data, the affinity of prazepam and N-desmethyl-diazepam was compared measuring their ability to displace 50% of 3H-flunitrazepam bound to benzodiazepine receptors contained in synaptosomal preparation obtained from rat brain. N-desmethyl-diazepam was 17-fold more potent than prazepam. This data suggests that prazepam is a pro-drug which is transformed to the active compound N-desmethyl-diazepam and that the difference in clinical observation with both administrations could be correlated to N-desmethyl-diazepam concentration-time curves. Nevertheless, the comparison of the area under the N-desmethyl-diazepam serum concentration-time curves, the maximum concentrations, the times when the maximum concentrations were observed and the times needed to detect a significant level after oral and sublingual administration did not show statistical difference.(ABSTRACT TRUNCATED AT 250 WORDS)