Urinary excretion kinetics of intact quinidine and 3-OH-quinidine after oral administration of a single oral dose of quinidine gluconate in the fasting and non-fasting state.

To obtain more precise urinary excretion data of intact quinidine (D) and its main metabolite, 3-OH-quinidine (DM), the specific HPLC method of Bonora et al has been used to follow its urinary excretion kinetics. In a cross-over study, 2 commercial dosage forms of quinidine gluconate, fast- and slow-release, were administered to 18 healthy subjects who had fasted for 10 hours in 3 treatments which were administered during the fasting period (T1), and before (T2) of after (T3) a standard breakfast. The urine was collected at fixed time intervals for 72 hours after the administration of a single dose (405 mg of quinidine base). The difference between the drug release characteristics of the two products was studied by analysing the cumulative amount of D and DM excreted as a function of time, and the time required to reach the maximum value for the urinary excretion rate of intact quinidine. A food effect could be noticed among treatments with the conventional fast-release dosage form when comparing the maximum values of the urinary excretion rate of D (T2 greater than T1). There was no significant difference in the percentage of drug absorbed from the 2 products, according to the data on the cumulative amount of D and DM. The parameters estimated for quinidine and the metabolite were: the apparent half-life of elimination, the urinary excretion rates and the time to reach a maximum value in the urinary excretion rate. The urinary excretion rate constant and the renal clearance were also quantified for quinidine by combining urinary parameters with the corresponding serum data previously reported.

Butriptyline: human pharmacokinetics and comparative bioavailability of conventional and sustained release formulations.

The pharmacokinetics and relative bioavailability of butriptyline from conventional and a sustained release (SR) formulation have been studied in a panel of 14 volunteers. A single oral dose of 75 mg butriptyline hydrochloride was administered and a 2 X 2 latin square design was followed. Pharmacokinetic modelling has shown that the plasma butriptyline concentration/time profile is adequately described by a two-compartment open model; good agreement was obtained for the model-fitted and measured parameters. The SR formulation was shown to possess sustained release characteristics as evidenced by the increase in Tmax for 2.6 to 7.5 h, the decrease in Cmax from 46.5 to 10.3 ng ml-1, and a three-fold increase in 'half-value duration' (HVD). The changes have been achieved without any significant decrease in the relative bioavailability of the SR formulation. The half-life of butriptyline in plasma was about 20 h and was not formulation dependent.

The effect of buffering on oxyphenbutazone absorption kinetics and systemic availability.

A systemic availability study comparing an investigational buffered tablet formulation of oxyphenbutazone and a commercially available product, the efficacy of which has been well established by usage, is reported. The experiment was designed to dissociate formulation factors from all other sources of variation including differences between subjects, sexes, sequences of administration, experimental periods, as well as sex by sequence, sex by period, and sex by formulation interactions. Systemic availability was assessed by conventional pharmacokinetic techniques. Results show that buffering of a tablet formulation consistently increased the rate and degree of absorption. Although the relative magnitude of bioavailability indicators is slightly different according to the method of calculation, the estimates are always higher with the buffered formulation. No statistical difference was observed for plasma concentration-time profiles between sexes. The wide range of observed concentrations over the time interval of this study confirms other reports of individual variations in handling oxyphenbutazone. The differences noted between the two formulations may be attributed to faster dissolution rate characteristics and better dispersion of oxyphenbutazone. Some aspects of the clinical relevance of this situation are discussed briefly.

Acupuncture for smokers: lack of long-term therapeutic effect in a controlled study.

Two types of acupuncture therapy, one aimed specifically at smoking withdrawal and the other aimed at enhancing relaxation, were compared with self-monitoring in 75 healthy men that wished to stop smoking. During the 2 weeks following treatment there was no significant difference in the adjusted mean daily smoking rates of the subjects receiving acupuncture therapy of the two types, but their combined rate was significantly lower than the rate of the subjects in the self-monitoring group. However, at 1, 3, and 6 months following treatment there were no longer statistically significant differences between the three treatment groups in the adjusted mean smoking rates. At no time were there significant differences between the three treatment groups in the proportion of subjects that stopped smoking during the study. Although acupuncture appears to have become a popular treatment for cigarette smokers, its effectiveness remains to be proven in the treatment of tobacco addiction.

Comparative biopharmaceutical performance of imipramine formulations in man.

The systemic availability of an investigational liquid formulation of imipramine was compared to that of a commercially available tablet (Tofranil) whose therapeutic efficacy has been established by usage. The experiment was conducted under controlled conditions and a balanced 2-by-2 crossover design was used to dissociate the significance of formulation effects from subject, group, and experimental period sources of variation. Pharmacokinetic interpretation and statistical analysis of plasma concentrations as a function of time and of systemic availability indicators reveal a nearly identical biopharmaceutical behavior for the two preparations. Significant differences (P less than 0.05) were found in the cumulative area under the plasma concentration--time curve (AUC) up to 4 hours after administration and the availability lag time, but not in the maximum plasma concentration, the time at which this concentration is reached, the first-order availability rate constant, and the AUC to infinity. These results collectively indicate a very similar biopharmaceutical performance, where the differences in the early AUC values are partly attributable to a longer availability lag time for the tablet formulation.

Quantitative determination of plasma oxyphenbutazone by gas-liquid chromatography with selective nitrogen detection.

A sensitive and specific gas chromatographic method, using the nitrogen-phosphorus detector for the detection and determination of oxyphenbutazone extracted from plasma is described. The method involves extraction and back-extraction steps followed by derivatization of both oxyphenbutazone and the internal standard with trifluoroacetic anhydride. The procedure permits the rapid and specific routine determination of oxyphenbutazone in plasma with a detection limit of 0.5 microgram/ml. The procedure is linear over the range of concentrations encountered after administration of a single oral therapeutic dose. No interference from the biological matrix is apparent. The suitability of the method for the analysis of biological samples was tested by studying the variation with time of oxyphenbutazone plasma concentrations in normal human volunteers over a period of several biological half-lives.

Clonazepam: its efficacy in association with phenytoin and phenobarbital in mental patients with generalized major motor seizures.

In a 36-week controlled study, the efficacy of clonazepam administered with phenytoin and phenobarbital was evaluated in twenty-four epileptic mental patients suffering from major motor seizures. The patients were distributed in two strata according to the presence or the absence of chlorpromazine. As compared with placebo treatment in the chlorpromazine-free patients, a significant reduction in the frequency of the tonic-clonic seizures was observed during the 24-week clonazepam treatment. This effect could not be observed in the patients requiring the antipsychotic drug. The EEG performed before and at the end of the experimental period did not show any significant change. The most common adverse reactions to clonazepam were drowsiness and ataxia; they diminished with continued treatment.

Nanogram-range determination of plasma imipramine by gas-liquid chromatography using a selective nitrogen/phosphorus detector.

A sensitive and specific gas chromatographic method for the quantitative determination of plasma concentrations resulting from a single normal therapeutic dose of imipramine has been developed and is descriged. After extraction into a mixture of n-heptane/isoamyl alcohol (98.5:1.5), imipramine is well separated from its main metabolite, desmethylimipramine, and both compounds are detected using a selective detector operating in the N/P mode. The procedure permits the rapid routine quantitative analysis of relatively small plasma volumes (1-2 ml) containing as little as 1-2 ng of imipramine. No interference from the biological matrix is apparent. The suitability of the method for the analysis of biological samples was tested by studying the time of course of imipramine plasma concentrations in normal human volunteers, after administration of a single therapeutic dose.

Thought-stopping as a treatment for reducing cigarette smoking.

Three treatments, thought-stopping, group discussion, and the wearing of a badge saying "I don't smoke", each combined with self-monitoring, were compared to one another and to self-monitoring alone for their ability to modify the smoking behavior of 60 volunteers. All procedures led to an important reduction of the smoking rate at the beginning of treatment, the reduction being significantly greater with thought-stopping. The latter remained the most successful treatment during the 6-month follow-up, although it did not differ significantly from self-monitoring alone.

Subjective phenomena in drug trials.

Three types of problem arise from subjective phenomena in drug trials: problems of control, measurement, and analysis. Examples are given in order to illustrate these three aspects and to present some recent advances in clinical pharmacology. The author discusses the control of drug compliance, the validity of questionnaires, the subjectivity of the observer and that of the observations. Drug side-effects and the statistical analysis of qualitative data are presented in more detail.

Hypolipidemic effect of tibric acid. A comparison with clofibrate and placebo in type IV hyperlipoproteinemia.

The effects of tibric acid, clofibrate, and placebo were compared in type IV hyperlipidemic patients for a 6-month period. The patients were divided into two pathological level groups according to their baseline triglyceride levels. Compared to the placebo, both tibric acid and clofibrate reduced the mean serum triglyceride concentration in the high pathological level group; however, clofibrate was also effective in the low pathological level group. The effects on total cholesterol were less pronounced with the two drugs. No effect was observed on esterified cholesterol, phospholipids, free fatty acids, and fasting blood sugar. After a 6-week follow-up period under placebo, no rebound of the triglyceride and cholesterol levels could be observed after discontinuation of the two active drugs. The other biochemical changes observed after each active treatment are discussed in relation to the different degree of activity of each active drug and to the different baseline levels of triglycerides.

[Physiological and psychological effects of biological feed-back training (alpha and EMG) among drug using college students]. / Effets physiologiques et psychologiques de l'entraînement à la rétroaction biologique (alpha et emg) chez des étudiants usagers de drogues.

Twenty-four volunteer college students, who were regular drug users, were randomly allocated to three training groups of equal size: alpha feedback, EMG feedback and a joked control group. Subjects, who were unaware of which feedback condition they received, were asked to practice at home during a six month follow-up period to achieve a relaxed state similar to that experienced during training. No group was successful in retaining gains made in their alpha levels during each session. The EMG group, however, significantly reduced their muscular activity during training and retained the improvement during follow-up. The alpha and joked groups did not significantly improve their EMG during training but at follow-up achieved the same levels as the EMG group. There was evidence to suggest a reduction in drug use among light and medium users that was maintained during follow-up. Significant and lasting improvements were made by each group in the duration and quality of their sleep. Anxiety levels were also reduced.