Absolute bioavailability and absorption profile of cyanamide in man.

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L.kg-1.min-1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg x +/- SEM values of Cmax, tmax (median) and AUC were 0.18 +/- 0.03, 0.91 +/- 0.11, and 1.65 +/- 0.27 micrograms.ml-1; 13.5, 13.5, and 12 min; and 8.59 +/- 1.32, 45.39 +/- 1.62, and 77.86 +/- 17.49 micrograms.ml-1.min, respectively. Absorption was not complete and the oral bioavailability, 45.55 +/- 9.22, 70.12 +/- 4.73, and 80.78 +/- 8.19% for the 0.3, 1.0, and 1.5 mg/kg doses, respectively, increased with the dose administered. The models that consider a first-order absorption process alone (whether with a fixed or variable bioavailability value as a function of dose) or with loss of drug due to presystemic metabolism (with zero-order or Michaelis-Menten kinetics) were simultaneously fitted to plasma level data obtained following 1 mg/kg i.v. and 0.3, 1.0, and 1.5 mg/kg oral administrations. The model that best fit the data was that with a first-order absorption process plus a loss by presystemic metabolism with Michaelis-Menten kinetics, suggesting the presence of a saturable first-pass effect.

Evaluation of the central effects of alcohol and caffeine interaction.

1. The dynamic and kinetic interactions of alcohol and caffeine were studied in a double-blind, placebo controlled, cross-over trial. Treatments were administered to eight healthy subjects in four experimental sessions, leaving a 1 week wash-out period between each, as follows: 1) placebo, 2) alcohol (0.8 g kg-1), 3) caffeine (400 mg) and 4) alcohol (0.8 g kg-1) + caffeine (400 mg). 2. Evaluations were performed by means of: 1) objective measures: a) psychomotor performance (critical flicker fusion frequency, simple reaction time and tapping test), b) long latency visual evoked potentials ('pattern reversal'); 2) subjective self-rated scales (visual analogue scales and profile of mood states); 3) caffeine and alcohol plasma concentration determinations. 3. The battery of pharmacodynamic tests was conducted at baseline and at +0.5 h, +1.5 h, +2.5 h, +4 h and +6 h. An analysis of variance was applied to the results, accepting a P < 0.05 as significant. The plasma-time curves for caffeine and alcohol were analysed by means of model-independent methods. 4. Results obtained with caffeine in the objective measures demonstrated a decrease in simple reaction time and an increase in the amplitude of the evoked potentials; the subjects' self-ratings showed a tendency to be more active. Alcohol increased simple reaction time and decreased amplitude of the evoked potentials, although the subjects rated themselves as being active. The combination of alcohol + caffeine showed no significant difference from placebo in the objective tests; nevertheless, the subjective feeling of drunkenness remained. The area under the curve (AUC) for caffeine was significantly higher when administered with alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple dose pharmacokinetic study of cicletanine in healthy volunteers.

Cicletanine hydrochloride, a furopyridine derivative, is a new type of antihypertensive drug. A pharmacokinetic study was performed in 8 non-patient subjects who were given 50 mg oral daily doses for 7 days. Cicletanine plasma levels were measured by HPLC. An open bicompartmental model was fitted to the experimental data using an extended non-linear regression method. Additionally plasma levels obtained after the first administration were used to determine pharmacokinetic parameters, which were considered as representative of a single dose administration. The results showed no significant differences between parameters estimated after the first dose and repeated dosing. Mean half-life values were 7.3 and 7.9 hours respectively. The mean peak and trough concentration values in the last interval studied were 1730 and 44 ng/mL respectively. The accumulation index was negligible (1.15). The similarity in the values obtained after the first and repeated administration suggests that cicletanine displays a linear pharmacokinetic behaviour at a dose of 50 mg.