Absence of a sertraline-mediated effect on digoxin pharmacokinetics and electrocardiographic findings.

UNLABELLED: The effects of oral administration of sertraline on the plasma concentration profile and renal clearance of digoxin were assessed in 20 healthy male subjects in a double-blind, randomized study. METHOD: All subjects first received digoxin 0.5 mg twice daily on Day 1, 0.25 mg twice daily on Day 2, and 0.25 mg daily thereafter. On Day 11, 10 subjects began concomitant sertraline administration with an initial dose of 50 mg/day that was titrated upward over 7 days to 200 mg/day, which was given over the remainder of the study period. The other 10 subjects received concomitant digoxin and placebo for 17 days beginning on Day 11. Trough plasma concentrations of digoxin were monitored daily beginning on Day 7. Blood samples and 24-hour urine collections were used to determine steady-state digoxin concentration and renal clearance before, during, and after sertraline coadministration. RESULTS: Sertraline had no effect on digoxin pharmacokinetics, except for a decrease in the time to reach the maximum plasma digoxin concentration (Tmax) compared with placebo (p = .0046), a finding thought to be of limited clinical significance. Side effects of mild-to-moderate severity were reported by 5 of 10 sertraline-treated subjects and by 6 of 10 placebo-treated subjects. CONCLUSION: The results of this study suggest that dosing adjustments of digoxin may not be necessary in patients receiving concomitant sertraline administration.

Absence of a sertraline-mediated effect on the pharmacokinetics and pharmacodynamics of carbamazepine.

UNLABELLED: A double-blind, randomized, placebo-controlled study was conducted in 14 healthy male volunteers to assess the effects of sertraline on the pharmacokinetics and pharmacodynamics of carbamazepine. METHOD: Subjects received carbamazepine 200 mg once daily for 2 days and every 12 hours thereafter. On Days 16 to 32, subjects also received either sertraline or placebo daily. The dose of sertraline was increased from 50 to 200 mg daily over 7 days; the 200-mg dose was given for 10 days. Samples for pharmacokinetic analyses were obtained on Days 15 and 32; trough plasma concentrations of carbamazepine and its principal metabolite, carbamazepine-10, 11-epoxide (CBZ-E), were determined daily beginning on Day 13. Cognitive function testing was performed on Day 1 before carbamazepine dosing (baseline), Day 15 (carbamazepine alone), and Day 32 (carbamazepine plus sertraline or placebo). RESULTS: There were no significant differences between the sertraline and placebo groups in any of the pharmacokinetic parameters for carbamazepine or CBZ-E. Carbamazepine alone impaired cognitive function. The addition of sertraline did not potentiate these effects. Side effects were reported by 2 subjects in each group, but none were severe. CONCLUSION: These findings indicate that sertraline does not affect the pharmacokinetics of carbamazepine or its principal metabolite and does not potentiate the cognitive effects of carbamazepine.

Effect of tenidap sodium on digoxin pharmacokinetics in healthy young men.

1. The effects of tenidap sodium and placebo on digoxin pharmacokinetics were compared in 14 healthy young men, in a double-blind, parallel-group study lasting for 24 days. 2. Subjects were administered digoxin alone for the first 10 days and digoxin plus tenidap 120 mg day-1 or placebo for the remaining 14 days. 3. Changes in the means between day 10 (digoxin monotherapy) and day 24 (combined therapy) for renal clearance, area under the plasma concentration-time curve during the dosing interval, and the minimum and maximum plasma digoxin concentrations did not differ significantly between the tenidap and placebo groups. There was a small but statistically significant increase (0.5 h) in the time taken to reach maximum plasma digoxin concentration following 14 days' continuous tenidap co-administration compared with placebo, but this was not considered to be clinically meaningful. 4. Co-administration of tenidap and digoxin was well tolerated. No subject withdrew from the study during combination treatment. Treatment-related adverse events were of mild to moderate severity and were reported by four subjects on digoxin monotherapy, four on tenidap and digoxin, and by two on digoxin and placebo. Those reported by the tenidap group predominantly affected the gastrointestinal system and were mild in severity. There were no reports of laboratory test abnormalities or cardiovascular abnormalities related to combined digoxin and tenidap administration. 5. The results of this study indicate that, in healthy young men, co-administration of tenidap with digoxin does not have any apparent clinically significant effects on the pharmacokinetic profile of digoxin, and the treatment is well tolerated.

Pharmacokinetics of cilazapril during repeated oral dosing in healthy young volunteers.

The pharmacokinetics of cilazapril and its active metabolite cilazaprilat in plasma were investigated in an open study of 13 healthy male volunteers, aged 18 to 43 years. One capsule containing 2.5 mg cilazapril was administered to each volunteer daily for 8 days. Plasma samples were obtained after the first and eighth doses. Concentrations of cilazapril, cilazaprilat and activities of angiotensin converting enzyme (ACE) were measured by radioenzymatic methods. For cilazapril, the values of apparent plasma clearance (about 15 l/h) and volume of distribution (around 28 l) were sufficiently high to suggest that significant pre-systemic hydrolysis to cilazaprilat occurred. There were no significant changes in these values after repeated dosing. There were small, but statistically significant, increases in mean peak concentrations, mean areas under concentration-time curves and mean trough concentrations from the first to the eighth dose. A steady state was achieved after eight doses with an accumulation of 20-30%. The mean effective half-life was approximately 9 h. Despite the accumulation of cilazaprilat in plasma, there were no significant differences in plasma ACE inhibition from the first to the eighth dose.

The effects of cicletanine, a new antihypertensive compound, on the flare and weal response to histamine.

This was an open experimental pilot study in five volunteers to identify any useful effect of cicletanine in the prevention or relief of the flare and weal response to histamine injection on the forearm. Areas of the flare and weal responses to three different concentrations of intradermal histamine injection were determined. Choice reaction time was measured to assess CNS performance. Heart rate, blood pressure and visual near-point were measured as indices of autonomic response. Oral cicletanine (200 mg) reduced the flare and weal response below pretreatment values for at least 8 h (p less than 0.05). There were no apparent changes in heart rate or visual near-point, nor any sedative effects. Diastolic blood pressure was significantly elevated 6 and 8 h after cicletanine (p less than 0.05) but systolic blood pressure was not affected. These results show that cicletanine is a potent non-sedative antihistamine compound.

Long-term monitoring of the effects of thymoxamine hydrochloride tablets in the management of patients with Raynaud's disease.

Seventeen patients with Raynaud's disease were followed whilst receiving treatment with 40 mg thymoxamine hydrochloride 4-times daily for period ranging between 11 and 19 months. Digital artery patency and blood flow changes, assessed by Doppler ultrasound techniques after different thermal stresses, were monitored regularly as were platelet aggregation to ADP and collagen, platelet adhesion to glass beads, measures of blood coagulation and fibrinolysis, and plasma viscosity. Significant clinical improvement noted at 1 month appeared to improve further at 3 months and was maintained thereafter. Vessel patency rates at 10 degrees C and 21 degrees C improved significantly during treatment and both collagen- induced aggregation and platelet retention were significantly inhibited. These unexpected effects on platelet function are not readily explained by the drug's documented activity as a selective alpha-adrenergic antagonist and they may represent other hitherto unrecognized pharmacological effects which merit further exploration. The study also confirmed the usefulness of Doppler techniques for continuous atraumatic evaluation of digital vessel patency and investigation of therapeutic regimens on intermittent digital artery obstruction in Raynaud's disease.