The effects of chronic oral diltiazem and cimetidine dosing on the pharmacokinetics and negative dromotropic action of intravenous and oral diltiazem in the dog.
ABSTRACT The kinetics and negative dromotropic action of intravenous (1 mg kg-1) and oral (5 mg kg-1) diltiazem were studied in dogs after acute doses, after treatment for 3 days with oral diltiazem (5 mg kg-1, t.i.d.), and after 3 days' treatment with oral diltiazem (5 mg kg-1 t.i.d.) and cimetidine (200 mg t.i.d.). Plasma concentrations of diltiazem and two of its metabolites, desacetyldiltiazem and desmethyldiltiazem were measured by HPLC. Chronic oral dosing significantly lowered both the systemic and oral clearance of diltiazem, with no changes in either the volume of distribution or blood binding of diltiazem. Cimetidine treatment resulted in a significant reduction in diltiazem oral clearance from chronic control with no effect on its systemic clearance. The AUCs of both metabolites increased by greater than threefold from acute to chronic oral dosing; however, the ratio of each metabolite's AUC to that of diltiazem AUC was not significantly altered. Cimetidine treatment significantly lowered these ratios. The negative dromotropic potency of diltiazem after the acute oral dose was three times greater than that after intravenous or chronic control dosing. Cimetidine treatment resulted in further lowering chronic oral diltiazem potency. These data indicate that the disposition and negative dromotropic action of diltiazem is dependent both on the route of administration and the duration of treatment, and can be altered by co-administration with cimetidine.
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ABSTRACT: Aqueous diltiazem was given to ten healthy male volunteers in a single oral dose of 2.5 mg/kg body weight. Serum diltiazem levels were measured at various intervals up to 24 hours after administration of the drug as were blood pressure, heart rate, and PR interval. The pharmacokinetics followed a one-compartment model in six and two-compartment model in four subjects. The mean distribution half-life in the latter four subjects was 15.8 +/- 3.7 minutes (range, 10.4-18.8 min). In the ten subjects, the peak serum diltiazem level was attained in 20 to 45 minutes (mean, 32.5 +/- 9.5 min) and ranged from 136 to 701 ng/mL (mean, 332 +/- 180 ng/mL). The elimination half-life ranged from 2.8 to 4.8 hours (mean, 3.8 +/- 0.6 hr). The area under the concentration-time curve varied from 508 to 2,245 ng-hr/mL, indicating differing bioavailability. Slight but significant blood pressure reduction was seen only at one to three hours. Changes in heart rate were not significant at any measurement. Transient facial flushing, beginning at ten to 20 minutes after administration, was noted in nine subjects, reflecting the vasodilatory effect of the drug. Significant prolongation (greater than 10%) of PR intervals began at ten minutes in three, at 20 minutes in six, and at 30 minutes in one participant, and progressed to second-degree Wenckebach atrioventricular (AV) block in six subjects 20 to 60 minutes after administration and third-degree AV block in one person 45 minutes after dosing. These AV blocks resolved by the third hour without treatment, and PR prolongation resolved by the fifth to seventh hours.(ABSTRACT TRUNCATED AT 250 WORDS)The Journal of Clinical Pharmacology 03/1987; 27(2):106-10. · 2.84 Impact Factor
- Clinical Pharmacology & Therapeutics 03/1978; 23(2):165-74. · 6.85 Impact Factor
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ABSTRACT: Fifty-eight patients with malignant pericardial effusion were seen from 1979 to 1986. A Kifa catheter was inserted into the pericardial sac and allowed to drain for 12 to 24 hours during electrocardiographic monitoring. Lidocaine hydrochloride, 100 mg, was instilled intrapericardially, followed by tetracycline hydrochloride, 500 to 1,000 mg, in 20 ml of normal saline solution. The catheter was clamped for 1 to 2 hours and then reopened. This procedure was repeated daily until the net drainage was less than 25 ml/24 hours. There were 22 male and 36 female patients (median age 58 years). The primary malignancy included lung (27 patients), breast (16 patients), stomach (3 patients), adenocarcinoma of unknown primary (7 patients), mesothelioma (2 patients) and chronic granulocytic leukemia, ovary and lymphoma (1 patient each). Fifty-six patients received 1 to 5 tetracycline instillations. In 1 patient, the catheter could not be inserted and in another, clotting occurred within the catheter before injection of tetracycline. Complications included transient atrial arrhythmias (5 patients), pain after injection (9 patients) and temperature higher than 37.5 °C (5 patients). One patient had a cardiac arrest during pericardiocentesis. Forty-three patients (74%) had control of their effusions for longer than 30 days (median survival 168 days, range 30 to 1,149 +), and 5 patients (9%) died before 30 days without effusion. Eight patients (14%) did not achieve control. One declined further therapy after 1 instillation, and 3 died within 6 days with progressive malignancy. One patient had persistent drainage after 3 instillations, and 3 had reaccumulation of fluid 2, 6 and 27 days after catheter removal. One patient had pericardial constriction secondary to pericardial metastases. No patient surviving longer than 30 days had recurrent effusion or constriction. Intrapericardial tetracycline is safe and efficacious and should be considered the first method of treatment for malignant pericardial effusion.The American Journal of Cardiology 12/1987; · 3.21 Impact Factor