A randomized, controlled trial comparing diltiazem, hydrochlorothiazide, and their combination in the therapy of essential hypertension.

STUDY OBJECTIVES: To compare the efficacy of combination therapy with sustained-release diltiazem and hydrochlorothiazide (DTZ SR-HCTZ) with that of monotherapy with DTZ SR, HCTZ, or placebo in the treatment of essential hypertension; and to determine whether the addition of a diuretic to diltiazem at apparent optimum doses of each agent significantly enhances their antihypertensive effects. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial with a 6-week treatment phase. SETTING: Private and university-based clinics. PATIENTS AND PARTICIPANTS: Subjects of either sex, ranging in age from 18-70 years, with a diagnosis of stable essential hypertension made from two consecutive weekly mean supine diastolic blood pressure (DBP) readings of 95 mm Hg or above to 110 mm Hg or less that varied 7 mm Hg or less after 4-6 weeks in the baseline phase. Of the patients enrolled, 298 met the inclusion criteria. INTERVENTIONS: Combination therapy with DTZ SR-HCTZ 120 mg-12.5 mg, or monotherapy with DTZ SR 120 mg or HCTZ 12.5 mg, or placebo was administered twice daily. MEASUREMENTS AND MAIN RESULTS: Combination therapy with DTZ SR-HCTZ lowered both supine DBP and SBP significantly (p < 0.005) more than either single agent. The combination also lowered DBP and SBP significantly more than either monotherapy. During a 12-hour in-clinic monitoring period spanning a dosing interval, both the combination and DTZ SR therapies maintained efficacy, whereas the antihypertensive effects of HCTZ dissipated after 8 hours. Treatment-related adverse events for the combination and HCTZ were similar but slightly greater than those for DTZ SR and placebo. CONCLUSIONS: The addition of a diuretic to sustained-release diltiazem produced an enhanced antihypertensive effect compared with monotherapy with either individual agent.

A dose escalation trial comparing the combination of diltiazem SR and hydrochlorothiazide with the monotherapies in patients with essential hypertension.

A multicentre, randomised, placebo-controlled parallel group study comparing various doses of the combination diltiazem SR (DTZ SR)/hydrochlorothiazide (HCTZ) with the monotherapies was performed to delineate the optimal antihypertensive dosage of the two drug combinations. The study was carried out in 298 patients with mild to moderate essential hypertension (stable supine diastolic blood pressure, DBP, greater than or equal to 95 and less than or equal to 110 mmHg). After a single-blind placebo lead-in period lasting 4-6 weeks to establish stable baseline BP, the patients were randomised to receive either placebo (n = 75), HCTZ (n = 76), DTZ SR (n = 72), or the combination of DTZ SR/HCTZ (n = 75). There were three 4-week evaluation periods with forced escalation of therapy as follows: HCTZ (6.25, 6.25, 12.5 mg twice daily), DTZ SR (60, 90, 120 mg twice daily), and the combination of DTZ SR/HCTZ (60/6.25, 90/6.25, 120/12.5 mg twice daily). DTZ SR/HCTZ (120/12.5 mg) produced statistically significantly greater reductions in supine DBP compared with each monotherapy and placebo. The lower doses of DTZ SR/HCTZ (60/6.25 mg and 90/6.25 mg) produced statistically significantly greater supine DBP reductions compared with DTZ SR monotherapy and placebo, but not compared with HCTZ monotherapy. A comparison of reduction in supine DBP between evaluation periods demonstrated a dose-response relationship for the combination therapy in reducing BP over the dosage range studied. Adverse clinical and laboratory events were not significantly different between the therapies.(ABSTRACT TRUNCATED AT 250 WORDS)

An assessment of diltiazem and hydrochlorothiazide in hypertension. Application of factorial trial design to a multicenter clinical trial of combination therapy.

This multicenter, factorial-design trial assessed the safety and additive antihypertensive efficacy of a slow-release (SR) formulation of diltiazem hydrochloride given alone or in combination with hydrochlorothiazide for treatment of mild to moderate hypertension. After a 4- to 6-week placebo run-in period, 297 qualifying patients were randomized to receive placebo, 1 of 4 doses of diltiazem SR monotherapy, 1 of 3 doses of hydrochlorothiazide monotherapy, or 1 of 12 possible combinations of diltiazem SR and hydrochlorothiazide for 6 weeks. A dose-related reduction in blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination. Absolute blood pressures of patients who received combination therapy were lower by an overall mean of 3.0 mm Hg diastolic and 8.0 mm Hg systolic vs diltiazem SR used alone and 3.5 mm Hg diastolic and 4.0 mm Hg systolic vs hydrochlorothiazide used alone. At the largest doses used, 50% of patients achieved goal blood pressure while taking hydrochlorothiazide, 57% while taking diltiazem SR, and 75% while taking combination therapy. Combination therapy was well tolerated. This trial clearly demonstrates that diltiazem SR and hydrochlorothiazide have additive antihypertensive effects.

Acute effects of increasing doses of urapidil in patients with hypertension.

In a randomized, double-blind, dose-ranging trial, the acute antihypertensive effects of 7.5, 15, 30, 45, 60, 90, and 120 mg single daily doses of urapidil were compared with those of placebo in 10 patients with essential hypertension. Patients were randomized to either urapidil or placebo, such that each active drug day was followed by a placebo washout day. Blood pressure and heart rate responses were measured in the supine position, immediately upon standing, and after 3 to 5 minutes of standing for each dose. A variable but significant reduction in systolic and diastolic blood pressures that lasted from 4.5 to 8 hours was observed primarily at the 60, 90, and 120 mg doses (P less than 0.05). The maximum reduction in diastolic blood pressure occurred in the standing position at 3 to 5 hours after dosing. When urapidil was compared with placebo, a change from the supine to the standing positions produced a significantly larger reduction in systolic and diastolic blood pressures (P less than 0.05) but no significant change in heart rate. This suggests an acute blood pressure lowering effect of urapidil that occurs predominantly in the standing position and that does not significantly increase heart rate.

Ceforanide vs. cephalothin concentrations in total joint arthroplasty.

Total joint arthroplasty is a common orthopedic procedure and requires prophylactic antibiotic coverage to prevent infections in the operated joint. The antibiotics routinely used for prophylaxis are the cephalosporins. This study compared bone, synovial fluid, and plasma concentrations of ceforanide with cephalothin concentrations in 30 patients undergoing elective total hip or total knee arthroplasty. Ceforanide provided significantly higher plasma concentrations for 61-110 minutes postdose than did cephalothin (p less than 0.025 and p less than 0.005). No difference was noted between the two antibiotics for the bone concentrations in the total hip arthroplasty group; however, cephalothin concentrated to a greater degree in the bone of patients undergoing total knee arthroplasty (p less than 0.05). Cephalothin achieved higher concentrations in the synovial fluid than did ceforanide (p less than 0.05). Both antibiotics were well tolerated and no postoperative infections were noted in either group.

Role of alpha-2 adrenergic affinity in the action of a non-sedative antispasticity agent.

Muscle hypertonus of central origin can be effectively reversed by either dopamine agonists or alpha-adrenergic antagonists. Because of its efficacy in reversing reserpine rigidity (a syndrome resembling Parkinsonism), SKF-7265 was examined to determine whether its action was mediated through alpha-adrenergic or dopaminergic receptors. The pharmacologic blocking activity of SKF-7265 was assessed by measuring blockade of the cardiovascular agonist responses induced by norepinephrine, epinephrine, isoproterenol, acetylcholine and histamine. The binding affinity of SKF-7265 was determined by displacement of 3H-spiperone from rat corpus striatum tissue and 3H-clonidine and 3H-WB-4101 displacement from rat cerebral cortical tissue. Using the cardiovascular responses, SKF-7265 was devoid of beta-adrenergic or cholinergic blocking effects and did not produce any behavioral or reflex deficits in awake animals. Receptor binding studies showed that SKF-7265 had equal affinity for alpha-1 and alpha-2 adrenergic receptors and little affinity for dopamine receptors. It is concluded that the efficacy which has been reported for the SKF-7265 induced reversal of reserpine rigidity and its potential value as an antispasticity agent may be attributed to its relatively high affinity for alpha-2 adrenergic receptors.

The effects of erythromycin on the absorption and disposition of kinetics of theophylline.

The effects of erythromycin on the kinetics of theophylline were investigated in eight female patients with documented asthma in a crossover study. Theophylline pharmacokinetics were determined at steady state before and after one-week treatment with erythromycin stearate 250 mg given four times a day. Multiple serum samples were collected for 12 h after an aminophylline dose in the two drug treatment phases and assayed by high performance liquid chromatography. The resultant serum theophylline concentration-time data were analyzed by weighted, nonlinear regression analysis to obtain various pharmacokinetic parameters. In this study, the elimination half-live increased from 7.8 +/- 1.7 h on the control day to 9.5 +/- 1.4 h following treatment with antibiotic (p less than 0.02). The estimated apparent volume of distribution for theophylline (V/F) was also observed to increase from 0.42 +/- 0.09 l/kg before treatment with erythromycin to 0.53 +/- 0.15 l/kg after antibiotic treatment (0.05 less than p less than 0.10). In this study, no difference was demonstrated in the apparent clearance rate (Clapp), apparent first-order absorption rate constant (ka), maximum serum drug concentration (Cmax), time of maximum drug concentration (Tmax) or absorption lag time (tlag) for theophylline before and after treatment with erythromycin. With no apparent alteration in theophylline clearance following erythromycin coadministration, the decrease in the first-order elimination rate constant suggested that the apparent volume of distribution of theophylline is increased in the presence of erythromycin. It is concluded that patients maintained on theophylline derivatives should be closely monitored when erythromycin is coadministered.

Effect of smoking on the elimination of propranolol hydrochloride.

The effect of smoking on the elimination characteristics of propranolol was determined in 20 patients, 10 smokers and 10 non-smokers, who were taking the drug on a continual basis. Smokers took larger doses than non-smokers. The apparent body clearance (ABC) of propranolol in the smoking group was significantly greater than in the non-smoking group (p less than 0.01). When the serum concentrations were adjusted for body weight and dose, the non-smoking group had significantly higher serum concentrations than did the smoking group. The values for half-live (t 1/2) and elimination (k) demonstrated a trend toward a decreases in t 1/2 and increase in k in the group of smokers.

Effects of acute alcohol administration on propranolol absorption.

Alterations in propranolol absorption secondary to concomitant ethanol administration was investigated in five normal adults. With alcohol administration, there was an increase in the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (CPmax). Ethanol caused a decrease in the rate of absorption and an increase in the rate of elimination of propranolol. It appears that the acute, concomitant administration of alcohol with propranolol will alter the bioavailability of propranolol.

Use of cholestyramine resin in the treatment of digitoxin toxicity.

Two case reports describing the treatment of digitoxin toxicity with cholestyramine resin are presented. Both female patients were receiving 100 microgram/day of digitoxin when toxicity occurred. In both patients, digitoxin was discontinued and hypokalemia was corrected. In patient 1, lidocaine hydrochloride and phenytoin sodium also were administered. Serum digitoxin levels were decreased from 43 ng/ml to 21.8 ng/ml and from 42 ng/ml to 29 ng/ml in patients 1 and 2, respectively, following administration of three 4-g doses of cholestyramine resin over a one-day period. Previous studies on the treatment of digitoxin intoxication with potassium chloride, phenytoin sodium, lidocaine hydrochloride, digitoxin-specific antibodies, colestipol hydrochloride and cholestyramine resin are discussed. Ion-exchange resins may be valuable adjuncts in the treatment of digitoxin intoxication but further studies of their utility are needed.

Increased doses of phenytoin for infants.

A case report describing the problems of using conventional phenytoin dosages to achieve control of myoclonic seizures in a 6-month-old infant weighing less than 10 kg is presented. The physiologic explanations for the necessary phenytoin dosage adjustment in infants weighing less than 20 kg are discussed. It is suggested that more rapid metabolism, a larger volume of distribution and impaired gastrointestinal absorption may be responsible for the higher phenytoin dosages needed in such patients. Methods of determining appropriate dosage regimens, based on Michaelis-Menten pharmacokinetic principles or on body surface area, are discussed. Monitoring of plasma phenytoin concentrations is necessary to provide therapeutic levels of phenytoin and to prevent toxicity.