The addition of mibefradil to chronic hydrochlorothiazide therapy in hypertensive patients is associated with a significant antihypertensive effect.

OBJECTIVE: To evaluate the antihypertensive efficacy, tolerability, safety, and dose-response characteristics of the novel calcium antagonist, mibefradil, in combination with a diuretic regimen. DESIGN: A multinational, double-blind, randomised, placebo-controlled, parallel-design trial. METHODS: Three hundred and seven patients whose mild-to-moderate essential hypertension remained uncontrolled after 4 weeks of treatment with hydrochlorothiazide (HCTZ) 25 mg/day and placebo were randomised to receive combined treatment with HCTZ and once-daily doses of 12.5, 25, 50, or 100 mg of mibefradil or placebo. After 8 weeks of combined treatment, HCTZ was withdrawn and the mibefradil groups continued on their respective doses for an additional 6 weeks. RESULTS: After 8 weeks, the addition of once-daily doses of mibefradil to the initial HCTZ regimen resulted in clinically relevant, dose-related reductions in sitting diastolic blood pressure (SDBP) and sitting systolic blood pressure (SSBP) at trough, which were significantly greater in the 50 and 100 mg dose groups compared to the placebo group (P < or = 0.003). Placebo-corrected treatment effects on SDBP and SSBP at the end of the combined treatment period relative to baseline were, respectively, -4.1 and -8.0 mm Hg in the 50 mg mibefradil group and -9.5 and -8.0 mm Hg in the 100 mg mibefradil group. Therapeutic response rates to combination mibefradil and HCTZ therapy were high and dose related, reaching 82% for SDBP in the 100 mg group. CONCLUSIONS: The addition of once-daily doses of 50 or 100 mg of mibefradil to patients whose hypertension is not controlled by HCTZ alone is well tolerated and effective in improving BP control.

Sodium kinetics in salt-sensitive and salt-resistant normotensive and hypertensive subjects.

OBJECTIVE: To test the hypotheses that sodium kinetics are not affected by blood pressure, salt sensitivity, salt resistance or race, and that the kinetics of sodium balance are not a first-order process. DESIGN, PARTICIPANTS AND INTERVENTIONS: Two studies were conducted. In the first, 18 normotensive and 36 hypertensive men and women were given sodium at 120 mmol/day for 6 days, followed by 10 mmol/day for 8 days, then 400 mmol/day for 8 more days. Salt sensitivity was defined as an increase in diastolic blood pressure from the 10 to the 400 mmol/day intake. Salt resistance was defined as no increase, or a decrease in diastolic blood pressure with the increased sodium intake. In the second study, 12 white and 12 black normotensive men ingested sodium at 10, 200 or 400 mmol/day in random order, each for 7 days. All urine was collected in both protocols. SETTING: Metabolic ward at the University of Greifswald (Greifswald, Germany; study 1), and Clinical Research Center (Indiana University, Indianapolis, Indiana, USA; study 2). MAIN OUTCOME MEASURE: In addition to conventional statistics, a pharmacokinetic analysis was carried out to determine the elimination rate constant and half-life. RESULTS: In the Greifswald study, when the sodium intake was decreased, a longer half-life was determined for the salt-sensitive than the salt-resistant hypertensive subjects. The half-life for the normotensive salt-sensitive and salt-resistant subjects did not differ. When the sodium intake was decreased, a monoexponential equation fitted the data for all subjects; when the sodium intake was increased, only data for half the subjects could be fitted to the same equation. In the Indianapolis study, black race had a significant influence upon urinary sodium excretion. Furthermore, the half-life for sodium elimination was dependent upon sodium intake; namely, the greater the intake, the longer the elimination half-life. CONCLUSIONS: The time required to reach sodium balance may increase following salt-sensitive increases in blood pressure rather than precede them. Race influences the time required to achieve salt balance. Sodium kinetics are not a first-order process.

[The quantitative determination of dihydralazine and selected metabolites in man]. / Zur quantitativen Bestimmung von Dihydralazin und ausgewählter Metabolite beim Menschen.

Dihydralazine and its metabolites were estimated in the steady-state in 9 hypertonic patients by gas chromatography. Serum levels of both dihydralazine and metabolites were very low and particularly below the detection limit. In urine and faeces about half of the dose was found mainly as metabolites, 2/3 of this in faeces. Acid labile hydrazones of dihydralazine (about 6% of the dose), primary acetylated and primary oxidized metabolites (both about 20%) were identified as main metabolites. Secondary metabolites (hydrazones, acetylated and oxidized products) were measured, too.

[The quantitative identification of metabolites of dihydralazine in the human]. / Zum qualitativen Nachweis von Metaboliten des Dihydralazins beim Menschen.

The metabolism of dihydralazine sulfate was studied in 11 hypertonic patients treated with that drug chronically. The metabolites were identified in urine with gc, dc, and hplc by comparison with synthesized reference compounds. Following metabolites could be verified: acetylated products, oxidation products, hydrazones and products of decomposition. Products resulting from reaction with nitrites could be not detected.

[Quantitative determination and kinetics of dihydralazine in hypertension patients]. / Quantitative Bestimmung und Kinetik von Dihydralazin bei Hypertoniepatienten.

For the quantitative determination of dihydralazine (1) a derivative with acetylacetone in biological material was formed at pH = 4.9, extracted with n-hexane, and measured gaschromatographically with N-P-FID. Acid labile 1 was hydrolyzed with HCl (1 mol/l) for 24 h. The detection limit was 25 nmol/l plasma. Kinetic studies were performed in 16 patients with essential hypertension under steady-state conditions after the oral application of 50 mg 1. The acetylator phenotype was determined with sulfamethazine. Complete dihydralazine plasma level-time courses were found in only 5 cases. The concentrations were below the detection limit in 4 patients for the whole period. Only single values could be registered in the remaining patients. Maximal plasma levels of the free (58-314 nmol/l) and acid labile 1 (147-367 nmol/l) were reached 20-40 min after the application. The elimination half life was 23-47 min for the free 1, 55-92 min for the acid labile 1. Less than 0.5% of the applied drug were excreted into the 24 h urine in its free form, about 0.4% as acid labile derivatives. No correlation could be found between the acetylator phenotype of the patients and the kinetic behaviour of the drug. Preliminary studies concerning the biliary excretion of 1 after i. m. application in two patients with T-drain showed an accumulation of the free compound with bile/plasma ratios up to 7.4.

The influence of the acetylator phenotype for the clinical use of dihydralazine.

Dihydralazine is a substrate of the human N-acetyltransferase. Therefore the acetylator phenotype could influence the pharmacodynamic response of dihydralazine and/or side effects of this drug. In this study it could be shown that: among patients with dihydralazine incompatibility slow acetylators preponderated; the risk of early side effects was higher in females than in males; and the ratio of fast/slow acetylators was higher in dihydralazine treated patients than in patients treated with other antihypertensives. Dihydralazine should be given very cautiously to female hypertonic patients that are slow acetylators.