title: Dose-response characteristics of mibefradil, a novel calcium antagonist, in the treatment of essential hypertension.
abstract: The aim of this study was to determine the dose-response characteristics of the calcium antagonist, mibefradil, and to evaluate its antihypertensive efficacy and safety in varying doses in patients with mild-to-moderate hypertension. Three hundred and three eligible patients were randomized to receive once-daily 6.25-, 12.5-, 25-, 50-, 100-, 150-, or 200-mg mibefradil doses or placebo for 4 weeks. Repeated blood pressure measurements and electrocardiographic recordings were obtained for the 24 h following the last dose of the placebo run-in period and for the first and last doses of randomized treatment. A statistically significant (P < .001 versus placebo) and clinically relevant drop in sitting diastolic blood pressure (SDBP) both at trough and at peak was observed in the 50-, 100-, 150-, and 200-mg mibefradil dose groups (trough placebo-corrected reductions: -4.9, -9.1, -9.9, and -11.9 mm Hg, respectively), with a significant dose-response relationship (P < .001) and high response rates. Trough/peak ratios for the placebo-corrected change from baseline to week 4 in SDBP were >85% for the 50- and 100-mg doses and 68% and 69% for the 150- and 200-mg doses, respectively. The full antihypertensive effect of mibefradil was achieved within 1 week of treatment. Reductions in sitting systolic blood pressure (SSBP) closely paralleled those in SDBP. The antihypertensive effect of mibefradil was associated with a slight dose-dependent decrease in heart rate and increase in the pulse rate (PR) electrocardiographic interval [corrected]. The appropriate therapeutic dose range of mibefradil in the management of mild-to-moderate essential hypertension is 50 to 100 mg.
authors.affiliation: University of Alabama at Birmingham, 35294, USA.
authors.forename: S
authors.initials: S
authors.lastname: Oparil
authors.forename: I
authors.initials: I
authors.lastname: Kobrin
authors.forename: D R
authors.initials: DR
authors.lastname: Abernethy
authors.forename: B S
authors.initials: BS
authors.lastname: Levine
authors.forename: M C
authors.initials: MC
authors.lastname: Reif
authors.forename: A M
authors.initials: AM
authors.lastname: Shepherd
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D020748:Mibefradil; D008875:Middle Aged; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil