Darusentan: an effective endothelinA receptor antagonist for treatment of hypertension.
BACKGROUND
The antihypertensive efficacy and safety of darusentan, a new selective endothelin, antagonist was investigated.


METHODS
In a multicenter randomized, double-blind, parallel-group, dose-response study, a 2-week placebo run-in period was followed by a 6-week treatment period and then a 2-week placebo withdrawal period. At baseline before darusentan therapy, the average blood pressure (BP) of the patient population studied was diastolic 103.49 (SD 3.55) and systolic 168.27 (SD 16.63) mm Hg. In total, 392 patients were randomized (darusentan 10 mg: 94 patients, 30 mg: 103 patients, 100 mg: 96 patients, placebo: 99 patients).


RESULTS
Darusentan significantly reduced diastolic (mean difference to placebo: 10 mg: -3.7 mm Hg, 95% confidence interval (CI): -6.6, -0.9, P = .009; 30 mg: -4.9 mm Hg, 95% CI: -7.7, -2.2, P = .0005; 100 mg: -8.3 mm Hg, 95% CI: -11.1, -5.5, P = .0001) and systolic BP (mean difference to placebo: 10 mg: -6.0 mm Hg, 95% CI: -11.0, -0.9, P = .02; 30 mg: -7.3 mm Hg, 95% CI: - 12.3, -2.4, P = .004; 100 mg: - 11.3 mm Hg, 95% CI: -16.3, -6.2, P = .0001). Pulse rate remained unchanged in all groups. There was a trend toward more adverse events in the active treatment groups (placebo: 30.3%, 10 mg: 44.7%, 30 mg: 40.8%, 100 mg: 49.0%). Headache was the most commonly reported adverse event, with no relevant difference among treatments. Flushing and peripheral edema were seen in a dose-dependent fashion in the active treatment groups only.


CONCLUSIONS
These data, the first, suggest the therapeutic benefit of selective endothelinA receptor antagonism in human hypertension.
Abbott GmbH & Co. KG, Ludwigshafen, Germany. nakov@gmx.de
Roumen
R
Nakov
Egon
E
Pfarr
Siegfried
S
Eberle
D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D044022:Receptor, Endothelin A; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan