Efficacy and safety of rilmenidine for arterial hypertension.

To assess the long-term acceptability and efficacy of rilmenidine (S 3341), patients with placebo-resistant hypertension (diastolic blood pressure [BP] greater than or equal to 95 mm Hg and less than 115 mm Hg) were included in an open 1-year treatment study. Eight examinations allowed treatment adaptation if diastolic BP remained greater than or equal to 90 mm Hg (monotherapy with rilmenidine, 1 or 2 mg/day, followed by the addition of a diuretic, then tritherapy). Three hundred seventeen patients, aged 58.0 +/- 0.7 years, were included. Two hundred sixty-nine were followed for 1 year and 48 withdrew from the trial without any symptom suggesting a withdrawal syndrome: 4 because of adverse effects; 6, lack of efficacy despite triple therapy; 9, intercurrent diseases; 10, noncompliance independent of adverse effects; 18, personal reasons not associated with treatment; and 1, lost to follow-up. On the 12th month, the decrease in supine systolic and diastolic BP reached 25 and 17 mm Hg with monotherapy (n = 150), 26 and 17 mm Hg with double therapy (n = 90) and 20 and 15 mm Hg with triple therapy (n = 29). BP was normalized (diastolic BP less than or equal to 90 mm Hg) on months 6 and 12 in 80 and 84% of the patients, respectively. Monotherapy was maintained in 66 and 60% of these patients, respectively, two-thirds being treated with 1 mg once daily. Adverse effects with monotherapy were mainly observed at the beginning of treatment in 3 to 8%: dry mouth, asthenia, gastralgia, palpitations, drowsiness, insomnia; other adverse effects were rare (1 to 2%).(ABSTRACT TRUNCATED AT 250 WORDS)

The imidazoline-preferring receptor.

Evidence gathered over the past ten years supports the existence of subtypes of alpha 2-adrenoceptors. A receptor which resembles the alpha 2-adrenoceptor, called the imidazoline-preferring receptor (IPR), is virtually insensitive to catecholamines but binds selectively imidazolines and oxazolines such as idazoxan and rilmenidine. In contrast, the catecholamine-preferring alpha 2-adrenoceptor is preferentially activated by catecholamines including alpha-methylnorepinephrine and epinephrine and is antagonized selectively by rauwolscine. In addition to different pharmacological profiles to agonists and antagonists, the IPR and alpha 2-adrenoceptors show differences in anatomical distribution and molecular properties. The evidence has been drawn primarily from in vitro physiological and radioligand binding studies, but is gradually extending into in vivo and even clinical studies.

Vasodilator therapy: interaction of nitrates with angiotensin-converting enzyme inhibitors.

Nitrates and other nitrosovasodilators are locally acting agents. Their efficacy is reported to depend upon the availability of sulfhydryl groups in vascular smooth muscle. Long term nitrosovasodilator therapy has limited effectiveness, and development of nitrate tolerance has been recognized to be due to exhaustion of the tissue sulfhydryl pool, in addition to vasodilation-induced reflex activation of the neurohumoral system. Under both experimental and clinical conditions it has been demonstrated that N-acetylcysteine and other exogenously introduced sulfhydryl donors potentiate hemodynamic responses to nitrates and reverse nitrate tolerance. The newer group of angiotensin-converting enzyme (ACE) inhibitor drugs has been reported to be effective in reducing afterload and preload in a variety of experimental and clinical trials. Captopril, the first developed ACE inhibitor, and its analogs contain sulfhydryl groups. Although the sulfhydryl group of captopril is not thought to be responsible for its vasodilator action, it can act as a sulfhydryl donor to promote nitrate effectiveness and prevent development of tolerance. Limited experimental and clinical trials on combined therapy with nitrates and captopril have produced promising results. An ingenious prototype compound, S-nitrosocaptopril, has recently been synthesized. This is an exciting new development in vasodilator therapy, but clinical application must await full experimental characterization of this and other identical compounds.

Comparative effects of rilmenidine and clonidine on bronchial responses to histamine in asthmatic subjects.

1. The effects of pretreatment with clonidine and rilmenidine, a new alpha 2-adrenoceptor agonist, on the bronchial responses to inhaled histamine were studied on 3 different days in a controlled, double-blind, randomized study in 12 asymptomatic asthmatic subjects. Clonidine and rilmenidine were orally administered as single and equipotent doses of 150 micrograms and 1 mg, respectively. All the subjects were non-smokers with normal lung function tests (forced expiratory volume in one second (FEV1) = 97 +/- 10% predicted FEV1). 2. Histamine (first dose = 543 nmol) was delivered by a breath activated dosimeter (DeVilbiss no. 646 nebulizer) every 5 min; FEV1 was measured in triplicate after each dose and the largest value was analyse. The three dose-response curves were compared by analysis of variance. 3. Both clonidine and rilmenidine decreased arterial blood pressure in all subjects. There was no difference in baseline values and pre-challenge values of FEV1 after placebo, clonidine and rilmenidine on the 3 study days. Compared with placebo, both rilmenidine and clonidine significantly increased the bronchial responses to histamine (P less than 0.05 and P less than 0.01 respectively) an effect which was significantly more marked with clonidine than rilmenidine (P less than 0.05). 4. We suggest that the enhancement of bronchial responsiveness to histamine by clonidine and rilmenidine may result from their effects on both central and peripheral alpha 2-adrenoceptors, and that the lesser aggravation of histamine-induced bronchial obstruction in asthmatic subjects on rilmenidine might be explained by its lesser central and/or greater peripheral effects than clonidine.