Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study.

OBJECTIVE: The goal of this study was to investigate the safety and tolerability of the novel endothelin A (ETA) receptor antagonist clazosentan in patients with subarachnoid hemorrhage (SAH) and its potential to reduce the incidence and severity of cerebral vasospasm following surgical clipping of the aneurysm. METHODS: This Phase IIa multicenter study had two parts: a double-blind, randomized Part A (some patients given clazosentan [0.2 mg/kg/hr] and others given placebo), in which statistical inference was performed, and an open-label Part B (patients with established vasospasm given clazosentan [0.4 mg/kg/hr for 12 hours followed by 0.2 mg/kg/hr]) for exploratory purposes only. Primary end points were the incidence and severity of angiographic vasospasm on Day 8 after SAH and the safety and tolerability of the drug. Thirty-four patients (Hunt and Hess Grades III and IV and Fisher Grade > or = 3) were recruited and 32 (15 in the clazosentan group and 17 in the placebo group) were retained in the intent-to-treat population; 19 patients entered Part B. In Part A, treatment with clazosentan resulted in a reduced incidence of angiographically evident cerebral vasospasm (40% compared with 88% of patients, p = 0.008). In addition, the severity of vasospasm was reduced in the clazosentan group (p = 0.012). In Part B of the study, in 50% of assessable patients who were initially treated with placebo reversal of vasospasm was observed following the initiation of clazosentan therapy. The incidence of new infarctions was 15% in the clazosentan group and 44% in the placebo group (p = 0.130). There was no adverse event pattern indicating a specific organ toxicity of clazosentan. CONCLUSIONS: This study indicates that clazosentan reduces the frequency and severity of cerebral vasospasm following severe aneurysmal SAH with the incidence and severity of adverse events comparable to that of placebo.

Role of endothelin in mediating neurogenic plasma extravasation in rat dura mater.

In addition to their potent vasoconstrictor properties, the endothelins (endothelin-1 and -3) may possess neurotransmitter/neuromediator and neuroendocrine actions. The aim of the present study was to evaluate the role of endothelins (ET) in mediating neurogenic inflammation of cephalic tissues in the rat. For this purpose, bosentan, a specific non-peptide mixed antagonist of ET receptors, was tested in rat models of neurogenic and non-neurogenic plasma extravasation in the dura mater and extracranial tissues (eyelid, conjunctiva, lip, tongue). Bosentan was effective for preventing neurogenic inflammation in the dura mater induced by unilateral electrical stimulation of the trigeminal ganglion or intravenous injection of capsaicin, whereas it was ineffective in extracranial tissues or after injection of substance P (non-neurogenic inflammation). The effect of nerve fiber stimulation on ET plasma concentrations in superior sagittal sinus was measured using selective radioimmunoassays for ET-1 and -3. Endothelin-3 concentration significantly increased after intravenous injection of capsaicin, whereas ET-1 levels remained unchanged. Competition binding assays on microsomal membranes from the trigeminal ganglion revealed a single class of binding sites with equal affinity for ET-1 and ET-3, suggesting a homogenous population of ETB receptors. The role of ETB receptors in mediating inflammation was evidenced by the lack of efficacy of a selective ETA receptor antagonist, in contrast to the full efficacy of a selective ETB receptor antagonist, for preventing neurogenic inflammation induced by unilateral stimulation of the trigeminal ganglion. The role of ETB receptors was finally confirmed by the observation that exogenous administration of the ETB receptor agonist sarafotoxin S6c also induced plasma protein extravasation in the dura mater. This extravasation was not a direct effect of ETB receptor stimulation, because it was inhibited by spantide, a selective tachykinin receptor antagonist. These data strongly suggest that ET, acting through ETB receptors, may play an important role in mediating neurogenic inflammation in the meninges of rats. Since the profile of activity of bosentan is similar to that of the 5-HT1D/B agonists, sumatriptan and ergot alkaloids, one may speculate that ET receptor antagonists might be potentially effective in the treatment of acute migraine attacks.