Effects of the selective endothelin A (ET(A)) receptor antagonist Clazosentan on cerebral perfusion and cerebral oxygenation following severe subarachnoid hemorrhage - preliminary results from a randomized clinical series.
OBJECTIVE
To study the effects of clazosentan, a new selective endothelin receptor subtype A antagonist, on cerebral perfusion and cerebral oxygenation following severe aneurysmal subarachnoid haemorrhage (aSAH).


METHODS
All 12 patients treated at our institution in the context of a phase IIa, multicenter, randomized trial on clazosentan's safety and efficacy in reducing the incidence of angiographic cerebral vasospasm were included in this substudy. The phase IIa study (n = 34) consisted of two parts: a double-blind, randomized Part A (clazosentan 0.2 mg/kg/h versus placebo) and an open-label Part B (clazosentan 0.4 mg/kg/h for 12 h followed by 0.2 mg/kg/h) for patients with established vasospasm. In parallel to the phase IIa study protocol, which included assessment of vasospasm by angiography and transcranial Doppler sonography, we determined regional cerebral blood flow (rCBF), cerebrovascular resistance, and regional tissue oxygenation.


RESULTS
Cerebral perfusion was comparable between treatment groups during the early post-bleeding period (rCBF placebo, 22.6 +/- 3.5 ml/100 g/min versus rCBF clazosentan, 23.9 +/- 1.1 ml/100 g/min). By the time of control angiography (day 8 after aSAH), rCBF decreased by 50% in the placebo group (11.3 +/- 6.7 ml/ 100 g/min) while it remained stable in the clazosentan group (23.5 +/- 12.9 ml/100 g/min). During Part B of the study, all 3 patients who developed haemodynamically relevant vasospasm during placebo treatment, showed a sustained improvement in rCBF upon conversion to clazosentan.


CONCLUSIONS
These preliminary data suggest that clazosentan reduces the extent of vasospasm-associated impairment of cerebral perfusion following aSAH. Furthermore, clazosentan may exert beneficial actions on overt vasospasm-associated hypoperfusion.
Barth
M
M
Department of Neurosurgery, Faculty for Clinical Medicine of the Karl-Ruprecht-University of Heidelberg, University Hospital Mannheim, Mannheim, Germany.
Capelle
H-H
HH
Münch
E
E
Thomé
C
C
Fiedler
F
F
Schmiedek
P
P
Vajkoczy
P
P
D000328:Adult; D001921:Brain / Q000378:metabolism*; D002533:Cerebral Angiography; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004146:Dioxanes / Q000009:adverse effects* / Q000627:therapeutic use*; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000378:metabolism*; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000503:physiopathology; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use*; D013777:Tetrazoles / Q000009:adverse effects* / Q000627:therapeutic use*; D017585:Ultrasonography, Doppler, Transcranial; D014655:Vascular Resistance; D020301:Vasospasm, Intracranial / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*
D004146:Dioxanes; D065130:Endothelin A Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan; D010100:Oxygen