Systemic Administration of the Endothelin- A Receptor Antagonist TBC 11251 At tenuates Cerebral Vasospasmafter Experimental Subarachnoid Hemorrhage: Dose Study and Review of End othelin-based Therapies in the Literatureon Cerebral Vasospasm

Systemic Administration of the Endothelin- A Receptor Antagonist TBC 11251 At tenuates Cerebral... AbstractOBJECTIVEIncreasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ETA receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH).METHODSEighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measuredRESULTSThe mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups Seated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups.CONCLUSIONThese findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Systemic Administration of the Endothelin- A Receptor Antagonist TBC 11251 At tenuates Cerebral Vasospasmafter Experimental Subarachnoid Hemorrhage: Dose Study and Review of End othelin-based Therapies in the Literatureon Cerebral Vasospasm

Systemic Administration of the Endothelin- A Receptor Antagonist TBC 11251 At tenuates Cerebral Vasospasmafter Experimental Subarachnoid Hemorrhage: Dose Study and Review of End othelin-based Therapies in the Literatureon Cerebral Vasospasm

E X P E R I M E N T A L S T U D I E S S y s t e m i c A d m i n i s t r a t i o n o f t h e E n d o t h e l i n - A R e c e p t o r A n t a g o n i s t T B C 1 1 2 5 1 A t t e n u a t e s C e r e b r a l V a s o s p a s m a f t e r E x p e r i m e n t a l S u b a r a c h n o i d H e m o r r h a g e : D o s e S t u d y a n d R e v i e w o f E n d o t h e l i n - b a s e d T h e r a p i e s i n t h e L i t e r a t u r e o n C e r e b r a l V a s o s p a s m John E. Wanebo, M.D., Adam S. Arthur, M.D., Hunter G. Louis, B.A., Kim West, Pharm.D., Neal F. Kassell, M.D., Kevin S. Lee, Ph.D., Gregory A. Helm, M.D., Ph.D. Department of Neurosurgery (JEW), National Naval Medical Center, Bethesda, Maryland; Washington University (JEW), Department of Neurological Surgery, St. Louis, Missouri; and Department of Neurological Surgery (ASA, HGL, KW, NFK, KSL, GAH), The Virginia Neurological Institute, University of Virginia, Charlottesville, Virginia OBJECTIVE: Increasing evidence im plicates endothelin (ET)-I in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ETA receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (B ID ), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID , 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in...
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Publisher
Congress of Neurological Surgeons
Copyright
© Published by Oxford University Press.
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1097/00006123-199812000-00086
Publisher site
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Abstract

AbstractOBJECTIVEIncreasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ETA receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH).METHODSEighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measuredRESULTSThe mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups Seated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups.CONCLUSIONThese findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.

Journal

NeurosurgeryOxford University Press

Published: Dec 1, 1998

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