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J Headache Pain. 2019 May 3;20(1):47. doi: 10.1186/s10194-019-1003-2.

Effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery - potential antimigraine efficacy.

Author information

1
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
2
Department of Neurosurgery, Erasmus MC, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
3
Department of Thoracic surgery, Erasmus MC, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
4
ETB-BISLIFE, Heart Valve Bank, Zeestraat 29, 1941 AJ, Beverwijk, The Netherlands.
5
Tonix Pharmaceuticals, Inc, 509 Madison Avenue, Suite 306, New York, NY, 10022, USA.
6
Departamento de Farmacobiología, Cinvestav-Coapa, Czda de los Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, C.P, 14330, Ciudad de México, Mexico.
7
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands. a.vanharen-maassenvandenbrink@erasmusmc.nl.

Abstract

BACKGROUND:

Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action.

METHODS:

Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model.

RESULTS:

The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 μM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses.

CONCLUSION:

The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.

KEYWORDS:

CGRP; Isolated vessels; Isometheptene; Migraine; Organ baths; Vasodilation

PMID:
31053059
DOI:
10.1186/s10194-019-1003-2
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