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Antimigraine

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Carlos M Villalon – 1st expert on this subject based on the ideXlab platform

  • effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery potential Antimigraine efficacy
    Journal of Headache and Pain, 2019
    Co-Authors: Alejandro Labastidaramirez, Eloisa Rubiobeltran, Kristian Agmund Haanes, Rene De Vries, Ruben Dammers, Ad J J C Bogers, Antoon J Van Den Bogaerdt, Bruce L Daugherty, A H J Danser, Carlos M Villalon

    Abstract:

    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. 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. 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. 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.

  • Effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery – potential Antimigraine efficacy
    The Journal of Headache and Pain, 2019
    Co-Authors: Alejandro Labastida-ramírez, Kristian Agmund Haanes, Rene De Vries, Ruben Dammers, Ad J J C Bogers, Antoon J Van Den Bogaerdt, Bruce L Daugherty, A H J Danser, Eloísa Rubio-beltrán, Carlos M Villalon

    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.

  • is selective 5 ht1f receptor agonism an entity apart from that of the triptans in Antimigraine therapy
    Pharmacology & Therapeutics, 2018
    Co-Authors: Eloisa Rubiobeltran, Alejandro Labastidaramirez, Carlos M Villalon, Antoinette Maassenvandenbrink

    Abstract:

    Abstract Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP). The gold standard for acute migraine treatment are the triptans, 5-HT1B/1D/(1F) receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT1B receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT1D receptors on trigeminal fibers that inhibit trigeminal CGRP release; and (iii) 5-HT1B/1D/1F receptors in central nervous system involved in (anti)nociceptive modulation. Unfortunately, coronary arteries also express 5-HT1B receptors whose activation would produce coronary vasoconstriction; hence, triptans are contraindicated in patients with cardiovascular disease. In addition, since migraineurs have an increased cardiovascular risk, it is important to develop Antimigraine drugs devoid of vascular (side) effects. Ditans, here defined as selective 5-HT1F receptor agonists, were developed on the basis that most of the triptans activate trigeminal 5-HT1F receptors, which may explain part of the triptans’ Antimigraine action. Amongst the ditans, lasmiditan: (i) fails to constrict human coronary arteries; and (ii) is effective for the acute treatment of migraine in preliminary Phase III clinical trials. Admittedly, the exact site of action is still unknown, but lasmiditan possess a high lipophilicity, which suggests a direct action on the central descending antinociceptive pathways. Furthermore, since 5-HT1F receptors are located on trigeminal fibers, they could modulate CGRP release. This review will be particularly focussed on the similarities and differences between the triptans and the ditans, their proposed sites of action, side effects and their cardiovascular risk profile.

Antoinette Maassenvandenbrink – 2nd expert on this subject based on the ideXlab platform

  • is selective 5 ht1f receptor agonism an entity apart from that of the triptans in Antimigraine therapy
    Pharmacology & Therapeutics, 2018
    Co-Authors: Eloisa Rubiobeltran, Alejandro Labastidaramirez, Carlos M Villalon, Antoinette Maassenvandenbrink

    Abstract:

    Abstract Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP). The gold standard for acute migraine treatment are the triptans, 5-HT1B/1D/(1F) receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT1B receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT1D receptors on trigeminal fibers that inhibit trigeminal CGRP release; and (iii) 5-HT1B/1D/1F receptors in central nervous system involved in (anti)nociceptive modulation. Unfortunately, coronary arteries also express 5-HT1B receptors whose activation would produce coronary vasoconstriction; hence, triptans are contraindicated in patients with cardiovascular disease. In addition, since migraineurs have an increased cardiovascular risk, it is important to develop Antimigraine drugs devoid of vascular (side) effects. Ditans, here defined as selective 5-HT1F receptor agonists, were developed on the basis that most of the triptans activate trigeminal 5-HT1F receptors, which may explain part of the triptans’ Antimigraine action. Amongst the ditans, lasmiditan: (i) fails to constrict human coronary arteries; and (ii) is effective for the acute treatment of migraine in preliminary Phase III clinical trials. Admittedly, the exact site of action is still unknown, but lasmiditan possess a high lipophilicity, which suggests a direct action on the central descending antinociceptive pathways. Furthermore, since 5-HT1F receptors are located on trigeminal fibers, they could modulate CGRP release. This review will be particularly focussed on the similarities and differences between the triptans and the ditans, their proposed sites of action, side effects and their cardiovascular risk profile.

  • side effects associated with current and prospective Antimigraine pharmacotherapies
    Expert Opinion on Drug Metabolism & Toxicology, 2018
    Co-Authors: Abimael Gonzalezhernandez, Antoinette Maassenvandenbrink, Bruno A Marichalcancino, Carlos M Villalon

    Abstract:

    Introduction: Migraine is a neurovascular disorder. Current acute specific Antimigraine pharmacotherapies target trigeminovascular 5-HT1B/1D, 5-HT1F and CGRP receptors but, unfortunately, they indu…

  • a human trigeminovascular biomarker for Antimigraine drugs a randomised double blind placebo controlled crossover trial with sumatriptan
    Cephalalgia, 2017
    Co-Authors: K Ibrahimi, A H J Danser, Gisela M Terwindt, A H Van Den Meiracker, Antoinette Maassenvandenbrink

    Abstract:

    Current Antimigraine drugs are believed, besides their direct vasoconstrictive effect, to inhibit calcitonin gene-related peptide (CGRP) release from trigeminal nerve endings during migraine.Object…

Michel D Ferrari – 3rd expert on this subject based on the ideXlab platform

  • ergotamine in the acute treatment of migraine a review and european consensus
    Brain, 2000
    Co-Authors: Peer Tfelthansen, Hans-christoph Diener, P. R. Saxena, Carl Dahlöf, Julio Pascual, Miguel J A Lainez, Patrick Henry, Jean Schoenen, Michel D Ferrari, Peter J Goadsby

    Abstract:

    Ergotamine has been used in clinical practice for the acute treatment of migraine for over 50 years, but there has been little agreement on its place in clinical practice. An expert group from Europe reviewed the pre-clinical and clinical data on ergotamine as it relates to the treatment of migraine. From this review, specific suggestions for the patient groups and appropriate use of ergotamine have been agreed. In essence, ergotamine, from a medical perspective, is the drug of choice in a limited number of migraine sufferers who have infrequent or long duration headaches and are likely to comply with dosing restrictions. For most migraine sufferers requiring a specific Antimigraine treatment, a triptan is generally a better option from both an efficacy and side-effect perspective.

  • auditory evoked potentials in the assessment of central nervous system effects of Antimigraine drugs
    Cephalalgia, 1999
    Co-Authors: Krista I Roon, Jean Schoenen, Michel D Ferrari, Peter S Sandor, G G Schoonman, F P Lamers, J G Van Dijk

    Abstract:

    Because the “intensity dependence” of cortical auditory evoked potentials (IDAP) is under serotonergic control, it can be used to assess central Antimigraine effects of 5HT1B/1D agonists. We measured IDAP before and 2 h after naratriptan (5 mg, n = 19) and zolmitriptan (5 mg, n = 19) in healthy volunteers. IDAP was expressed as the amplitude-stimulus intensity function (“ASF slope”). Naratriptan tended to increase ASF slope (mean difference 0.23 ± 0.62 μV/10 dB, p = 0.06) while zolmitriptan (0.08 ± 0.95 μV/10 dB, p = 0.35) did not. We assessed the suitability of IDAP for measuring central Antimigraine drug effects using repeatability data (see companion paper). We calculated the trade-off between the size of the expected drug effects (ASF slope difference) and the necessary sample size. Because of poor repeatability 36 to 80 subjects are required to detect ASF slope changes in the 0.25–0.5 μV/10 dB range. These data can be used to design trials using IDAP.

  • bovine isolated middle cerebral artery contractions to Antimigraine drugs
    Naunyn-schmiedebergs Archives of Pharmacology, 1999
    Co-Authors: K I Roon, Antoinette Maassenvandenbrink, Michel D Ferrari, P. R. Saxena

    Abstract:

    Ergot alkaloids, sumatriptan and the newer 5-HT1B/1D receptor agonists all contract cranial blood vessels and this effect seems to be primarily responsible for their efficacy in migraine. We have compared the contractile effects of a number of ergot and triptan derivatives on the bovine isolated middle cerebral artery and characterised the 5-hydroxytryptamine (5-HT) receptors involved by using 5-HT2A (ketanserin: 10, 30, 100 nM) and 5-HT1B/1D (GR127935: 30, 100, 300 nM) receptor antagonists. The rank order of agonist potency (pD2) was ergotamine (8.0±0.1) ≈ dihydroergotamine (8.0±0.1) > avitriptan (7.4±0.3) >5-HT (7.0±0.1) > naratriptan (6.8±0.1) > methylergometrine (major metabolite of methysergide; 6.5±0.2) > rizatriptan (6.3±0.3) ≈ zolmitriptan (6.2±0.1) ≈ sumatriptan (6.0±0.2) ≈ methysergide (5.9±0.3). The rank order of efficacy (Emax expressed as % of contraction to 100 mM K+) was 5-HT (127±11) > sumatriptan (56±5) > ergotamine (48±5) ≈ dihydroergotamine (44±8) ≈ methylergometrine (44±7) > avitriptan (37±7) ≈ rizatriptan (33±5) ≈ methysergide (29±10) ≈ zolmitriptan (28±3) ≈ naratriptan (23±2). The concentration-response curve to 5-HT appeared to be biphasic in the presence of 100 nM ketanserin, which hardly affected sumatriptan-induced contractions, but clearly antagonised the second more efficacious phase of the curve to 5-HT. On the other hand, GR127935 caused a rightward shift of the concentration-response curves to 5-HT (in the presence of 10 µM ketanserin) and sumatriptan with pA2 values of 7.0 and 8.1, respectively. In conclusion, all acutely acting Antimigraine drugs contract the bovine isolated middle cerebral artery. Whereas sumatriptan contracts the artery via the 5-HT1B/1D receptor, the 5-HT-induced contraction is mediated partly by the 5-HT2A receptor and partly by another, possibly novel receptor differing from the 5-HT1B/1D receptor. This receptor may be a target for the development of future Antimigraine drugs.