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Carlos M Villalon - One of the best experts on this subject based on the ideXlab platform.
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effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery potential Antimigraine efficacy
Journal of Headache and Pain, 2019Co-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 VillalonAbstract: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.
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Effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery – potential Antimigraine efficacy
The Journal of Headache and Pain, 2019Co-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 VillalonAbstract: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.
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is selective 5 ht1f receptor agonism an entity apart from that of the triptans in Antimigraine therapy
Pharmacology & Therapeutics, 2018Co-Authors: Eloisa Rubiobeltran, Alejandro Labastidaramirez, Carlos M Villalon, Antoinette MaassenvandenbrinkAbstract: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.
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side effects associated with current and prospective Antimigraine pharmacotherapies
Expert Opinion on Drug Metabolism & Toxicology, 2018Co-Authors: Abimael Gonzalezhernandez, Antoinette Maassenvandenbrink, Bruno A Marichalcancino, Carlos M VillalonAbstract: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...
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activation of 5 hydroxytryptamine1b 1d 1f receptors as a mechanism of action of Antimigraine drugs
Expert Opinion on Pharmacotherapy, 2013Co-Authors: Martha Ramirez B Rosas, Sieneke Labruijere, Carlos M Villalon, Antoinette Maassen VandenbrinkAbstract:Introduction: The introduction of the triptans (5-hydroxytryptamine (5-HT)1B/1D receptor agonists) was a great improvement in the acute treatment of migraine. However, shortcomings of the triptans have prompted research on novel serotonergic targets for the treatment of migraine. Areas covered: In this review the different types of Antimigraine drugs acting at 5-HT receptors, their discovery and development are discussed. The first specific Antimigraine drugs were the ergot alkaloids, consisting of ergotamine, dihydroergotamine and methysergide, which are agonists at 5-HT receptors, but can also bind α-adrenoceptors and dopamine receptors. In the 1990s, the triptans became available on the market. They are 5-HT1B/1D receptor agonists, showing fewer side effects due to their receptor specificity. In the last years, compounds that bind specifically to 5-HT1D, 5-HT1F and 5-HT7 receptors have been explored for their Antimigraine potential. Furthermore, the serotonergic system seems to act in tight connection ...
Antoinette Maassenvandenbrink - One of the best experts on this subject based on the ideXlab platform.
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is selective 5 ht1f receptor agonism an entity apart from that of the triptans in Antimigraine therapy
Pharmacology & Therapeutics, 2018Co-Authors: Eloisa Rubiobeltran, Alejandro Labastidaramirez, Carlos M Villalon, Antoinette MaassenvandenbrinkAbstract: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.
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side effects associated with current and prospective Antimigraine pharmacotherapies
Expert Opinion on Drug Metabolism & Toxicology, 2018Co-Authors: Abimael Gonzalezhernandez, Antoinette Maassenvandenbrink, Bruno A Marichalcancino, Carlos M VillalonAbstract: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...
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a human trigeminovascular biomarker for Antimigraine drugs a randomised double blind placebo controlled crossover trial with sumatriptan
Cephalalgia, 2017Co-Authors: K Ibrahimi, A H J Danser, Gisela M Terwindt, A H Van Den Meiracker, Antoinette MaassenvandenbrinkAbstract: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...
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potential mechanisms of prospective Antimigraine drugs a focus on vascular side effects
Pharmacology & Therapeutics, 2011Co-Authors: Kayi Y Chan, Carlos M Villalon, Steve Vermeersch, Jan De Hoon, Antoinette MaassenvandenbrinkAbstract:Abstract Currently available drugs for the acute treatment of migraine, i.e. ergot alkaloids and triptans, are cranial vasoconstrictors. Although cranial vasoconstriction is likely to mediate—at least a part of—their therapeutic effects, this property also causes vascular side-effects. Indeed, the ergot alkaloids and the triptans have been reported to induce myocardial ischemia and stroke, albeit in extremely rare cases, and are contraindicated in patients with known cardiovascular risk factors. In view of these limitations, novel Antimigraine drugs devoid of vascular (side) effects are being explored. Currently, calcitonin gene-related peptide (CGRP) receptor antagonists, which do not have direct vasoconstrictor effects, are under clinical development. Other classes of drugs, such as 5-HT 1F receptor agonists, glutamate receptor antagonists, nitric oxide synthase inhibitors, VPAC/PAC receptor antagonists and gap junction modulators, have also been proposed as potential targets for acute Antimigraine drugs. Although these prospective drugs do not directly induce vasoconstriction, they may well induce indirect vascular effects by inhibiting or otherwise modulating the responses to endogenous vasoactive substances. These indirect vascular effects might contribute to the therapeutic efficacy of the previously mentioned compounds, but may alternatively also lead to vascular side-effects. As described in the current review, some of the prospective Antimigraine drugs with a proposed non-vascular mechanism of action may still have direct or indirect vascular effects.
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Current and prospective pharmacological targets in relation to Antimigraine action
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: Suneet Mehrotra, Pramod R Saxena, Carlos M Villalon, Kayi Y Chan, David Centurion, Saurabh Gupta, Antoinette MaassenvandenbrinkAbstract:Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT_1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT_2 receptor antagonists, Ca^2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT_1–7), adrenergic (α_1, α_2, and β), calcitonin gene-related peptide (CGRP_1 and CGRP_2), adenosine (A_1, A_2, and A_3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to Antimigraine therapy. Finally, the cardiovascular safety of current and prospective Antimigraine therapies is touched upon.
Michel D Ferrari - One of the best experts on this subject based on the ideXlab platform.
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ergotamine in the acute treatment of migraine a review and european consensus
Brain, 2000Co-Authors: Peer Tfelthansen, Miguel J A Lainez, P. R. Saxena, Michel D Ferrari, Patrick Henry, Carl Dahlöf, Jean Schoenen, Hans-christoph Diener, Julio Pascual, Peter J GoadsbyAbstract: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.
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auditory evoked potentials in the assessment of central nervous system effects of Antimigraine drugs
Cephalalgia, 1999Co-Authors: Krista I Roon, Michel D Ferrari, Jean Schoenen, Peter S Sandor, G G Schoonman, F P Lamers, J G Van DijkAbstract: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.
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bovine isolated middle cerebral artery contractions to Antimigraine drugs
Naunyn-schmiedebergs Archives of Pharmacology, 1999Co-Authors: K I Roon, Antoinette Maassenvandenbrink, Michel D Ferrari, P. R. SaxenaAbstract: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.
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coronary side effect potential of current and prospective Antimigraine drugs
Circulation, 1998Co-Authors: Antoinette Maassenvandenbrink, Michel D Ferrari, Marije Reekers, Pramod R SaxenaAbstract:Background—The Antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective Antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan). Methods and Results—Concentration-response curves to the Antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (Emax) and the concentration eliciting 50% of Emax (EC50). The EC50 values were related to maximum plasma concentrations (Cmax) reported in patients, obtaining Cmax/EC50 ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting Antimigraine drugs to assess their disappearance from the receptor biophase. Compared...
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assessment of peripheral vascular effects of Antimigraine drugs in humans
Cephalalgia, 1995Co-Authors: T A Bruning, Michel D Ferrari, Pramod R Saxena, Jan A J Camps, P C Chang, G J Blauw, P A Van ZwietenAbstract:The vascular beds of the forearm and finger can be used to study the peripheral effects of Antimigraine drugs under normal and pathologic circumstances. We have investigated the novel Antimigraine drug sumatriptan, a selective agonist for 5HT 1 receptors. Its Antimigraine effect may be attributed, at least in part, to constriction of cranial arteriovenous anastomoses (AVAs). In assessing the peripheral vascular effects of sumatriptan we used a forearm and finger blood flow model. Forearm blood flow (FBF) is mainly determined by resistance vessels, whereas finger blood flow (FiBF) mainly involves skin vessels, which contain many AVAs. Changes in FBF and FiBF can be assessed using venous occlusion plethysmography. Changes in AVA flow are determined by measuring the patency of the vascular beds of the forearm and hand to well-defined radiolabelled microspheres, which are injected into the brachial artery. We report the effects of sumatriptan on FBF, FiBF and AVA flow when administered into the brachial artery of healthy volunteers, and discuss the peripheral vascular effects of therapeutic doses of sumatriptan when given subcutaneously in migraine patients during and between attacks.
Pramod R Saxena - One of the best experts on this subject based on the ideXlab platform.
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Current and prospective pharmacological targets in relation to Antimigraine action
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: Suneet Mehrotra, Pramod R Saxena, Carlos M Villalon, Kayi Y Chan, David Centurion, Saurabh Gupta, Antoinette MaassenvandenbrinkAbstract:Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT_1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT_2 receptor antagonists, Ca^2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT_1–7), adrenergic (α_1, α_2, and β), calcitonin gene-related peptide (CGRP_1 and CGRP_2), adenosine (A_1, A_2, and A_3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to Antimigraine therapy. Finally, the cardiovascular safety of current and prospective Antimigraine therapies is touched upon.
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Effects of current and prospective Antimigraine drugs on the porcine isolated meningeal artery
Naunyn-Schmiedeberg's Archives of Pharmacology, 2006Co-Authors: Suneet Mehrotra, Pramod R Saxena, Carlos M Villalon, Ad J J C Bogers, Saurabh Gupta, Ingrid M. Garrelds, Antoinette MaassenvandenbrinkAbstract:Vasoconstriction to agonists at serotonin (5-hydroxytryptamine; 5-HT) receptors and α-adrenoceptors, as well as vasodilatation induced by α-CGRP, have been well described in the porcine carotid circulation in vivo. The present study sets out to investigate the effects of current and prospective Antimigraine drugs on porcine meningeal artery segments in vitro. Sumatriptan, ergotamine, dihydroergotamine, isometheptene and clonidine failed to contract the meningeal artery, but 5-HT, noradrenaline and phenylephrine induced concentration-dependent contractions. The contractions to 5-HT were competitively antagonized by the 5-HT_2A receptor antagonist ketanserin, whilst those to noradrenaline were antagonized by α_1-(prazosin), α_2-(rauwolscine and yohimbine) and α_2C/2B-(OPC-28326) adrenoceptor antagonists. Whilst dobutamine and salbutamol were ineffective, α-CGRP produced concentration-dependent relaxations that were antagonized by the CGRP_1 receptor antagonist olcegepant. In agreement with their lack of contractile effect, sumatriptan and ergotamine failed to influence forskolin-stimulated cyclic AMP accumulation in the porcine meningeal artery; in contrast, both compounds decreased forskolin-stimulated cyclic AMP accumulation in the human isolated saphenous vein, where they induced contractions. Finally, using RT-PCR, we could demonstrate the presence of mRNAs encoding for several 5-HT receptors (5-HT_1B, 5-HT_1D, 5-HT_1F, 5-HT_2A and 5-HT_7) and adrenoceptors (α_1A, α_1B, α_1D, α_2A, α_2B, α_2C, β_1 and β_2), as well as that for the calcitonin receptor like receptor, a component of the CGRP_1 receptor. These results suggest that: (i) the porcine meningeal artery may not be involved in the vasoconstriction of the carotid vascular bed elicited by Antimigraine drugs in anaesthetized pigs, and (ii) the mismatch between the presence of receptor mRNA and the lack of response to sumatriptan, dobutamine and salbutamol implies that mRNAs for the 5-HT_1B receptor and β_1- and β_2-adrenoceptors are probably unstable, or that their density is too low for being translated as receptor protein in sufficient quantities.
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coronary side effect potential of current and prospective Antimigraine drugs
Circulation, 1998Co-Authors: Antoinette Maassenvandenbrink, Michel D Ferrari, Marije Reekers, Pramod R SaxenaAbstract:Background—The Antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective Antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan). Methods and Results—Concentration-response curves to the Antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (Emax) and the concentration eliciting 50% of Emax (EC50). The EC50 values were related to maximum plasma concentrations (Cmax) reported in patients, obtaining Cmax/EC50 ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting Antimigraine drugs to assess their disappearance from the receptor biophase. Compared...
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assessment of peripheral vascular effects of Antimigraine drugs in humans
Cephalalgia, 1995Co-Authors: T A Bruning, Michel D Ferrari, Pramod R Saxena, Jan A J Camps, P C Chang, G J Blauw, P A Van ZwietenAbstract:The vascular beds of the forearm and finger can be used to study the peripheral effects of Antimigraine drugs under normal and pathologic circumstances. We have investigated the novel Antimigraine drug sumatriptan, a selective agonist for 5HT 1 receptors. Its Antimigraine effect may be attributed, at least in part, to constriction of cranial arteriovenous anastomoses (AVAs). In assessing the peripheral vascular effects of sumatriptan we used a forearm and finger blood flow model. Forearm blood flow (FBF) is mainly determined by resistance vessels, whereas finger blood flow (FiBF) mainly involves skin vessels, which contain many AVAs. Changes in FBF and FiBF can be assessed using venous occlusion plethysmography. Changes in AVA flow are determined by measuring the patency of the vascular beds of the forearm and hand to well-defined radiolabelled microspheres, which are injected into the brachial artery. We report the effects of sumatriptan on FBF, FiBF and AVA flow when administered into the brachial artery of healthy volunteers, and discuss the peripheral vascular effects of therapeutic doses of sumatriptan when given subcutaneously in migraine patients during and between attacks.
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Lack of effect of the Antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig.
British Journal of Pharmacology, 1992Co-Authors: Marinus O. Den Boer, Judith A.e. Somers, Pramod R SaxenaAbstract:: 1. In anaesthetized animals, the Antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine, reduce carotid arteriovenous anastomotic shunting. Within the carotid vascular bed arteriovenous anastomoses are located, amongst other places in the dura mater, which is a putative site of the pain during a migraine attack. 2. In this investigation, we have localized and measured the arteriovenous shunting within the carotid vascular bed of the pig by using simultaneous intracarotid injections of radiolabelled microspheres of three different sizes (10, 15 and 50 microns), which provides an index of blood flow via arteriovenous anastomoses larger than approximately 14, 27 and 90 microns diameter, respectively. The effects of sumatriptan (0.3 mg kg-1), ergotamine (0.02 mg kg-1), dihydroergotamine (0.1 mg kg-1) and saline were studied by repeating the injections of 15 and 50 microns spheres after the treatments. 3. There was no difference in shunting or entrapment between the 10 and 15 microns microsphere, indicating the absence of arteriovenous anastomoses with a diameter between 14 and 27 microns. 4. Arteriovenous anastomoses with a diameter between 27 and 90 microns, as indicated by the difference in blood flow measured by 15 and 50 microns spheres, were located in the dura mater, ears, skin, fat and, to a lesser extent, in the skeletal muscles and eyes. 5. Sumatriptan, ergotamine and dihydroergotamine reduced the overall flow in the smaller arteriovenous anastomoses (diameter between 27 and 90 microns), and even more in larger shunts (wider than 90 microns). 6. Locally, blood flow in the smaller arteriovenous shunts was reduced in the skin and fat, but not in the dura mater, ears, eyes and muscles.It is not possible to determine in which tissues blood flow in the larger arteriovenous anastomoses was reduced.7. Tissue blood flow measured with 15 gm microspheres remained unchanged after the three Antimigraine drugs, implying a lack of effect on capillary flow.8. It is concluded that in the anaesthetized pigs the only evident effect of these Antimigraine drugs on carotid haemodynamics is a decrease in blood flow in both smaller and larger arteriovenous anastomoses;the smaller arteriovenous anastomoses were affected in the skin and fat, but not in other tissues.
David Centurion - One of the best experts on this subject based on the ideXlab platform.
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effect of some acute and prophylactic Antimigraine drugs on the vasodepressor sensory cgrpergic outflow in pithed rats
Life Sciences, 2009Co-Authors: Jair Lozanocuenca, Abimael Gonzalezhernandez, Enriqueta Munozislas, Araceli Sanchezlopez, David Centurion, Luis E Cobospuc, Carlos M VillalonAbstract:article i nfo Aims: This study analyzed in pithed rats the effect of several acute and prophylactic Antimigraine drugs on the CGRPergic vasodepressor sensory outflow, in an attempt to investigate systemic cardiovascular effects in a model unrelated to migraine. Main methods: Male Wistar pithed rats were pretreated with continuous i.v. infusions of hexamethonium (2 μg/kg.min; to block autonomic outflow) and methoxamine (15-20 μg/kg.min; to maintain diastolic blood pressure at around 130 mmHg). Under these conditions, the effect of both electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T9-T12) or i.v. bolus injections of exogenous α-CGRP (0.1-1 µg/kg) were studied in animals pretreated with continuous i.v. infusions of sumatriptan (1-100 μg/kg.min), ergotamine (0.18-0.56 μg/kg.min), dihydroergotamine (1-10 μg/kg.min), magnesium valproate (1000-1800 μg/kg.min), propranolol (100-300 μg/kg.min) or their respective vehicles. Key findings: Electrical stimulation of the spinal cord and i.v. bolus injections of exogenous α-CGRP resulted in, respectively, frequency- and dose-dependent decreases in diastolic blood pressure without affecting heart rate. Moreover, the infusions of sumatriptan, ergotamine and dihydroergotamine, but not of magnesium valproate, propranolol or their respective vehicles, dose-dependently inhibited the vasodepressor responses to electrical stimulation. In contrast, sumatriptan (10 μg/kg.min), ergotamine (0.31 μg/kg.min) and dihydroergotamine (3 μg/kg.min) failed to inhibit the vasodepressor responses to exogenous α-CGRP. Significance: The above findings suggest that the acute (rather than the prophylactic) Antimigraine drugs attenuate the vasodepressor sensory outflow mainly by prejunctional mechanisms. This may be of particular relevance when considering potential cardiovascular adverse effects by acute Antimigraine drugs.
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Effect of some acute and prophylactic Antimigraine drugs on the vasodepressor sensory CGRPergic outflow in pithed rats.
Life sciences, 2008Co-Authors: Jair Lozano-cuenca, David Centurion, Abimael González-hernández, Enriqueta Muñoz-islas, Araceli Sánchez-lópez, Luis E Cobos-puc, Carlos M VillalonAbstract:This study analyzed in pithed rats the effect of several acute and prophylactic Antimigraine drugs on the CGRPergic vasodepressor sensory outflow, in an attempt to investigate systemic cardiovascular effects in a model unrelated to migraine. Male Wistar pithed rats were pretreated with continuous i.v. infusions of hexamethonium (2 microg/kg.min; to block autonomic outflow) and methoxamine (15-20 microg/kg.min; to maintain diastolic blood pressure at around 130 mmHg). Under these conditions, the effect of both electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T(9)-T(12)) or i.v. bolus injections of exogenous alpha-CGRP (0.1-1 microg/kg) were studied in animals pretreated with continuous i.v. infusions of sumatriptan (1-100 microg/kg.min), ergotamine (0.18-0.56 microg/kg.min), dihydroergotamine (1-10 microg/kg.min), magnesium valproate (1000-1800 microg/kg.min), propranolol (100-300 microg/kg.min) or their respective vehicles. Electrical stimulation of the spinal cord and i.v. bolus injections of exogenous alpha-CGRP resulted in, respectively, frequency- and dose-dependent decreases in diastolic blood pressure without affecting heart rate. Moreover, the infusions of sumatriptan, ergotamine and dihydroergotamine, but not of magnesium valproate, propranolol or their respective vehicles, dose-dependently inhibited the vasodepressor responses to electrical stimulation. In contrast, sumatriptan (10 microg/kg.min), ergotamine (0.31 microg/kg.min) and dihydroergotamine (3 microg/kg.min) failed to inhibit the vasodepressor responses to exogenous alpha-CGRP. The above findings suggest that the acute (rather than the prophylactic) Antimigraine drugs attenuate the vasodepressor sensory outflow mainly by prejunctional mechanisms. This may be of particular relevance when considering potential cardiovascular adverse effects by acute Antimigraine drugs.
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Current and prospective pharmacological targets in relation to Antimigraine action
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: Suneet Mehrotra, Pramod R Saxena, Carlos M Villalon, Kayi Y Chan, David Centurion, Saurabh Gupta, Antoinette MaassenvandenbrinkAbstract:Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT_1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT_2 receptor antagonists, Ca^2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT_1–7), adrenergic (α_1, α_2, and β), calcitonin gene-related peptide (CGRP_1 and CGRP_2), adenosine (A_1, A_2, and A_3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to Antimigraine therapy. Finally, the cardiovascular safety of current and prospective Antimigraine therapies is touched upon.
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an introduction to migraine from ancient treatment to functional pharmacology and Antimigraine therapy
Proceedings of the Western Pharmacology Society, 2002Co-Authors: Carlos M Villalon, David Centurion, Luis Felipe Valdivia, De Vries P, P. R. SaxenaAbstract:SUMMARY: Migraine treatment has evolved from the realms of the supernatural into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5-hydroxytryptamine; 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an iv infusion of 5-HT can abort migraine. In fact, 5-HT as well as ergotamine, dihydroergotamine and other Antimigraine agents invariably produce vasoconstriction in the external carotid circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan, rizatriptan, naratriptan), which belong to a new class of drugs, now known as 5-HT1B/1D/1F receptor agonists. Compared to sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half-life. In line with the vascular and neurogenic theories of migraine, all triptans produce selective carotid vasoconstriction (via 5-HT1B receptors) and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5-HT1D/5-ht1F receptors). Moreover, selective agonists at 5-HT1D (PNU-142633) and 5-ht1F (LY344864) receptors inhibit the trigeminovascular system without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the acute treatment of migraine, whilst LY344864 did show some efficacy when used in doses which interact with 5-HT1B receptors. Finally, although the triptans are effective Antimigraine agents producing selective cranial vasoconstriction, efforts are being made to develop other effective Antimigraine alternatives acting via the direct blockade of vasodilator mechanisms (e.g. antagonists at CGRP receptors, antagonists at 5-HT7 receptors, inhibitors of nitric oxide biosynthesis, etc). These alternatives will hopefully lead to fewer side-effects.
