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Carlos M. Villalón - 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, Alexander H. J. Danser, Carlos M. VillalónAbstract: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, Eloísa Rubio-beltrán, Bruce L. Daugherty, Alexander H. J. Danser, Carlos M. VillalónAbstract: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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Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-Isometheptene and (R)-Isometheptene in pithed rats
The Journal of Headache and Pain, 2017Co-Authors: Alejandro Labastida-ramírez, Eloísa Rubio-beltrán, Oswaldo Hernández-abreu, Bruce L. Daugherty, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Background Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of ( S )- Isometheptene and ( R )-Isometheptene, and the pharmacological profile of the more potent enantiomer. Methods The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of Isometheptene racemate, ( S )-Isometheptene or ( R )-Isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results Compared to ( R )-Isometheptene, ( S )-Isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to ( S )-Isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to ( S )-Isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to ( S )-Isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions The different cardiovascular effects of the Isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for ( S )-Isometheptene (a tyramine-like action and a direct stimulation of α_1-adrenoceptors); and (ii) exclusively a tyramine like action for ( R )-Isometheptene. Thus, ( R )-Isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
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Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-Isometheptene and (R)-Isometheptene in pithed rats.
The journal of headache and pain, 2017Co-Authors: Alejandro Labastida-ramírez, Eloísa Rubio-beltrán, Oswaldo Hernández-abreu, Bruce L. Daugherty, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- Isometheptene and (R)-Isometheptene, and the pharmacological profile of the more potent enantiomer. The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of Isometheptene racemate, (S)-Isometheptene or (R)-Isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Compared to (R)-Isometheptene, (S)-Isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-Isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-Isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-Isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. The different cardiovascular effects of the Isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-Isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-Isometheptene. Thus, (R)-Isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
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Current and prospective pharmacological targets in relation to antimigraine action
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: Suneet Mehrotra, David Centurion, Carlos M. Villalón, Saurabh Gupta, Kayi Y Chan, 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.
Antoinette Maassenvandenbrink - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-Isometheptene and (R)-Isometheptene in pithed rats
The Journal of Headache and Pain, 2017Co-Authors: Alejandro Labastida-ramírez, Eloísa Rubio-beltrán, Oswaldo Hernández-abreu, Bruce L. Daugherty, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Background Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of ( S )- Isometheptene and ( R )-Isometheptene, and the pharmacological profile of the more potent enantiomer. Methods The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of Isometheptene racemate, ( S )-Isometheptene or ( R )-Isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results Compared to ( R )-Isometheptene, ( S )-Isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to ( S )-Isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to ( S )-Isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to ( S )-Isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions The different cardiovascular effects of the Isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for ( S )-Isometheptene (a tyramine-like action and a direct stimulation of α_1-adrenoceptors); and (ii) exclusively a tyramine like action for ( R )-Isometheptene. Thus, ( R )-Isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
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Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-Isometheptene and (R)-Isometheptene in pithed rats.
The journal of headache and pain, 2017Co-Authors: Alejandro Labastida-ramírez, Eloísa Rubio-beltrán, Oswaldo Hernández-abreu, Bruce L. Daugherty, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- Isometheptene and (R)-Isometheptene, and the pharmacological profile of the more potent enantiomer. The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of Isometheptene racemate, (S)-Isometheptene or (R)-Isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Compared to (R)-Isometheptene, (S)-Isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-Isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-Isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-Isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. The different cardiovascular effects of the Isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-Isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-Isometheptene. Thus, (R)-Isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
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Current and prospective pharmacological targets in relation to antimigraine action
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: Suneet Mehrotra, David Centurion, Carlos M. Villalón, Saurabh Gupta, Kayi Y Chan, 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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REVIEW Current and prospective pharmacological targets in relation to antimigraine action
2008Co-Authors: Suneet Mehrotra, David Centurion, Carlos M. Villalón, Saurabh Gupta, Kayi Y Chan, Pramod R. Saxena, Antoinette MaassenvandenbrinkAbstract:Abstract Migraine is a recurrent incapacitating neuro-vascular 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-HT1B/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-HT2 receptor antagonists, Ca2+ 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-HT1–7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP1 and CGRP2), adenosine (A1, A2, and A3), 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, Ad J.j.c. Bogers, Carlos M. Villalón, Ingrid M Garrelds, Saurabh Gupta, 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.
Bruce L. Daugherty - 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, Alexander H. J. Danser, Carlos M. VillalónAbstract: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, Eloísa Rubio-beltrán, Bruce L. Daugherty, Alexander H. J. Danser, Carlos M. VillalónAbstract: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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Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-Isometheptene and (R)-Isometheptene in pithed rats
The Journal of Headache and Pain, 2017Co-Authors: Alejandro Labastida-ramírez, Eloísa Rubio-beltrán, Oswaldo Hernández-abreu, Bruce L. Daugherty, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Background Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of ( S )- Isometheptene and ( R )-Isometheptene, and the pharmacological profile of the more potent enantiomer. Methods The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of Isometheptene racemate, ( S )-Isometheptene or ( R )-Isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results Compared to ( R )-Isometheptene, ( S )-Isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to ( S )-Isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to ( S )-Isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to ( S )-Isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions The different cardiovascular effects of the Isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for ( S )-Isometheptene (a tyramine-like action and a direct stimulation of α_1-adrenoceptors); and (ii) exclusively a tyramine like action for ( R )-Isometheptene. Thus, ( R )-Isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
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Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-Isometheptene and (R)-Isometheptene in pithed rats.
The journal of headache and pain, 2017Co-Authors: Alejandro Labastida-ramírez, Eloísa Rubio-beltrán, Oswaldo Hernández-abreu, Bruce L. Daugherty, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- Isometheptene and (R)-Isometheptene, and the pharmacological profile of the more potent enantiomer. The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of Isometheptene racemate, (S)-Isometheptene or (R)-Isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Compared to (R)-Isometheptene, (S)-Isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-Isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-Isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-Isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. The different cardiovascular effects of the Isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-Isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-Isometheptene. Thus, (R)-Isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
Alejandro Labastida-ramírez - 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
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, Eloísa Rubio-beltrán, Bruce L. Daugherty, Alexander H. J. Danser, Carlos M. VillalónAbstract: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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Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-Isometheptene and (R)-Isometheptene in pithed rats
The Journal of Headache and Pain, 2017Co-Authors: Alejandro Labastida-ramírez, Eloísa Rubio-beltrán, Oswaldo Hernández-abreu, Bruce L. Daugherty, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Background Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of ( S )- Isometheptene and ( R )-Isometheptene, and the pharmacological profile of the more potent enantiomer. Methods The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of Isometheptene racemate, ( S )-Isometheptene or ( R )-Isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results Compared to ( R )-Isometheptene, ( S )-Isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to ( S )-Isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to ( S )-Isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to ( S )-Isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions The different cardiovascular effects of the Isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for ( S )-Isometheptene (a tyramine-like action and a direct stimulation of α_1-adrenoceptors); and (ii) exclusively a tyramine like action for ( R )-Isometheptene. Thus, ( R )-Isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
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Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-Isometheptene and (R)-Isometheptene in pithed rats.
The journal of headache and pain, 2017Co-Authors: Alejandro Labastida-ramírez, Eloísa Rubio-beltrán, Oswaldo Hernández-abreu, Bruce L. Daugherty, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- Isometheptene and (R)-Isometheptene, and the pharmacological profile of the more potent enantiomer. The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of Isometheptene racemate, (S)-Isometheptene or (R)-Isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Compared to (R)-Isometheptene, (S)-Isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-Isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-Isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-Isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. The different cardiovascular effects of the Isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-Isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-Isometheptene. Thus, (R)-Isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
F Michael Cutrer - One of the best experts on this subject based on the ideXlab platform.
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Migraine: Diagnosis, management, and new treatment options
The American Journal of Managed Care, 2002Co-Authors: R. Michael Gallagher, F Michael CutrerAbstract:OBJECTIVE The safety and tolerability of medications used to treat acute migraine attacks are summarized, the classification of headaches and the causes of and diagnostic criteria for migraine are reviewed, and the clinical tolerability profiles and therapeutic benefits of second-generation triptans are presented. BACKGROUND Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia. Drugs used to prevent migraine and those that effectively treat acute migraine attacks are readily available. METHODS Mild or moderate migraines are often treated with aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, antiemetic drugs, or Isometheptene. Triptans (5-HT1 receptor agonists) are used to treat moderate or severe migraine and when nonspecific medications have been ineffective. Because sumatriptan, the first triptan used, is effective but can induce adverse events, second-generation triptans (zolmitriptan, naratriptan, rizatriptan, and almotriptan) were developed to increase the benefit-to-risk ratio in migraine management. RESULTS Important pharmacologic, pharmacokinetic, and clinical differences exist among those drugs, but the tolerability profile of the newer triptans is very good, and they provide rapid relief from headache and sustained duration of effect. CONCLUSION Primary care physicians must manage migraine patients with treatments that demonstrate a balance between efficacy and tolerability.
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Migraine: diagnosis, management, and new treatment options.
The American journal of managed care, 2002Co-Authors: R. Michael Gallagher, F Michael CutrerAbstract:The safety and tolerability of medications used to treat acute migraine attacks are summarized, the classification of headaches and the causes of and diagnostic criteria for migraine are reviewed, and the clinical tolerability profiles and therapeutic benefits of second-generation triptans are presented. Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia. Drugs used to prevent migraine and those that effectively treat acute migraine attacks are readily available. Mild or moderate migraines are often treated with aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, antiemetic drugs, or Isometheptene. Triptans (5-HT1 receptor agonists) are used to treat moderate or severe migraine and when nonspecific medications have been ineffective. Because sumatriptan, the first triptan used, is effective but can induce adverse events, second-generation triptans (zolmitriptan, naratriptan, rizatriptan, and almotriptan) were developed to increase the benefit-to-risk ratio in migraine management. Important pharmacologic, pharmacokinetic, and clinical differences exist among those drugs, but the tolerability profile of the newer triptans is very good, and they provide rapid relief from headache and sustained duration of effect. Primary care physicians must manage migraine patients with treatments that demonstrate a balance between efficacy and tolerability.
