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Antoinette Maassenvandenbrink - One of the best experts on this subject based on the ideXlab platform.
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pharmacological treatment of migraine cgrp and 5 ht beyond the triptans
Pharmacology & Therapeutics, 2020Co-Authors: Tessa De Vries, Carlos M. Villalón, Antoinette MaassenvandenbrinkAbstract:Migraine is a highly disabling neurovascular disorder characterized by a severe headache (associated with nausea, photophobia and/or phonophobia), and trigeminovascular system activation involving the release of calcitonin-gene related peptide (CGRP). Novel anti-migraine drugs target CGRP signaling through either stimulation of 5-HT1F Receptors on trigeminovascular nerves (resulting in inhibition of CGRP release) or direct blockade of CGRP or its Receptor. Lasmiditan is a highly selective 5-HT1F Receptor agonist and, unlike the triptans, is devoid of vasoconstrictive properties, allowing its use in patients with cardiovascular risk. Since lasmiditan can actively penetrate the blood-brain barrier, central therapeutic as well as side effects mediated by 5-HT1F Receptor activation should be further investigated. Other novel anti-migraine drugs target CGRP signaling directly. This neuropeptide can be targeted by the monoclonal antibodies eptinezumab, fremanezumab and galcanezumab, or by CGRP-neutralizing L-aptamers called Spiegelmers. The CGRP Receptor can be targeted by the monoclonal antibody erenumab, or by small-molecule antagonists called gepants. Currently, rimegepant and ubrogepant have been developed for acute migraine treatment, while atogepant is studied for migraine prophylaxis. Of these drugs targeting CGRP signaling directly, eptinezumab, erenumab, fremanezumab, galcanezumab, rimegepant and ubrogepant have been approved for clinical use, while atogepant is in the last stage before approval. Although all of these drugs seem highly promising for migraine treatment, their safety should be investigated in the long-term. Moreover, the exact mechanism(s) of action of these drugs need to be elucidated further, to increase both safety and efficacy and to increase the number of responders to the different treatments, so that all migraine patients can satisfactorily be treated.
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lasmiditan inhibits calcitonin gene related peptide release in the rodent trigeminovascular system
Pain, 2020Co-Authors: Alejandro Labastidaramirez, Kirk W Johnson, Eloisa Rubiobeltran, Kristian Agmund Haanes, Carlos M. Villalón, Ingrid M Garrelds, Alexander H. J. Danser, Kayi Y Chan, Antoinette MaassenvandenbrinkAbstract:Migraine headache pathophysiology involves trigeminovascular system activation, calcitonin gene-related peptide (CGRP) release, and dysfunctional nociceptive transmission. Triptans are 5-HT1B/1D/(1F) Receptor agonists that prejunctionally inhibit trigeminal CGRP release, but their vasoconstrictor properties limit their use in migraine patients with cardiovascular disease. By contrast, lasmiditan is a novel antimigraine and selective 5-HT1F Receptor agonist devoid of vasoconstrictor properties. On this basis, this study has investigated the modulation of trigeminal CGRP release by lasmiditan. For this purpose, we have comparatively analysed the inhibition of several components of the trigeminovascular system induced by lasmiditan and sumatriptan through: ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion, and trigeminal nucleus caudalis of mice; and in vivo dural vasodilation in the rat closed-cranial window model induced by endogenous (electrical stimulation and capsaicin) and exogenous CGRP. The ex vivo release of CGRP was similarly inhibited by sumatriptan and lasmiditan in all trigeminovascular system components. In vivo, intravenous (i.v.) lasmiditan or higher doses of sumatriptan significantly attenuated the vasodilatory responses to endogenous CGRP release, but not exogenous CGRP effects. These data suggest that lasmiditan prejunctionally inhibits CGRP release in peripheral and central trigeminal nerve terminals. Because lasmiditan is a lipophilic drug that crosses the blood-brain barrier, additional central sites of action remain to be determined.
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the need for new acutely acting antimigraine drugs moving safely outside acute medication overuse
Journal of Headache and Pain, 2019Co-Authors: Willem Sebastiaan Van Hoogstraten, Antoinette MaassenvandenbrinkAbstract:The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs are currently being developed, among which the small molecule CGRP Receptor antagonists, gepants, and the 5-HT1F Receptor agonist lasmiditan. Whether treatment with these drugs carries the same risk for developing MOH is currently unknown. Pathophysiological studies on MOH in animal models have suggested that decreased 5-hydroxytryptamine (5-HT, serotonin) levels, increased calcitonin-gene related peptide (CGRP) expression and changes in 5-HT Receptor expression (lower 5-HT1B/D and higher 5-HT2A expression) may be involved in MOH. The decreased 5-HT may increase cortical spreading depression frequency and induce central sensitization in the cerebral cortex and caudal nucleus of the trigeminal tract. Additionally, low concentrations of 5-HT, a feature often observed in MOH patients, could increase CGRP expression. This provides a possible link between the pathways of 5-HT and CGRP, targets of lasmiditan and gepants, respectively. Since lasmiditan is a 5-HT1F Receptor agonist and gepants are CGRP Receptor antagonists, they could have different risks for developing MOH because of the different (over) compensation mechanisms following prolonged agonist versus antagonist treatment. The acute treatment of migraine will certainly improve with the advent of two novel classes of drugs, i.e., the 5-HT1F Receptor agonists (lasmiditan) and the small molecule CGRP Receptor antagonists (gepants). Data on the effects of 5-HT1F Receptor agonism in relation to MOH, as well as the effects of chronic CGRP Receptor blockade, are awaited with interest.
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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. Villalón, 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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lasmiditan inhibits cgrp release in the mouse trigeminovascular system s32 008
Neurology, 2018Co-Authors: Antoinette Maassenvandenbrink, Kayi Chan, Joe Kovalchin, Kirk W Johnson, Eloisa Rubiobeltran, Kristian Agmund Haanes, Carlos M. Villalón, Ingrid M Garrelds, Alexander H. J. Danser, Alejandro LabastidaramirezAbstract:Objective: To investigate the modulation of trigeminal CGRP release by lasmiditan and sumatriptan. Background: Migraine pathophysiology is associated with activation of the trigeminovascular system, CGRP release and cranial vasodilatation. Triptans are 5-HT1B/1D/(1F) Receptor agonists with vasoconstrictive effects that inhibit trigeminal CGRP release prejunctionally, but they are contraindicated in patients with cardiovascular disease. In contrast, lasmiditan is a selective 5-HT1F Receptor agonist devoid of vasoconstrictor properties. Design/Methods: The effects of sumatriptan and lasmiditan (both 30 μM) were investigated on KCl-induced CGRP release from isolated preparations of dura mater, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) from mice. The release of CGRP was measured by enzyme-linked immunoassay. Experiments were approved by the Erasmus University Medical Center’s institutional ethics committee, in accordance with National Institute of Health guidelines. Results: In contrast to vehicle, sumatriptan significantly inhibited (p Conclusions: Based on our results, the clinical efficacy observed with lasmiditan and sumatriptan may be due to inhibition of CGRP release from peripheral and central trigeminal nerve terminals. In mice, the 5-HT Receptor subtypes activated by lasmiditan at the concentration evaluated could be 5-HT1F or 5-HT1A. However, prior publications would support that the release of CGRP is most likely mediated by the 5-HT1F Receptor, not 5-HT1A. Since activation of 5-HT1F Receptors is not associated with vasoconstriction, this may represent a therapeutic advantage over the vasoactive triptans. Study Supported by: CoLucid Pharmaceuticals and Eli Lilly and Company Disclosure: Dr. Maassen Van Den Brink has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with CoLucid, Teva, Eli Lilly and Company, Novartis. Dr. Maassen Van Den Brink has received research support from Eli Lilly and Company, Novartis, ATI (Autonomic Technologies). Dr. Rubio-Beltran has nothing to disclose. Dr. Garrelds has nothing to disclose. Dr. Haanes has nothing to disclose. Dr. Chan has nothing to disclose. Dr. Kovalchin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with CoLucid Pharmaceuticals. Dr. Kovalchin has received compensation for serving on the Board of Directors of CoLucid Pharmaceuticals. Dr. Kovalchin holds stock and/or stock options in CoLucid Pharmaceuticals, which sponsored research in which Dr. Kovalchin was involved as an investigator. Dr. Johnson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eli Lilly and Company. Dr. Johnson holds stock and/or stock options in Eli Lilly and Company, which sponsored research in which Dr. Johnson was involved as an investigator. Dr. Johnson has received research support from Eli Lilly and Company. Dr. Danser has received research support from Alnylam Pharmaceuticals. Dr. Villalon has received research support from CoLucid Pharmaceuticals. Dr. Labastida-Ramirez has nothing to disclose.
Peter J Goadsby - One of the best experts on this subject based on the ideXlab platform.
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therapeutic targeting of nitroglycerin mediated trigeminovascular neuronal hypersensitivity predicts clinical outcomes of migraine abortives
Pain, 2020Co-Authors: Simon Akerman, Nazia Karsan, Marcela Romeroreyes, Pyari Bose, Jan Hoffmann, Philip R Holland, Peter J GoadsbyAbstract:Cranial hypersensitivity is a prominent symptom of migraine, exhibited as migraine headache exacerbated with physical activity, and cutaneous facial allodynia and hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms, and as a tool to screen therapeutics. We have previously shown that nitroglycerin triggers cranial allodynia in association with migraine-like headache, and this translates to neuronal cranial hypersensitivity in rats. Further, responses in both humans and rats are aborted by triptan administration, similar to responses in spontaneous migraine. Here, our objective was to study the nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically gepants and ditans, for the acute treatment of migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to nitroglycerin, followed by treatment with a CGRP Receptor antagonist, gepant (olcegepant), a 5-HT1F Receptor agonist, ditan (LY344864) and an NK1 Receptor antagonist (GR205171). Nitroglycerin induced activation of migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal hypersensitivity. These responses were aborted by olcegepant and LY344864. However, GR205171, which failed in clinical trial for both abortive and preventive treatment of migraine, had no effect. These data support the nitroglycerin model as a valid approach to study cranial hypersensitivity and putative mechanisms involved in migraine, and as a screen to dissect potentially efficacious migraine therapeutic targets.
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phase 3 randomized placebo controlled double blind study of lasmiditan for acute treatment of migraine
Brain, 2019Co-Authors: Peter J Goadsby, Linda Wietecha, Ellen B Dennehy, Bernice Kuca, Michael Case, Sheena K Aurora, Charly GaulAbstract:Lasmiditan, a serotonin 5-HT1F Receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.
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pathophysiology of migraine a disorder of sensory processing
Physical Review, 2017Co-Authors: Peter J Goadsby, Jan Hoffmann, Philip R Holland, Margarida Martinsoliveira, Christoph J Schankin, Simon AkermanAbstract:Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D Receptor agonists; gepants, calcitonin gene-related peptide (CGRP) Receptor antagonists; ditans, 5-HT1F Receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.
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distribution of 5 ht1b 5 ht1d and 5 ht1f Receptor expression in rat trigeminal and dorsal root ganglia neurons relevance to the selective anti migraine effect of triptans
Brain Research, 2010Co-Authors: Jd Classey, T Bartsch, Peter J GoadsbyAbstract:Triptans, acting as serotonin, 5-HT(1B/1D/1F), Receptor agonists, provide an effective and established treatment option in migraine and cluster headache. Clinical observations suggest a relatively specific effect of these compounds on primary headache disorders, but not in other pain syndromes. The mechanism of this specificity, however, is not well understood. Hence, we systematically studied primary sensory ganglia in rat to determine if the peripheral distribution of 5HT(1B/1D/1F) Receptors showed any anatomical difference that would account for the specificity of clinical effect. Rat primary afferent and sensory ganglia neurons--trigeminal ganglia (Vg), and dorsal root ganglia (DRG): C(2), C(5), T(5), L(5)--were examined using paraffin-embedded, slide-bound tissue sections reacted with specific primary antibodies for rat 5-HT(1B, 1D) and (1F) Receptors in a peroxidase-based immunohistochemical method. Immunoreactivity specific for all three serotonergic Receptor subtypes was demonstrated in the five peripheral nervous system regions examined and quantitated. There was a good agreement for 5-HT(1B) and 5-HT(1D) Receptors to that previously demonstrated in Vg and DRG L(5), while this was the first characterisation for 5-HT(1F) Receptor in any of the five regions, as well as for 5-HT(1B) and 5HT(1D) Receptors in DRG C(2), C(5) and T(5). In summary, all three 5-HT Receptors are equally represented in Vg and the DRGs examined. We conclude that the triptans are theoretically able to bind to Receptors at each level of the peripheral neuraxis without any apparent anatomical preference for the head.
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evidence for serotonin 5 ht 1b 5 ht1d and 5 ht1f Receptor inhibitory effects on trigeminal neurons with craniovascular input
Neuroscience, 2003Co-Authors: Peter J Goadsby, Jd ClasseyAbstract:Abstract Development of serotonin (5HT 1B/1D ) agonists for the acute attack of migraine resulted in considerable interest in their action. The superior sagittal sinus (SSS) was isolated in α-chloralose (60 mg/kg, i.p. and 20 mg/kg i.v.i. supplementary 2 hourly) anaesthetised cats. The SSS was stimulated electrically (100 V, 250 μs duration, 0.3 Hz) and neurons of the trigeminocervical complex monitored using electrophysiological methods. To test 5-HT 1B Receptor-mediated activity common carotid blood flow (CCF) was monitored with a transonic flow probe placed around the vessel. Naratriptan (5-HT 1B/1D/1F Receptor agonist) and alniditan (5-HT 1B/1D Receptor agonist) produced reductions in carotid blood flow of 38±5% and 42±6%, respectively. These effects were attenuated by the 5-HT 1B Receptor antagonist SB224289 ( P 1F Receptor agonist) had no effect on CCF. Naratriptan inhibited SSS-evoked activity (61±7%), an effect partially inhibited by the 5-HT 1B Receptor antagonist SB224289 (30±5%), or by the 5-HT 1D Receptor antagonist BRL-15572 (37±6%). There remained an inhibitory effect of naratriptan after both 5-HT 1B and 5-HT 1D Receptor blockade (22±5%). Alniditan inhibited SSS-evoked trigeminal activity (53±6%), an effect abolished after 5-HT 1B and 5-HT 1D Receptor blockade. LY344864 (5-HT 1F Receptor agonist) inhibited SSS-evoked trigeminal activity (28±5%), an effect unaltered by either SB224289 or BRL-15572. It can be concluded that there are inhibitory 5-HT 1B , 5-HT 1D and 5-HT 1F Receptors in the trigeminocervical complex of the cat. 5-HT 1B Receptor-mediated inhibition is the most potent of the three in terms of inhibition of trigeminovascular nociceptive traffic.
Jd Classey - One of the best experts on this subject based on the ideXlab platform.
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distribution of 5 ht1b 5 ht1d and 5 ht1f Receptor expression in rat trigeminal and dorsal root ganglia neurons relevance to the selective anti migraine effect of triptans
Brain Research, 2010Co-Authors: Jd Classey, T Bartsch, Peter J GoadsbyAbstract:Triptans, acting as serotonin, 5-HT(1B/1D/1F), Receptor agonists, provide an effective and established treatment option in migraine and cluster headache. Clinical observations suggest a relatively specific effect of these compounds on primary headache disorders, but not in other pain syndromes. The mechanism of this specificity, however, is not well understood. Hence, we systematically studied primary sensory ganglia in rat to determine if the peripheral distribution of 5HT(1B/1D/1F) Receptors showed any anatomical difference that would account for the specificity of clinical effect. Rat primary afferent and sensory ganglia neurons--trigeminal ganglia (Vg), and dorsal root ganglia (DRG): C(2), C(5), T(5), L(5)--were examined using paraffin-embedded, slide-bound tissue sections reacted with specific primary antibodies for rat 5-HT(1B, 1D) and (1F) Receptors in a peroxidase-based immunohistochemical method. Immunoreactivity specific for all three serotonergic Receptor subtypes was demonstrated in the five peripheral nervous system regions examined and quantitated. There was a good agreement for 5-HT(1B) and 5-HT(1D) Receptors to that previously demonstrated in Vg and DRG L(5), while this was the first characterisation for 5-HT(1F) Receptor in any of the five regions, as well as for 5-HT(1B) and 5HT(1D) Receptors in DRG C(2), C(5) and T(5). In summary, all three 5-HT Receptors are equally represented in Vg and the DRGs examined. We conclude that the triptans are theoretically able to bind to Receptors at each level of the peripheral neuraxis without any apparent anatomical preference for the head.
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Evidence for serotonin (5-HT)(1B), 5-HT1D and 5-HT1F Receptor inhibitory effects on trigeminal neurons with craniovascular input
PERGAMON-ELSEVIER SCIENCE LTD, 2003Co-Authors: Pj Goadsby, Jd ClasseyAbstract:Development of serotonin (5HT(1B/1D)) agonists for the acute attack of migraine resulted in considerable interest in their action. The superior sagittal sinus (SSS) was isolated in a-chloralose (60 mg/kg, i.p. and 20 mg/kg i.v.i. supplementary 2 hourly) anaesthetised cats. The SSS was stimulated electrically (100 V, 250 mus duration, 0.3 Hz) and neurons of the trigeminocervical complex monitored using electrophysiological methods. To test 5-HT1B Receptor-mediated activity common carotid blood flow (CCF) was monitored with a transonic flow probe placed around the vessel. Naratriptan (5-HT1B/1D/1F Receptor agonist) and alniditan (5-HT1B/1D Receptor agonist) produced reductions in carotid blood flow of 38+/-5% and 42+/-6%, respectively. These effects were attenuated by the 5-HT1B Receptor antagonist SB224289 (P
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evidence for serotonin 5 ht 1b 5 ht1d and 5 ht1f Receptor inhibitory effects on trigeminal neurons with craniovascular input
Neuroscience, 2003Co-Authors: Peter J Goadsby, Jd ClasseyAbstract:Abstract Development of serotonin (5HT 1B/1D ) agonists for the acute attack of migraine resulted in considerable interest in their action. The superior sagittal sinus (SSS) was isolated in α-chloralose (60 mg/kg, i.p. and 20 mg/kg i.v.i. supplementary 2 hourly) anaesthetised cats. The SSS was stimulated electrically (100 V, 250 μs duration, 0.3 Hz) and neurons of the trigeminocervical complex monitored using electrophysiological methods. To test 5-HT 1B Receptor-mediated activity common carotid blood flow (CCF) was monitored with a transonic flow probe placed around the vessel. Naratriptan (5-HT 1B/1D/1F Receptor agonist) and alniditan (5-HT 1B/1D Receptor agonist) produced reductions in carotid blood flow of 38±5% and 42±6%, respectively. These effects were attenuated by the 5-HT 1B Receptor antagonist SB224289 ( P 1F Receptor agonist) had no effect on CCF. Naratriptan inhibited SSS-evoked activity (61±7%), an effect partially inhibited by the 5-HT 1B Receptor antagonist SB224289 (30±5%), or by the 5-HT 1D Receptor antagonist BRL-15572 (37±6%). There remained an inhibitory effect of naratriptan after both 5-HT 1B and 5-HT 1D Receptor blockade (22±5%). Alniditan inhibited SSS-evoked trigeminal activity (53±6%), an effect abolished after 5-HT 1B and 5-HT 1D Receptor blockade. LY344864 (5-HT 1F Receptor agonist) inhibited SSS-evoked trigeminal activity (28±5%), an effect unaltered by either SB224289 or BRL-15572. It can be concluded that there are inhibitory 5-HT 1B , 5-HT 1D and 5-HT 1F Receptors in the trigeminocervical complex of the cat. 5-HT 1B Receptor-mediated inhibition is the most potent of the three in terms of inhibition of trigeminovascular nociceptive traffic.
Alejandro Labastidaramirez - One of the best experts on this subject based on the ideXlab platform.
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lasmiditan inhibits calcitonin gene related peptide release in the rodent trigeminovascular system
Pain, 2020Co-Authors: Alejandro Labastidaramirez, Kirk W Johnson, Eloisa Rubiobeltran, Kristian Agmund Haanes, Carlos M. Villalón, Ingrid M Garrelds, Alexander H. J. Danser, Kayi Y Chan, Antoinette MaassenvandenbrinkAbstract:Migraine headache pathophysiology involves trigeminovascular system activation, calcitonin gene-related peptide (CGRP) release, and dysfunctional nociceptive transmission. Triptans are 5-HT1B/1D/(1F) Receptor agonists that prejunctionally inhibit trigeminal CGRP release, but their vasoconstrictor properties limit their use in migraine patients with cardiovascular disease. By contrast, lasmiditan is a novel antimigraine and selective 5-HT1F Receptor agonist devoid of vasoconstrictor properties. On this basis, this study has investigated the modulation of trigeminal CGRP release by lasmiditan. For this purpose, we have comparatively analysed the inhibition of several components of the trigeminovascular system induced by lasmiditan and sumatriptan through: ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion, and trigeminal nucleus caudalis of mice; and in vivo dural vasodilation in the rat closed-cranial window model induced by endogenous (electrical stimulation and capsaicin) and exogenous CGRP. The ex vivo release of CGRP was similarly inhibited by sumatriptan and lasmiditan in all trigeminovascular system components. In vivo, intravenous (i.v.) lasmiditan or higher doses of sumatriptan significantly attenuated the vasodilatory responses to endogenous CGRP release, but not exogenous CGRP effects. These data suggest that lasmiditan prejunctionally inhibits CGRP release in peripheral and central trigeminal nerve terminals. Because lasmiditan is a lipophilic drug that crosses the blood-brain barrier, additional central sites of action remain 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. Villalón, 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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lasmiditan inhibits cgrp release in the mouse trigeminovascular system s32 008
Neurology, 2018Co-Authors: Antoinette Maassenvandenbrink, Kayi Chan, Joe Kovalchin, Kirk W Johnson, Eloisa Rubiobeltran, Kristian Agmund Haanes, Carlos M. Villalón, Ingrid M Garrelds, Alexander H. J. Danser, Alejandro LabastidaramirezAbstract:Objective: To investigate the modulation of trigeminal CGRP release by lasmiditan and sumatriptan. Background: Migraine pathophysiology is associated with activation of the trigeminovascular system, CGRP release and cranial vasodilatation. Triptans are 5-HT1B/1D/(1F) Receptor agonists with vasoconstrictive effects that inhibit trigeminal CGRP release prejunctionally, but they are contraindicated in patients with cardiovascular disease. In contrast, lasmiditan is a selective 5-HT1F Receptor agonist devoid of vasoconstrictor properties. Design/Methods: The effects of sumatriptan and lasmiditan (both 30 μM) were investigated on KCl-induced CGRP release from isolated preparations of dura mater, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) from mice. The release of CGRP was measured by enzyme-linked immunoassay. Experiments were approved by the Erasmus University Medical Center’s institutional ethics committee, in accordance with National Institute of Health guidelines. Results: In contrast to vehicle, sumatriptan significantly inhibited (p Conclusions: Based on our results, the clinical efficacy observed with lasmiditan and sumatriptan may be due to inhibition of CGRP release from peripheral and central trigeminal nerve terminals. In mice, the 5-HT Receptor subtypes activated by lasmiditan at the concentration evaluated could be 5-HT1F or 5-HT1A. However, prior publications would support that the release of CGRP is most likely mediated by the 5-HT1F Receptor, not 5-HT1A. Since activation of 5-HT1F Receptors is not associated with vasoconstriction, this may represent a therapeutic advantage over the vasoactive triptans. Study Supported by: CoLucid Pharmaceuticals and Eli Lilly and Company Disclosure: Dr. Maassen Van Den Brink has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with CoLucid, Teva, Eli Lilly and Company, Novartis. Dr. Maassen Van Den Brink has received research support from Eli Lilly and Company, Novartis, ATI (Autonomic Technologies). Dr. Rubio-Beltran has nothing to disclose. Dr. Garrelds has nothing to disclose. Dr. Haanes has nothing to disclose. Dr. Chan has nothing to disclose. Dr. Kovalchin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with CoLucid Pharmaceuticals. Dr. Kovalchin has received compensation for serving on the Board of Directors of CoLucid Pharmaceuticals. Dr. Kovalchin holds stock and/or stock options in CoLucid Pharmaceuticals, which sponsored research in which Dr. Kovalchin was involved as an investigator. Dr. Johnson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eli Lilly and Company. Dr. Johnson holds stock and/or stock options in Eli Lilly and Company, which sponsored research in which Dr. Johnson was involved as an investigator. Dr. Johnson has received research support from Eli Lilly and Company. Dr. Danser has received research support from Alnylam Pharmaceuticals. Dr. Villalon has received research support from CoLucid Pharmaceuticals. Dr. Labastida-Ramirez has nothing to disclose.
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The pharmacological profile and clinical prospects of the oral 5-HT1F Receptor agonist lasmiditan in the acute treatment of migraine
SAGE Publishing, 2015Co-Authors: Uwe Reuter, Heike Israel, Lars NeebAbstract:More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT 1F Receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50–400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient
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efficacy and tolerability of lasmiditan an oral 5 ht1f Receptor agonist for the acute treatment of migraine a phase 2 randomised placebo controlled parallel group dose ranging study
Lancet Neurology, 2012Co-Authors: Markus Färkkilä, Gilles Geraud, Nadja Harner, Alison Pilgrim, Hans-christoph Diener, Miguel J A Lainez, Jean Schoenen, Uwe ReuterAbstract:Summary Background Lasmiditan (COL-144) is a novel, centrally acting, highly selective 5-HT 1F Receptor agonist without vasoconstrictor activity that seemed effective when given as an intravenous infusion in a proof-of-concept migraine study. We aimed to assess the efficacy and safety of oral lasmiditan for the acute treatment of migraine. Methods In this multicentre, double-blind, parallel-group, dose-ranging study in 43 headache centres in five European countries, patients with migraine with and without aura and who were not using prophylaxis were randomly assigned (1:1:1:1:1) to treat one moderate or severe attack at home with 50 mg, 100 mg, 200 mg, or 400 mg lasmiditan, or placebo. Study drug and placebo were supplied in identical numbered tablet packs. The randomisation code was generated by an independent statistician. Patients and investigators were masked to treatment allocation. The primary endpoint was dose response for headache relief (moderate or severe becoming mild or none) at 2 h. The primary analysis was done in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00883051. Findings Between July 8 2009, and Feb 18, 2010, 512 patients were randomly assigned to treatment, 391 of whom received treatment. 86 patients received placebo (81 included in primary analysis) and 305 received lasmiditan (50 mg n=79, 100 mg n=81, 200 mg n=69, and 400 mg n=68 included in primary analysis). There was a linear association between headache response rate at 2 h and lasmiditan dose (Cochran-Armitage test p vs 19/86 [22%] for placebo). Most adverse events were mild or moderate in intensity, with 16 of 82 (20%), 23 of 82 (28%), 28 of 71 (39%), and 31 of 70 (44%) of patients on lasmiditan 50, 100, 200, and 400 mg, respectively reporting a severe adverse event compared with five of 86 (6%) on placebo. The most common adverse events were CNS related and included dizziness, fatigue, vertigo, paraesthesia, and somnolence. Interpretation Oral lasmiditan seems to be safe and effective in the acute treatment of migraine. Further assessment in larger placebo-controlled and triptan-controlled trials are needed to assess the potential role of lasmiditan in acute migraine therapy. Funding CoLucid Pharmaceuticals.
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acute treatment of migraine with the selective 5 ht1f Receptor agonist lasmiditan a randomised proof of concept trial
Cephalalgia, 2010Co-Authors: Michel D Ferrari, Alison Pilgrim, Uwe Reuter, Markus Färkkilä, Charles Davis, Martin Krauss, Hans-christoph DienerAbstract:Introduction: Lasmiditan (COL-144; LY573144) is a novel, highly selective and potent agonist at 5-HT1F Receptors that lacks vasoconstrictor activity. Preclinical and early clinical experiments predict acute antimigraine efficacy of COL-144 that is mediated through a non-vascular, primarily neural, mechanism. Subjects and methods: In a randomised, multicentre, placebo-controlled, double-blind, group-sequential, adaptive treatment-assignment, proof-of-concept and dose-finding study, we treated 130 subjects in-hospital during a migraine attack. Subjects were allocated to an intravenous dose level of lasmiditan or placebo in small cohorts. The starting dose was 2.5mg. Subsequent doses were adjusted, up or down, according to the safety and efficacy seen in the preceding cohort. The primary outcome measure was headache response defined as improvement from moderate or severe headache at baseline to mild or no headache at 2h post-dose. The study was designed to explore the overall dose response relationship but was not powered to differentiate individual doses from placebo, nor to detect effect differences for other migraine symptoms. Results: Forty-two subjects received placebo and 88 received lasmiditan in doses of 2.5–45mg. Subjects were observed in the clinic for 4h after treatment and used a diary card to record symptoms and adverse events for up to 24h. The study was terminated when the 20mg dose met predefined efficacy stopping rules. Of subjects treated in the 10, 20, 30 and 45mg lasmiditan dose groups, 54–75% showed a 2h headache response, compared to 45% in the placebo group (P ¼0.0126 for the linear association between response rates and dose levels). Patient global impression at 2h and lack of need for rescue medication also showed statistically significant linear correlations with dose. Lasmiditan was generally well tolerated. Adverse events were reported by 65% of subjects on lasmiditan and by 43% on placebo and were generally mild. Dizziness, paresthesia and sensations of heaviness (usually limb) were more common on lasmiditan. Conclusions: At intravenous doses of 20mg and higher, lasmiditan proved effective in the acute treatment of migraine. Further studies to assess the optimal oral dose and full efficacy and tolerability profile are under way. The non-vascular, neural mechanism of action of lasmiditan may offer an alternative means to treat migraine especially in patients who have contra-indications for agents with vasoconstrictor activity. The clinicaltrials.gov identifier for this study is NCT00384774.
