Telcagepant

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Lars Edvinsson - One of the best experts on this subject based on the ideXlab platform.

  • differential inhibitory response to Telcagepant on αcgrp induced vasorelaxation and intracellular ca2 levels in the perfused and non perfused isolated rat middle cerebral artery
    Journal of Headache and Pain, 2017
    Co-Authors: Andre Erdling, Majid Sheykhzade, Lars Edvinsson
    Abstract:

    Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist Telcagepant on intracellular Ca2+ -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry. A pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or Telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry. Abluminal but not luminal αCGRP (10-12-10-6 M) caused concentration-dependent vasorelaxation in rat MCA. Luminal Telcagepant (10-6 M) failed to inhibit this relaxation, while abluminal Telcagepant inhibited the relaxation (10-6 M). Using the FURA-2 method in combination with wire myography we observed that αCGRP reduced intracellular calcium levels and in parallel the vascular tone. Telcagepant (10-6 M) inhibited both vasorelaxation and drop in intracellular calcium levels. Both functional components of the CGRP receptor, CLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity modifying peptide 1) were found in the smooth muscle cells but not in the endothelial cells of the cerebral vasculature. This study thus demonstrates the relaxant effect of αCGRP on rat MCA. The vasorelaxation is associated with a simultaneous decrease in intracellular calcium levels. Telcagepant reduced relaxation and thwarted the reduction in intracellular calcium levels localized in the vascular smooth muscle cells. In addition, Telcagepant may act as a non-competitive antagonist at concentrations greater than 10-8 M.

  • Differential inhibitory response to Telcagepant on αCGRP induced vasorelaxation and intracellular Ca2+ levels in the perfused and non-perfused isolated rat middle cerebral artery
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Andre Erdling, Majid Sheykhzade, Lars Edvinsson
    Abstract:

    Abstract Background Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist Telcagepant on intracellular Ca2+ -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry. Methods A pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or Telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry. Results Abluminal but not luminal αCGRP (10-12-10-6 M) caused concentration-dependent vasorelaxation in rat MCA. Luminal Telcagepant (10-6 M) failed to inhibit this relaxation, while abluminal Telcagepant inhibited the relaxation (10-6 M). Using the FURA-2 method in combination with wire myography we observed that αCGRP reduced intracellular calcium levels and in parallel the vascular tone. Telcagepant (10-6 M) inhibited both vasorelaxation and drop in intracellular calcium levels. Both functional components of the CGRP receptor, CLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity modifying peptide 1) were found in the smooth muscle cells but not in the endothelial cells of the cerebral vasculature. Conclusions This study thus demonstrates the relaxant effect of αCGRP on rat MCA. The vasorelaxation is associated with a simultaneous decrease in intracellular calcium levels. Telcagepant reduced relaxation and thwarted the reduction in intracellular calcium levels localized in the vascular smooth muscle cells. In addition, Telcagepant may act as a non-competitive antagonist at concentrations greater than 10-8 M

  • randomized controlled trial of the cgrp receptor antagonist Telcagepant for migraine prevention
    Neurology, 2014
    Co-Authors: Tony W Ho, Christopher Lines, Peter J. Goadsby, Lars Edvinsson, Kathryn M Connor, Ying Zhang, Eric Pearlman, Janelle Koppenhaver, David Michelson
    Abstract:

    Objective: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist Telcagepant might be effective for migraine prevention. Methods: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.govNCT00797667), patients experiencing 3–14 migraine days during a 4-week baseline were randomized to Telcagepant 140 mg, Telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥1 associated symptom). Results: The trial was terminated following a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48–50 days. Thirteen patients, all in the Telcagepant groups, had an alanine aminotransferase (ALT) elevation ≥3× the upper limit of normal and 7 of these also had an aspartate aminotransferase elevation ≥3× the upper limit of normal. Two patients had very high symptomatic transaminase elevations that occurred within 2–6 weeks of treatment initiation and resolved after treatment discontinuation. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points, but there was evidence that Telcagepant resulted in a larger reduction from baseline than placebo for mean monthly headache days (month 1: 140 mg = −2.9, 280 mg = −3.1, placebo = −1.7; p p Conclusions: These data suggest a potential role for CGRP receptor antagonism in migraine prophylaxis. However, the observed aminotransferase elevations do not support the use of Telcagepant for daily administration. Classification of evidence: This study provides Class II evidence that in patients with migraine, Telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations of serum ALT levels.

  • Topical non-peptide antagonists of sensory neurotransmitters substance P and CGRP do not modify patch test and prick test reactions: a vehicle-controlled, double-blind pilot study
    Archives of Dermatological Research, 2014
    Co-Authors: Joanna Wallengren, Lars Edvinsson
    Abstract:

    Immunologic responses in the skin can be modulated by such neurotransmitters of sensory nerve fibers as substance P (SP) and calcitonin gene-related peptide (CGRP). The first-generation receptor antagonists were peptides with large molecules and had to be injected intracutaneously. The aim of this study was to examine the topical effects of non-peptide antagonists to substance P (aprepitant) and CGRP (Telcagepant), respectively, on delayed and immediate reactions in the skin and on associated pruritus. A lipophilic formulation of aprepitant 5 % and a hydrophilic formulation of Telcagepant 1 % were developed. Their effect on the skin barrier was measured in terms of transepidermal water loss (TEWL) while permeation was calculated using permeation coefficients. Patch tests in patients allergic to nickel and prick test reactions to histamine were used as models. None of the treatments increased TEWL, suggesting there to be no impairment of the skin barrier. Permeation coefficients indicated moderate permeation. Histamine prick tests induced a flare with a mean area of 662  +  275 mm^2 and a weal with a mean volume of 49  +  11 mm^3. These reactions as well as histamine-induced pruritus were not affected significantly by any of the treatments. Treatment with aprepitant and its vehicle alone resulted in a potentiating of the infiltration of nickel reactions compared with test reactions obtained after no treatment (1147  +  423 mm^3 and 1427  +  566 mm^3 vs 683 +202 mm^3) (p = 0.03). Telcagepant induced vasoconstriction in the skin but did not change the infiltration of nickel reactions. None of the treatments influenced the nickel patch test induced pruritus. The data suggest that the topical application of non-peptide antagonists penetrates the skin but does not inhibit contact dermatitis or pruritus.

  • effect of the calcitonin gene related peptide cgrp receptor antagonist Telcagepant in human cranial arteries
    Cephalalgia, 2010
    Co-Authors: Lars Edvinsson, Kayi Y Chan, Sajedeh Eftekhari, Elisabeth Nilsson, Rene De Vries, Hans Saveland, Clemens M F Dirven, A Jan H Danser, Antoinette Maassenvandenbrink
    Abstract:

    INTRODUCTION: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. MATERIALS AND METHODS: We investigated the effect of the CGRP receptor antagonist, Telcagepant, on CGRP-induced cranial vasodilatation in human isolated cerebral and middle meningeal arteries. We also studied the expression of the CGRP receptor components in cranial arteries with immunocytochemistry. Concentration response curves to αCGRP were performed in human isolated cerebral and middle meningeal arteries in the absence or presence of Telcagepant. Arterial slices were stained for RAMP1, CLR and actin in a double immunofluorescence staining. RESULTS: In both arteries, we found that: (i) Telcagepant was devoid of any contractile or relaxant effects per se; (ii) pretreatment with Telcagepant antagonised the αCGRP-induced relaxation in a competitive manner; and (iii) immunohistochemistry revealed expression and co-localisation of CLR and RAMP1 in the smooth muscle cells in the media layer of both arteries. CONCLUSIONS: Our findings provide morphological and functional data on the presence of CGRP receptors in cerebral and meningeal arteries, which illustrates a possible site of action of Telcagepant in the treatment of migraine. (Less)

Christopher Lines - One of the best experts on this subject based on the ideXlab platform.

  • randomized controlled trial of the cgrp receptor antagonist Telcagepant for prevention of headache in women with perimenstrual migraine
    Cephalalgia, 2016
    Co-Authors: Christopher Assaid, Michel D. Ferrari, Christopher Lines, Regina Gottwald, Janelle Koppenhaver, Anne E Macgregor, Lisa K Mannix, Willebrordus P J Van Oosterhout, David Michelson
    Abstract:

    AimThe aim of this article is to evaluate the safety and efficacy of perimenstrual Telcagepant, a CGRP receptor antagonist, for headache prophylaxis.MethodsWe conducted a randomized, double-blind, ...

  • randomized controlled trial of the cgrp receptor antagonist Telcagepant for migraine prevention
    Neurology, 2014
    Co-Authors: Tony W Ho, Christopher Lines, Peter J. Goadsby, Lars Edvinsson, Kathryn M Connor, Ying Zhang, Eric Pearlman, Janelle Koppenhaver, David Michelson
    Abstract:

    Objective: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist Telcagepant might be effective for migraine prevention. Methods: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.govNCT00797667), patients experiencing 3–14 migraine days during a 4-week baseline were randomized to Telcagepant 140 mg, Telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥1 associated symptom). Results: The trial was terminated following a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48–50 days. Thirteen patients, all in the Telcagepant groups, had an alanine aminotransferase (ALT) elevation ≥3× the upper limit of normal and 7 of these also had an aspartate aminotransferase elevation ≥3× the upper limit of normal. Two patients had very high symptomatic transaminase elevations that occurred within 2–6 weeks of treatment initiation and resolved after treatment discontinuation. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points, but there was evidence that Telcagepant resulted in a larger reduction from baseline than placebo for mean monthly headache days (month 1: 140 mg = −2.9, 280 mg = −3.1, placebo = −1.7; p p Conclusions: These data suggest a potential role for CGRP receptor antagonism in migraine prophylaxis. However, the observed aminotransferase elevations do not support the use of Telcagepant for daily administration. Classification of evidence: This study provides Class II evidence that in patients with migraine, Telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations of serum ALT levels.

  • 55 ORIGINAL ARTICLE The Dose Proportionality of Telcagepant after Administration of Single Oral and Intravenous Doses in Healthy Adult Subjects
    2013
    Co-Authors: Tae H Han, Christopher Lines, Rebecca L Blanchard, John Palcza, Ashley Martucci, Maria Gutierrez, Deborah Panebianco, Cynthia M. Miller-stein, Gail M Murphy
    Abstract:

    Introduction. Telcagepant (MK-0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine. Early clinical data suggested greater than dose proportional increases in exposure following oral administration. The aim of the present studies was to definitively characterize the oral and IV dose proportionality of Telcagepant. Methods. Healthy adult subjects were enrolled in two separate open-label randomized dose proportionality studies

  • randomized controlled study of Telcagepant in patients with migraine and coronary artery disease
    Headache, 2012
    Co-Authors: Bernard R Chaitman, James Kost, Jan Lewis Brandes, Constance Johnson, Ninan T Mathew, Xiaoyin Fan, Sheena K Aurora, Kaiyin Fei, Louise Beebe, Christopher Lines
    Abstract:

    Objective.— To evaluate the efficacy of Telcagepant in patients with migraine and coronary artery disease. Background.— Calcitonin gene-related peptide receptor antagonists, such as Telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. Methods.— Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: Telcagepant (280-mg tablet/300-mg capsule), Period 2: acetaminophen (1000-mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: Telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of Telcagepant. The primary efficacy analysis evaluated Telcagepant vs placebo on 2-hour pain freedom during the first attack of Period 1. Results.— One hundred and sixty-five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2-hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. Conclusion.— The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between Telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.

  • randomized controlled study of Telcagepant plus ibuprofen or acetaminophen in migraine
    Headache, 2011
    Co-Authors: David J Hewitt, Vincent T Martin, Richard B Lipton, Jan Lewis Brandes, Paulette Ceesay, Regina Gottwald, Eleanor Schaefer, Christopher Lines
    Abstract:

    (Headache 2011;51:533-543) Objective.— To evaluate the efficacy and tolerability of Telcagepant when co-administered with ibuprofen or acetaminophen for the acute treatment of migraine. Background.— Telcagepant is an oral calcitonin gene-related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. Combining Telcagepant with analgesics that have a different mechanism of action could produce greater efficacy. Methods.— Randomized, double-blind, placebo-controlled study. Patients were randomized to treat a moderate or severe migraine headache with either Telcagepant 280 mg + ibuprofen 400 mg (N = 171), Telcagepant 280 mg + acetaminophen 1000 mg (N = 171), Telcagepant 280 mg (N = 170), or placebo (N = 171). The primary efficacy endpoint was 2-hour pain freedom. The study had approximately 88% power to detect an additive effect of at least 15 percentage points (Telcagepant combination vs Telcagepant monotherapy) and 48% power to detect an additive effect of at least 10 percentage points. Safety and tolerability were assessed by adverse events and laboratory tests. Results.— The percentages of patients with 2-hour pain freedom were greater in each active treatment group compared to placebo (P < .001): Telcagepant + ibuprofen = 35.2%, Telcagepant + acetaminophen = 38.3%, Telcagepant = 31.2%, placebo = 10.9%. No significant differences were seen for either of the combination groups vs Telcagepant monotherapy, but both were numerically larger than Telcagepant monotherapy. All the active treatments were generally well tolerated. The percentage of patients reporting any adverse event within 48 hours was higher in the active treatment groups than placebo: Telcagepant + ibuprofen = 30.3%, Telcagepant + acetaminophen = 31.6%, Telcagepant = 24.8%, placebo = 18.2%. The most common adverse events reported by ≥4 patients in one or more of the treatment groups that included Telcagepant were fatigue, nausea, dizziness, somnolence, dry mouth, and tremor. Conclusions.— The combination of Telcagepant 280 mg with either ibuprofen 400 mg or acetaminophen 1000 mg did not show a statistically significant difference from Telcagepant alone. Numerically greater treatment effects in the combination treatment groups over the Telcagepant 280 mg monotherapy suggest that Telcagepant combination treatments may merit further evaluation in studies powered to detect smaller additive benefits. (Clinicaltrials.gov; NCT00758836).

Stefanie A. Kane - One of the best experts on this subject based on the ideXlab platform.

  • characterization of the calcitonin gene related peptide receptor antagonist Telcagepant mk 0974 in human isolated coronary arteries
    Journal of Pharmacology and Experimental Therapeutics, 2010
    Co-Authors: Kayi Y Chan, Lars Edvinsson, Sajedeh Eftekhari, Rene De Vries, Stefanie A. Kane, Per Ola Kimblad, Joseph J Lynch, Richard Hargreaves, Ingrid M Garrelds, A J Van Den Bogaerdt
    Abstract:

    The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist Telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; E(max) = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E(max) = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E(max) = 11 +/- 3%), and coronary arterioles (i.d. 200-300 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with Telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM Telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with Telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that Telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.

  • comparison of the vasoconstrictor effects of the calcitonin gene related peptide cgrp receptor antagonist Telcagepant mk 0974 and zolmitriptan in human isolated coronary arteries
    Journal of Cardiovascular Pharmacology, 2010
    Co-Authors: Joseph J Lynch, Lars Edvinsson, Richard Hargreaves, Christopher P Regan, Stefanie A. Kane
    Abstract:

    Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist Telcagepant, and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl-precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 muM Telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1, slope 0.94), with the greatest contraction obtained between 1-10 muM in most tissues. In contrast, Telcagepant at concentrations up to 30 muM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone. (Less)

  • comparison of the vasoconstrictor effects of the calcitonin gene related peptide cgrp receptor antagonist Telcagepant mk 0974 and zolmitriptan in human isolated coronary arteries
    Journal of Cardiovascular Pharmacology, 2010
    Co-Authors: Joseph J Lynch, Lars Edvinsson, Richard Hargreaves, Christopher P Regan, Stefanie A. Kane
    Abstract:

    Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist Telcagepant and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 microM Telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1; slope 0.94), with the greatest contraction obtained between 1 and 10 microM in most tissues. In contrast, Telcagepant at concentrations up to 30 microM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone.

  • Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, Telcagepant (MK-0974).
    British journal of clinical pharmacology, 2010
    Co-Authors: S.r. Sinclair, Bart Van Der Schueren, Inge De Lepeleire, Janet Boyle, Stefanie A. Kane, Alan Xiao, Kenneth J. Willson, Lisa Hickey, William S. Denney
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Calcitonin gene-related peptide (CGRP) was first described as a potent vasodilator. • CGRP is also increasingly recognized as a key player in the pathophysiology of migraine, and CGRP receptor antagonists potentially offer a new approach for treating migraine. • A novel pharmacodynamic assay to measure CGRP receptor antagonist activity non-invasively in humans has been developed, which involves measuring the increase in dermal blood flow induced by topical application of capsaicin on the forearm. WHAT THIS STUDY ADDS • This study shows that the novel oral CGRP receptor antagonist, Telcagepant, inhibits the increases in dermal blood flow induced by the topical application of capsaicin on the human forearm. • This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists. AIMS To evaluate inhibition of capsaicin-induced increase in dermal blood flow (DBF) following Telcagepant (MK-0974), a potent and selective orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist being developed for the acute treatment of migraine. METHODS A three-period crossover study in 12 healthy adult men. Each subject received a single oral dose of Telcagepant 300 mg, Telcagepant 800 mg or placebo at 0 h, followed 0.5 and 3.5 h later by two topical doses of 300 and 1000 µg capsaicin per 20 µl water–ethanol mixture. Capsaicin was applied at two sites on the volar surface of the subjects' left and right forearms. DBF was assessed by laser Doppler perfusion imaging immediately before (‘baseline’), and 0.5 h after each capsaicin application at 1 and 4 h. Plasma samples to determine Telcagepant concentrations were collected immediately after laser Doppler perfusion imaging. A pharmacodynamic model was developed to explore the relationship between plasma concentration and inhibition of capsaicin-induced increase in DBF. RESULTS Geometric mean plasma concentrations after dosing with 300 mg and 800 mg Telcagepant were 720 and 1146 nm, respectively, at 1 h, vs. 582 and 2548 nm, respectively, at 4 h. The pharmacodynamic model suggested that the EC90 for Telcagepant inhibition of capsaicin-induced increases in DBF was 909 nm. CONCLUSIONS Telcagepant inhibits the increases in DBF induced by the topical application of capsaicin on the human forearm. This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.

Richard Hargreaves - One of the best experts on this subject based on the ideXlab platform.

  • calcitonin gene related peptide modulators the history and renaissance of a new migraine drug class
    Headache, 2019
    Co-Authors: Richard Hargreaves, Jes Olesen
    Abstract:

    Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain-producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP-RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo-controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [11 C]MK-4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of Telcagepant, a prototypic CGRP-RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP-RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood-brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next-generation small molecule CGRP-RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP-based therapeutic options for migraine patients.

  • characterization of the calcitonin gene related peptide receptor antagonist Telcagepant mk 0974 in human isolated coronary arteries
    Journal of Pharmacology and Experimental Therapeutics, 2010
    Co-Authors: Kayi Y Chan, Lars Edvinsson, Sajedeh Eftekhari, Rene De Vries, Stefanie A. Kane, Per Ola Kimblad, Joseph J Lynch, Richard Hargreaves, Ingrid M Garrelds, A J Van Den Bogaerdt
    Abstract:

    The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist Telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; E(max) = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E(max) = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E(max) = 11 +/- 3%), and coronary arterioles (i.d. 200-300 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with Telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM Telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with Telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that Telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.

  • comparison of the vasoconstrictor effects of the calcitonin gene related peptide cgrp receptor antagonist Telcagepant mk 0974 and zolmitriptan in human isolated coronary arteries
    Journal of Cardiovascular Pharmacology, 2010
    Co-Authors: Joseph J Lynch, Lars Edvinsson, Richard Hargreaves, Christopher P Regan, Stefanie A. Kane
    Abstract:

    Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist Telcagepant, and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl-precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 muM Telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1, slope 0.94), with the greatest contraction obtained between 1-10 muM in most tissues. In contrast, Telcagepant at concentrations up to 30 muM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone. (Less)

  • comparison of the vasoconstrictor effects of the calcitonin gene related peptide cgrp receptor antagonist Telcagepant mk 0974 and zolmitriptan in human isolated coronary arteries
    Journal of Cardiovascular Pharmacology, 2010
    Co-Authors: Joseph J Lynch, Lars Edvinsson, Richard Hargreaves, Christopher P Regan, Stefanie A. Kane
    Abstract:

    Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist Telcagepant and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 microM Telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1; slope 0.94), with the greatest contraction obtained between 1 and 10 microM in most tissues. In contrast, Telcagepant at concentrations up to 30 microM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone.

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  • randomized controlled study of Telcagepant in patients with migraine and coronary artery disease
    Headache, 2012
    Co-Authors: Bernard R Chaitman, James Kost, Jan Lewis Brandes, Constance Johnson, Ninan T Mathew, Xiaoyin Fan, Sheena K Aurora, Kaiyin Fei, Louise Beebe, Christopher Lines
    Abstract:

    Objective.— To evaluate the efficacy of Telcagepant in patients with migraine and coronary artery disease. Background.— Calcitonin gene-related peptide receptor antagonists, such as Telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. Methods.— Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: Telcagepant (280-mg tablet/300-mg capsule), Period 2: acetaminophen (1000-mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: Telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of Telcagepant. The primary efficacy analysis evaluated Telcagepant vs placebo on 2-hour pain freedom during the first attack of Period 1. Results.— One hundred and sixty-five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2-hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. Conclusion.— The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between Telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.

  • sustained pain freedom and no adverse events as an endpoint in clinical trials of acute migraine treatments application to patient level data from a trial of the cgrp receptor antagonist Telcagepant and zolmitriptan
    Cephalalgia, 2011
    Co-Authors: David William Dodick, James Kost, Christopher Lines, Christopher Assaid, Tony W Ho
    Abstract:

    Background: Endpoints used to evaluate the efficacy of acute anti-migraine drugs do not measure the tolerability. Sustained pain-free response with no adverse events has been recommended as a composite endpoint which measures the efficacy and tolerability attributes that patients desire.Methods: The aim of this study was to evaluate new composite efficacy-plus-tolerability endpoints based on a post-hoc analysis of patient-level data from a previous randomized, placebo-controlled trial of the calcitonin gene-related peptide (CGRP) receptor antagonist, Telcagepant, and zolmitriptan in the acute treatment of migraine. Endpoints were 2–24-hour sustained pain freedom and no adverse events from 0–24 hours (SPF24NAE), 2–24 hour sustained pain relief and no adverse events from 0–24 hours (SPR24NAE), pain freedom at 2 hours and no adverse events from 0–24 hours (PF2NAE), and pain relief at 2 hours and no adverse events from 0–24 hours (PR2NAE).Results: Compared with placebo, both Telcagepant 300 mg and 150 mg achi...

  • antimigraine efficacy of Telcagepant based on patient s historical triptan response
    Headache, 2011
    Co-Authors: Tony W Ho, Jes Olesen, James Kost, David William Dodick, Christopher Lines, Michel D. Ferrari
    Abstract:

    (Headache 2011;51:64-72) Objective.— To evaluate whether the same or different patients respond to triptans and Telcagepant. Background.— Telcagepant is an oral calcitonin gene-related peptide receptor antagonist with acute antimigraine efficacy comparable to oral triptans. It is currently unknown whether migraine patients who cannot be adequately helped with triptans might benefit from treatment with Telcagepant. Methods.— Post-hoc analysis of data from a randomized, controlled trial of Telcagepant (150 mg, 300 mg) zolmitriptan 5 mg, or placebo for a moderate/severe migraine. Responder rates were analyzed according to patients' self-reported historical triptan response (HTR): (1) good HTR (N = 660): response in 75-100% of attacks; (2) intermediate HTR (N = 248): response in 25-74% of attacks; (3) poor HTR/no use (N = 407): response in <25% of attacks, or patient did not take triptans. A limitation of the analysis is that the last subgroup comprised mainly (91%) patients who reported that they did not take triptans, but it was not known whether these patients were triptan-naive or had previously used triptans and stopped taking them. Results.— For zolmitriptan, 2-hour pain relief rates were higher in the good HTR subgroup (116/162, 72%) than in the intermediate (29/62, 47%) and poor/no use (44/111, 40%) HTR subgroups. The 2-hour pain relief rates were similar across HTR subgroups for Telcagepant 150 mg (48-58%), 300 mg (52-58%), and placebo (26-31%). In the poor/no use HTR subgroup, more patients receiving Telcagepant 300 mg (56/98, 57.1%) had 2-hour pain relief than those receiving zolmitriptan (44/111, 39.6%; odds ratio = 2.11 [95% CI: 1.20,3.71], P = .009); the percentage for Telcagepant 150 mg (57/119, 47.9%) was not significantly different from zolmitriptan (odds ratio = 1.41 [95% CI: 0.82, 2.40], P = .211). Conclusions.— This suggests that different patients may respond to triptans or Telcagepant 300 mg. Caution should be exercised in interpreting the results because of the post-hoc nature of the analysis (clinical trial registry: NCT00442936).

  • randomized controlled trial of Telcagepant over four migraine attacks
    Cephalalgia, 2010
    Co-Authors: Carl Dahlof, James Kost, Stephen D Silberstein, Joel R Saper, Messoud Ashina, Samar Froman, Heather Leibensperger, Christopher Lines
    Abstract:

    Methods: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist Telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with...

  • randomized controlled trial of Telcagepant for the acute treatment of migraine
    Neurology, 2009
    Co-Authors: Kathryn M Connor, James Kost, Xiaoyin Fan, Kaiyin Fei, Christopher Assaid, Robert E Shapiro, H C Diener, Sylvia Lucas, Christopher Lines
    Abstract:

    Connor et al.1 report that the use of 150 mg of Telcagepant results in pain relief at 2 hours in 54% of patients with migraine compared to 33% of patients achieving this endpoint with placebo. Merck Research Laboratories funded this study and all the authors were employees of Merck or had financial ties to Merck or other large pharmaceutical companies. The publication of this trial raises serious concerns. Triptans are the standard care for moderate to severe migraine. Sumatriptan 50 mg, now available as a generic, results in pain relief at 2 hours in 50% to 59% of patients with migraine compared to 17% to 26% for placebo.2 The relevant question for patients and physicians is whether Telcagepant offers any advantage over sumatriptan. The authors justify comparing Telcagepant to placebo—rather than to active treatment— because it may be used in patients with coronary artery or cerebrovascular disease, in whom triptans are contraindicated. However, if this is the population of interest for Telcagepant, it should be tested in this population. There are sufficient preliminary data supporting the superiority of Telcagepant to placebo. A placebo-controlled trial in the population of patients eligible for triptan treatment before a trial in the clinically …

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