Sildenafil and calcitonin gene-related peptide dilate intradural arteries: A 3T MR angiography study in healthy volunteers

Cephalalgia ◽  
2018 ◽  
Vol 39 (2) ◽  
pp. 264-273 ◽  
Author(s):  
Casper Emil Christensen ◽  
Faisal Mohammad Amin ◽  
Samaira Younis ◽  
Ulrich Lindberg ◽  
Patrick de Koning ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Mr Angiography ◽  
Area Under The Curve ◽  
Middle Meningeal Artery ◽  
Calcitonin Gene Related Peptide ◽  
Double Blind ◽  
Related Peptide ◽  
Peptide T ◽  
Calcitonin Gene ◽  
Meningeal Artery

Background Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined in vivo. Sildenafil is the only migraine-inducing compound for which cephalic, extracranial artery dilation is not reported. Here, we investigate the effects of sildenafil and calcitonin gene-related peptide on the extracranial and intradural parts of the middle meningeal artery. Methods In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison study, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug (sildenafil/ calcitonin gene-related peptide/saline) administration. Circumferences of extracranial and intradural middle meningeal artery segments were measured using semi-automated analysis software. The area under the curve for circumference change was compared using paired t-tests between study days. Results Twelve healthy volunteers completed the study. The area under the curveBaseline-120min was significantly larger on both the sildenafil and the calcitonin gene-related peptide day in the intradural middle meningeal artery (calcitonin gene-related peptide, p = 0.013; sildenafil, p = 0.027) and the extracranial middle meningeal artery (calcitonin gene-related peptide, p = 0.0003; sildenafil, p = 0.021), compared to placebo. Peak intradural middle meningeal artery dilation was 9.9% (95% CI [2.9–16.9]) after sildenafil (T30min) and 12.5% (95% CI [8.1–16.8]) after calcitonin gene-related peptide (T30min). Peak dilation of the extracranial middle meningeal artery after calcitonin gene-related peptide (T30min) was 15.7% (95% CI [11.2–20.1]) and 18.9% (95% CI [12.8–24.9]) after sildenafil (T120min). Conclusion An important novel finding is that both sildenafil and calcitonin gene-related peptide dilate intradural arteries, supporting the notion that all known pharmacological migraine triggers dilate cephalic vessels. We suggest that intradural artery dilation is associated with headache induced by calcitonin gene-related peptide and sildenafil.

Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models

Cephalalgia ◽  
2019 ◽  
Vol 39 (11) ◽  
pp. 1421-1434 ◽  
Author(s):  
Kristian A Haanes ◽  
Alejandro Labastida-Ramírez ◽  
Frank W Blixt ◽  
Eloisa Rubio-Beltrán ◽  
Clemens M Dirven ◽  
...  
Keyword(s):  
Trigeminal Ganglion ◽  
Purinergic Receptors ◽  
Middle Meningeal Artery ◽  
Calcitonin Gene Related Peptide ◽  
P2x3 Receptor ◽  
Related Peptide ◽  
Migraine Pain ◽  
Calcitonin Gene ◽  
Peptide Release ◽  
Meningeal Artery

Background The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine. Objective We aimed to explore purinergic receptors as potential anti-migraine targets. Methods We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents. Results We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction in vitro; b) reduced dural artery dilation following periarterial electrical stimulation in vivo and c) a reduction of CGRP release from both the dura and the trigeminal ganglion in situ. Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation. Conclusion Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.

Calcitonin gene-related peptide (CGRP) levels during glyceryl trinitrate (GTN)-induced headache in healthy volunteers

Cephalalgia ◽  
2009 ◽  
Vol 30 (4) ◽  
pp. 467-474 ◽  
Author(s):  
C Kruuse ◽  
HK Iversen ◽  
I Jansen-Olesen ◽  
L Edvinsson ◽  
J Olesen
Keyword(s):  
Glyceryl Trinitrate ◽  
Healthy Volunteers ◽  
Rating Scale ◽  
Calcitonin Gene Related Peptide ◽  
Trigeminovascular System ◽  
Double Blind ◽  
No Donor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Before And After

The role of nitric oxide (NO) in migraine has been studied in the experimental glyceryl trinitrate (GTN)-infusion headache model. We hypothesized that GTN-induced headache may activate the trigeminovascular system and be associated with increased levels of sensory neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers received subcutaneous sumatriptan 6 mg or placebo. This was succeeded by 20 min of GTN (0.12 µg kg−1 min−1) infusion. At baseline no subject reported headache (using verbal rating scale from 0 to 10) and the jugular CGRP-like immunoreactivity (-LI) level was 18.6 ± 2.5 pmol/l. After a 20-min intravenous infusion of GTN 0.12 µg kg−1 min−1, median peak headache intensity was 4 (range 2–6) ( P < 0.05), while jugular CGRP-LI levels were unchanged (19.0 ± 2.8 pmol/l; P > 0.05). There were no changes in VIP-, NPY- or somatostatin-LI. In conclusion, the NO donor GTN appears not to induce headache via immediate CGRP release.

scholarly journals Rimegepant: first novel oral calcitonin gene-related peptide inhibitor for migraine

2020 ◽  
Vol 9 (5) ◽  
pp. 829
Author(s):  
Saravana Kumar Ramasubbu ◽  
Senkadhirdasan Dakshinamurthy ◽  
Sarika Palepu ◽  
Arkapal Bandyopadhyay ◽  
Sathish Kumar Rajendran
Keyword(s):  
Area Under The Curve ◽  
Cardiovascular Effects ◽  
Calcitonin Gene Related Peptide ◽  
Causative Role ◽  
Acute Migraine ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Effective Option ◽  
Inflammatory Drugs ◽  
Cgrp Antagonist

Migraine is a neurological condition characterized by intense, debilitating headaches. Symptoms may include nausea, vomiting, numbness or tingling, sensitivity to light and sound. There are multitude of drugs available to treat migraine like triptans, non-steroidal anti-inflammatory drugs, ergots and opioids. But these drugs are associated with adverse effects especially triptans causing cardiovascular effects limiting its use. During last decade, calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for management of migraine. CGRP has been shown to release during episode of migraine attack and it may play a causative role in induction of migraine. Rimegepant is a novel CGRP antagonist has been approved by FDA for treatment of acute migraine. Rimegepant is a first oral CGRP antagonist compared to other gepants. The oral bioavailability of Rimegepant is 64% and high fat meal can decrease the Cmax, Tmax and area under the curve. This drug is mainly metabolized by CYP3A4 and to lesser extent by CYP2C9. Most common adverse reactions associated with this drug were nausea and urinary tract infection. Clinical trials for Rimegepant have been positive, and results suggest that the drug may be a new safe and effective option for treatment of acute migraine.

Eptinezumab for prevention of chronic migraine: A randomized phase 2b clinical trial

Cephalalgia ◽  
2019 ◽  
Vol 39 (9) ◽  
pp. 1075-1085 ◽  
Author(s):  
David W Dodick ◽  
Richard B Lipton ◽  
Stephen Silberstein ◽  
Peter J Goadsby ◽  
David Biondi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Chronic Migraine ◽  
Development Program ◽  
Calcitonin Gene Related Peptide ◽  
Electronic Diary ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Double Blind ◽  
Related Peptide ◽  
Calcitonin Gene

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. Methods This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Results The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo ( p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. Conclusions The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. Trial Registration ClinicalTrials.gov identifier: NCT02275117.

Haemodynamic effects of intravenous human calcitonin-gene-related peptide in man

1988 ◽  
Vol 74 (4) ◽  
pp. 413-418 ◽  
Author(s):  
C. W. Howden ◽  
Catherine Logue ◽  
Karen Gavin ◽  
Lizbeth Collie ◽  
P. C. Rubin
Keyword(s):  
Blood Pressure ◽  
Standing Position ◽  
Calcitonin Gene Related Peptide ◽  
Double Blind Study ◽  
Human Calcitonin ◽  
Facial Flushing ◽  
Double Blind ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Higher Doses

1. The effects of intravenous bolus doses of human calcitonin-gene-related peptide (hCGRP) were studied in ten healthy male volunteers. 2.5, 10 and 25 μg of hCGRP and placebo were administered to each subject in a randomized double-blind study. 2. hCGRP had no effect on systolic or diastolic blood pressure in the supine or standing position. 3. hCGRP increased supine and standing heart rate. Both the extent and duration of the tachycardia were dose related. 4. Plasma noradrenaline levels were transiently increased after 10 and 25 μg of hCGRP. 5. All subjects displayed marked facial flushing after the two higher doses of hCGRP. 6. We conclude that systemic administration of hCGRP produces tachycardia and stimulation of the sympathetic nervous system in the absence of any change in blood pressure.

scholarly journals Calcitonin Gene-Related Peptide Modulates Heat Nociception in the Human Brain - An fMRI Study in Healthy Volunteers

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0150334 ◽  
Author(s):  
Mohammad Sohail Asghar ◽  
Lino Becerra ◽  
Henrik B. W. Larsson ◽  
David Borsook ◽  
Messoud Ashina
Keyword(s):  
Human Brain ◽  
Healthy Volunteers ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Fmri Study ◽  
Calcitonin Gene

scholarly journals Sumatriptan does not change calcitonin gene-related peptide in the cephalic and extracephalic circulation in healthy volunteers

2009 ◽  
Vol 10 (2) ◽  
pp. 85-91 ◽  
Author(s):  
Jakob Møller Hansen ◽  
Jesper Petersen ◽  
Troels Wienecke ◽  
Karsten Skovgaard Olsen ◽  
Lars Thorbjørn Jensen ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene

Calcitonin gene related peptide released from dural nerve fibers mediates increase of meningeal blood flow in the rat

1995 ◽  
Vol 73 (7) ◽  
pp. 1020-1024 ◽  
Author(s):  
K. Meßlinger ◽  
U. Hanesch ◽  
M. Kurosawa ◽  
M. Pawlak ◽  
R. F. Schmidt
Keyword(s):  
Blood Flow ◽  
Dura Mater ◽  
Calcitonin Gene Related Peptide ◽  
Nerve Fibers ◽  
Dura Mater Encephali ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Meningeal Blood Flow ◽  
Meningeal Artery ◽  
Stimulation Of

The parietal dura mater encephali of the rat was shown by immunohistochemistry to be densely innervated by calcitonin gene related peptide (CGRP) immunoreactive nerve fibers spreading around the medial meningeal artery and its branches. Electrical stimulation of the dural surface (10–20 V, 5–10 Hz, 10–30 min) caused a depletion of CGRP-immunopositive fibers, suggesting a release of CGRP. The dural blood flow around branches of the medial meningeal artery was also monitored with a laser Doppler flowmeter. Short periods (30 s) of electrical stimulation with parameters that presumably released CGRP from nerve fibers caused a repeatable and constant increase of the blood flow for 1–2 min. This evoked increase could dose dependently be inhibited by topical application of the CGRP antagonist hCGRP8–37. Accordingly, administration of hCGRP increased the basal blood flow. We conclude that stimulation of trigeminal afferents innervating the dura mater releases CGRP from peptidergic afferent terminals, thereby causing vasodilatation and increasing the meningeal blood flow, an important element of neurogenic inflammation.Key words: dura mater encephali, afferent nerve fibers, calcitonin gene related peptide, immunohistochemistry, laser Doppler flowmetry.

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