Toward a pragmatic migraine model for drug testing: 1. Cilostazol in healthy volunteers

Hansen, Emma Katrine; Guo, Song; Ashina, Messoud; Olesen, Jes

doi:10.1177/0333102415583986

Cited by 13 publications

(30 citation statements)

References 27 publications

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“…It has been suggested that sumatriptan prevents headache in these models by inhibiting accumulation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). Interestingly, posttreatment with triptans failed to antagonize GTN and cilostazol induced headache in healthy volunteers [23,46]. In line with this, we also show that post-treatment with intravenous administration of sumatriptan failed to prevent PACAP38-induced headache in healthy volunteers.…”

Section: Experimentally Induced Headache and Anti-migraine Medicationsupporting

confidence: 86%

“…However, our results should be interpreted with caution because sumatriptan infusion caused immediate but short exacerbation of PACAP38-induced headache. The sumatriptan-induced headache was previously observed after infusion of calcitonin gene-related peptide (CGRP), levcromakalim, isosorbide-5-mononitrate (NO donor) and cilostazol in healthy volunteers [2,9,23,24]. It is also a well-known side effect of sumatriptan treatment in migraine patients [15,39].…”

Section: Experimentally Induced Headache and Anti-migraine Medicationmentioning

confidence: 99%

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Investigation of sumatriptan and ketorolac trometamol in the human experimental model of headache

et al. 2020

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Background: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache in healthy volunteers but the precise mechanisms by which PACAP38 leads to headache are unclear. We investigated the headache preventive effect of sumatriptan and ketorolac on PACAP38-induced headache in healthy volunteers. In addition, we explored contribution of vascular mechanisms to PACAP38-induced headache using high resolution magnetic resonance angiography. Methods: Thirty-four healthy volunteers were divided in two groups (A and B) and received infusion of PACAP38 (10 picomol/kg/min) over 20 min. Group A was pretreated with intravenous sumatriptan (4 mg) or ketorolac (30 mg) 20 min before infusion of PACAP38. Group B received infusion of sumatriptan or ketorolac as post-treatment 90 min after infusion of PACAP38. In both experiments, we used a randomized, double-blind, cross-over design. We recorded headache characteristics and circumference of extra-intracerebral arteries. Results: We found no difference in AUC (0-6 h) of PACAP38-induced headache in group A, pretreated with sumatriptan or ketorolac (p = 0.297). There was no difference between sumatriptan and ketorolac in PACAP38induced circumference change (AUC Baseline-110 min) of MMA (p = 0.227), STA (p = 0.795) and MCA (p = 0.356). In group B, post-treatment with ketorolac reduced PACAP38-headache compared to sumatriptan (p < 0.001). Posttreatment with sumatriptan significantly reduced the circumference of STA (p = 0.039) and MMA (p = 0.015) but not of MCA (p = 0.981) compared to ketorolac. In an explorative analysis, we found that pre-treatment with sumatriptan reduced PACAP38-induced headache compared to no treatment (AUC 0-90min). Conclusions: Post-treatment with ketorolac was more effective in attenuating PACAP38-induced headache compared to sumatriptan. Ketorolac exerted its effect without affecting PACAP38-induced arterial dilation, whereas sumatriptan post-treatment attenuated PACAP38-induced dilation of MMA and STA. Pre-treatment with sumatriptan attenuated PACAP38-induced headache without affecting PACAP38-induced arterial dilation. Our findings suggest that ketorolac and sumatriptan attenuated PACAP38-induced headache in healthy volunteers without vascular effects. Trial registration: Clinicaltrials.gov (NCT03585894). Registered

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Section: Experimentally Induced Headache and Anti-migraine Medicationsupporting

confidence: 86%

Section: Experimentally Induced Headache and Anti-migraine Medicationmentioning

confidence: 99%

Investigation of sumatriptan and ketorolac trometamol in the human experimental model of headache

et al. 2020

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“…The study was blinded for both participants and investigators. Sumatriptan was chosen as treatment since the present study is part of a series where the effect of sumatriptan on different headache inducing substances are being tested 15‐17 …”

Section: Methodsmentioning

confidence: 99%

Two‐Hour CGRP Infusion Causes Gastrointestinal Hyperactivity: Possible Relevance for CGRP Antibody Treatment

2020

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Objective.-The monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double-blind cross-over study of CGRP infusion for 2 hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies.Methods.-Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP 1.5 µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2 × 50 mg) 1 day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12-hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018.Results.-On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment.Conclusion.-We conclude that a 2-hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists.

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“…It has previously been attempted to develop a human model for testing new anti‐migraine drugs, using cilostazol (a phosphodiesterase 3 inhibitor) and a long‐lasting nitric oxide donor; isosorbide‐5‐mononitrate (5‐ISMN) . Cilostazol induced a headache with migraine‐like features in healthy volunteers and migraine‐like attacks in migraine without aura patients.…”

Section: Introductionmentioning

confidence: 99%

Sumatriptan Does Not Antagonize CGRP‐Induced Symptoms in Healthy Volunteers

et al. 2020

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Objective Previous attempts to develop a pragmatic human model for testing new anti‐migraine drugs, have failed. Calcitonin gene‐related peptide (CGRP) induces a mild headache in healthy volunteers and migraine‐like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP‐induced symptoms in an attempt to validate CGRP‐induced headache as a model for drug testing. Methods Thirty healthy volunteers were recruited to receive a 2‐hour infusion of CGRP on 2 separate days. The participants were pretreated with sumatriptan 1 day and with placebo the other day in a randomized double‐blind cross‐over fashion. During the infusion, a questionnaire about headache and side effects was administered. Electrocardiography, heart rate, blood pressure, dermal blood flow, and diameter of peripheral arteries were monitored during the infusion. Participants were carefully instructed to fill out a headache questionnaire at home until 12 hours after the infusion start. Primary endpoints are difference between the sumatriptan day and the placebo day in area under the headache score curve (AUC) 0‐2 hours after infusion start and in headache intensity 2 hours after infusion start. The study was conducted at the Danish Headache Center in Glostrup, Denmark. Results CGRP‐induced headache in 86% (25/29) of the participants on the sumatriptan day and in 96% (28/29) of the participants on the placebo day. There was no difference in AUCheadache, 0‐2 hours between the days (P = .794). There was a statistically significant decrease in mean atrial pressure (MAP) over time on both days with a16.2% reduction on the sumatriptan day and a 14.8% reduction on the placebo day (P < .001) and a statistically significant increase in heart rate (HR) over time on both days (from mean 57.5 at baseline to mean 105.4 at 120 minutes on the sumatriptan day and from mean 60.2 at baseline to 105.8 at 120 minutes on the placebo day, P < .001). The diameter of peripheral arteries increased statistically significant on both days (P < .001). Conclusion Sumatriptan does not influence headache score, accompanying symptoms or other symptoms induced by CGRP. Furthermore, a 2‐hour CGRP infusion causes a wide range of side effects and does not induce more headache than the usual 20‐minute infusion. Thus, the prolonged infusion of CGRP in healthy volunteers is not a valid and pragmatic model for testing new anti‐migraine drugs.

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Toward a pragmatic migraine model for drug testing: 1. Cilostazol in healthy volunteers

Abstract: Despite similarities with migraine headache, cilostazol-induced headache in healthy volunteers does not respond to sumatriptan.

Cited by 13 publications

References 27 publications

Investigation of sumatriptan and ketorolac trometamol in the human experimental model of headache

Investigation of sumatriptan and ketorolac trometamol in the human experimental model of headache

Two‐Hour CGRP Infusion Causes Gastrointestinal Hyperactivity: Possible Relevance for CGRP Antibody Treatment

Sumatriptan Does Not Antagonize CGRP‐Induced Symptoms in Healthy Volunteers

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