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

Background A model for the testing of novel antimigraine drugs should ideally use healthy volunteers for ease of recruiting. Cilostazol provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation. The hypothesis of the present study was that sumatriptan but not placebo is effective in cilostazol-induced headache in healthy individuals. Methods In a double-blind, randomized, cross-over design, 30 healthy volunteers of both sexes received cilostazol 200 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. Results Cilostazol induced a reproducible headache in 90% of the participants. The headache had several migraine-like features in most individuals. Median peak headache score was 2 on the sumatriptan day and 3 on the placebo day ( p = 0.17). There was no reduction in headache intensity two hours after sumatriptan ( p = 0.97) and difference in AUC 0 to four hours between two experimental days was not significant ( p = 0.18). On the placebo day eight participants took rescue medication compared to 3 on the sumatriptan day ( p = 0.13). Conclusion Despite similarities with migraine headache, cilostazol-induced headache in healthy volunteers does not respond to sumatriptan.

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Towards a pragmatic human migraine model for drug testing: 2. Isosorbide-5-mononitrate in healthy individuals

Cephalalgia ◽

10.1177/0333102416636095 ◽

2016 ◽

Vol 37 (1) ◽

pp. 11-19 ◽

Cited By ~ 12

Author(s):

Emma Katrine Hansen ◽

Jes Olesen

Keyword(s):

Physical Activity ◽

Healthy Volunteers ◽

Drug Testing ◽

No Reduction ◽

Crossover Design ◽

Healthy Individuals ◽

Double Blind ◽

Future Drug ◽

Accompanying Symptoms ◽

Human Migraine Model

Background A model for the testing of novel anti-migraine drugs should preferably use healthy volunteers for ease of recruiting. Isosorbide-5-mononitrate (5-ISMN) provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation of any model. The hypothesis of the present study was that sumatriptan is effective in 5-ISMN-induced headache in healthy individuals. Methods In a double-blind, randomised, crossover design, 30 healthy volunteers of both sexes received 5-ISMN 60 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. Results 5-ISMN induced a reproducible headache in all 30 participants. The headache had several migraine-like features in all participants and 20 individuals developed a migraine-like attack. Median peak headache score was 5 on both experimental days ( p = 1.00). There was no reduction, but instead an increase in headache intensity 2 hours after sumatriptan ( p = 0.003). Difference in area under the headache score curve (AUC) 0–4 hours between sumatriptan and placebo was not significant ( p = 0.30). Conclusion 5-ISMN is a very powerful inducer of migraine-like headache in healthy individuals but the headache does not respond to sumatriptan. The model is not useful for future drug testing.

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Effect of KATP channel blocker glibenclamide on levcromakalim-induced headache

Cephalalgia ◽

10.1177/0333102420949863 ◽

2020 ◽

Vol 40 (10) ◽

pp. 1045-1054 ◽

Cited By ~ 1

Author(s):

Mohammad Al-Mahdi Al-Karagholi ◽

Hashmat Ghanizada ◽

Lili Kokoti ◽

Joachim S Paulsen ◽

Jakob Møller Hansen ◽

...

Keyword(s):

Confidence Interval ◽

Potassium Channel ◽

Healthy Volunteers ◽

Channel Blocker ◽

Area Under The Curve ◽

Mean Difference ◽

Double Blind ◽

Headache Intensity ◽

Primary Endpoints ◽

The Difference

Introduction Administration of ATP-sensitive potassium channel opener levcromakalim triggers headache in healthy volunteers and migraine attacks in migraine patients. Here, we investigated the effect of ATP-sensitive potassium channel blocker glibenclamide on levcromakalim-induced headache in healthy volunteers. Methods In a randomized, double-blind, placebo-controlled, three-way cross-over study, 15 healthy volunteers aged 18–40 years were randomly allocated to receive glibenclamide and levcromakalim (day 1), glibenclamide and placebo (day 2), and placebo and placebo (day 3) on three different days separated by at least 1 week. The primary endpoints were the difference in incidence of headache and the difference in area under the curve for headache intensity scores (0–12 hours) between the days. Results Fifteen healthy volunteers completed the 3 days of the study. More participants (12/15, 80%) developed headache on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day (5/15, 33%) ( p = 0.01; mean difference 47%; 95% confidence interval 18–75%) and compared to the placebo-placebo day (1/15, 7%) ( p = 0.001; mean difference 73%; 95% confidence interval 48–99%). We found no difference in headache incidence between glibenclamide-placebo day and placebo-placebo day ( p = 0.12; mean difference 27%; 95% confidence interval 1.3–52%). The area under the curve for headache intensity was significantly larger on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day ( p = 0.003); and compared to the placebo-placebo day ( p = 0.001). We found no difference in the area under the curve between the glibenclamide-placebo day compared to the placebo-placebo day ( p = 0.07). The median time to onset for headache after levcromakalim infusion with glibenclamide pretreatment was delayed (180 min) compared to levcromakalim without pretreatment (30 min) from a previously published study. Conclusion Glibenclamide administration did not cause headache, and glibenclamide pretreatment did not prevent levcromakalim-induced headache. However, glibenclamide delayed the onset of levcromakalim-induced headache. More selective blockers are needed to further elucidate the role of the ATP-sensitive potassium channel in headache initiation. Trial Registration: ClinicalTrials.gov NCT03886922.

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The Effect of KATP Channel Blocker Glibenclamide on CGRP-Induced Headache and Hemodynamic in Healthy Volunteers

Frontiers in Physiology ◽

10.3389/fphys.2021.652136 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hande Coskun ◽

Fatima Azzahra Elbahi ◽

Mohammad Al-Mahdi Al-Karagholi ◽

Hashmat Ghanizada ◽

Majid Sheykhzade ◽

...

Keyword(s):

Blood Flow ◽

Healthy Volunteers ◽

Channel Blocker ◽

Superficial Temporal Artery ◽

Sulfonylurea Receptor ◽

Double Blind ◽

Headache Intensity ◽

Arterial Blood ◽

Significant Difference ◽

The Difference

BackgroundCalcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (KATP) channels. Here, we investigated the effect of the KATP channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.MethodsIn a randomized, double-blind, placebo-controlled, cross-over study, 20 healthy volunteers aged 18–27 years were randomly allocated to receive an intravenous infusion of 1.5 μg/min CGRP after oral pretreatment with glibenclamide (glibenclamide-CGRP day) or placebo (placebo-CGRP day). The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0–14 h) between glibenclamide and placebo. The secondary endpoints were the difference in AUC for middle cerebral artery blood flow velocity (VMCA), superficial temporal artery (STA) and radial artery (RA) diameter, facial flushing, heart rate (HR) and mean arterial blood pressure (MAP) (0–4 h) between glibenclamide and placebo.ResultsWe found no significant difference in the incidence of headache between glibenclamide-CGRP day (14/20, 70%) and placebo-CGRP day (19/20, 95%) (P = 0.06). The AUC for headache intensity, VMCA, STA, RA, facial skin blood flow, HR, and MAP did not differ between glibenclamide-CGRP day compared to placebo-CGRP day (P > 0.05).ConclusionPretreatment with a non-selective KATP channel inhibitor glibenclamide did not attenuate CGRP-induced headache and hemodynamic changes in healthy volunteers. We suggest that CGRP-induced responses could be mediated via activation of specific isoforms of sulfonylurea receptor subunits of KATP channel.

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Opening of BKCa channels alters cerebral hemodynamic and causes headache in healthy volunteers

Cephalalgia ◽

10.1177/0333102420940681 ◽

2020 ◽

Vol 40 (11) ◽

pp. 1145-1154

Author(s):

Mohammad Al-Mahdi Al-Karagholi ◽

Hashmat Ghanizada ◽

Cherie Amalie Waldorff Nielsen ◽

Camilla Skandarioon ◽

Josefin Snellman ◽

...

Keyword(s):

Healthy Volunteers ◽

Radial Artery ◽

Superficial Temporal Artery ◽

Area Under The Curve ◽

Temporal Artery ◽

Bkca Channels ◽

Double Blind ◽

Headache Intensity ◽

The Difference

Introduction Preclinical data implicate large conductance calcium-activated potassium (BKCa) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BKCa channels would cause headache and vascular effects in healthy volunteers. Methods In a randomized, double-blind, placebo-controlled, cross-over study, 21 healthy volunteers aged 18–39 years were randomly allocated to receive an intravenous infusion of 0.05 mg/min BKCa channel opener MaxiPost and placebo on two different days. The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0–12 hours) and for middle cerebral artery blood flow velocity (VMCA) (0–2 hours) between MaxiPost and placebo. The secondary endpoints were the differences in area under the curve for superficial temporal artery and radial artery diameter (0–2 hours) between MaxiPost and placebo. Results Twenty participants completed the study. Eighteen participants (90%) developed headache after MaxiPost compared with six (30%) after placebo ( p = 0.0005); the difference of incidence is 60% (95% confidence interval 36–84%). The area under the curve for headache intensity (AUC0–12 hours, p = 0.0003), for mean VMCA (AUC0–2 hours, p = 0.0001), for superficial temporal artery diameter (AUC0–2 hours, p = 0.003), and for radial artery diameter (AUC0–2 hours, p = 0.03) were significantly larger after MaxiPost compared to placebo. Conclusion MaxiPost caused headache and dilation in extra- and intracerebral arteries. Our findings suggest a possible role of BKCa channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325.

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