Publications by authors named "Mohammad Al-Mahdi Al-Karagholi"

26 Publications

  • Page 1 of 1

Opening of BKCa channels causes migraine attacks: a new downstream target for the treatment of migraine.

Pain 2021 Mar 16. Epub 2021 Mar 16.

Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Novartis Pharma AG, Basel, Switzerland Danish Knowledge Center on Headache Disorders, Rigshospitalet-Glostrup, Denmark.

Abstract: Migraine is a common and frequently disabling neurological disorder, but the initiating migraine mechanisms are still poorly understood. Potassium channel opening may cause migraine, and we therefore examined the migraine-inducing effect of MaxiPost, a large (big)-conductance calcium-activated potassium (BKCa) channel opener, on migraine induction and cephalic vasodilation in individuals with migraine. Twenty-six patients with migraine without aura were randomly allocated to receive an infusion of MaxiPost or placebo on 2 study days separated by at least 1 week. The primary endpoint was the difference in incidence of migraine attacks after MaxiPost compared with placebo. The secondary endpoints were the difference in incidence of headaches and the difference in area under the curve for headache intensity scores (0-12 hours), for middle cerebral artery blood flow velocity (VMCA) (0-2 hours), and for superficial temporal artery and radial artery diameter. Twenty-two patients completed the study. Twenty-one of 22 (95%) developed migraine attacks after MaxiPost compared with none after placebo (P < 0.0001); the difference of incidence is 95% (95% confidence interval 86%-100%). The incidence of headache over the 12-hour observation period was higher after MaxiPost day (n = 22) than after placebo (n = 7) (P < 0.0001). We found a significant increase of VMCA and superficial temporal and radial arteries' diameter. Because BKCa channel opening initiates migraine attacks, we suggest that BKCa channel blockers could be potential candidates for novel antimigraine drugs.
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http://dx.doi.org/10.1097/j.pain.0000000000002238DOI Listing
March 2021

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

Front Physiol 2021 11;12:652136. Epub 2021 Jun 11.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Calcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (K ) channels. Here, we investigated the effect of the K channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.

Methods: In 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 (V ), 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.

Results: We found no significant difference in the incidence of headache between glibenclamide-CGRP day (14/20, 70%) and placebo-CGRP day (19/20, 95%) ( = 0.06). The AUC for headache intensity, V , STA, RA, facial skin blood flow, HR, and MAP did not differ between glibenclamide-CGRP day compared to placebo-CGRP day ( 0.05).

Conclusion: Pretreatment with a non-selective K 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 K channel.
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http://dx.doi.org/10.3389/fphys.2021.652136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226177PMC
June 2021

Effect of Adrenomedullin on Migraine-Like Attacks in Patients With Migraine: A Randomized Crossover Study.

Neurology 2021 05 7;96(20):e2488-e2499. Epub 2021 Apr 7.

From the Danish Headache Center and Department of Neurology (H.G., M.A.-M.A.-K., N.A., M.M.-R., M.A.), Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; School of Biological Sciences and Centre for Brain Research (C.S.W., D.L.H.), University of Auckland; and Department of Pharmacology and Toxicology (D.L.H.), University of Otago, Dunedin, New Zealand.

Objective: To determine whether the IV infusion of adrenomedullin, a potent vasodilator belonging to calcitonin family of peptides, provokes attacks of migraine in patients.

Methods: Twenty patients with migraine without aura participated in a placebo-controlled and double-blind clinical study. In a randomized crossover design, the patients received an IV infusion of human adrenomedullin (19.9 pmol/kg/min) or placebo (saline) administrated via an automated IV pump (20 minutes). The patients participated in 2 study days with a washout period of minimum of 7 days. The primary outcome of the study was predefined as a difference in migraine incidence (0-12 hours), and the secondary outcomes were the area under curve (AUC hours) for the headache intensity score and AUC for mean arterial blood pressure (MAP), flushing, and heart rate (HR).

Results: Eleven patients with migraine without aura (55%) fulfilled migraine attacks criteria after adrenomedullin infusion compared to only 3 patients who reported attack (15%) after placebo ( 0.039). We found that patients reported in a period of 0 to 12 hours stronger headache intensity after adrenomedullin compared to placebo infusion ( 0.035). AUC value for HR and flushing ( < 0.05) was significant and for MAP ( = 0.502) remained unchanged. Common reported adverse events were facial flushing, heat sensation, and palpitation ( < 0.001).

Conclusion: Our data implicate adrenomedullin in migraine pathogenesis. This suggests that adrenomedullin or its receptors are novel therapeutic targets for the treatment of migraine. However, we cannot discount the possibility that adrenomedullin may be acting through the canonical calcitonin gene-related peptide receptor.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT04111484.
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http://dx.doi.org/10.1212/WNL.0000000000011930DOI Listing
May 2021

Migraine: disease characterisation, biomarkers, and precision medicine.

Lancet 2021 04 25;397(10283):1496-1504. Epub 2021 Mar 25.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.
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http://dx.doi.org/10.1016/S0140-6736(20)32162-0DOI Listing
April 2021

Amylin Analog Pramlintide Induces Migraine-like Attacks in Patients.

Ann Neurol 2021 06 8;89(6):1157-1171. Epub 2021 Apr 8.

Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Objective: Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood, and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene-related peptide (CGRP).

Methods: Thirty-six migraine without aura patients were enrolled in a randomized, double-blind, 2-way, crossover, positive-controlled clinical trial study to receive infusion of an amylin analogue pramlintide or human αCGRP on 2 different experimental days. Furthermore, translational studies in cells and mouse models, and rat, mouse and human tissue samples were conducted.

Results: Thirty patients (88%) developed headache after pramlintide infusion, compared to 33 (97%) after CGRP (p = 0.375). Fourteen patients (41%) developed migraine-like attacks after pramlintide infusion, compared to 19 patients (56%) after CGRP (p = 0.180). The pramlintide-induced migraine-like attacks had similar clinical characteristics to those induced by CGRP. There were differences between treatments in vascular parameters. Human receptor pharmacology studies showed that an amylin receptor likely mediates these pramlintide-provoked effects, rather than the canonical CGRP receptor. Supporting this, preclinical experiments investigating symptoms associated with migraine showed that amylin treatment, like CGRP, caused cutaneous hypersensitivity and light aversion in mice.

Interpretation: Our findings propose amylin receptor agonism as a novel contributor to migraine pathogenesis. Greater therapeutic gains could therefore be made for migraine patients through dual amylin and CGRP receptor antagonism, rather than selectively targeting the canonical CGRP receptor. ANN NEUROL 2021;89:1157-1171.
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http://dx.doi.org/10.1002/ana.26072DOI Listing
June 2021

Opening of ATP sensitive potassium channels causes migraine attacks with aura.

Brain 2021 Mar 26. Epub 2021 Mar 26.

Danish Headache Center, Dept. of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

Migraine afflicts more than one billion individuals worldwide and is a leading cause of years lived with disability. In about a third of individuals with migraine aura occur in relation to migraine headache. The common pathophysiological mechanisms underlying migraine headache and migraine aura are yet to be identified. Based on recent data, we hypothesized that levcromakalim, an ATP-sensitive potassium channel opener, would trigger migraine attacks with aura in migraine with aura patients.
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http://dx.doi.org/10.1093/brain/awab136DOI Listing
March 2021

Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers.

Pharmacol Res Perspect 2021 04;9(2):e00741

Danish Headache Center, Department of Neurology, University of Copenhagen, Denmark.

The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L-kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open-label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well-tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first-in-human study of LKYN showed that LKYN was safe and well-tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed-back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.
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http://dx.doi.org/10.1002/prp2.741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937944PMC
April 2021

Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.

Cephalalgia 2021 May 10;41(6):731-748. Epub 2021 Feb 10.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Objective: To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks.

Methods: A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study.

Results: Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo ( = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) ( = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of placebo ( < 0.001). Early treatment with intravenously administered sumatriptan prevented PACAP38-induced migraine. Prevention of migraine attacks was associated with vasoconstriction by sumatriptan in the earliest phases of PACAP provocation. These results suggest that sumatriptan prevents PACAP38-induced migraine by modulation of nociceptive transmission within the trigeminovascular system. ClinicalTrials.gov (NCT03881644).
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http://dx.doi.org/10.1177/0333102420975395DOI Listing
May 2021

A systematic review, meta-analysis and meta-regression evaluating the adverse reactions to erenumab in the preventive treatment of migraine.

Expert Opin Drug Saf 2021 Apr 29;20(4):467-474. Epub 2020 Dec 29.

Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

: Erenumab has recently been approved as a pharmacological treatment for the prevention of migraine. However, the incidence estimates of adverse drug reactions (ADRs) were not consistent among studies. Consequently, pooled measures of the incidences of ADRs that accounts for inter-study heterogeneity are desirable. In addition, little is known on the factors leading to such heterogeneity.: Clinical trials evaluating the occurrence of ADRs related to erenumab in migraine patients were searched with Ovid MEDLINE until April 2020. Random intercept models were used to estimate the pooled incidence of the ADRs reported at least in 5 different study populations. To examine whether specific factors correlated with the pooled incidence, we performed random-effects meta-regression.: Of 138 retrieved references, 8 clinical trials were included in the meta-analysis. We observed a significant heterogeneity of the incidence estimates of back pain, influenza, nasopharyngitis, and upper respiratory tract infection (URTI). Most of the observed heterogeneity is ascribed to treatment duration for back pain ( = 0.045), influenza ( < 0.001) and URTI ( < 0.001), and significantly attributed to Body Mass Index (BMI) for nasopharyngitis ( < 0.001).: Back pain, influenza, nasopharyngitis and URTI showed a significant heterogeneity of incidence estimates.
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http://dx.doi.org/10.1080/14740338.2021.1866537DOI Listing
April 2021

Latest Insights into the Pathophysiology of Migraine: the ATP-Sensitive Potassium Channels.

Curr Pain Headache Rep 2020 Dec 3;24(12):77. Epub 2020 Dec 3.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansen Vej 5, Glostrup, DK-2600, Copenhagen, Denmark.

Purpose Of Review: Migraine remains a challenging condition to treat, thus highlighting the need for a better understanding of its molecular mechanisms. This review intends to unravel a new emerging target in migraine pathophysiology, the adenosine 5'-triphosphate-sensitive K (K) channel.

Recent Findings: K channel is a common denominator in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) mediated intracellular cascades, both of which are involved in migraine. Intravenous infusion of K channel opener, levcromakalim, provoked migraine attack associated with dilation of extracerebral arteries in all persons with migraine. Preclinical and clinical studies implicate K channels in migraine initiation. K channel is a novel therapeutic target for the acute and preventive treatment of migraine. Future studies are warranted to provide a better understanding of the role of K channel subgroups in migraine.
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http://dx.doi.org/10.1007/s11916-020-00911-6DOI Listing
December 2020

Nocebo response in human models of migraine: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled, two-way crossover trials in migraine without aura and healthy volunteers.

Cephalalgia 2021 01 26;41(1):99-111. Epub 2020 Nov 26.

Danish Headache Center, Department of Neurology, 70590Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Human models of migraine have been used for the past 30 years to test putative 'trigger' molecules and ascertain whether they induce migraine attacks in humans. However, nocebo effects using this model have never been systematically explored.

Objective: To assess the nocebo response rate in randomised clinical trials conducted at the Danish Headache Center, and in which human models of migraine were used.

Methods: In this systematic review and meta-analysis, we searched PubMed for studies of human models of migraine with a randomised, double-blind, placebo-controlled, two-way crossover design that included data on the incidence of migraine attacks or headache after infusion of placebo. A total of 943 articles were screened by title and abstract. Of these, 27 studies met the inclusion criteria (published between 1994 and 2020) and were included in the qualitative and quantitative analysis. We performed a random effects meta-analysis for the incidence of migraine attacks or delayed headache after placebo infusion.

Results: Twenty-seven studies were eligible for inclusion: 12 studies reported data for adults with migraine (n = 182), whereas 16 studies reported data on healthy volunteers (n = 210). For adults with migraine, the incidence of migraine attacks after placebo was 8.1% (95% CI = 2.5-15.5%, I = 50.8%). The incidence of delayed headache was 25.9% (95% CI = 18.5-34.1%, I = 18.9%). For healthy volunteers, the incidence of migraine attacks after placebo was 0.5% (95% CI = 0.0-3.6%, I = 0.0%) while the incidence of delayed headache was 10.5% (95% CI = 4.8-17.6%, I = 45.2%).

Conclusion: The nocebo response in randomised, placebo-controlled two-way crossover trials with intravenous infusions of placebo in migraine is negligible. Future studies using human models of migraine can be conducted by assuming a nocebo response rate of 15.5%.
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http://dx.doi.org/10.1177/0333102420970489DOI Listing
January 2021

Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers.

J Cereb Blood Flow Metab 2021 06 7;41(6):1328-1337. Epub 2020 Oct 7.

Department of Neurology, Faculty of Health and Medical Sciences, Danish Headache Center, University of Copenhagen, Rigshospitalet Glostrup, Denmark.

Glibenclamide inhibits sulfonylurea receptor (SUR), which regulates several ion channels including SUR1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel and ATP-sensitive potassium (K) channel. Stroke upregulates SURl-TRPM4 channel, which causes a rapid edema formation and brain swelling. Glibenclamide may antagonize the formation of cerebral edema during stroke. Preclinical studies showed that glibenclamide inhibits K channel-induced vasodilation without altering the basal vascular tone. The in vivo human cerebrovascular effects of glibenclamide have not previously been investigated.In a randomized, double-blind, placebo-controlled, three-way cross-over study, we used advanced 3 T MRI methods to investigate the effects of glibenclamide and K channel opener levcromakalim on mean global cerebral blood flow (CBF) and intra- and extracranial artery circumferences in 15 healthy volunteers. Glibenclamide administration did not alter the mean global CBF and the basal vascular tone. Following levcromakalim infusion, we observed a 14% increase of the mean global CBF and an 8% increase of middle cerebral artery (MCA) circumference, and glibenclamide did not attenuate levcromakalim-induced vascular changes. Collectively, the findings demonstrate the vital role of K channels in cerebrovascular hemodynamic and indicate that glibenclamide does not inhibit the protective effects of K channel activation during hypoxia and ischemia-induced brain injury.
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http://dx.doi.org/10.1177/0271678X20959294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142144PMC
June 2021

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

Cephalalgia 2020 10 26;40(11):1145-1154. Epub 2020 Aug 26.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Introduction: Preclinical data implicate large conductance calcium-activated potassium (BK) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BK 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 BK 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 (V) (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 ( = 0.0005); the difference of incidence is 60% (95% confidence interval 36-84%). The area under the curve for headache intensity (AUC,  = 0.0003), for mean V (AUC,  = 0.0001), for superficial temporal artery diameter (AUC,  = 0.003), and for radial artery diameter (AUC,  = 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 BK channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325.
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http://dx.doi.org/10.1177/0333102420940681DOI Listing
October 2020

Effect of K channel blocker glibenclamide on levcromakalim-induced headache.

Cephalalgia 2020 09 17;40(10):1045-1054. Epub 2020 Aug 17.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

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%) ( = 0.01; mean difference 47%; 95% confidence interval 18-75%) and compared to the placebo-placebo day (1/15, 7%) ( = 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 ( = 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 ( = 0.003); and compared to the placebo-placebo day ( = 0.001). We found no difference in the area under the curve between the glibenclamide-placebo day compared to the placebo-placebo day ( = 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. ClinicalTrials.gov NCT03886922.
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http://dx.doi.org/10.1177/0333102420949863DOI Listing
September 2020

Reducing Episodic Cluster Headaches: Focus on Galcanezumab.

J Pain Res 2020 2;13:1591-1599. Epub 2020 Jul 2.

Danish Headache Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The involvement of calcitonin gene-related peptide in migraine and cluster headache has led to the recent development of new therapies. Galcanezumab, a novel monoclonal antibody targeting the calcitonin gene-related peptide, is approved for the migraine prevention and has recently been tested for the prevention of cluster headache. Two clinical trials have been conducted to investigate the efficacy and safety of galcanezumab in episodic cluster headache and chronic cluster headache. While efficacy endpoints were not met in the chronic subtype, galcanezumab reduced the weekly frequency of attacks in patients with episodic cluster headaches. In both studies, the antibody was well tolerated. This review summarizes and critically reviews the available data regarding the rationale behind targeting the calcitonin gene-related peptide with galcanezumab for the prevention of cluster headache.
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http://dx.doi.org/10.2147/JPR.S222604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342329PMC
July 2020

Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteers.

Cephalalgia 2020 10 27;40(11):1212-1223. Epub 2020 Jun 27.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: In recent years, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) have gained special interest in headache science. VIP and PACAPs (two isoforms, PACAP27 and PACAP38) are related in structure and function, as are their receptors, but they show differences in vasodilating- and headache-inducing properties. Intravenous infusion of PACAP27 or PACAP38, but not VIP, induces a long-lasting dilation of cranial arteries and delayed headache. The relationship between the long-lasting cranial vasodilation and headache development is not fully clarified.

Methods: In a double-blinded, placebo-controlled, crossover study in 12 healthy volunteers, diameter changes of cranial arteries, occurrence of headache and the parasympathetic system were examined before, during and after a 2-hour continuous intravenous infusion of VIP and placebo. Primary endpoints were the differences in area under the curve for the superficial temporal artery diameter and headache intensity scores, as well as in headache incidence, between VIP and placebo.

Results: The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo ( < 0.001) and the dilation lasted for more than 2 h. The incidence of headache was higher ( = 0.003) on the VIP day compared to the placebo day. The difference in headache intensity scores was more evident in the post-infusion period (120-200 min,  = 0.034) and in the post-hospital phase (4-12 h,  = 0.025). Cranial parasympathetic activity, measured through the production of tears, was higher during VIP compared to placebo ( = 0.033).

Conclusion: Continuous intravenous infusion of VIP over 2 h induced a long-lasting cranial vasodilation, activation of the cranial parasympathetic system, and delayed mild headaches in healthy volunteers. The study is registered at ClinicalTrials.gov (NCT03989817).
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http://dx.doi.org/10.1177/0333102420937655DOI Listing
October 2020

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

J Headache Pain 2020 Feb 24;21(1):19. Epub 2020 Feb 24.

Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansens Vej 5, DK-2600, Glostrup, Denmark.

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 of PACAP38-induced headache in group A, pretreated with sumatriptan or ketorolac (p = 0.297). There was no difference between sumatriptan and ketorolac in PACAP38-induced circumference change (AUC) 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). Post-treatment 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).

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 13 July 2018.
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http://dx.doi.org/10.1186/s10194-020-01089-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038568PMC
February 2020

Targeting BK Channels in Migraine: Rationale and Perspectives.

CNS Drugs 2020 04;34(4):325-335

Danish Headache Center, Department of Neurology, University of Copenhagen, Valdemar Hansen Vej 5, 2600, Glostrup, Denmark.

Large (big)-conductance calcium-activated potassium (BK) channels are expressed in migraine-related structures such as the cranial arteries, trigeminal ganglion and trigeminal spinal nucleus, and they play a substantial role in vascular tonus and neuronal excitability. Using synthetic BK channels openers was associated with headache as a frequent adverse effect in healthy volunteers. Additionally, BK channels are downstream molecules in migraine signalling pathways that are activated by several compounds known to provoke migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (GTN). Also, there is a high affinity and a close coupling between BK channels and ATP-sensitive potassium (K) channels, the role of which has recently been established in migraine pathophysiology. These observations raise the question as to whether direct BK channel activation can provoke migraine in migraine patients, and whether the BK channel could be a potential novel anti-migraine target. Hence, randomized and placebo-controlled clinical studies on BK channel openers or blockers in migraine patients are needed.
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http://dx.doi.org/10.1007/s40263-020-00706-8DOI Listing
April 2020

Reply: Hyperpolarization through ATP-sensitive potassium channels; relevance to migraine pathology.

Brain 2020 02;143(2):e14

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1093/brain/awaa004DOI Listing
February 2020

Extracranial activation of ATP-sensitive potassium channels induces vasodilation without nociceptive effects.

Cephalalgia 2019 Dec 7;39(14):1789-1797. Epub 2019 Nov 7.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Introduction: Levcromakalim opens ATP-sensitive potassium channels (K channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. K channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans.

Methods: To assess the local effect of K channel opening in trigeminal and extra-trigeminal regions, we performed a crossover, double-blind, placebo-controlled study in healthy volunteers. Participants received intradermal and intramuscular injections of levcromakalim and placebo in the forehead and the forearms.

Results: Intradermal and intramuscular injections of levcromakalim did not evoke more pain compared to placebo in the forehead ( > 0.05) and the forearms ( > 0.05). Intradermal injection of levcromakalim caused more flare ( < 0.001, skin temperature increase ( < 0.001), and skin blood flow increase ( < 0.001) compared to placebo in the forehead and the forearms.

Conclusion: These findings suggest that it is unlikely that levcromakalim induces head pain by direct activation of peripheral neurons.
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http://dx.doi.org/10.1177/0333102419888490DOI Listing
December 2019

Levcromakalim, an Adenosine Triphosphate-Sensitive Potassium Channel Opener, Dilates Extracerebral but not Cerebral Arteries.

Headache 2019 10 18;59(9):1468-1480. Epub 2019 Sep 18.

Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: ATP-sensitive potassium (K ) channel opener levcromakalim induces migraine attacks in migraine patients. Underlying mechanisms responsible for headache and migraine induction after levcromakalim infusion are unknown.

Objective: To investigate the effect of levcromakalim on the cranial arteries and to explore the possible relationship between the middle meningeal artery (MMA) dilation and headache.

Methods: In a double-blind, randomized, placebo-controlled study, 20 healthy volunteers were scanned at the baseline and repeatedly after infusion of levcromakalim (n = 14) and placebo (n = 6). All participants received a subcutaneous injection of sumatriptan 6 mg before the last scanning.

Results: The MMA circumference was significantly larger after levcromakalim compared with placebo (P < .0001). The MMA dilation lasted over 5 hours during observational period. We found a significant association between headache and MMA dilation (P < .0001). The superficial temporal artery (STA) circumference was significantly larger after levcromakalim compared with placebo (P = .03) over the initial period (110 minutes). Over the entire observational period, there was no difference in circumference of the STA and the middle cerebral artery (MCA) between levcromakalim and placebo.

Conclusion: Levcromakalim dilated the MMA but not MCA. The MMA dilation was associated with headache. Future studies should investigate whether opening of K channels can activate and sensitize the perivascular nociceptors.
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http://dx.doi.org/10.1111/head.13634DOI Listing
October 2019

Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial.

Cephalalgia 2019 Oct 15;39(12):1475-1487. Epub 2019 Sep 15.

Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data.

Methods: This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6-8 hours apart).

Results: Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) ( = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53;  = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common.

Conclusions: Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The "sham" device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844.
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http://dx.doi.org/10.1177/0333102419876920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791025PMC
October 2019

Effect of pituitary adenylate cyclase-activating polypeptide-27 on cerebral hemodynamics in healthy volunteers: A 3T MRI study.

Peptides 2019 11 23;121:170134. Epub 2019 Aug 23.

Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address:

Pituitary adenylate cyclase-activating polypeptide (PACAP) has emerged as an important signaling peptide in migraine pathogenesis. Recently, we have shown that the less-abundant PACAP isoform, PACAP27, induced migraine and headache in patients equipotently to PACAP38. The present study examined the effect of PACAP27 on cerebral hemodynamics in healthy volunteers using high resolution magnetic resonance angiography (MRA). Eighteen healthy volunteers received infusion of PACAP27 (10 pmol/kg/min) or placebo over 20 min and were scanned repeatedly in fixed intervals for 5 h in a double-blind, randomized, placebo-controlled study. The circumference of extra-intracerebral arteries was measured and compared with PACAP38 data. We found significant dilation of middle meningeal artery (MMA) (p = 0.019), superficial temporal artery (p = 0.001) and external carotid artery (p = 0.039) after PACAP27 infusion compared to placebo. Whereas the middle cerebral artery (MCA) (p = 0.011) and internal carotid artery (ICA) (p = 0.015, p = 0.019) were constricted. No effects on basilar artery (p = 0.708) and cavernous portion of ICA were found. Post hoc analyses revealed significant larger area under the curve for MMA after PACAP38 compared to PACAP27 (p = 0.033). We also found that PACAP27 induced headache in nine out of twelve (75%) volunteers and one (17%) after placebo. In conclusion, PACAP27 induced headache and dilated extracerebral arteries (>5 h) and slightly constricted MCA in healthy volunteers. Post hoc analysis of PACAP38 data compared with PACAP27 showed that PACAP isoforms dilates MMA with significantly different magnitude.
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http://dx.doi.org/10.1016/j.peptides.2019.170134DOI Listing
November 2019

PACAP27 induces migraine-like attacks in migraine patients.

Cephalalgia 2020 01 12;40(1):57-67. Epub 2019 Jul 12.

Danish Headache Center and Department of Neurology, Rigshospitalet-Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Introduction: Pituitary adenylate cyclase-activating polypeptide (PACAP) is found in two functional isoforms, namely PACAP38 and PACAP27. The migraine-inducing properties of PACAP38 are well studied. However, it is not known whether the lesser-known and under-studied protein isoform, PACAP27, can also induce migraine attacks. Here, we studied the effect of human PACAP27 infusion on induction of migraine in a provocation model.

Methods: In a crossover study, 20 migraine without aura patients were randomly assigned to receive human PACAP27 (10 picomol/kg/min) or saline (placebo) infusion over 20 min. We recorded the migraine and associated symptoms.

Results: All patients completed the study. PACAP27 provoked migraine-like attacks in 11 patients (55%) and two developed attacks after placebo (10%) ( = 0.022). The headache intensity and duration after PACAP27 was significantly greater compared to placebo ( = 0.003).

Conclusion: PACAP27 triggers migraine attacks without aura. These novel data strengthen the role of PACAP and its receptors in migraine pathogenesis.
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http://dx.doi.org/10.1177/0333102419864507DOI Listing
January 2020

Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine.

Brain 2019 09;142(9):2644-2654

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

Migraine is one of the most disabling and prevalent of all disorders. To improve understanding of migraine mechanisms and to suggest a new therapeutic target, we investigated whether opening of ATP-sensitive potassium channels (KATP) would cause migraine attacks. In this randomized, double-blind, placebo-controlled, crossover study, 16 patients aged 18-49 years with one to five migraine attacks a month were randomly allocated to receive an infusion of 0.05 mg/min KATP channel opener levcromakalim and placebo on two different days (ClinicalTrials.gov number, NCT03228355). The primary endpoints were the difference in incidence of migraine attacks, headaches and the difference in area under the curve (AUC) for headache intensity scores (0-12 h) and for middle cerebral artery blood flow velocity (0-2 h) between levcromakalim and placebo. Between 24 May 2017 and 23 November 2017, 16 patients randomly received levcromakalim and placebo on two different days. Sixteen patients (100%) developed migraine attacks after levcromakalim compared with one patient (6%) after placebo (P = 0.0001); the difference of incidence is 94% [95% confidence interval (CI) 78-100%]. The incidence of headache over the 12 h observation period was higher but not significant after levcromakalim (n = 16) than after placebo (n = 7) (P = 0.016) (95% CI 16-71%). The AUC for headache intensity was significantly larger after levcromakalim compared to placebo (AUC0-12h, P < 0.0001). There was no change in mean middle cerebral artery blood flow velocity after levcromakalim compared to placebo (AUC0-2hP = 0.46). Opening of KATP channels caused migraine attacks in all patients. This suggests a crucial role of these channels in migraine pathophysiology and that KATP channel blockers could be potential targets for novel drugs for migraine.
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http://dx.doi.org/10.1093/brain/awz199DOI Listing
September 2019

The K channel in migraine pathophysiology: a novel therapeutic target for migraine.

J Headache Pain 2017 Aug 23;18(1):90. Epub 2017 Aug 23.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Nordre Ringvej 57, DK-2600, Copenhagen, Denmark.

Background: To review the distribution and function of K channels, describe the use of K channels openers in clinical trials and make the case that these channels may play a role in headache and migraine.

Discussion: K channels are widely present in the trigeminovascular system and play an important role in the regulation of tone in cerebral and meningeal arteries. Clinical trials using synthetic K channel openers report headache as a prevalent-side effect in non-migraine sufferers, indicating that K channel opening may cause headache, possibly due to vascular mechanisms. Whether K channel openers can provoke migraine in migraine sufferers is not known.

Conclusion: We suggest that K channels may play an important role in migraine pathogenesis and could be a potential novel therapeutic anti-migraine target.
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http://dx.doi.org/10.1186/s10194-017-0800-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567577PMC
August 2017
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