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Migraine Disorders: HELP
Articles by Lars Edvinsson
Based on 49 articles published since 2010
(Why 49 articles?)
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Between 2010 and 2020, L. Edvinsson wrote the following 49 articles about Migraine Disorders.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Is CGRP a marker for chronic migraine? 2013

Silberstein, Stephen D / Edvinsson, Lars. ·From the Jefferson Headache Center (S.D.S.), Jefferson Hospital for Neuroscience, Philadelphia, PA · and Internal Medicine (L.E.), Lund University, Sweden. ·Neurology · Pubmed #23975870.

ABSTRACT: -- No abstract --

2 Editorial Role of VIP/PACAP in primary headaches. 2013

Edvinsson, Lars. ·Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Sweden. ·Cephalalgia · Pubmed #23575820.

ABSTRACT: -- No abstract --

3 Review Some aspects on the pathophysiology of migraine and a review of device therapies for migraine and cluster headache. 2019

Rapoport, Alan M / Edvinsson, Lars. ·Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. alanrapoport@gmail.com. · Department of Medicine, Institute of Clinical Sciences, Lund University, Lund, Sweden. ·Neurol Sci · Pubmed #30906962.

ABSTRACT: Migraine is a common, severe disease, affecting the brain and blood vessels, causing much pain, time missed from work and family, and severe disability. It affects approximately 12% of most Western populations studied and affects women three times more than men. Cluster headache is a much less common dysfunction of the hypothalamus, involving the sphenopalatine ganglion and other areas; it causes more frequent, shorter, and even more intense pain than migraine. The pain usually comes in cycles and is associated with ipsilateral autonomic features and associated with irritability and inability to stay still. It affects less than 0.1% of the population and is slightly more prevalent in men than women. Although we have some acute care and preventive medications for both types of headache, no treatment is optimal for each patient and some will not respond well or have significant adverse events to existing therapies.

4 Review The Therapeutic Impact of New Migraine Discoveries. 2019

Vécsei, László / Lukács, Melinda / Tajti, János / Fülöp, Ferenc / Toldi, József / Edvinsson, Lars. ·Department of Neurology, University of Szeged, Szeged, Hungary. · MTASZTE Neuroscience Research Group, Szeged, Hungary. · Institute of Pharmaceutical Chemistry and MTA-SZTE Research Group for Stereochemistry, University of Szeged, Szeged, Hungary. · Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary. · Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. · Department of Clinical Experimental Research, Copenhagen University, Glostrup Hospital, Copenhagen, Denmark. ·Curr Med Chem · Pubmed #29848264.

ABSTRACT: BACKGROUND: Migraine is one of the most disabling neurological conditions and associated with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered to be the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. OBJECTIVE: The present study is a review of the current literature regarding new therapeutic lines in migraine research. METHODS: A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in a migraine published until July 2017. RESULTS: Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. CONCLUSION: Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies.

5 Review CGRP Antibodies as Prophylaxis in Migraine. 2018

Edvinsson, Lars. ·Department of Medicine, University Hospital, Lund, Sweden. Electronic address: lars.edvinsson@med.lu.se. ·Cell · Pubmed #30550780.

ABSTRACT: Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (CLR + RAMP1) offer considerable improvements over existing drugs in migraine prophylaxis and are the first designed to act on the trigeminal pain system. Erenumab is approved by the FDA and EMA and has reached the market since May 2018. Two antibodies, fremanezumab and galcanezumab, directed towards the CGRP ligand, were approved by the FDA in September 2018. To view this Bench to Bedside, open or download the PDF.

6 Review PACAP38 and PAC 2018

Rubio-Beltrán, Eloisa / Correnti, Edvige / Deen, Marie / Kamm, Katharina / Kelderman, Tim / Papetti, Laura / Vigneri, Simone / MaassenVanDenBrink, Antoinette / Edvinsson, Lars / Anonymous4410957. ·Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. a.rubiobeltran@erasmusmc.nl. · Department of Child Neuropsychiatry, University of Palermo, Palermo, Italy. · Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark. · Department of Neurology, University Hospital, LMU Munich, Munich, Germany. · Department of Neurology, Ghent University Hospital, Ghent, Belgium. · Headache Center, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. · Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo; Pain Medicine Unit, Santa Maria Maddalena Hospital, Occhiobello, Italy. · Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Internal Medicine, Institute of Clinical Sciences, Lund University, Lund, Sweden. ·J Headache Pain · Pubmed #30088106.

ABSTRACT: Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC

7 Review The CGRP Pathway in Migraine as a Viable Target for Therapies. 2018

Edvinsson, Lars. ·Institute of Clinical Sciences, Lund University, Lund, Sweden. ·Headache · Pubmed #29697153.

ABSTRACT: The neuropeptide calcitonin gene-related peptide is well established as a key player in the pathogenesis of migraine. Clinical studies show calcitonin gene-related peptide levels correlate with migraine attacks, and decreases in this neuropeptide can indicate antimigraine therapy effectiveness. Research has revealed a wide distribution of expression sites for calcitonin gene-related peptide in the central and peripheral nervous system. Of these, the calcitonin gene-related peptide receptor, which binds calcitonin gene-related peptide with high affinity, has attracted growing interest as a viable target for antimigraine therapies. An incentive to pursue such research is the continuing unmet medical need of patients. Triptans have offered some clinical benefit, but many patients do not respond and these drugs have important safety considerations. Initial calcitonin gene-related peptide-focused research led to development of the "gepant" small-molecule calcitonin gene-related peptide receptor blockers. Positive efficacy reports concerning the gepants have been tempered by safety findings which led to the discontinuation of some of these agents. Currently, there is considerable excitement regarding monoclonal antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab, fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To date, these monoclonal antibodies have shown promising efficacy in clinical trials, with no major safety concerns. If ongoing long-term studies show that their efficacy can be maintained, this may herald a new era for effective antimigraine therapies.

8 Review CGRP as the target of new migraine therapies - successful translation from bench to clinic. 2018

Edvinsson, Lars / Haanes, Kristian Agmund / Warfvinge, Karin / Krause, Diana N. ·Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. lars.edvinsson@med.lu.se. · Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet, Glostrup, Denmark. lars.edvinsson@med.lu.se. · Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet, Glostrup, Denmark. · Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. · Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA, USA. ·Nat Rev Neurol · Pubmed #29691490.

ABSTRACT: Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

9 Review PACAP and its role in primary headaches. 2018

Edvinsson, Lars / Tajti, János / Szalárdy, Levente / Vécsei, László. ·Department of Medicine, Institute of Clinical Sciences, Lund University, 221 84, Lund, Sweden. lars.edvinsson@med.lu.se. · Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary. · MTA-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary. ·J Headache Pain · Pubmed #29523978.

ABSTRACT: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide implicated in a wide range of functions, such as nociception and in primary headaches. Regarding its localization, PACAP has been observed in the sensory trigeminal ganglion (TG), in the parasympathetic sphenopalatine (SPG) and otic ganglia (OTG), and in the brainstem trigeminocervical complex. Immunohistochemistry has shown PACAP-38 in numerous cell bodies of SPG/OTG, co-stored with vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS) and, to a minor degree, with choline acetyltransferase. PACAP has in addition been found in a subpopulation of calcitonin gene-related peptide (CGRP)-immunoreactive cells in the trigeminal system. The PACAP/VIP receptors (PAC

10 Review Blocking CGRP in migraine patients - a review of pros and cons. 2017

Deen, Marie / Correnti, Edvige / Kamm, Katharina / Kelderman, Tim / Papetti, Laura / Rubio-Beltrán, Eloisa / Vigneri, Simone / Edvinsson, Lars / Maassen Van Den Brink, Antoinette / Anonymous5470920. ·Danish Headache Center, Department of Neurology, Rigshospitalet, Copenhagen, Denmark. mariedeen85@gmail.com. · Department of Child Neuropsychiatry, University of Palermo, Palermo, Italy. · Department of Neurology, University Hospital, LMU, Munich, Germany. · Department of Neurology, Ghent University Hospital, Ghent, Belgium. · Headache Center, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. · Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo; Advanced Algology Research and Pain Medicine Unit, Santa Maria Maddalena Hospital, Occhiobello, Italy. · Department of Internal Medicine, Institute of Clinical Sciences, Lund University, Lund, Sweden. ·J Headache Pain · Pubmed #28948500.

ABSTRACT: Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.

11 Review Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects. 2017

Lukacs, Melinda / Tajti, Janos / Fulop, Ferenc / Toldi, Jozsef / Edvinsson, Lars / Vecsei, Laszlo. ·Department of Neurology, University of Szeged, Szeged. Hungary. · Institute of Pharmaceutical Chemistry and MTA-SZTE Research Group for Stereochemistry, University of Szeged. Hungary. · Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged. Hungary. · Department of Clinical Experimental Research, Copenhagen University, Glostrup Hospital, Copenhagen. Denmark. · Department of Neurology, University of Szeged, Hungary and MTA-SZTE Neuroscience Research Group, Szeged. Hungary. ·Curr Med Chem · Pubmed #28707585.

ABSTRACT: BACKGROUND: Migraine is a primary headache disorder. Despite numerous studies conducted with the aim to understand the pathophysiology of migraine, several aspects are still unclear. The trigeminovascular system plays a key role. Neurogenic inflammation is presumed to be an important factor in migraine pathophysiology, mediated by the activation of primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide (PACAP) and Glutamate (Glu) also play an important role in the modulation of inflammatory mechanisms. OBJECTIVE: To review the literature focusing on novel therapeutic targets in migraine, related to neurogenic inflammation. METHOD: A systematic literature search in the database of PUBMED was conducted regarding therapeutic strategies in migraine, focusing on substances and cytokines released during neurogenic inflammation, published until January 2017. RESULTS: Ongoing phase III clinical studies with monoclonal antibodies against CGRP and CGRP receptors offer promising novel aspects for migraine treatment. Preclinical and clinical studies targeting SP and nitric oxide synthase (NOS) were all terminated with no significant results compared to placebo. New promising therapeutic goal could be PACAP and its receptor (PAC1), and kynurenic acid (KYNA) analogues. CONCLUSION: Current migraine treatment offers pain relief only for a small proportion of migraine patients and might not be adequate for patients with cardiovascular comorbidity due to side effects. Better understanding of migraine pathophysiology might, therefore, lead to novel therapeutic lines both in migraine attack treatment and prophylaxis.

12 Review The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine. 2017

Edvinsson, Lars. ·Department of Medicine, Lund University, Lund, Sweden. ·Headache · Pubmed #28485848.

ABSTRACT: The trigeminal ganglion plays a key role in primary headache pathophysiology. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in trigeminal neurons that form C-fibers and A-fibers, respectively. In acute migraine and cluster headache attacks, there is release of CGRP into the cranial venous outflow. In addition, intravenous CGRP can induce migraine-like symptoms in migraine patients. These findings led to the development of anti-migraine therapies that inhibit CGRP action. Currently, CGRP receptor antagonists, the gepants, and monoclonal antibodies towards CGRP and the CGRP receptor are all showing positive relief of acute and chronic migraine in clinical trials. However, there is still much to learn about the role of CGRP and CGRP receptors in headache pathophysiology, the critical anatomical sites, peripheral or central, of anti-CGRP agents, and the potential involvement of CGRP-related peptides and receptors. This review provides a brief history of the discovery of the role of CGRP in migraine and highlights current progress in understanding the complexity of the trigeminovascular pathway and its peptide transmitters.

13 Review CGRP receptor antagonism and migraine therapy. 2013

Edvinsson, Lars / Warfvinge, Karin. ·Department of Medicine, Institute of Clinical Sciences, Lund University and Lund University Hospital, Lund, Sweden. lars.edvinsson@med.lu.se ·Curr Protein Pept Sci · Pubmed #23745702.

ABSTRACT: Migraine is the most prevalent of the neurological disorders and can affect the patient throughout the lifetime. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is expressed in the central and peripheral nervous systems. It is now 2 decades since it was proposed to be involved in migraine pathophysiology. The cranial sensory system contains C-fibers storing CGRP and trigeminal nerve activation and acute migraine attacks result in release of CGRP. The CGRP receptor consists of a complex of calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP). At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via brainstem and midbrain to thalamus and higher cortical pain regions. CLR and RAMPs are widely expressed throughout the brain, in the trigeminal ganglion and in intracranial arteries. CGRP does not induce neurogenic inflammation or sensitization at peripheral meningeal sites but relays nociceptive information from trigeminal primary afferent neurons to the second-order neurons in the spinal trigeminal nucleus neurons. CGRP receptor antagonists have been developed as novel antimigraine drugs and found to be effective in the treatment of acute migraine attacks. Other ways to stop CGRP activity has been introduced recently through antibodies against CGRP and the CGRP receptor. While the CGRP receptors are expressed both in the CNS and at various places related to the trigeminal system the exact site of action for their therapy effect is still unresolved but the new approaches may resolve this.

14 Review Pearls and pitfalls in neural CGRP immunohistochemistry. 2013

Warfvinge, Karin / Edvinsson, Lars. ·Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup University Hospital, Denmark. Karin.Warfvinge@sciencesupport.se ·Cephalalgia · Pubmed #23671255.

ABSTRACT: PEARLS: In 1985, CGRP was first described in cerebral arteries using immunohistochemistry. Since then, cerebral CGRP (and, using novel antibodies, its receptor components) has been widely scrutinized. Here, we describe the distribution of cerebral CGRP and pay special attention to the surprising reliability of results over time. PITFALLS: Pitfalls might include a fixation procedure, antibody clone and dilution, and interpretation of results. Standardization of staining protocols and true quantitative methods are lacking. The use of computerized image analysis has led us to believe that our examination is objective. However, in the steps of performing such an analysis, we make subjective choices. By pointing out these pitfalls, we aim to further improve immunohistochemical quality. RECOMMENDATIONS: Having a clear picture of the tissue/cell morphology is a necessity. A primary morphological evaluation with, for example, hematoxylin-eosin, helps to ensure that small changes are not missed and that background and artifactual changes, which may include vacuoles, pigments, and dark neurons, are not over-interpreted as compound-related changes. The antigen-antibody reaction appears simple and clear in theory, but many steps might go wrong. Remember that methods including the antigen-antibody complex rely on handling/fixation of tissues or cells, antibody shipping/storing issues, antibody titration, temperature/duration of antibody incubation, visualization of the antibody and interpretation of the results. Optimize staining protocols to the material you are using.

15 Review [Calcitonin gene-related peptide and migraine. Increases understanding of physiopathology can lead to new drug therapy]. 2010

Edvinsson, Lars. ·Avdelningen för medicin, institutionen för kliniska vetenskaper, Skånes universitetssjukhus, Lund. lars.edvinsson@med.lu.se ·Lakartidningen · Pubmed #21294334.

ABSTRACT: -- No abstract --

16 Review CGRP and its receptors provide new insights into migraine pathophysiology. 2010

Ho, Tony W / Edvinsson, Lars / Goadsby, Peter J. ·Clinical Neuroscience, Merck Research Laboratories, North Wales, PA 19454-1099, USA. ·Nat Rev Neurol · Pubmed #20820195.

ABSTRACT: Over the past 300 years, the migraine field has been dominated by two main theories-the vascular theory and the central neuronal theory. The success of vasoconstrictors such as ergotamine and the triptans in treating acute migraine bolstered the vascular theory, but evidence is now emerging that vasodilatation is neither necessary nor sufficient to induce a migraine attack. Attention is now turning to the core migraine circuits in the brain, which include the trigeminal ganglia, trigeminal nucleus, medullary modulatory regions, pons, periaqueductal gray matter, hypothalamus and thalamus. Migraine triggers are likely to reflect a disturbance in overall balance of the circuits involved in the modulation of sensory activity, particularly those with relevance to the head. In this Review, we consider the evidence pointing towards a neuronal mechanism in migraine development, highlighting the role of calcitonin gene-related peptide (CGRP), which is found in small to medium-sized neurons in the trigeminal ganglion. CGRP is released during migraine attacks and can trigger migraine in patients, and CGRP receptor antagonists can abort migraine. We also examine whether other drugs, such as triptans, might exert their antimigraine effects via their actions on the neuronal circuit as opposed to the intracranial vasculature.

17 Review CGRP receptor antagonism and migraine. 2010

Edvinsson, Lars / Ho, Tony W. ·Department of Medicine, Institute of Clinical Sciences, Lund University Hospital, Lund University, 22185 Lund, Sweden. lars.edvinsson@med.lu.se ·Neurotherapeutics · Pubmed #20430315.

ABSTRACT: Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. alphaCGRP is prominently localized in primary spinal afferent C and ADelta fibers of sensory ganglia, and betaCGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.

18 Review New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. 2010

Edvinsson, Lars / Linde, Mattias. ·Department of Internal Medicine, University Hospital, Lund, Sweden. lars.edvinsson@med.lu.se ·Lancet · Pubmed #20416945.

ABSTRACT: Although the triptan drugs provide effective relief from migraine for many patients, a substantial number of affected individuals are unresponsive to these compounds, and such therapy can also lead to a range of adverse effects. Telcagepant represents a new class of antimigraine drug-the calcitonin gene-related peptide receptor blockers. This compound exerts its effects by blocking receptors for the calcitonin-gene-related peptide at several sites in the trigeminal and central nervous systems, resulting in pain relief. Telcagepant does not cause vasoconstriction, a major limitation in the use of triptans. Comparisons with triptans in clinical trials for acute treatment of migraine attacks revealed clinical effects similar to those of triptans but better than those of placebo. Telcagepant might provide hope for those who have a poor response to, or are unable to use, older drugs. In patients who need prophylaxis because of frequent attacks of migraine, topiramate is a first-line drug for migraine prevention in many countries; it is generally safe and reasonably well tolerated. Data suggest that topiramate could aid reversion of chronic migraine to episodic migraine.

19 Clinical Trial Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. 2015

Bigal, Marcelo E / Edvinsson, Lars / Rapoport, Alan M / Lipton, Richard B / Spierings, Egilius L H / Diener, Hans-Christoph / Burstein, Rami / Loupe, Pippa S / Ma, Yuju / Yang, Ronghua / Silberstein, Stephen D. ·Research and Development Department, Teva Pharmaceuticals, Frazer, PA, USA. Electronic address: marcelo.bigal@tevapharm.com. · Department of Internal Medicine, Lund University Hospital, Lund, Sweden. · The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA. · Clinical Research, MedVadis Research, Boston, MA, USA. · Department of Neurology, Essen Headache Center, Essen, Germany. · Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Research and Scientific Affairs Department, Teva Pharmaceuticals, Frazer, PA, USA. · Statistics Department, Teva Pharmaceuticals, Frazer, PA, USA. · Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA. ·Lancet Neurol · Pubmed #26432181.

ABSTRACT: BACKGROUND: Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine. METHODS: In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9-12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9-12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773. FINDINGS: Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9-12 was -59.84 h (SD 80.38) in the 675/225 mg group and -67.51 h (79.37) in the 900 mg group, compared with -37.10 h (79.44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was -22.74 h (95% CI -44.28 to -1.21; p=0.0386), whereas the difference between placebo and 900 mg dose groups was -30.41 h (-51.88 to -8.95; p=0.0057). Adverse events were reported by 36 (40%) patients in the placebo group, 47 (53%) patients in the 675/225 mg dose group, and 41 (47%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17%) patients, 25 (29%) patients, and 28 (32%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1%) patients had serious non-treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment-related adverse events were serious and there were no relevant changes in blood pressure or other vital signs. INTERPRETATION: TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial. FUNDING: Teva Pharmaceuticals.

20 Article Cellular distribution of PACAP-38 and PACAP receptors in the rat brain: Relation to migraine activated regions. 2019

Warfvinge, Karin / Edvinsson, Lars. ·Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet, Glostrup, Denmark. · Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden. ·Cephalalgia · Pubmed #31810401.

ABSTRACT: BACKGROUND: Pituitary adenylate cyclase-activating polypeptide (PACAP) occurs as either a 27- or 38-amino acid neuropeptide and belongs to the vasoactive intestinal polypeptide/glucagon/secretin family of peptides. PACAP and vasoactive intestinal polypeptide have a 68% homology of their amino acid sequences and share three B-type G-protein coupled receptors: VPAC METHODS/RESULTS: The distribution of PACAP-38 and its receptors in the brain is only partly described in the literature. Here, we have performed a study to provide the more general picture of this system in rat brain in order to understand a putative role in primary headaches and partly in relation to the calcitonin gene-related peptide system. We observed a rich expression of PACAP-38 and PAC CONCLUSION: The findings suggest that the rich supply of PACAP-38 and PAC

21 Article Characterisation of the calcitonin gene-related peptide receptor antagonists ubrogepant and atogepant in human isolated coronary, cerebral and middle meningeal arteries. 2019

Rubio-Beltran, Eloísa / Chan, Ka Yi / Danser, Ah Jan / MaassenVanDenBrink, Antoinette / Edvinsson, Lars. ·Division of Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands. · Department of Internal Medicine, Institute of Clinical Sciences, Lund University Hospital, Lund, Sweden. ·Cephalalgia · Pubmed #31674221.

ABSTRACT: BACKGROUND: Migraine has been associated with a dysfunctional activation of the trigeminovascular system. Calcitonin gene-related peptide, a neuropeptide released from the trigeminal nerve fibres, has an important role in the pathophysiology of migraine and is a current therapeutic target for migraine treatment. METHODS: We examined the effects of two novel calcitonin gene-related peptide receptor antagonists, ubrogepant and atogepant, on the relaxations induced by α calcitonin gene-related peptide in human isolated middle meningeal, cerebral and coronary arteries. Furthermore, the contractile responses to atogepant and ubrogepant RESULTS: In intracranial arteries, both blockers antagonized the calcitonin gene-related peptide-induced relaxations more potently when compared to the inhibition observed in distal human coronary arteries, with atogepant showing a higher potency. When analysing their antagonistic profile in HCA, ubrogepant showed a competitive antagonist profile, while atogepant showed a non-competitive one. Neither of the gepants had vasoconstrictor effect at any of the concentrations studied in human coronary arteries, whereas zolmitriptan elicited concentration-dependent contractions. CONCLUSION: ubrogepant and atogepant differentially inhibit the calcitonin gene-related peptide-dependent vasodilatory responses in intracranial arteries when compared to distal human coronary arteries. Also, both gepants are devoid of vasoconstrictive properties in human coronary arteries.

22 Article Rimegepant oral disintegrating tablet for migraine. 2019

Edvinsson, Lars. ·Department of Medicine, Lund University, Lund 22185, Sweden. Electronic address: lars.edvinsson@med.lu.se. ·Lancet · Pubmed #31311675.

ABSTRACT: -- No abstract --

23 Article Role of CGRP in Migraine. 2019

Edvinsson, Lars. ·Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden. lars.edvinsson@med.lu.se. · Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup Hospital, Glostrup, Denmark. lars.edvinsson@med.lu.se. ·Handb Exp Pharmacol · Pubmed #30725283.

ABSTRACT: Migraine is a common neurological disorder that afflicts up to 15% of the adult population in most countries, with predominance in females. It is characterized by episodic, often disabling headache, photophobia and phonophobia, autonomic symptoms (nausea and vomiting), and in a subgroup an aura in the beginning of the attack. Although still debated, many researchers consider migraine to be a disorder in which CNS dysfunction plays a pivotal role while various parts of the trigeminal system are necessary for the expression of associated symptoms.Treatment of migraine has in recent years seen the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are now approved for use in frequent episodic and in chronic migraine. CGRP-related therapies offer considerable improvements over existing drugs, as they are the first to be designed specifically to act on the trigeminal pain system: they are more specific and have little or no adverse effects. Small molecule CGRP receptor antagonists, gepants, are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (Eptinezumab, Fremanezumab, and Galcanezumab) or the CGRP receptor (Erenumab) effectively prevent migraine attacks. The neurobiology of CGRP signaling is briefly summarized together with key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatments.

24 Article Perivascular neurotransmitters: Regulation of cerebral blood flow and role in primary headaches. 2019

Frederiksen, Simona D / Haanes, Kristian A / Warfvinge, Karin / Edvinsson, Lars. ·1 Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, Glostrup, Denmark. · 2 Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden. ·J Cereb Blood Flow Metab · Pubmed #29251523.

ABSTRACT: In order to understand the nature of the relationship between cerebral blood flow (CBF) and primary headaches, we have conducted a literature review with particular emphasis on the role of perivascular neurotransmitters. Primary headaches are in general considered complex polygenic disorders (genetic and environmental influence) with pathophysiological neurovascular alterations. Identified candidate headache genes are associated with neuro- and gliogenesis, vascular development and diseases, and regulation of vascular tone. These findings support a role for the vasculature in primary headache disorders. Moreover, neuronal hyperexcitability and other abnormalities have been observed in primary headaches and related to changes in hemodynamic factors. In particular, this relates to migraine aura and spreading depression. During headache attacks, ganglia such as trigeminal and sphenopalatine (located outside the blood-brain barrier) are variably activated and sensitized which gives rise to vasoactive neurotransmitter release. Sympathetic, parasympathetic and sensory nerves to the cerebral vasculature are activated. During migraine attacks, altered CBF has been observed in brain regions such as the somatosensory cortex, brainstem and thalamus. In regulation of CBF, the individual roles of neurotransmitters are partly known, but much needs to be unraveled with respect to headache disorders.

25 Article CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior. 2019

Filiz, Aslı / Tepe, Nermin / Eftekhari, Sajedeh / Boran, H Evren / Dilekoz, Ergin / Edvinsson, Lars / Bolay, Hayrunnisa. ·1 Department of Neurology and Algology, Gazi University Medical School, Besevler, Ankara, Turkey. · 2 Neuropsychiatry Centre, Gazi University, Besevler, Ankara, Turkey. · 3 Lund University, Department of Medicine, Institute of Clinical Sciences, Lund, Sweden. · 4 Department of Pharmacology, Gazi University Faculty of Medicine, Besevler, Ankara, Turkey. ·Cephalalgia · Pubmed #28971699.

ABSTRACT: BACKGROUND AND OBJECTIVE: The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. METHODS: CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. RESULTS: MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. CONCLUSION: CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.

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