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https://www.readbyqxmd.com/read/29226741/side-effects-associated-with-current-and-prospective-antimigraine-pharmacotherapies
#1
Abimael González-Hernández, Bruno A Marichal-Cancino, Antoinette MaassenVanDenBrink, Carlos M Villalón
Migraine is a neurovascular disorder. Current acute specific antimigraine pharmacotherapies target trigeminovascular 5-HT1B/1D, 5-HT1F and CGRP receptors but, unfortunately, they induce some cardiovascular and central side effects that lead to poor treatment adherence/compliance. Therefore, new antimigraine drugs are being explored. Areas covered. This review considers the adverse (or potential) side effects produced by current and prospective antimigraine drugs, including medication overuse headache (MOH) produced by ergots and triptans, the side effects observed in clinical trials for the new gepants and CGRP antibodies, and a section discussing the potential effects resulting from disruption of the cardiovascular CGRPergic neurotransmission...
December 9, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29136283/population-pk-analyses-of-ubrogepant-mk-1602-a-cgrp-receptor-antagonist-enriching-in-clinic-plasma-pk-sampling-with-outpatient-dried-blood-spot-sampling
#2
Chi-Chung Li, Marissa Dockendorf, Ken Kowalski, Bei Yang, Yang Xu, Iris Xie, Huub Jan Kleijn, Rolien Bosch, Christopher Jones, Bob Thornton, Eugene E Marcantonio, Tiffini Voss, Kevin P Bateman, Prajakti A Kothare
Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling...
November 14, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29134730/role-of-central-versus-peripheral-opioid-system-in-antinociceptive-and-anti-inflammatory-effect-of-botulinum-toxin-type-a-in-trigeminal-region
#3
V Drinovac Vlah, B Filipović, L Bach-Rojecky, Z Lacković
BACKGROUND: Although botulinum toxin type A (BT-A) is approved for chronic migraine treatment, its site and mechanism of action are still elusive. Recently our group discovered that suppression of CGRP release from dural nerve endings might account for antimigraine action of pericranially injected BT-A. We demonstrated that central antinociceptive effect of BT-A in sciatic region involves endogenous opioid system as well. Here we investigated possible interaction of BT-A with endogenous opioid system within the trigeminal region...
November 13, 2017: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/29116598/cgrp-monoclonal-antibodies-for-migraine-rationale-and-progress
#4
Hsiangkuo Yuan, Clinton G Lauritsen, Eric A Kaiser, Stephen D Silberstein
Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising target for migraine management. While known as a potent arterial vasodilator, the role of CGRP in migraine is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization. Functional blockade of CGRP, which involves either CGRP receptor antagonists or monoclonal antibodies (mAbs) to CGRP or its receptor, has recently shown clinical efficacy in migraine management...
November 7, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/29059473/update-on-the-pharmacology-of-calcitonin-cgrp-family-of-peptides-iuphar-review-x
#5
REVIEW
Debbie L Hay, Michael L Garelja, David R Poyner, Christopher S Walker
The calcitonin/calcitonin gene-related peptide (CGRP) family of peptides includes calcitonin, α and β CGRP, amylin, adrenomedullin (AM) and adrenomedullin 2/intermedin (AM2/IMD). Their receptors consist of one of two G protein-coupled receptors (GPCRs), the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CLR). Further diversity arises from heterodimerisation of these GPCRs with one of three receptor activity-modifying proteins (RAMPs). This gives the CGRP receptor (CLR/RAMP1), the AM1 and AM2 receptors (CLR/RAMP2 or RAMP3) and the AMY1, AMY2 and AMY3 receptors (CTR/RAMPs1-3 complexes, respectively)...
October 23, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29023985/interaction-between-calcitonin-gene-related-peptide-immunoreactive-neurons-and-satellite-cells-via-p2y12-r-in-the-trigeminal-ganglion-is-involved-in-neuropathic-tongue-pain-in-rats
#6
Shiori Sugawara, Shinji Okada, Ayano Katagiri, Hiroto Saito, Tatsuro Suzuki, Hiroki Komiya, Kohei Kanno, Kinuyo Ohara, Toshimitsu Iinuma, Akira Toyofuku, Koichi Iwata
The P2Y12 receptor expressed in satellite cells of the trigeminal ganglion is thought to contribute to neuropathic pain. The functional interaction between neurons and satellite cells via P2Y12 receptors and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) underlying neuropathic pain in the tongue was evaluated in this study. Expression of P2Y12 receptor was enhanced in pERK1/2-immunoreactive cells encircling trigeminal ganglion neurons after lingual nerve crush. The administration to lingual nerve crush rats of a selective P2Y12 receptor antagonist, MRS2395, attenuated tongue hypersensitivity to mechanical and heat stimulation and suppressed the increase in the relative numbers of calcitonin gene-related peptide (CGRP)-immunoreactive neurons and neurons encircled by pERK1/2-immunoreactive cells...
October 11, 2017: European Journal of Oral Sciences
https://www.readbyqxmd.com/read/29019093/triptans-and-cgrp-blockade-impact-on-the-cranial-vasculature
#7
REVIEW
Silvia Benemei, Francesca Cortese, Alejandro Labastida-Ramírez, Francesca Marchese, Lanfranco Pellesi, Michele Romoli, Anne Luise Vollesen, Christian Lampl, Messoud Ashina
The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT1B and 5-HT1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine...
October 10, 2017: Journal of Headache and Pain
https://www.readbyqxmd.com/read/28971699/cgrp-receptor-antagonist-mk-8825-attenuates-cortical-spreading-depression-induced-pain-behavior
#8
Aslı Filiz, Nermin Tepe, Sajedeh Eftekhari, H Evren Boran, Ergin Dilekoz, Lars Edvinsson, Hayrunnisa Bolay
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...
January 1, 2017: Cephalalgia: An International Journal of Headache
https://www.readbyqxmd.com/read/28948500/blocking-cgrp-in-migraine-patients-a-review-of-pros-and-cons
#9
REVIEW
Marie Deen, Edvige Correnti, Katharina Kamm, Tim Kelderman, Laura Papetti, Eloisa Rubio-Beltrán, Simone Vigneri, Lars Edvinsson, Antoinette Maassen Van Den Brink
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...
September 25, 2017: Journal of Headache and Pain
https://www.readbyqxmd.com/read/28884307/the-role-of-the-transient-receptor-potential-ankyrin-type-1-trpa1-channel-in-migraine-pain-evaluation-in-an-animal-model
#10
Chiara Demartini, Cristina Tassorelli, Anna Maria Zanaboni, Germana Tonsi, Oscar Francesconi, Cristina Nativi, Rosaria Greco
BACKGROUND: Clinical and experimental studies have pointed to the possible involvement of the transient receptor potential ankyrin type-1 (TRPA1) channels in migraine pain. In this study, we aimed to further investigate the role of these channels in an animal model of migraine using a novel TRPA1 antagonist, ADM_12, as a probe. METHODS: The effects of ADM_12 on nitroglycerin-induced hyperalgesia at the trigeminal level were investigated in male rats using the quantification of nocifensive behavior in the orofacial formalin test...
September 7, 2017: Journal of Headache and Pain
https://www.readbyqxmd.com/read/28862769/histamine-and-migraine
#11
Hsiangkuo Yuan, Stephen D Silberstein
BACKGROUND: Histamine is an ancient "tissue amine" preceding multicellular organisms. In the central nervous system (CNS), its fibers originate solely from the tuberomammillary nucleus and travel throughout the brain. It is mainly responsible for wakefulness, energy homeostasis, and memory consolidation. Recently, several studies suggest a potential role of histamine in migraine pathogenesis and management. METHODS: Narrative review of current literature regarding histamine and migraine...
September 1, 2017: Headache
https://www.readbyqxmd.com/read/28856479/calcitonin-gene-related-peptide-antagonism-and-cluster-headache-an-emerging-new-treatment
#12
REVIEW
Håkan Ashina, Lawrence Newman, Sait Ashina
Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials...
August 30, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28822016/in-situ-imaging-reveals-properties-of-purinergic-signalling-in-trigeminal-sensory-ganglia-in-vitro
#13
Arletta Nowodworska, Arn M J M van den Maagdenberg, Andrea Nistri, Elsa Fabbretti
Chronic pain is supported by sterile inflammation that induces sensitisation of sensory neurons to ambient stimuli including extracellular ATP acting on purinergic P2X receptors. The development of in vitro methods for drug screening would be useful to investigate cell crosstalk and plasticity mechanisms occurring during neuronal sensitisation and sterile neuroinflammation. Thus, we studied, at single-cell level, membrane pore dilation based on the uptake of a fluorescent probe following sustained ATP-gated P2X receptor function in neurons and non-neuronal cells of trigeminal ganglion cultures from wild-type (WT) and R192Q CaV2...
August 18, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28817088/the-role-of-neurogenic-inflammation-in-blood-brain-barrier-disruption-and-development-of-cerebral-oedema-following-acute-central-nervous-system-cns-injury
#14
REVIEW
Annabel J Sorby-Adams, Amanda M Marcoionni, Eden R Dempsey, Joshua A Woenig, Renée J Turner
Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide, largely attributable to the development of cerebral oedema and elevated intracranial pressure (ICP). Despite this, clinical treatments are limited and new therapies are urgently required to improve patient outcomes and survival. Originally characterised in peripheral tissues, such as the skin and lungs as a neurally-elicited inflammatory process that contributes to increased microvascular permeability and tissue swelling, neurogenic inflammation has now been described in acute injury to the brain where it may play a key role in the secondary injury cascades that evolve following both TBI and stroke...
August 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28762564/capsaicin-induced-rapid-neutrophil-leukocyte-activation-in-the-rat-urinary-bladder-microcirculatory-bed
#15
Péter Járomi, Dénes Garab, Petra Hartmann, Dóra Bodnár, Sándor Nyíri, Péter Sántha, Mihály Boros, Gábor Jancsó, Andrea Szabó
AIMS: This study was initiated to investigate the involvement of neutrophil leukocyte activation in neurogenic inflammation, a process also involved in human urinary pathologies, elicited in the rat urinary bladder by the local administration of capsaicin, the archetypal TRPV1 agonist. The contribution of afferent nerves and sensory neuropeptides to leukocyte activation in the urinary bladder microcirculatory bed was examined. METHODS: Following a 15-min topical application of capsaicin (50 μM), leukocyte-endothelial interactions were examined for an observation period of 45 min with intravital microscopy...
August 1, 2017: Neurourology and Urodynamics
https://www.readbyqxmd.com/read/28736918/phase-1-randomized-double-blind-placebo-controlled-single-dose-and-multiple-dose-studies-of-erenumab-in-healthy-subjects-and-patients-with-migraine
#16
Jan de Hoon, Anne Van Hecken, Corinne Vandermeulen, Lucy Yan, Brian Smith, Jiyun Sunny Chen, Edgar Bautista, Lisa Hamilton, Javier Waksman, Thuy Vu, Gabriel Vargas
Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase 1 studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin (Ig)G2 antibodies...
July 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28720830/effect-of-cxcl12-cxcr4-signaling-on-neuropathic-pain-after-chronic-compression-of-dorsal-root-ganglion
#17
Yang Yu, Xini Huang, Yuwei Di, Lintao Qu, Ni Fan
Neuropathic pain is a complex, chronic pain state that often accompanies tissue damage, inflammation or injury of the nervous system. However the underlying molecular mechanisms still remain unclear. Here, we showed that CXCL12 and CXCR4 were upregulated in the dorsal root ganglion (DRG) after chronic compression of DRG (CCD), and some CXCR4 immunopositive neurons were also immunopositive for the nociceptive neuronal markers IB4, TRPV1, CGRP, and substance P. The incidence and amplitude of CXCL12-induced Ca(2+) response in primary sensory neurons from CCD mice was significantly increased compared to those from control animals...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28695626/mucosal-glucagon-like-peptide-1-glp-1-responses-are-mediated-by-calcitonin-gene-related-peptide-cgrp-in-the-mouse-colon-and-both-peptide-responses-are-area-specific
#18
I R Tough, R Moodaley, H M Cox
BACKGROUND: Glucagon-like peptide (GLP)-1 is an incretin hormone and its mimetics are proven antidiabetic and antiobesity drugs. GLP-1 exerts antimotility and mucosal proliferative activities but its epithelial ion transport effects are uncharacterized and these may contribute to the gastrointestinal (GI) disturbance, i.e., diarrhea experienced with some GLP-1 mimetics. Our aim was to establish GLP-1 agonist mechanisms and identify potential mucosal mediator(s) in the colonic tissue from C57BL/6J mice...
July 11, 2017: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/28694067/pharmacological-analysis-of-the-inhibition-produced-by-moxonidine-and-agmatine-on-the-vasodepressor-sensory-cgrpergic-outflow-in-pithed-rats
#19
Eloísa Rubio-Beltrán, Alejandro Labastida-Ramírez, Oswaldo Hernández-Abreu, Antoinette MaassenVanDenBrink, Carlos M Villalón
Calcitonin gene-related peptide (CGRP) plays a role in several (patho)physiological functions, and modulation of its release is considered a therapeutic target. In this respect, electrical spinal (T9--T12) stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. This study investigated the role of imidazoline I1 and I2 receptors in the inhibition by moxonidine and agmatine of these vasodepressor responses. Male Wistar pithed rats (pretreated i...
July 8, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28691801/relative-antagonism-of-mutants-of-the-cgrp-receptor-extracellular-loop-2-domain-ecl2-using-a-truncated-competitive-antagonist-cgrp8-37-evidence-for-the-dual-involvement-of-ecl2-in-the-two-domain-binding-model
#20
COMPARATIVE STUDY
Michael J Woolley, John Simms, Sifat Uddin, David R Poyner, Alex C Conner
The second extracellular loop (ECL2) of the G protein-coupled receptor (GPCR) family is important for ligand interaction and drug discovery. ECL2 of the family B cardioprotective calcitonin gene-related peptide (CGRP) receptor is required for cell signaling. Family B GPCR ligands have two regions; the N-terminus mediates receptor activation, and the remainder confers high-affinity binding. Comparing antagonism of CGRP8-37 at a number of point mutations of ECL2 of the CGRP receptor, we show that the ECL2 potentially facilitates interaction with up to the 18 N-terminal residues of CGRP...
August 1, 2017: Biochemistry
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