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[PMID]:28460892
[Au] Autor:Tepper S; Ashina M; Reuter U; Brandes JL; Dolezil D; Silberstein S; Winner P; Leonardi D; Mikol D; Lenz R
[Ad] Endereço:Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Electronic address: stewart.j.tepper@dartmouth.edu.
[Ti] Título:Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial.
[So] Source:Lancet Neurol;16(6):425-434, 2017 Jun.
[Is] ISSN:1474-4465
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The calcitonin gene-related peptide (CGRP) pathway is important in migraine pathophysiology. We assessed the efficacy and safety of erenumab, a fully human monoclonal antibody against the CGRP receptor, in patients with chronic migraine. METHODS: This was a phase 2, randomised, double-blind, placebo-controlled, multicentre study of erenumab for adults aged 18-65 years with chronic migraine, enrolled from 69 headache and clinical research centres in North America and Europe. Chronic migraine was defined as 15 or more headache days per month, of which eight or more were migraine days. Patients were randomly assigned (3:2:2) to subcutaneous placebo, erenumab 70 mg, or erenumab 140 mg, given every 4 weeks for 12 weeks. Randomisation was centrally executed using an interactive voice or web response system. Patients, study investigators, and study sponsor personnel were masked to treatment assignment. The primary endpoint was the change in monthly migraine days from baseline to the last 4 weeks of double-blind treatment (weeks 9-12). Safety endpoints were adverse events, clinical laboratory values, vital signs, and anti-erenumab antibodies. The efficacy analysis set included patients who received at least one dose of investigational product and completed at least one post-baseline monthly measurement. The safety analysis set included patients who received at least one dose of investigational product. The study is registered with ClinicalTrials.gov, number NCT02066415. FINDINGS: From April 3, 2014, to Dec 4, 2015, 667 patients were randomly assigned to receive placebo (n=286), erenumab 70 mg (n=191), or erenumab 140 mg (n=190). Erenumab 70 mg and 140 mg reduced monthly migraine days versus placebo (both doses -6·6 days vs placebo -4·2 days; difference -2·5, 95% CI -3·5 to -1·4, p<0·0001). Adverse events were reported in 110 (39%) of 282 patients, 83 (44%) of 190 patients, and 88 (47%) of 188 patients in the placebo, 70 mg, and 140 mg groups, respectively. The most frequent adverse events were injection-site pain, upper respiratory tract infection, and nausea. Serious adverse events were reported by seven (2%), six (3%), and two (1%) patients, respectively; none were reported in more than one patient in any group or led to discontinuation. 11 patients in the 70 mg group and three in the 140 mg group had anti-erenumab binding antibodies; none had anti-erenumab neutralising antibodies. No clinically significant abnormalities in vital signs, laboratory results, or electrocardiogram findings were identified. Of 667 patients randomly assigned to treatment, 637 completed treatment. Four withdrew because of adverse events, two each in the placebo and 140 mg groups. INTERPRETATION: In patients with chronic migraine, erenumab 70 mg and 140 mg reduced the number of monthly migraine days with a safety profile similar to placebo, providing evidence that erenumab could be a potential therapy for migraine prevention. Further research is needed to understand long-term efficacy and safety of erenumab, and the applicability of this study to real-world settings. FUNDING: Amgen.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Transtornos de Enxaqueca/prevenção & controle
Avaliação de Resultados (Cuidados de Saúde)
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Anticorpos Monoclonais/administração & dosagem
Anticorpos Monoclonais/efeitos adversos
Doença Crônica
Método Duplo-Cego
Feminino
Seres Humanos
Injeções Subcutâneas
Masculino
Meia-Idade
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Receptors, Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180121
[Lr] Data última revisão:
180121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE


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[PMID]:29226741
[Au] Autor:González-Hernández A; Marichal-Cancino BA; MaassenVanDenBrink A; Villalón CM
[Ad] Endereço:a Instituto de Neurobiología , Universidad Nacional Autónoma de México , Querétaro , México.
[Ti] Título:Side effects associated with current and prospective antimigraine pharmacotherapies.
[So] Source:Expert Opin Drug Metab Toxicol;14(1):25-41, 2018 Jan.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Migraine is a neurovascular disorder. Current acute specific antimigraine pharmacotherapies target trigeminovascular 5-HT , 5-HT 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. Expert opinion: The last decades have witnessed remarkable developments in antimigraine therapy, which includes acute (e.g. triptans) and prophylactic (e.g. ß-adrenoceptor blockers) antimigraine drugs. Indeed, the triptans represent a considerable advance, but their side effects (including nausea, dizziness and coronary vasoconstriction) preclude some patients from using triptans. This has led to the development of the ditans (5-HT receptor agonists), the gepants (CGRP receptor antagonists) and the monoclonal antibodies against CGRP or its receptor. The latter drugs represent a new hope in the antimigraine armamentarium, but as CGRP plays a role in cardiovascular homeostasis, the potential for adverse cardiovascular side effects remains latent.
[Mh] Termos MeSH primário: Desenho de Drogas
Transtornos de Enxaqueca/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/administração & dosagem
Anticorpos Monoclonais/efeitos adversos
Anticorpos Monoclonais/farmacologia
Transtornos da Cefaleia Secundários/etiologia
Seres Humanos
Transtornos de Enxaqueca/fisiopatologia
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/antagonistas & inibidores
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
Receptores de Serotonina/efeitos dos fármacos
Receptores de Serotonina/metabolismo
Agonistas de Receptores de Serotonina/administração & dosagem
Agonistas de Receptores de Serotonina/efeitos adversos
Agonistas de Receptores de Serotonina/farmacologia
Triptaminas/administração & dosagem
Triptaminas/efeitos adversos
Triptaminas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Receptors, Calcitonin Gene-Related Peptide); 0 (Receptors, Serotonin); 0 (Serotonin Receptor Agonists); 0 (Tryptamines); 0 (serotonin 1F receptor)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2018.1416097


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[PMID]:28835404
[Au] Autor:Ashina M; Dodick D; Goadsby PJ; Reuter U; Silberstein S; Zhang F; Gage JR; Cheng S; Mikol DD; Lenz RA
[Ad] Endereço:From the Department of Neurology (M.A.), Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Neurology (D.D.), Mayo Clinic, Scottsdale, AZ; NIHR-Wellcome Trust King's Clinical Research Facility (P.J.G.), Kings Coll
[Ti] Título:Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open-label study.
[So] Source:Neurology;89(12):1237-1243, 2017 Sep 19.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To assess long-term safety and efficacy of anti-calcitonin gene-related peptide receptor erenumab in patients with episodic migraine (EM). METHODS: Patients enrolled in a 12-week, double-blind, placebo-controlled clinical trial (NCT01952574) who continued in an open-label extension (OLE) study will receive erenumab 70 mg every 4 weeks for up to 5 years. This preplanned interim analysis, conducted after all participants had completed the 1-year open-label follow-up, evaluated changes in monthly migraine days (MMD), achievement of ≥50%, ≥75%, and 100% reductions, Headache Impact Test (HIT-6) score, Migraine-Specific Quality of Life (MSQ), Migraine Disability Assessment (MIDAS), and safety. Data reported as observed without imputation for missing data. RESULTS: Of 472 patients enrolled in the parent study, 383 continued in the OLE with a median exposure to erenumab of 575 days (range 28-822 days). Mean (SD) MMD were 8.8 (2.6) at parent study baseline, 6.3 (4.2) at week 12 (beginning of OLE), and 3.7 (4.0) at week 64 (mean change from baseline [reduction] of 5.0 days). At week 64, 65%, 42%, and 26% achieved ≥50%, ≥75%, and 100% reduction in MMD, respectively. Mean HIT-6 scores were 60.2 (6.3) at baseline and 51.7 (9.2) at week 64. MSQ and MIDAS improvements from baseline were maintained through week 64. Safety profiles during the OLE were similar to those in the double-blind phase, which overall were similar to placebo. CONCLUSIONS: One-year efficacy, supported by functional improvements and favorable safety and tolerability profiles, supports further investigation of erenumab as a preventive treatment in patients with EM. CLINICALTRIALSGOV IDENTIFIER: NCT01952574. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with episodic migraine, erenumab reduces long-term MMD and improves headache-related disability and migraine-specific quality of life.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Transtornos de Enxaqueca/prevenção & controle
Avaliação de Resultados (Cuidados de Saúde)
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adulto
Anticorpos Monoclonais/administração & dosagem
Anticorpos Monoclonais/efeitos adversos
Método Duplo-Cego
Feminino
Seres Humanos
Masculino
Meia-Idade
Medidas de Resultados Relatados pelo Paciente
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; CONTROLLED CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AMG 334); 0 (Antibodies, Monoclonal); 0 (Receptors, Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170825
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000004391


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[PMID]:28691801
[Au] Autor:Woolley MJ; Simms J; Uddin S; Poyner DR; Conner AC
[Ad] Endereço:College of Medical and Dental Sciences, University of Birmingham , Edgbaston, Birmingham B15 2TT, U.K.
[Ti] Título:Relative Antagonism of Mutants of the CGRP Receptor Extracellular Loop 2 Domain (ECL2) Using a Truncated Competitive Antagonist (CGRP ): Evidence for the Dual Involvement of ECL2 in the Two-Domain Binding Model.
[So] Source:Biochemistry;56(30):3877-3880, 2017 Aug 01.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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 CGRP 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. This has implications for understanding family B GPCR activation and for drug design at the CGRP receptor.
[Mh] Termos MeSH primário: Peptídeo Relacionado com Gene de Calcitonina/farmacologia
Proteína Semelhante a Receptor de Calcitonina/agonistas
Mióticos/farmacologia
Modelos Moleculares
Fragmentos de Peptídeos/farmacologia
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/agonistas
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Sítios de Ligação
Ligação Competitiva
Células COS
Peptídeo Relacionado com Gene de Calcitonina/química
Peptídeo Relacionado com Gene de Calcitonina/genética
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Proteína Semelhante a Receptor de Calcitonina/química
Proteína Semelhante a Receptor de Calcitonina/genética
Proteína Semelhante a Receptor de Calcitonina/metabolismo
Cercopithecus aethiops
Cinética
Ligantes
Mióticos/química
Mióticos/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Mutação Puntual
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Mapeamento de Interação de Proteínas
Multimerização Proteica
Proteína 1 Modificadora da Atividade de Receptores/química
Proteína 1 Modificadora da Atividade de Receptores/genética
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/química
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genética
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Proteínas Recombinantes/farmacologia
Homologia Estrutural de Proteína
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CALCRL protein, human); 0 (Calcitonin Receptor-Like Protein); 0 (Ligands); 0 (Miotics); 0 (Peptide Fragments); 0 (RAMP1 protein, human); 0 (RCP9 protein, human); 0 (Receptor Activity-Modifying Protein 1); 0 (Receptors, Calcitonin Gene-Related Peptide); 0 (Recombinant Proteins); 119911-68-1 (calcitonin gene-related peptide (8-37)); 83652-28-2 (Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00077


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[PMID]:28602628
[Au] Autor:Hou X; Li H; Zhang C; Wang J; Li X; Li X
[Ad] Endereço:Department of Burn Plastic Surgery, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061001, China. Electronic address: xiaoqianhoucz@163.com.
[Ti] Título:Overexpression of Fibulin-5 attenuates burn-induced inflammation via TRPV1/CGRP pathway.
[So] Source:Exp Cell Res;357(2):320-327, 2017 Aug 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibulin-5, a multifunctional extracellular matrix protein, is up-regulated in response to mechanical injury and can promote dermal wound healing. This study aimed to explore the role and mechanism of Fibulin-5 in the pathogenesis of post-burn inflammation in thermally-injured mice. Here, we found that Fibulin-5 was up-regulated in the dorsal root ganglion (DRG) of burn-injured mice. After nociceptive behavioral testing, DRG was isolated and cultured to detect the mechanism of Fibulin-5 in thermal injury models by recombinant adenovirus overexpressing Fibulin-5, RT-qPCR, Western Blot, ELISA, AP20187 (an activator of one kind of kinase phosphorylating the α subunit of eukaryotic initiation factor 2, eIF2α), capsaicin (an agonist of transient receptor potential vanilloid (TRPV)-1), and an anti-CGRP neutralizing antibody. Also, the pathological state of skin tissues and the expression of cyclooxygenase 2 and myeloperoxidase were examined by Hematoxylin-Eosin staining and immunohistochemistry, respectively. We found that overexpression of Fibulin-5 attenuated the pain, inhibited the inflammatory response, and improved the pathologic condition induced by burn injury. Fibulin-5 overexpression significantly down-regulated the phosphorylation level of eIF2α and subsequently inhibited the TRPV1 channel and CREB/CGRP signaling. Additionally, anti-CGRP neutralizing antibody dramatically suppressed the inflammatory response induced by burn injury. The results suggest that overexpression of Fibulin-5 attenuates thermal inflammation via suppressing TRPV1/CGRP pathway. This may provide a potential therapy target to alleviate excessive inflammation in burn patients.
[Mh] Termos MeSH primário: Queimaduras/metabolismo
Proteínas da Matriz Extracelular/metabolismo
Gânglios Espinais/metabolismo
Proteínas Recombinantes/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Queimaduras/tratamento farmacológico
Imuno-Histoquímica/métodos
Inflamação/tratamento farmacológico
Inflamação/metabolismo
Camundongos
Fosforilação
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
Canais de Cátion TRPV/metabolismo
Tacrolimo/análogos & derivados
Tacrolimo/farmacologia
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP20187); 0 (Crcp protein, mouse); 0 (Extracellular Matrix Proteins); 0 (Fbln5 protein, mouse); 0 (Receptors, Calcitonin Gene-Related Peptide); 0 (Recombinant Proteins); 0 (TRPV Cation Channels); 0 (TRPV1 protein, mouse); WM0HAQ4WNM (Tacrolimus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE


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[PMID]:28389966
[Au] Autor:Hou M; Xing H; Cai Y; Li B; Wang X; Li P; Hu X; Chen J
[Ad] Endereço:Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, People's Republic of China.
[Ti] Título:The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis.
[So] Source:J Headache Pain;18(1):42, 2017 Dec.
[Is] ISSN:1129-2377
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Migraine has been recognized as one of the leading causes of disability in the 2013 Global Burden of Disease Study and seriously affects the quality of patients' life, current treatment options are not ideal. Monoclonal antibodies to calcitonin gene-related peptide and its receptor (CGRP-mAbs) appear more promising for migraine because of considerably better effect and safety profiles. The objective of this study is to systematically assess the clinical efficacy and safety of CGRP-mAbs for migraine therapy. METHODS: A systematic literature search in PubMed, Cochrane Library and Baidu Scholar was performed to identify randomized controlled trials (RCTs), which compared the effect and safety of CGRP-mAbs with placebo on migraine. Regarding the efficacy, the reduction of monthly migraine days from baseline to weeks 1-4, 5-8, and 9-12; responder rates were extracted as the outcome measures of the effects of CGRP-mAbs. Regarding the safety, total adverse events, the main adverse events, and other adverse events were evaluated. RESULTS: We found significant reduction of monthly migraine days in CGRP-mAbs vs. placebo (weeks 1-4: SMD -0.49, 95% CI -0.61 to -0.36; weeks 5-8: SMD -0.43, 95% CI -0.56 to -0.30; weeks 9-12: SMD -0.37, 95% CI -0.49 to -0.24). 50% and 75% responder rates (OR 2.59, 95% CI 1.99 to 3.37; and OR 2.91, 95% CI 2.06 to 4.10) were significantly increased compared with placebo. There was no significant difference in total adverse events (OR 1.17, 95% CI 0.91 to 1.51), and the main adverse events including upper respiratory tract infection (OR 1.44, 95% CI 0.82 to 2.55), nasopharyngitis (OR 0.59, 95% CI 0.30 to 1.16), nausea (OR 0.61, 95% CI 0.29 to 1.32), injection-site pain (OR 1.73, 95% CI 0.95 to 3.16) and back pain (OR 0.97, 95% CI 0.49 to 1.90) were not obviously changed compared with placebo control, but the results showed significant increase of dizziness in CGRP-mAbs vs. placebo (OR 3.22, 95% CI 1.09 to 9.45). CONCLUSIONS: This meta-analysis suggests that CGRP-mAbs are effective in anti-migraine therapy with few adverse reactions, but more and larger sample-size RCTs are required to verify the current findings.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/uso terapêutico
Peptídeo Relacionado com Gene de Calcitonina
Transtornos de Enxaqueca/tratamento farmacológico
Receptores de Peptídeo Relacionado com o Gene de Calcitonina
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/efeitos adversos
Anticorpos Monoclonais/metabolismo
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Ensaios Clínicos como Assunto/métodos
Tontura/induzido quimicamente
Seres Humanos
Transtornos de Enxaqueca/metabolismo
Náusea/induzido quimicamente
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Receptors, Calcitonin Gene-Related Peptide); 83652-28-2 (Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170523
[Lr] Data última revisão:
170523
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170409
[St] Status:MEDLINE
[do] DOI:10.1186/s10194-017-0750-1


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[PMID]:28233915
[Au] Autor:Hay DL; Walker CS
[Ad] Endereço:School of Biological Sciences, The University of Auckland, Auckland, New Zealand.
[Ti] Título:CGRP and its receptors.
[So] Source:Headache;57(4):625-636, 2017 Apr.
[Is] ISSN:1526-4610
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The calcitonin gene-related peptide (CGRP) neuropeptide system is an important but still evolving target for migraine. A fundamental consideration for all of the current drugs in clinical trials and for ongoing development in this area is the identity, expression pattern, and function of CGRP receptors because this knowledge informs safety and efficacy considerations. In recent years, only the calcitonin receptor-like receptor/receptor activity-modifying protein 1 (RAMP1) complex, known as the CGRP receptor, has generally been considered relevant. However, CGRP is capable of activating multiple receptors and could have more than one endogenous receptor. The recent identification of the CGRP-responsive calcitonin receptor/RAMP1 complex (AMY receptor - amylin subtype 1 receptor) in the trigeminovascular system warrants a deeper consideration of the molecular identity of CGRP receptor(s) involved in the pathophysiology, and thus potential treatment of migraine. This perspective considers some of the issues and implications.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Proteína Semelhante a Receptor de Calcitonina/metabolismo
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genética
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/imunologia
[Mh] Termos MeSH secundário: Proteína Semelhante a Receptor de Calcitonina/antagonistas & inibidores
Proteína Semelhante a Receptor de Calcitonina/genética
Seres Humanos
Transtornos de Enxaqueca/tratamento farmacológico
Transtornos de Enxaqueca/genética
Transtornos de Enxaqueca/metabolismo
Modelos Moleculares
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcitonin Receptor-Like Protein); 0 (Receptors, Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170418
[Lr] Data última revisão:
170418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1111/head.13064


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[PMID]:28192258
[Au] Autor:Sheykhzade M; Amandi N; Pla MV; Abdolalizadeh B; Sams A; Warfvinge K; Edvinsson L; Pickering DS
[Ad] Endereço:Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: mash@sund.ku.dk.
[Ti] Título:Binding and functional pharmacological characteristics of gepant-type antagonists in rat brain and mesenteric arteries.
[So] Source:Vascul Pharmacol;90:36-43, 2017 Mar.
[Is] ISSN:1879-3649
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIM: The neuropeptide calcitonin gene-related peptide (CGRP) is found in afferent sensory nerve fibers innervating the resistance arteries and plays a pivotal role in a number of neurovascular diseases such as migraine and subarachnoid bleedings. The present study investigates the binding and antagonistic characteristics of small non-peptide CGRP receptor antagonists (i.e. gepants) in isolated rat brain and mesenteric resistance arteries. METHODS: The antagonistic behavior of gepants was investigated in isolated rat mesenteric arteries using a wire myograph setup while binding of gepants to CGRP receptors was investigated in rat brain membranes using a radioligand competitive binding assay. Furthermore, the histological location of the key components of CGRP receptor (RAMP1 and CLR) was assessed by immunohistochemistry. RESULTS: Our functional studies clearly show that all gepants are reversible competitive antagonists producing Schild plot slopes not significantly different from unity and thus suggesting presence of a uniform CGRP receptor population in the arteries. A uniform receptor population was also confirmed by radioligand competitive binding studies showing similar affinities for the gepants in rat brain and mesenteric arteries, the exception being rimegepant which had 50-fold lower affinity in brain than mesenteric arteries. CLR and RAMP1 were shown to be located in both vascular smooth muscle and endothelial cells of rat mesenteric arteries by immunohistochemistry. CONCLUSION: The present results indicate that, despite species differences in the CGRP receptor affinity, the antagonistic nature of these gepants, the distribution pattern of CGRP receptor components and the mechanism behind CGRP-induced vasodilation seem to be similar in resistance-sized arteries of human and rats.
[Mh] Termos MeSH primário: Azepinas/farmacologia
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Cerebelo/irrigação sanguínea
Artérias Cerebrais/efeitos dos fármacos
Dipeptídeos/farmacologia
Imidazóis/farmacologia
Artérias Mesentéricas/efeitos dos fármacos
Piperidinas/farmacologia
Piridinas/farmacologia
Quinazolinas/farmacologia
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/antagonistas & inibidores
Compostos de Espiro/farmacologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Animais
Ligação Competitiva
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Peptídeo Relacionado com Gene de Calcitonina/farmacologia
Proteína Semelhante a Receptor de Calcitonina/metabolismo
Artérias Cerebrais/metabolismo
Relação Dose-Resposta a Droga
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/metabolismo
Feminino
Seres Humanos
Técnicas In Vitro
Ligantes
Masculino
Artérias Mesentéricas/metabolismo
Músculo Liso Vascular/efeitos dos fármacos
Músculo Liso Vascular/metabolismo
Miografia
Ligação Proteica
Ensaio Radioligante
Ratos Sprague-Dawley
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
Sus scrofa
Vasodilatação/efeitos dos fármacos
Vasodilatadores/metabolismo
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta(b)pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)piperidine-1-carboxylate); 0 (2-(8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro(4.5)dec-9-yl)-N-(2'-oxo-1,1',2',3-tetrahydrospiro(indene-2,3'-pyrrolo(2,3-b)pyridin)-5-yl)acetamide); 0 (Azepines); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Calcitonin Receptor-Like Protein); 0 (Calcrl protein, rat); 0 (Dipeptides); 0 (Imidazoles); 0 (Ligands); 0 (Piperidines); 0 (Pyridines); 0 (Quinazolines); 0 (Ramp1 protein, rat); 0 (Receptor Activity-Modifying Protein 1); 0 (Receptors, Calcitonin Gene-Related Peptide); 0 (Spiro Compounds); 0 (Vasodilator Agents); 83652-28-2 (Calcitonin Gene-Related Peptide); D42O649ALL (telcagepant); WOA5J8TX6M (olcegepant)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170214
[St] Status:MEDLINE


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[PMID]:28179394
[Au] Autor:Goadsby PJ; Holland PR; Martins-Oliveira M; Hoffmann J; Schankin C; Akerman S
[Ad] Endereço:Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom; Department of Neurology, University of California, San Francisco, San Francisco, California; Department of Neurology, University of Hamburg-Eppendorf, Hamburg, Germany; and
[Ti] Título:Pathophysiology of Migraine: A Disorder of Sensory Processing.
[So] Source:Physiol Rev;97(2):553-622, 2017 04.
[Is] ISSN:1522-1210
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Cognição/fisiologia
Transtornos de Enxaqueca/fisiopatologia
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Transtornos de Enxaqueca/diagnóstico
Transtornos de Enxaqueca/metabolismo
Receptores de Serotonina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Receptors, Calcitonin Gene-Related Peptide); 0 (Receptors, Serotonin); 0 (serotonin 1F receptor); 83652-28-2 (Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1152/physrev.00034.2015


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[PMID]:27919795
[Au] Autor:Akerman S; Romero-Reyes M; Holland PR
[Ad] Endereço:Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, NY 10010, USA. Electronic address: simon.akerman@nyu.edu.
[Ti] Título:Current and novel insights into the neurophysiology of migraine and its implications for therapeutics.
[So] Source:Pharmacol Ther;172:151-170, 2017 Apr.
[Is] ISSN:1879-016X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Migraine headache and its associated symptoms have plagued humans for two millennia. It is manifest throughout the world, and affects more than 1/6 of the global population. It is the most common brain disorder, and is characterized by moderate to severe unilateral headache that is accompanied by vomiting, nausea, photophobia, phonophobia, and other hypersensitive symptoms of the senses. While there is still a clear lack of understanding of its neurophysiology, it is beginning to be understood, and it seems to suggest migraine is a disorder of brain sensory processing, characterized by a generalized neuronal hyperexcitability. The complex symptomatology of migraine indicates that multiple neuronal systems are involved, including brainstem and diencephalic systems, which function abnormally, resulting in premonitory symptoms, ultimately evolving to affect the dural trigeminovascular system, and the pain phase of migraine. The migraineur also seems to be particularly sensitive to fluctuations in homeostasis, such as sleep, feeding and stress, reflecting the abnormality of functioning in these brainstem and diencephalic systems. Implications for therapeutic development have grown out of our understanding of migraine neurophysiology, leading to major drug classes, such as triptans, calcitonin gene-related peptide receptor antagonists, and 5-HT receptor agonists, as well as neuromodulatory approaches, with the promise of more to come. The present review will discuss the current understanding of the neurophysiology of migraine, particularly migraine headache, and novel insights into the complex neural networks responsible for associated neurological symptoms, and how interaction of these networks with migraine pain pathways has implications for the development of novel therapeutics.
[Mh] Termos MeSH primário: Desenho de Drogas
Transtornos de Enxaqueca/tratamento farmacológico
Rede Nervosa/metabolismo
[Mh] Termos MeSH secundário: Animais
Tronco Encefálico/patologia
Diencéfalo/patologia
Homeostase
Seres Humanos
Transtornos de Enxaqueca/epidemiologia
Transtornos de Enxaqueca/fisiopatologia
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/antagonistas & inibidores
Receptores de Serotonina/efeitos dos fármacos
Agonistas de Receptores de Serotonina/farmacologia
Triptaminas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Calcitonin Gene-Related Peptide); 0 (Receptors, Serotonin); 0 (Serotonin Receptor Agonists); 0 (Tryptamines); 0 (serotonin 1F receptor)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161207
[St] Status:MEDLINE



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