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-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 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.
Assuntos
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 , Animais , Humanos , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/metabolismo , Receptores de Serotonina/metabolismo , Receptor 5-HT1F de SerotoninaRESUMO
OBJECTIVE: To incorporate recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults. BACKGROUND: The American Headache Society previously published a Consensus Statement on the use of newly introduced treatments for adults with migraine. This update, which is based on the expanded evidence base and emerging expert consensus concerning postapproval usage, provides practical recommendations in the absence of a formal guideline. METHODS: This update involved four steps: (1) review of data about the efficacy, safety, and clinical use of migraine treatments introduced since the previous Statement was published; (2) incorporation of these data into a proposed update; (3) review and commentary by the Board of Directors of the American Headache Society and patients and advocates associated with the American Migraine Foundation; (4) consideration of these collective insights and integration into an updated Consensus Statement. RESULTS: Since the last Consensus Statement, no evidence has emerged to alter the established principles of either acute or preventive treatment. Newly introduced acute treatments include two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (ubrogepant, rimegepant); a serotonin (5-HT1F ) agonist (lasmiditan); a nonsteroidal anti-inflammatory drug (celecoxib oral solution); and a neuromodulatory device (remote electrical neuromodulation). New preventive treatments include an intravenous anti-CGRP ligand monoclonal antibody (eptinezumab). Several modalities, including neuromodulation (electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation) and biobehavioral therapy (cognitive behavioral therapy, biofeedback, relaxation therapies, mindfulness-based therapies, acceptance and commitment therapy) may be appropriate for either acute and/or preventive treatment; a neuromodulation device may be appropriate for acute migraine treatment only (remote electrical neuromodulation). CONCLUSIONS: The integration of new treatments into clinical practice should be informed by the potential for benefit relative to established therapies, as well as by the characteristics and preferences of individual patients.
Assuntos
Terapia Comportamental , Consenso , Transtornos de Enxaqueca/terapia , Guias de Prática Clínica como Assunto , Sociedades Médicas , Anticorpos Monoclonais Humanizados/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Terapia por Estimulação Elétrica , Humanos , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Fragmentos de Peptídeos/imunologia , Receptores de Serotonina , Agonistas do Receptor de Serotonina/uso terapêutico , Estimulação Magnética Transcraniana , Estados Unidos , Receptor 5-HT1F de SerotoninaRESUMO
OBJECTIVE: To review the efficacy, safety, and cost of 3 newly approved agents-ubrogepant, lasmiditan, and rimegepant-representing 2 therapeutic classes, calcitonin gene-related peptide (CGRP) receptor antagonist and serotonin 1F (5-HT1F) agonists, for the acute treatment of migraine with or without aura. DATA SOURCES: The Institute of Health US National Library of Medicine Clinical Trials, PubMed, and Cochrane databases were queried. Abstracts, journal articles, and other relevant sources published or present were reviewed. Search terms included the following: ubrogepant, MK-1602, Ubrelvy®, rimegepant, Nurtec®, BHV-3000, BMS-927711, lasmiditan, Reyvow®, LY573144. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language articles from June 30, 2010, to August 31, 2020, were evaluated and included in the narrative. DATA SYNTHESIS: CGRP receptor antagonists, ubrogepant and rimegepant, achieved 2-hour pain freedom and freedom from the most bothersome migraine symptom (MBS) at 2 hours. Both agents were well tolerated, with adverse effects similar to placebo. Lasmiditan, a 5-HT1F receptor antagonist, also improved 2-hour pain freedom and freedom from the MBS at 2 hours. Lasmiditan is associated with dizziness, paresthesia, somnolence, nausea, fatigue, and lethargy. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Ubrogepant, rimegepant, and lasmiditan represent a new and exciting chapter in acute migraine therapy. To date, no head-to-head studies have compared these agents with the triptans. Ubrogepant and lasmiditan are effective in triptan nonresponders. None of the 3 agents is contraindicated in cardiovascular disease, unlike the triptans. CONCLUSIONS: Based on available data, ubrogepant, rimegepant, and lasmiditan should be reserved as second-line therapy and may be safe in patients with cardiovascular risk. Lasmiditan's adverse effect profile may limit its use.
Assuntos
Calcitonina , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Receptores da Calcitonina , Receptores de Serotonina , Receptor 5-HT1F de SerotoninaRESUMO
Medication overuse headache is estimated to affect 2% of the population, and is ranked in the top 20 most disabling disorders due to its high level of disability. Several therapies used in the treatment of acute migraine are thought to be associated with medication overuse headache, including opioids and triptans. With limited treatment options, it is critical to determine the risk profile of novel therapies prior to their widespread use. The current study explores the potential medication overuse risk of two novel therapeutic drug classes, namely the ditans: 5-HT1F receptor agonists, and the gepants: calcitonin gene-related peptide receptor antagonists, in a preclinical model of medication overuse. Persistent exposure of mice to the 5-HT1F agonist LY344864, but not olcegepant produced a significant reduction in hind paw and orofacial mechanical withdrawal thresholds as a surrogate readout of allodynia. In agreement, only LY344864 induced neuroplastic changes in trigeminal sensory afferents, increasing calcitonin gene-related peptide expression and basal trigeminal nociception. Our data highlight a differential medication overuse headache risk profile for the ditan and gepant classes of drugs that has important implications for their clinical use and patient education to help reduce the burden of medication overuse headache.
Assuntos
Transtornos da Cefaleia Secundários/metabolismo , Transtornos de Enxaqueca/metabolismo , Medição da Dor/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Receptores de Serotonina/metabolismo , Animais , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Fluorbenzenos/farmacologia , Fluorbenzenos/uso terapêutico , Transtornos da Cefaleia Secundários/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos de Enxaqueca/tratamento farmacológico , Medição da Dor/métodos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Fatores de Risco , Receptor 5-HT1F de SerotoninaRESUMO
Spinal cord injury (SCI) is characterized by vascular disruption leading to ischemia, decreased oxygen delivery, and loss of mitochondrial homeostasis. This mitochondrial dysfunction results in loss of cellular functions, calcium overload, and oxidative stress. Pharmacological induction of mitochondrial biogenesis (MB) may be an effective approach to treat SCI. LY344864, a 5-hydroxytryptamine 1F (5-HT1F) receptor agonist, is a potent inducer of MB in multiple organ systems. To assess the efficacy of LY344864-induced MB on recovery post-SCI, female mice were subjected to moderate force-controlled impactor-induced contusion SCI followed by daily LY344864 administration for 21 days. Decreased mitochondrial DNA and protein content was present in the injury site 3 days post-SCI. LY344864 treatment beginning 1 h after injury attenuated these decreases, indicating MB. Additionally, injured mice treated with LY344864 displayed decreased Evan's Blue dye accumulation in the spinal cord compared with vehicle-treated mice 7 days after injury, suggesting restoration of vascular integrity. LY344864 also increased locomotor capability, with treated mice reaching a Basso-Mouse Scale score of 3.4 by 21 days, whereas vehicle-treated mice exhibited a score of 1.9. Importantly, knockout of the 5-HT1F receptor blocked LY344864-induced recovery. Remarkably, a similar degree of locomotor restoration was observed when treatment initiation was delayed until 8 h after injury. Furthermore, cross-sectional analysis of the spinal cord 21 days after injury revealed decreased lesion volume with delayed LY344864 treatment initiation, emphasizing the potential clinical applicability of this therapeutic approach. These data provide evidence that induction of MB via 5-HT1F receptor agonism may be a promising strategy for the treatment of SCI. SIGNIFICANCE STATEMENT: Treatment with LY344864 induces mitochondrial biogenesis in both the naive and injured mouse spinal cord. In addition, treatment with LY344864 beginning after impactor-induced contusion spinal cord injury improves mitochondrial homeostasis, blood-spinal cord barrier integrity, and locomotor function within 7 days. Importantly, similar locomotor results are observed whether treatment is initiated at 1 h after injury or 8 h after injury. These data indicate the potential for pharmacological induction of mitochondrial biogenesis through a 5-hydroxytryptamine 1F agonist as a novel therapeutic approach for spinal cord injury.
Assuntos
Carbazóis/química , Fluorbenzenos/química , Biogênese de Organelas , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Carbazóis/farmacologia , Estudos Transversais , Feminino , Fluorbenzenos/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Medula Espinal/efeitos dos fármacos , Fatores de Tempo , Receptor 5-HT1F de SerotoninaRESUMO
OBJECTIVE: To identify factors predicting response (2-hour headache pain freedom or most bothersome symptom freedom) to lasmiditan based on individual patient characteristics, migraine disease characteristics, and migraine attack characteristics. Further, efficacy specifically in difficult-to-treat patient/migraine disease characteristics or attack characteristics (ie, historically considered less responsive to certain acute therapies) subgroups was analyzed. BACKGROUND: Knowledge of factors associated with a positive or negative response to acute treatment would be useful to practitioners prescribing acute treatments for migraine. Additionally, practitioners and patients would benefit from understanding the efficacy of lasmiditan specifically in subgroups of patients with migraine disease characteristics and migraine attack characteristics historically associated with decreased pain threshold, reduced efficacy of acute treatment, or increased burden of migraine. METHODS: Pooled analyses were completed from 2 Phase 3 double-blind clinical trials, SPARTAN and SAMURAI. Data from baseline to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to assess efficacy based on patient characteristics, migraine disease characteristics, and migraine attack characteristics. A total of 3981 patients comprising the intent-to-treat population were treated with placebo (N = 1130), lasmiditan 50 mg (N = 598), lasmiditan 100 mg (N = 1133), or lasmiditan 200 mg (N = 1120). Data were analyzed for the following efficacy measures at 2 hours: headache pain freedom and most bothersome symptom freedom. RESULTS: None of the analyzed subgroups based on individual patient characteristics, migraine disease characteristics, or migraine attack characteristics predicted headache pain freedom or most bothersome symptom freedom response at 2 hours following lasmiditan treatment (interaction P ≥ .1). For the difficult-to-treat patient/migraine disease characteristics subgroups (defined as those with ≥24 headache days in the past 3 months, duration of migraine history ≥20 years, severe disability [Migraine Disability Assessment score ≥21], obesity [≥30 kg/m2 ], and history of psychiatric disorder), single doses of lasmiditan (100 or 200 mg) were significantly more effective than placebo (P ≤ .002) in achieving both endpoints. Headache pain freedom response rates for higher doses of lasmiditan were numerically greater than for lower doses of lasmiditan. For the difficult-to-treat migraine attack subgroups, patients with severe headache, co-existent nausea at the time of treatment, or who delayed treatment for ≥2 hours from the time of headache onset, both endpoint response rates after lasmiditan 100 or 200 mg were significantly greater than after placebo. Among those who delayed treatment for ≥4 hours from the time of headache onset, headache pain freedom response rates for the 200 mg dose of lasmiditan met statistical significance vs placebo (32.4% vs 15.9%; odds ratio = 2.7 [1.17, 6.07]; P = .018). While the predictors of response interaction test showed similar efficacy of lasmiditan vs placebo across subgroups defined by baseline functional disability (mild, moderate, or needs complete bed rest) at the time of treatment, analyses of lasmiditan efficacy within the subgroup "needs complete bed rest" appeared to show less efficacy (eg, in the 200 mg vs placebo group, 25.9% vs 18.5%; odds ratio = 1.56 [0.96, 2.53]; P = .070). CONCLUSIONS: Efficacy of lasmiditan 200 and 100 mg for headache pain freedom and most bothersome symptom freedom at 2 hours post-treatment was generally not influenced by the individual patient characteristics, migraine disease history, or migraine attack characteristics that were analyzed. In the analyses of difficult-to-treat subgroups, patients receiving lasmiditan achieved greater responses (2-hour headache pain freedom and most bothersome symptom freedom) vs placebo recipients.
Assuntos
Benzamidas/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Piperidinas/farmacologia , Piridinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Adolescente , Adulto , Idoso , Benzamidas/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/administração & dosagem , Fatores de Tempo , Adulto Jovem , Receptor 5-HT1F de SerotoninaRESUMO
OBJECTIVE: To evaluate the impact of lasmiditan, an oral, centrally-penetrant, selective serotonin 1F (5-HT1F ) receptor agonist developed for the acute treatment of migraine, on simulated driving. METHODS: Healthy adult volunteers enrolled in two randomized, placebo and active comparator-controlled, crossover studies. Study 1 (N = 90) tested lasmiditan (50-, 100-, 200-mg), alprazolam (1-mg), and placebo at 1.5 hr post-dose. Study 2 (N = 68) tested lasmiditan (100-, 200-mg), diphenhydramine (50-mg, administered 2 hr pre-assessments), and placebo at 8, 12 and 24 hr post-dose. Driving performance was assessed using a validated driving simulator employing a 100 km driving scenario. Standard deviation of lateral position (SDLP), a measure of lane position control, was the primary endpoint. RESULTS: Assay sensitivity was confirmed by increased SDLP for active comparators at 1.5- and 8-hr time points. Lasmiditan doses showed significant driving impairment versus placebo at 1.5 hr post-dose. Lasmiditan doses were non-inferior to placebo at 8 hr. Driving impairment was concentration-dependent at 1.5 hr but not at 8 hr. Common adverse events were central nervous system-related and mild-to-moderate in severity. CONCLUSIONS: Lasmiditan was associated with impaired simulated driving performance at 1.5 hr post-dose, but showed no clinically meaningful impairment at 8 hr post-dose.
Assuntos
Condução de Veículo , Benzamidas/efeitos adversos , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Agonistas do Receptor de Serotonina/efeitos adversos , Adulto , Benzamidas/administração & dosagem , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/administração & dosagem , Fatores de Tempo , Adulto Jovem , Receptor 5-HT1F de SerotoninaRESUMO
BACKGROUND: Migraine has been recognized as one of common diseases in the world whose current treatment options are not ideal. Lasmiditan, an oral 5-hydroxytryptamine (HT)1F receptor agonist, appears more promising for the acute treatment of migraine because of considerably better effect profiles with no severe adverse events (AEs). This review aimed to systematically evaluate the efficacy and safety of lasmiditan from the results of randomized controlled trials (RCTs). METHODS: PubMed, Cochrane Library, Embase were searched on lasmiditan for the acute treatment of migraine from inception of the databases to Feb 1, 2020. Pain free and pain relief, global impression (very much/much better), and no/mild disability at 2 h in efficacy; total treatment-emergent adverse events (TEAEs), dizziness, nausea, fatigue, paraesthesia and somnolence in safety were extracted from the included studies. A systematic review and meta-analysis was performed using Review Manager Software version 5.3 (RevMan 5.3). RESULTS: Four RCTs with a total of 4960 subjects met our inclusion criteria. The overall effect estimate showed that lasmiditan was significantly superior to placebo in terms of pain free (RR 1.71, 95% CI 1.55-1.87), pain relief (RR 1.40, 95% CI 1.33-1.47), global impression (very much/much better) (RR 1.55, 95% CI 1.44-1.67), and no/mild disability (RR 1.15, 95% CI 1.10-1.20) at 2 h. For the safety, significant number of patients experienced TEAEs with lasmiditan than with placebo (RR 2.77, 95% CI 2.53-3.03), most TEAEs were central nervous system (CNS)-related and included dizziness (RR 5.81, 95% CI 4.72-7.14), nausea (RR 2.58, 95% CI 1.87-3.57), fatigue (RR 5.38, 95% CI 3.78-7.66), paraesthesia (RR 4.48, 95% CI 3.33-6.02), and somnolence (RR 2.82, 95% CI 2.18-3.66). CONCLUSIONS: This meta-analysis suggests that lasmiditan is effective for the acute treatment of migraine with a higher incidence of CNS-related adverse reactions compared with placebo. Long-term, open-label, multi-dose trials are required to verify the current findings.
Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/uso terapêutico , Benzamidas/efeitos adversos , Tontura/induzido quimicamente , Humanos , Náusea/induzido quimicamente , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Agonistas do Receptor de Serotonina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Vertigem/induzido quimicamente , Receptor 5-HT1F de SerotoninaRESUMO
Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.
Assuntos
Benzamidas/farmacologia , Transtornos de Enxaqueca/fisiopatologia , Piperidinas/farmacologia , Piridinas/farmacologia , Receptores de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Humanos , Neurônios/metabolismo , Gânglio Trigeminal/metabolismo , Gânglio Trigeminal/fisiopatologia , Triptaminas , Vasoconstrição/efeitos dos fármacos , Receptor 5-HT1F de SerotoninaRESUMO
OBJECTIVE: To describe the new classes of medication for headache management and their roles in clinical practice. BACKGROUND: Calcitonin gene-related peptide (CGRP) is a key component in the underlying pathophysiology of migraine. Research focused on targeting CGRP for headache treatment has led to the development of entirely new classes of medications - the gepants and the CGRP monoclonal antibodies (mAbs) - for both acute and preventive treatment. A third class, the ditans, is being developed to target the 5-HT1F receptor to provide acute treatment without vasoconstrictive effects. METHODS: This article reviews the pathophysiology of migraine that has led to these new pharmacologic developments. Available information from randomized controlled trials, abstracts, press releases, and relevant preclinical studies is summarized for each class of medications. RESULTS: At the time of this writing, one ditan has been submitted to the U.S. Food and Drug Administration (FDA) for approval. One gepant is anticipated to be submitted within the first quarter of 2019, and others are in clinical trials. Three CGRP mAbs have been FDA approved and are now available in clinical practice, and a fourth was submitted in the first quarter of 2019. CONCLUSIONS: The development of new migraine-specific classes of medications provides more treatment options for both acute and preventive treatment of migraine.
Assuntos
Analgésicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/uso terapêutico , Analgésicos/farmacologia , Benzamidas/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Ensaios Clínicos como Assunto , Contraindicações de Medicamentos , Aprovação de Drogas , Humanos , Transtornos de Enxaqueca/fisiopatologia , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Estados Unidos , United States Food and Drug Administration , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/efeitos adversos , Vasoconstritores/uso terapêutico , Receptor 5-HT1F de SerotoninaRESUMO
BACKGROUND: In addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs. METHODS: SAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects. RESULTS: In this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations. CONCLUSIONS: When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: ClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.
Assuntos
Benzamidas/uso terapêutico , Doenças Cardiovasculares/fisiopatologia , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Cefaleia , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Serotonina , Resultado do Tratamento , Receptor 5-HT1F de SerotoninaRESUMO
Our laboratory previously reported that agonists of the 5-hydoxytryptamine 1F (5-HT1F) receptor induce renal mitochondrial biogenesis (MB) and that stimulation of the 5-HT1F receptor following ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) accelerated the recovery of renal function in mice. The goal of this study was to examine the contribution of the 5-HT1F receptor in the regulation of renal mitochondrial homeostasis and renal function in naïve and injured mice. Although 5-HT1F receptor knockout (KO) mice were healthy and fertile, and did not exhibit renal dysfunction, renal mitochondrial DNA copy number and mitochondrial fission gene expression increased at 10 wk of age. The 5-HT1F receptor KO mice exhibited greater proximal tubular injury and diminished renal recovery after I/R-induced AKI compared with wild-type mice. These findings were associated with persistent suppression of renal cortical MB and ATP levels after injury. In summary, the 5-HT1F receptor is a component of physiological MB regulation in the kidney, and its absence potentiates renal injury and impedes recovery.
Assuntos
Injúria Renal Aguda/metabolismo , Homeostase/fisiologia , Mitocôndrias/metabolismo , Receptores de Serotonina/metabolismo , Animais , DNA Mitocondrial/metabolismo , Rim/metabolismo , Córtex Renal/metabolismo , Masculino , Camundongos Knockout , Biogênese de Organelas , Receptores de Serotonina/genética , Traumatismo por Reperfusão/metabolismo , Receptor 5-HT1F de SerotoninaRESUMO
Our laboratory recently made the novel observation that 5-hydroxytryptamine 1F (5-HT1F) receptor activation induces mitochondrial biogenesis (MB), the production of new, functional mitochondria, in vitro and in vivo. We sought to determine the mechanism linking the 5-HT1F receptor to MB in renal proximal tubule cells. Using LY344864 , a selective 5-HT1F receptor agonist, we determined that the 5-HT1F receptor is coupled to Gαi/o and induces MB through Gßγ-dependent activation of Akt, endothelial nitric oxide synthase (eNOS), cyclic guanosine-monophosphate (cGMP), protein kinase G (PKG), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). We also report that the 5-HT1F receptor signals through a second, Gßγ-dependent pathway that is linked by Akt phosphorylation of Raf. In contrast to the activated Akt pathway, Raf phosphorylation reduced extracellular signal regulated kinases (ERK1/2) and foxhead box O3a (FOXO3a) phosphorylation, suppressing an inhibitory MB pathway. These results demonstrate that the 5-HT1F receptor regulates MB through Gßγ-dependent dual mechanisms that activate a stimulatory MB pathway, Akt/eNOS/cGMP/PKG/PGC-1α, while simultaneously repressing an inhibitory MB pathway, Raf/MEK/ERK/FOXO3a. Novel mechanisms of MB provide the foundation for new chemicals that induce MB to treat acute and chronic organ injuries.
Assuntos
Túbulos Renais Proximais/metabolismo , Mitocôndrias/metabolismo , Biogênese de Organelas , Receptores de Serotonina/metabolismo , Animais , Carbazóis/farmacologia , Células Cultivadas , Feminino , Fluorbenzenos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fosforilação , Coelhos , Receptores de Serotonina/efeitos dos fármacos , Sistemas do Segundo Mensageiro , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Receptor 5-HT1F de SerotoninaRESUMO
Serotonin (5-hydroxytryptamine; 5-HT) inhibits the rat cardioaccelerator sympathetic outflow by 5-HT1B/1D/5 receptors. Because chronic blockade of sympatho-excitatory 5-HT2 receptors is beneficial in several cardiovascular pathologies, this study investigated whether sarpogrelate (a 5-HT2 receptor antagonist) alters the pharmacological profile of the above sympatho-inhibition. Rats were pretreated for 2 weeks with sarpogrelate in drinking water (30 mg/kg per day; sarpogrelate-treated group) or equivalent volumes of drinking water (control group). Animals were pithed and prepared for spinal stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or for intravenous (i.v.) bolus injections of noradrenaline. Both procedures produced tachycardic responses remaining unaltered after saline. Continuous i.v. infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT receptor agonists 5-carboxamidotryptamine (5-CT; 5-HT1/5A), CP 93,129 (5-HT1B), or PNU 142633 (5-HT1D), but not by indorenate (5-HT1A) in both groups; whereas LY344864 (5-HT1F) mimicked 5-HT only in sarpogrelate-treated rats. In sarpogrelate-treated animals, i.v. GR 127935 (310 µg/kg; 5-HT1B/1D/1F receptor antagonist) attenuated 5-CT-induced sympatho-inhibition and abolished LY344864-induced sympatho-inhibition; while GR 127935 plus SB 699551 (1 mg/kg; 5-HT5A receptor antagonist) abolished 5-CT-induced inhibition. These results confirm the cardiac sympatho-inhibitory role of 5-HT1B, 5-HT1D, and 5-HT5A receptors in both groups; nevertheless, sarpogrelate treatment specifically unmasked a cardiac sympatho-inhibition mediated by 5-HT1F receptors.
Assuntos
Miocárdio/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Sistema Nervoso Simpático/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Carbazóis/farmacologia , Diástole/efeitos dos fármacos , Estimulação Elétrica , Fluorbenzenos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Norepinefrina/farmacologia , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Ratos Wistar , Serotonina/análogos & derivados , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico , Cloreto de Sódio/farmacologia , Succinatos/farmacologia , Succinatos/uso terapêutico , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Taquicardia/tratamento farmacológico , Taquicardia/fisiopatologia , Receptor 5-HT1F de SerotoninaRESUMO
Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1-100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazone-uncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase ß, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1ß subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferator-activated receptor coactivator 1-α, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Injúria Renal Aguda/fisiopatologia , Animais , Benzamidas/farmacologia , Carbazóis/farmacologia , DNA Mitocondrial/análise , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Fluorbenzenos/farmacologia , Indóis/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Fosforilação Oxidativa/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Coelhos , Traumatismo por Reperfusão/tratamento farmacológico , Fatores de Transcrição/genética , Receptor 5-HT1F de SerotoninaRESUMO
The serotonin (5-hydroxytryptamine, 5-HT) 5-HT1 G-protein coupled receptor subtypes (5-HT1A/1B/1D/1E/1F) share a high sequence homology, confounding development of subtype-specific ligands. This study used a 5-HT1 structure-based ligand design approach to develop subtype-selective ligands using a 5-substituted-2-aminotetralin (5-SAT) chemotype, leveraging results from pharmacological, molecular modeling, and mutagenesis studies to delineate molecular determinants for 5-SAT binding and function at 5-HT1 subtypes. 5-SATs demonstrated high affinity (Ki ≤ 25 nM) and at least 50-fold stereoselective preference ([2S] > [2R]) at 5-HT1A, 5-HT1B, and 5-HT1D receptors but essentially nil affinity (Ki > 1 µM) at 5-HT1F receptors. The 5-SATs tested were agonists with varying degrees of potency and efficacy, depending on chemotype substitution and 5-HT1 receptor subtype. Models were built from the 5-HT1A (cryo-EM), 5-HT1B (crystal), and 5-HT1D (cryo-EM) structures, and 5-SATs underwent docking studies with up to 1 µs molecular dynamics simulations. 5-SAT interactions observed at positions 3.33, 5.38, 5.42, 5.43, and 7.39 of 5-HT1 subtypes were confirmed with point mutation experiments. Additional 5-SATs were designed and synthesized to exploit experimental and computational results, yielding a new full efficacy 5-HT1A agonist with 100-fold selectivity over 5-HT1B/1D receptors. The results presented lay the foundation for the development of additional 5-HT1 subtype selective ligands for drug discovery purposes.
Assuntos
Receptor 5-HT1F de Serotonina , Serotonina , Tetra-Hidronaftalenos , Serotonina/metabolismo , Receptores de Serotonina/genética , Agonistas do Receptor de Serotonina/farmacologia , Ligantes , Receptores 5-HT1 de Serotonina , Receptor 5-HT1B de SerotoninaRESUMO
This short review aims to give a focus on news in the migraine attack treatment and discusses the CGRP receptor antagonists (gepants), the 5-HT1F receptors agonists (ditans), the transcranial magnetic stimulation for the treatment of migraine attack with aura, innovative delivery systems for sumatriptan and the oral inhalation of dihydroergotamine.
Assuntos
Transtornos de Enxaqueca/terapia , Manejo da Dor/métodos , Manejo da Dor/tendências , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Di-Hidroergotamina/administração & dosagem , Di-Hidroergotamina/uso terapêutico , Humanos , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/uso terapêutico , Sumatriptana/uso terapêutico , Estimulação Magnética Transcraniana , Receptor 5-HT1F de SerotoninaRESUMO
Serotonin is a neurotransmitter, which is involved in memory via its receptors. The 5-HT1D and 5-HT1F receptors mainly exist in the hippocampus, which plays an important role in memory processing. However, few studies have assessed the effect of these serotonin receptors on memory. We evaluated the effect of a 5-HT1D receptor agonist, PNU142633, 5-HT1D receptor antagonist, BRL15572 hydrochloride, and 5-HT1F receptor agonist, LY344864, on the recognition and avoidance memory in the hippocampus area. Fifty adult male Wistar rats weighing 200-250 g were divided into the control, sham-operated, PNU, BRL, and LY groups (n=10 per group). Bilateral guide cannulas were implanted into the dentate gyrus area of the hippocampus. The drugs were administered at the dose of 1 µg/µl before the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The results showed that in the NOR test, the administration of PNU and LY had no significant effect on recognition index; however, the recognition index was increased by BRL. In the PAL test, the administration of PNU had no significant effect on recognition index, but the administration of BRL and LY increased the time spent in the dark compartment of the apparatus and decreased the step-through latency into the dark compartment apparatus. It can be concluded that the inhibition of the hippocampal 5-HT1D receptor improved cognition memory but impaired avoidance memory. Activation of the hippocampal 5-HT1F receptor had no effect on cognitive memory but impaired avoidance memory.
Assuntos
Receptores de Serotonina , Serotonina , Ratos , Masculino , Animais , Serotonina/farmacologia , Ratos Wistar , Receptor 5-HT1D de Serotonina , Receptores de Serotonina/metabolismo , Hipocampo , Transtornos da Memória , Aprendizagem da Esquiva , Receptor 5-HT1F de SerotoninaRESUMO
Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans - a group of selective serotonin 5-HT1F receptor agonists - has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency.
Assuntos
Transtornos de Enxaqueca , Receptores de Serotonina , Humanos , Receptores de Serotonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/induzido quimicamente , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina , Receptor 5-HT1F de SerotoninaRESUMO
Spasticity is a common complication in patients with spinal cord injury (SCI) and adversely affects patients' quality of life. Little is known about the distribution of the serotonin 1F receptor (5-HT1FR) in the spinal cord, especially in relation to the spasticity caused by SCI. Adult male Wistar rats were divided into a sham-operation group and spinalized group. SCI-induced spasticity was caused by spinal transection at the second sacral segment. The spinal cord below the transection was obtained at the end of the experiment. The expression and distribution of 5-HT1FR in the spinal cord were analyzed. The results showed that the expression of 5-HT1FR (mRNA and protein) exhibited the same downward trend after spinal transection and reached the lowest expression level at 2 and 5 days, respectively. The expression of 5-HT1FR (mRNA and protein) thereafter gradually approached the levels in the sham-operation group after 60 days. Immunostaining suggested that 5-HT1FR showed particularly strong expression in the ventral horn (VH) region. The time course of 5-HT1FR mRNA downregulation is positively correlated with the development of tail spasticity after sacral spinal cord transection. There may be a connection between 5-HT1FR and the occurrence of spasticity, but elucidation of the specific mechanism needs further experimental verification.