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2.
J Med Chem ; 63(19): 10946-10971, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32883072

RESUMO

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and ß-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated ß-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.


Assuntos
Desenho de Fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Agonistas do Receptor de Serotonina/uso terapêutico , beta-Arrestinas/metabolismo , Animais , Células CHO , Cálcio/metabolismo , Cricetulus , AMP Cíclico/metabolismo , Fosforilação , Ratos , Agonistas do Receptor de Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
3.
J Headache Pain ; 21(1): 66, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503415

RESUMO

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
4.
Expert Opin Pharmacother ; 21(2): 147-153, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31766908

RESUMO

Introduction: In recent years, research into acute migraine treatment has aimed to develop molecules capable of inhibiting trigeminal pathways, mediated by agonism to 5-HT1F receptors in order to avoid the vasoconstrictive action due to the stimulation of 5-HT 1B/1D receptors. A novel migraine drug class, called 'neurally acting anti-migraine agents', has been developed for the management of acute migraine attacks. Lasmiditan is the only compound of this drug class that has been evaluated in Phase III clinical trials.Areas covered: This review discusses lasmiditan including its pharmacokinetics, pharmacodynamics, efficacy and safety profile. Original research and review articles, relative to the period 2010-2019, were included in the reviewed literature.Expert opinion: The most recent phase III trials have demonstrated the efficacy of lasmiditan for acute migraine treatment, even if compared only with placebo. Nevertheless, the low rate of cardiovascular side effects with lasmiditan might offer a potential therapeutic option for migraine patients with cardiovascular disorders. With the lack of data on lasmiditan's pharmacokinetic features, several phase I clinical trials are still ongoing in order to evaluate half-life, metabolism, excretion and the potential production of active metabolites. Possible pharmacodynamic interaction with drugs acting on central nervous system should be evaluated in future studies.


Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Benzamidas/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Humanos , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/efeitos adversos
5.
Hum Psychopharmacol ; 34(6): e2714, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31774584

RESUMO

RATIONALE: Impulsive aggressive behavior is associated with reduced central function of serotonin (5-HT). Although selective serotonin reuptake inhibitors can reduce such behaviors, many with history of impulsive aggression do not respond adequately to selective serotonin reuptake inhibitors and may require treatment with a direct 5-HT agonist. OBJECTIVES: To test the hypothesis that pretreatment with the selective 5-HT2c agonist, lorcaserin, can reduce aggressive responding in impulsively aggressive individuals. METHODS: Ten male and female adults were given lorcaserin (20 mg), or a matching placebo, in random order, on 2 days separated by at least 1 week. The Taylor aggression paradigm was used to assess aggressive responding, which was represented by mean shock setting administered to an opponent and by frequency of setting high and extreme shock levels to the opponent. RESULTS: Compared with placebo, lorcaserin attenuated provoked, but not unprovoked, aggression during the Taylor aggression paradigm. This was manifest by reduction in the frequency of selecting high and extreme levels of shock against the opponent. CONCLUSION: Lorcaserin may possess anti-aggressive properties that could prove useful in the treatment of impulsive aggressive behavior in human subjects. These data, thus, provide a rationale for a follow-up randomized clinical trial of lorcaserin in individuals with prominent histories of impulsive aggressive behavior.


Assuntos
Agressão/efeitos dos fármacos , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Projetos Piloto , Agonistas do Receptor de Serotonina/uso terapêutico , Adulto Jovem
7.
Headache ; 59(9): 1597-1608, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31559638

RESUMO

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
8.
Headache ; 59(10): 1788-1801, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31529622

RESUMO

OBJECTIVE: To expand on available information on the efficacy of oral lasmiditan for the acute treatment of migraine with particular focus on the timing of the effect and on its impact on migraine-associated symptoms. BACKGROUND: Lasmiditan is a novel selective 5-hydroxytryptamine 1F receptor agonist that lacks vasoconstrictive activity. In 2 phase 3 studies, SAMURAI and SPARTAN, lasmiditan met primary and key secondary efficacy endpoints at 2 hours following initial dose. METHODS: Integrated analyses were completed from 2 phase 3 clinical trials, SPARTAN and SAMURAI. Baseline data and data collected every 30 minutes up to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to determine the onset of efficacy. A total of 5236 patients were randomized to be treated with placebo (N = 1493), lasmiditan 50 mg (N = 750), lasmiditan 100 mg (N = 1498), or lasmiditan 200 mg (N = 1495). Data were analyzed to determine the onset of improvement for the following efficacy measures: pain freedom, most bothersome symptom freedom, pain relief, freedom from associated individual symptoms (photophobia, phonophobia, or nausea), total migraine freedom (defined as pain freedom and freedom from associated symptoms), and freedom from migraine-related functional disability. Time to meaningful headache relief and time to first become pain free were also analyzed. RESULTS: Significantly higher rates of pain freedom (100 mg, 10.0%, P = .012; 200 mg, 15.5%, P < .001; Placebo, 7.0%) and total migraine freedom (100 mg, 8.9%, P = .017; 200 mg, 12.4%, P < .001; Placebo, 6.1%) were achieved starting at 60 minutes in 100- and 200-mg lasmiditan-treated groups compared with placebo group. Rates of freedom from most bothersome symptom (100 mg, 11.1%, P = .015; 200 mg, 13.0%, P < .001; Placebo, 7.9%), and pain relief (100 mg, 17.5%, P = .007; 200 mg, 19.1%, P < .001; Placebo, 13.4%) were significantly higher starting as early as 30 minutes in lasmiditan 100- and 200-mg lasmiditan-treated groups. A significantly higher percentage of patients in the 200-mg lasmiditan-treated group achieved freedom from photophobia (13.7%, P = .005; Placebo, 9.2%) and phonophobia (17.4%, P = .042; Placebo, 13.4%) starting at 30 minutes. A significantly greater proportion of patients in the 200-mg lasmiditan-treated group achieved freedom from migraine-related functional disability starting at 60 minutes (16.4%, P < .001; Placebo, 11.1%). All efficacy measures, except for freedom from nausea, were statistically significant after lasmiditan treatment (50, 100, or 200 mg) compared with placebo at 90 and 120 minutes. Finally, patients taking lasmiditan had a higher likelihood of achieving meaningful headache relief and becoming headache pain free within 24 hours compared with those taking placebo (P < .001). CONCLUSIONS: Patients treated with lasmiditan for a migraine attack reported an earlier onset of efficacy compared with those treated with placebo. Some of the efficacy measures such as pain relief demonstrated improvement as early as the first assessment at 30 minutes after 100- or 200-mg lasmiditan treatment.


Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Administração Oral , Adulto , Benzamidas/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Resultado do Tratamento
9.
J Headache Pain ; 20(1): 90, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464581

RESUMO

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
10.
Cephalalgia ; 39(11): 1343-1357, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433669

RESUMO

OBJECTIVES: To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year. METHODS: In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit. RESULTS: As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time. CONCLUSIONS: The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186.


Assuntos
Benzamidas/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Agonistas do Receptor de Serotonina/uso terapêutico , Adolescente , Adulto , Idoso , Benzamidas/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Estudos Prospectivos , Piridinas/efeitos adversos , Resultado do Tratamento , Adulto Jovem
11.
J Pharmacokinet Pharmacodyn ; 46(5): 485-498, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432345

RESUMO

We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defecation frequency in slow transit constipation while avoiding the onset of diarrhea. Model sensitivity analysis predicted that changes in HAPC frequency and liquid secretion have the greatest impact on colonic motility. However, exclusively increasing the liquid secretion can lead to diarrhea. In contrast, increasing HAPC frequency alone can enhance bowel frequency without leading to diarrhea. The quantitative systems pharmacology approach used here demonstrates how mechanistic modeling of disease pathophysiology expands our understanding of biology and supports judicious hypothesis generation for therapeutic intervention.


Assuntos
Colo/fisiologia , Desenvolvimento de Medicamentos/métodos , Motilidade Gastrointestinal/fisiologia , Modelos Biológicos , Constipação Intestinal/complicações , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/fisiopatologia , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/uso terapêutico
12.
Int J Mol Sci ; 20(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336820

RESUMO

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient "druglikeness" properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1-4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.


Assuntos
Receptores de Serotonina/química , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Triazinas/química , Triazinas/farmacologia , Animais , Disfunção Cognitiva/tratamento farmacológico , Dopamina/química , Dopamina/farmacologia , Células HEK293 , Humanos , Ligantes , Masculino , Memória/efeitos dos fármacos , Redes e Vias Metabólicas , Estrutura Molecular , Ratos , Receptores de Serotonina/metabolismo , Serotonina/química , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico
13.
Cephalalgia ; 39(12): 1569-1576, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31266353

RESUMO

BACKGROUND: Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT1F agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose. STUDY DESIGN AND METHODS: Data from the similarly designed, Phase 3, double-blind studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were pooled to more precisely estimate efficacy effects in these post-hoc analyses. In both studies, inclusion criteria were 3-8 migraine attacks per month and Migraine Disability Assessment Score of ≥ 11 (at least moderate disability). Patients were randomized equally to lasmiditan 200 mg, 100 mg, 50 mg (50 mg only in SPARTAN), or to placebo. The study drug was to be taken within 4 hours of onset of pain for non-improving headache of at least moderate severity. Sustained pain freedom was defined as being pain free at 2 hours and at the given time point (24 or 48 hours) post-dose without use of additional study drug or migraine medications. Sustained responses were assessed similarly for most bothersome symptom-free, total migraine-free, and disability-free outcomes. For comparisons with previously published data on other acute medications, an additional endpoint of modified sustained pain freedom at 24 hours was defined as being pain free at 2 hours and no moderate-to-severe headache at 24 hours post-dose without use of additional study drug or migraine medications. RESULTS: Significantly higher proportions of patients treated with lasmiditan versus placebo achieved headache pain freedom at 2 hours post-dose: 200 mg: 35.6%; 100 mg: 29.9%; 50 mg: 28.6%; placebo: 18.3% (all p < 0.001). Sustained pain freedom was significantly higher in patients treated with lasmiditan versus placebo at 24 hours: 200 mg: 21.2%; 100 mg: 16.9%; 50 mg: 17.4%; placebo: 10.3% (all p < 0.01); and at 48 hours: 200 mg: 18.4%; 100 mg: 15.2%; 50 mg: 14.9%; placebo: 9.6% (all p < 0.05). Similar sustained benefits of lasmiditan versus placebo at 24 and 48 hours were noted for most bothersome symptom-free, total migraine-free and disability-free responses. Modified sustained pain freedom at 24 hours was also observed in significantly higher proportions of lasmiditan-treated patients versus placebo: 200 mg: 27.0%; 100 mg: 21.7%; 50 mg: 21.7%; placebo: 12.9% (all p < 0.01). CONCLUSION: Sustained responses at 24 and 48 hours were noted in significantly more patients treated with lasmiditan versus placebo for several efficacy outcomes including pain freedom, most bothersome symptom-free, total migraine-free and disability-free responses. CLINICALTRIALS.GOV IDENTIFIER NUMBERS: SAMURAI: NCT02439320; SPARTAN: NCT02605174.


Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Brain ; 142(7): 1894-1904, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132795

RESUMO

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.


Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Adulto , Benzamidas/efeitos adversos , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/complicações , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Fatores de Risco , Agonistas do Receptor de Serotonina/uso terapêutico , Fatores de Tempo , Adulto Jovem
16.
J Headache Pain ; 20(1): 54, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31096904

RESUMO

BACKGROUND: The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs are currently being developed, among which the small molecule CGRP receptor antagonists, gepants, and the 5-HT1F receptor agonist lasmiditan. Whether treatment with these drugs carries the same risk for developing MOH is currently unknown. MAIN BODY: Pathophysiological studies on MOH in animal models have suggested that decreased 5-hydroxytryptamine (5-HT, serotonin) levels, increased calcitonin-gene related peptide (CGRP) expression and changes in 5-HT receptor expression (lower 5-HT1B/D and higher 5-HT2A expression) may be involved in MOH. The decreased 5-HT may increase cortical spreading depression frequency and induce central sensitization in the cerebral cortex and caudal nucleus of the trigeminal tract. Additionally, low concentrations of 5-HT, a feature often observed in MOH patients, could increase CGRP expression. This provides a possible link between the pathways of 5-HT and CGRP, targets of lasmiditan and gepants, respectively. Since lasmiditan is a 5-HT1F receptor agonist and gepants are CGRP receptor antagonists, they could have different risks for developing MOH because of the different (over) compensation mechanisms following prolonged agonist versus antagonist treatment. CONCLUSION: The acute treatment of migraine will certainly improve with the advent of two novel classes of drugs, i.e., the 5-HT1F receptor agonists (lasmiditan) and the small molecule CGRP receptor antagonists (gepants). Data on the effects of 5-HT1F receptor agonism in relation to MOH, as well as the effects of chronic CGRP receptor blockade, are awaited with interest.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos da Cefaleia Secundários/induzido quimicamente , Transtornos da Cefaleia Secundários/prevenção & controle , Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Humanos , Uso Excessivo de Medicamentos Prescritos/prevenção & controle , Agonistas do Receptor de Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/farmacologia
17.
Schizophr Res ; 209: 135-140, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31101513

RESUMO

We conducted a 24-week, randomized, double-blind parallel-controlled trial to test whether buspirone is beneficial to improve cognitive deficits of schizophrenia because it remains unclear. Two hundred patients received in random order either co-treatment buspirone with AAPDs or monotherapy with AAPDs. All patients had been treated with a stable dosage of AAPDs for at least three months. The positive and negative syndrome scale (PANSS), Hamilton Depression Scale-24 (HAMD-24), and 14-item Hamilton Rating Scale for Anxiety (HAMA-14) were used to evaluate clinical symptoms. The short version of Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC) was used to assess neurocognitive function. Social function and family burden were evaluated by Social Disability Screening Schedule (SDSS) and Family Burden Interview Schedule (FBIS). All patients were enrolled at baseline and followed up after 12 and 24 weeks. A total of 196 patients completed the trial, with 99 in the combined treatment group and 97 in the control group. During the intervention, the score of PANSS, HAMD-24, and HAMA-14 decreased slightly without group differences. Repeated measures ANOVA showed significant differences between the two groups in the score of arithmetic, similarities, picture completion, block design, SDSS, and FBIS (P < 0.05), but no difference was found with regard to the score of information, digital span test, or digital symbols (P > 0.05). In conclusion, co-treatment with buspirone and APPDs outperformed APPDs alone in improving cognitive deficit and reducing family burden of schizophrenia. Buspirone may be a promising candidate for co-treatment of schizophrenia-associated cognitive deficits.


Assuntos
Antipsicóticos/uso terapêutico , Buspirona/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Agonistas do Receptor de Serotonina/uso terapêutico , Adolescente , Adulto , Ansiedade/psicologia , Cognição , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Depressão/psicologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/complicações , Esquizofrenia/fisiopatologia , Resultado do Tratamento , Escalas de Wechsler , Adulto Jovem
18.
Adv Emerg Nurs J ; 41(2): 150-162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31033663

RESUMO

Migraine headaches account for approximately 1.2 million emergency department (ED) visits annually. Despite the prevalence of this condition, there is little consensus on the best pharmacotherapeutic interventions to use in the ED setting. Guidelines published by the American Headache Society and the Canadian Headache Society offer some direction to ED providers but are not widely utilized. This article reviews the best evidence behind some of the medications frequently used to treat acute migraines in the ED setting, including dopamine receptor antagonists, serotonin receptor agonists, anti-inflammatory medications, opioids, magnesium, valproate, and propofol. The evaluation of patients presenting to the ED with an acute headache, the diagnostic criteria for migraines, and implications for advanced practice are also discussed.


Assuntos
Dor Aguda/diagnóstico , Dor Aguda/tratamento farmacológico , Serviço Hospitalar de Emergência , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Dor Aguda/enfermagem , Dor Aguda/fisiopatologia , Corticosteroides/uso terapêutico , Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Humanos , Magnésio/uso terapêutico , Transtornos de Enxaqueca/enfermagem , Transtornos de Enxaqueca/fisiopatologia , Medição da Dor , Propofol/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Ácido Valproico/uso terapêutico
19.
Eur J Med Chem ; 170: 261-275, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30904783

RESUMO

The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, Ki 5-HT7R = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain Cmax = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.


Assuntos
Imidazóis/química , Imidazóis/farmacocinética , Indóis/química , Indóis/farmacocinética , Neuralgia/tratamento farmacológico , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Células HEK293 , Halogenação , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Indóis/administração & dosagem , Indóis/uso terapêutico , Masculino , Camundongos , Modelos Moleculares , Neuralgia/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/uso terapêutico
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