RESUMO
OBJECTIVE: The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period. METHODS: A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose time points over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times. RESULTS: The mean difference in time-weighted (0-2.5 h) MAP (90% confidence interval) was 1.2 mmHg (-0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6h and C(max) of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels. CONCLUSION: Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.
Assuntos
Analgésicos/administração & dosagem , Azepinas/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Imidazóis/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Sumatriptana/administração & dosagem , Adulto , Azepinas/efeitos adversos , Azepinas/farmacocinética , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Sumatriptana/efeitos adversos , Sumatriptana/farmacocinética , Adulto JovemRESUMO
BACKGROUND: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC. PATIENTS AND METHODS: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab. CONCLUSIONS: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.
Assuntos
Antineoplásicos Imunológicos , Neoplasias Colorretais , Humanos , Anticorpos Monoclonais , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fadiga/induzido quimicamente , Inibidores de Checkpoint Imunológico , Repetições de Microssatélites , Receptor de Morte Celular Programada 1RESUMO
Essential tremor (ET) is a common movement disorder. Animal studies show that histaminergic modulation may affect the pathological processes involved in the generation of ET. Histamine-3 receptor inverse agonists (H3RIA) have demonstrated attenuating effects on ET in the harmaline rat model. In this double-blind, three-way cross-over, single-dose, double-dummy study the effects of 25 mg of a novel H3RIA (MK-0249) and a stable alcohol level (0.6 g L(-1)) were compared with placebo, in 18 patients with ET. Tremor was evaluated using laboratory tremorography, portable tremorography and a clinical rating scale. The Leeds Sleep Evaluation Questionnaire (LSEQ) and a choice reaction time (CRT) test were performed to evaluate potential effects on sleep and attention, respectively. A steady state of alcohol significantly diminished tremor as assessed by laboratory tremorography, portable tremorography and clinical ratings compared with placebo. A high single MK-0249 dose was not effective in reducing tremor, but caused significant effects on the LSEQ and the CRT test. These results suggest that treatment with a single dose of MK-0249 does not improve tremor in alcohol-responsive patients with ET, whereas stable levels of alcohol as a positive control reproduced the commonly reported tremor-diminishing effects of alcohol.
Assuntos
Tremor Essencial/tratamento farmacológico , Etanol/metabolismo , Agonistas dos Receptores Histamínicos/uso terapêutico , Quinazolinonas/uso terapêutico , Atenção/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Tremor Essencial/metabolismo , Feminino , Agonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinonas/farmacocinética , Tempo de Reação/efeitos dos fármacos , Receptores Histamínicos H3/metabolismoRESUMO
Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.
Assuntos
Angina Estável/tratamento farmacológico , Azepinas/uso terapêutico , Teste de Esforço/métodos , Imidazóis/uso terapêutico , Angina Estável/fisiopatologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Estudos Cross-Over , Método Duplo-Cego , Eletrocardiografia/métodos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Vasodilatadores/uso terapêuticoRESUMO
The alertness-promoting effect of MK-0249 (10 or 50 mg), a histamine subtype-3 receptor (HRH3) inverse agonist (IA), was evaluated in the stimulant reference sleep deprivation model (SRSDM) using a double-blind, double-dummy, placebo- and modafinil- (200 mg) controlled, four-period crossover design in 24 healthy young men. The two primary hypotheses were related to sleep latency (first appearance of one epoch of stage 2, 3, or 4 or REM sleep, as detected using polysomnography (PSG)) at 8:00 AM on day 2. Statistically significant increases in sleep latency were observed in association with the use of modafinil 200 mg (9.07 min; P < 0.0001), MK-0249 50 mg (5.17 min; P = 0.008), and MK-0249 10 mg (5.45 min; P = 0.005) at the maintenance of wakefulness test (MWT) at 8:00 AM. Sleep latency was higher when averaged over all MWT time points (P < 0.0001 for modafinil and for both doses of MK-0249). The alertness-promoting effect with the use of MK-0249 in the SRSDM suggests that HRH3 IAs may be effective in disorders involving excessive somnolence.