RESUMEN
Zavegepant, a high-affinity, selective, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is approved in the United States for acute treatment of migraine in adults. The effects of moderate hepatic impairment (8 participants with Child-Pugh score 7-9 points) on the pharmacokinetics of a single 10-mg intranasal dose of zavegepant versus eight matched participants with normal hepatic function were evaluated in a phase I study. Pharmacokinetic sampling determined total and unbound plasma zavegepant concentrations. Moderate hepatic impairment increased the exposure of total zavegepant (~2-fold increase in AUC0-inf and 16% increase in Cmax) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC0-inf and Cmax were 193% (90% confidence interval [CI]: 112, 333; p = 0.051) and 116% (90% CI: 69, 195; p = 0.630), respectively. The geometric mean fraction unbound of zavegepant was similar for participants with moderate hepatic impairment (0.13; coefficient of variation [CV] 13.71%) versus those with normal hepatic function (0.11; CV 21.43%). Similar exposure findings were observed with unbound zavegepant versus normal hepatic function (~2.3-fold increase in AUC0-inf and 39% increase in Cmax). One treatment-emergent adverse event (mild, treatment-related headache) was reported in a participant with normal hepatic function. No dosage adjustment of intranasal zavegepant is required in adults with mild or moderate hepatic impairment.
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Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Humanos , Masculino , Femenino , Persona de Mediana Edad , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacocinética , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Adulto , Trastornos Migrañosos/tratamiento farmacológico , Anciano , Hepatopatías/metabolismo , Administración Intranasal , Área Bajo la Curva , Azepinas/farmacocinética , Azepinas/administración & dosificación , Azepinas/efectos adversos , Hígado/metabolismo , Hígado/efectos de los fármacosRESUMEN
Purpose: This study compared the efficacy, tolerability, and safety of rimegepant 75 mg oral tablet - a small molecule calcitonin-gene receptor peptide (CGRP) receptor antagonist - with placebo in the acute treatment of migraine. Methods: This double-blind, randomized, placebo-controlled trial enrolled adults aged ≥18 years with at least a 1-year history of migraine. Participants randomized to rimegepant 75 mg oral tablet or placebo treated a single migraine attack of moderate or severe pain intensity. The coprimary endpoints, pain freedom and freedom from the most bothersome symptom ([MBS] nausea, photophobia, or phonophobia) at 2 hours postdose, were evaluated using Mantel-Haenszel risk estimation. Results: Of the 1485 participants enrolled, 1162 (78.2%) were randomized to rimegepant (n = 582) or placebo (n = 580). Most participants (85.5%) were female; the population had a mean (SD) age of 41.6 (12.2) years and a history of 4.7 (1.8) migraine attacks per month. At 2 hours postdose, rimegepant-treated participants had higher pain freedom rates (19.2% [104/543] vs 14.2% [77/541]; risk difference 4.9; 95% confidence interval [CI] 0.5 to 9.3; P=0.0298) and MBS freedom rates (36.6% [199/543] vs 27.7% [150/541]; risk difference 8.9; 95% CI 3.4 to 14.4; P=0.0016) than placebo-treated participants. Rimegepant-treated participants also had higher rates of pain relief (56.0% [304/543] vs 45.7% [247/541]; risk difference 10.3; 95% CI 4.4 to 16.2, P=0.0006) at 2 hours postdose. The most common adverse events were nausea (0.9% [5/546] vs 1.1% [6/549]) and dizziness (0.7% [4/546] vs 0.4% [2/549]). No signal of drug-induced liver injury due to rimegepant was identified. Conclusion: Rimegepant 75 mg oral tablet was effective in the acute treatment of migraine. Tolerability and safety were similar to placebo, with no evidence of hepatotoxicity. Trial Registration: Clinicaltrials.gov Identifier: NCT03235479.
Researchers wanted to know if rimegepant 75 mg is effective and safe for the acute treatment of migraine. They gave half the participants rimegepant and half placebo and waited 2 hours. Then, they measured the percentages of participants whose headache and most bothersome migraine symptom besides pain (nausea, sensitivity to light or sound) were gone. They also measured side effects to make sure rimegepant is safe. The study included 1084 adults with migraine, 927 (86%) of whom were women. Two hours after taking the medicine: pain freedom was 19% with rimegepant and 14% with placebo. Freedom from the most bothersome symptom was 37% with rimegepant and 28% with placebo. Pain relief rates, defined as the transition from moderate or severe pain to pain that was mild or absent, occurred in 56% with rimegepant and 46% with placebo. The most common side effects were nausea and dizziness, which affected fewer than 1% of rimegepant patients. Rimegepant 75 mg was more effective than placebo for migraine, with similar tolerability and safety.
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PURPOSE: With epilepsy increasingly affecting older adults, seizure-related care needs arise in new settings. Persons in these settings must receive optimal support and challenges identified for remediation. This may entail the epilepsy community researching in unfamiliar environments. One setting is care homes. Seizure-related ambulance incidents in them are common. We conducted the first qualitative study with care home staff to explore their experiences and challenges in managing suspected seizures. METHODS: Three online focus groups were organised for January 2024 to explore ambulance calls, post-incident procedures, and challenges faced by care home staff when managing seizures. Persons were eligible to participate if they worked as a care assistant, nurse or manager in a care home in North-West England. Different recruitment pathways were employed including direct approach, a managers' network, social media and a register of research interested homes. Focus group audio recordings were transcribed and analysed using Hamilton's Rapid Analysis. RESULTS: Recruitment was difficult; 13 care home staff from 12 different homes were ultimately recruited. Despite data saturation not being achieved, insights were gained regarding ambulance call decisions, paperwork navigation, and follow-up care challenges. Patients not having meaningful seizure action plans in place and regulatory restrictions were identified as factors that contributed to potentially avoidable calls for ambulance help being made. CONCLUSION: This study highlights systemic issues in care homes' seizure care, emphasizing the need for further research. The epilepsy community may need to innovate to better research within this increasingly important setting. This study offers insights into the effectiveness of different recruitment strategies.
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Epilepsia , Grupos Focales , Convulsiones , Humanos , Inglaterra , Epilepsia/terapia , Convulsiones/terapia , Masculino , Femenino , Adulto , Investigación Cualitativa , Personal de Salud/psicología , Persona de Mediana Edad , AmbulanciasRESUMEN
Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.
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Relación Dosis-Respuesta a Droga , Electrocardiografía , Voluntarios Sanos , Frecuencia Cardíaca , Rociadores Nasales , Humanos , Masculino , Electrocardiografía/efectos de los fármacos , Adulto , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Método Doble Ciego , Adulto Joven , Persona de Mediana Edad , Azepinas/farmacocinética , Azepinas/administración & dosificación , Azepinas/efectos adversos , Administración Intranasal , Síndrome de QT Prolongado/inducido químicamente , AdolescenteRESUMEN
INTRODUCTION: Adults presenting to the ambulance service for diagnosed epilepsy are often transported to emergency departments (EDs) despite no clinical need. An alternative care pathway (CP) could allow paramedics to divert them from ED and instigate ambulatory care improvements. To identify the most promising CP configuration for subsequent testing, the COLLABORATE project surveyed people with epilepsy and family/friends who had recently used the English ambulance service to elicit preferences for 288 CP configurations for different seizures. This allowed CPs to be ranked according to alignment with service users' preferences. However, as well as being acceptable to users, a CP must be feasible. We thus engaged with paramedics, epilepsy specialists and commissioners to identify the optimal configuration. METHODS: Three Knowledge Exchange workshops completed. Participants considered COLLABORATE's evidence on service users' preferences for the different configurations. Nominal group techniques elicited views on the feasibility of users' preferences according to APEASE criteria. Workshop groups specified the configuration/s considered optimum. Qualitative data was analysed thematically. Utility to users of the specified CP configurations estimated using the COLLABORATE preference survey data. RESULTS: Twenty-seven participants found service users' preferences broadly feasible and outlined delivery recommendations. They identified enough commonality in preferences for different seizures to propose a single CP. Its configuration comprised: 1) patients staying where they were; 2) paramedics having access to medical records; 3) care episodes lasting <6 h; 4) paramedics receiving specialist advice on the day; 5) patient's GP being notified; and 6) a follow-up appointment being arranged with an epilepsy specialist. Preference data indicated higher utility for this configuration compared to current care. DISCUSSION: Stakeholders are of the view that the CP configuration favoured by service users could be NHS feasible. It should be developed and evaluated.
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Ambulancias , Epilepsia , Estudios de Factibilidad , Prioridad del Paciente , Humanos , Adulto , Epilepsia/terapia , Femenino , Masculino , Servicios Médicos de Urgencia , Persona de Mediana Edad , Atención Ambulatoria , Servicio de Urgencia en HospitalRESUMEN
A single-center, phase I, partially double-blind (double-blind regarding doses of rimegepant and placebo, and open label with respect to moxifloxacin), randomized, 12-sequence, four-period crossover study of therapeutic (75 mg) and supratherapeutic (300 mg) doses of rimegepant with placebo and moxifloxacin (400 mg) controls was designed to evaluate drug effect on the Fridericia corrected QT (QTcF) interval in healthy fasted adults. A total of 38 participants were randomized and dosed in the study. Electrocardiogram (ECG) data were available from 37 participants in the rimegepant 75-mg group, 38 participants in the rimegepant 300-mg group, and 36 participants in the moxifloxacin and placebo groups. Both the 75- and 300-mg doses of rimegepant had no clinically relevant effect on ECG parameters, including QTcF, heart rate, PR and QRS interval, T-wave morphology, and U-wave presence. All upper 90% confidence intervals for the QTcF effect with rimegepant were less than or equal to 4.69 ms, well below the 10-ms threshold for potential clinical significance. Assay sensitivity was demonstrated by the QT effect of moxifloxacin. Using both by-timepoint and concentration-QTc analysis, a placebo-corrected change-from-baseline QTcF greater than 10 ms could be excluded for rimegepant plasma concentrations up to ~10,000 ng/mL, representing concentrations at least 10.8-fold the maximum observed concentration of the 75-mg therapeutic dose of rimegepant.
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Electrocardiografía , Piperidinas , Piridinas , Adulto , Humanos , Estudios Cruzados , MoxifloxacinoRESUMEN
INTRODUCTION: The aim of this study was to gain consensus among young people with a stoma due to inflammatory bowel disease (IBD) on the priorities for the content of an intervention for the self-management of stoma-related distress. The current identification and management of distress in young people with a stoma is often suboptimal in clinical settings and there is a need for improved support resources. METHODS: Two consensus group meetings were carried out via online video conferencing, using nominal group technique. Participants generated, rated on a Likert scale and discussed, topics for inclusion in a future self-management intervention. RESULTS: Nineteen young people, aged 19-33, with a stoma due to IBD took part in one of two group meetings. Participants were located across England, Scotland, and Northern Ireland. Twenty-nine topics were generated by participants, seven of which reached consensus of ≥80%, that is, a mean of ≥5.6 on a 7-point Likert scale. These were: receiving advice from young people with lived experience of stoma surgery; advice on/addressing concerns about romantic relationships, sex and intimacy; information about fertility and pregnancy related to stoma surgery; stoma 'hacks', for example, useful everyday tips regarding clothing, making bag changes easier and so forth; reflecting on and recognising own emotional response to surgery; tips on managing the stoma during the night; and processing trauma related to the illness and surgery journey. CONCLUSIONS: Findings extend previous research on young people's experiences of stoma surgery, by generating consensus on young people's priorities for managing distress related to surgery and living with a stoma. These priorities include topics not previously reported in the literature, including the need for information about fertility and pregnancy. Findings will inform the development of a self-management resource for young people with an IBD stoma and have relevance for the clinical management of stoma-related distress in this population. PATIENT OR PUBLIC CONTRIBUTION: Three patient contributors are co-authors on this paper, having contributed to the study design, interpretation of results and writing of the manuscript. The study's Patient and Public Involvement and Engagement advisory group also had an integral role in the study. They met with the research team for four 2-h virtual meetings, giving input on the aims and purpose of the study, recruitment methods, and interpretation of findings. The group also advised on the age range for participants. The views of young people with a stoma are the central component of the study reported in this paper, which aims to gain consensus among young people with an IBD stoma on their priorities for the content of a resource to self-manage distress related to stoma surgery.
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Enfermedades Inflamatorias del Intestino , Automanejo , Femenino , Embarazo , Humanos , Adolescente , Emociones , Consenso , Inglaterra , Enfermedades Inflamatorias del Intestino/cirugía , Enfermedades Inflamatorias del Intestino/psicologíaRESUMEN
Rimegepant is a calcitonin gene-related peptide receptor antagonist approved for migraine treatment. This phase 1, open-label, single-center, fixed-sequence study evaluated the effect of rimegepant on the pharmacokinetics (PK) of metformin. Twenty-eight healthy participants received metformin 500 mg twice daily from Days 1 to 4 and Days 7 to 10, and once daily on Days 5 and 11. Rimegepant, 75 mg tablet, was administered once daily from Days 9 to 12. At pre-specified time points, plasma metformin concentration, serum glucose levels, and safety and tolerability were evaluated. A 16% increase in the area under the plasma metformin concentration-time curve (AUC) for 1 dosing interval (AUC0-τ,ss), a statistically insignificant increase in maximum and minimum steady-state metformin concentration (Cmax,ss and Cmin,ss), and a decrease in metformin renal clearance were observed on Day 11 following metformin-rimegepant coadministration compared with metformin alone; however, the changes were not clinically relevant. Additionally, coadministration of rimegepant with metformin did not induce clinically meaningful change in the maximum observed glucose concentration (Gmax) or AUCgluc compared with metformin alone. Overall, rimegepant and metformin coadministration did not result in clinically relevant changes in metformin PK, renal clearance, or the antihyperglycemic effects of metformin. Rimegepant is considered safe for use with metformin.
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Área Bajo la Curva , Interacciones Farmacológicas , Voluntarios Sanos , Hipoglucemiantes , Metformina , Proteínas de Transporte de Catión Orgánico , Transportador 2 de Cátion Orgánico , Piperidinas , Piridinas , Humanos , Metformina/farmacocinética , Metformina/administración & dosificación , Metformina/farmacología , Masculino , Adulto , Femenino , Proteínas de Transporte de Catión Orgánico/metabolismo , Adulto Joven , Piridinas/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacología , Piridinas/efectos adversos , Piperidinas/farmacocinética , Piperidinas/administración & dosificación , Piperidinas/farmacología , Piperidinas/efectos adversos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Transportador 2 de Cátion Orgánico/metabolismo , Persona de Mediana Edad , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacocinética , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Transporte BiológicoRESUMEN
PURPOSE: Suspected seizures present challenges for ambulance services, with paramedics reporting uncertainty over whether or not to convey individuals to emergency departments. The Risk of ADverse Outcomes after a Suspected Seizure (RADOSS) project aims to address this by developing a risk assessment tool utilizing structured patient care record and dispatch data. It proposes a tool that would provide estimates of an individual's likelihood of death and/or recontact with emergency care within 3 days if conveyed compared to not conveyed, and the likelihood of an 'avoidable attendance' occurring if conveyed. Knowledge Exchange workshops engaged stakeholders to resolve key design uncertainties before model derivation. METHOD: Six workshops involved 26 service users and their significant others (epilepsy or nonepileptic attack disorder), and 25 urgent and emergency care clinicians from different English ambulance regions. Utilizing Nominal Group Techniques, participants shared views of the proposed tool, benefits and concerns, suggested predictors, critiqued outcome measures, and expressed functionality preferences. Data were analysed using Hamilton's Rapid Analysis. RESULTS: Stakeholders supported tool development, proposing 10 structured variables for predictive testing. Emphasis was placed on the tool supporting, not dictating, care decisions. Participants highlighted some reasons why RADOSS might struggle to derive a predictive model based on structured data alone and suggested some non-structured variables for future testing. Feedback on prediction timeframes for service recontact was received, along with advice on amending the 'avoidable attendance' definition to prevent the tool's predictions being undermined by potential overuse of certain investigations in hospital. CONCLUSION: Collaborative stakeholder engagement provided crucial insights that can guide RADOSS to develop a user-aligned, optimized tool.
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Servicios Médicos de Urgencia , Humanos , Servicios Médicos de Urgencia/métodos , Ambulancias , Servicio de Urgencia en Hospital , Convulsiones/diagnóstico , Convulsiones/terapia , Medición de RiesgoRESUMEN
Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine ± aura and preventive treatment of migraine in adults. The pharmacokinetics of rimegepant in elderly and nonelderly subjects were evaluated. In an open-label Phase 1 study, 14 elderly (aged 65 years or older) and 14 nonelderly (aged 18 to less than 45 years) subjects each received a single oral dose of rimegepant 75 mg. Blood samples were collected before dosing and through 96 hours after dosing. The pharmacokinetic parameters of rimegepant after a single dose were similar in both age groups. Geometric least-squares mean ratios (elderly/nonelderly) of the natural log-transformed maximum observed plasma concentration and natural log-transformed area under the plasma concentration-time curve from time 0 extrapolated to infinity were 96.6 and 104.6, respectively. Eight (28.6%) subjects (4 elderly, 4 nonelderly) experienced 1 or more adverse events (AEs); all AEs were mild in intensity, and no serious AEs or AEs leading to discontinuation were reported. Following a single 75-mg dose of oral rimegepant, pharmacokinetic parameters were similar in elderly and nonelderly adults; no dose adjustment is warranted in elderly subjects.
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Trastornos Migrañosos , Piperidinas , Adulto , Anciano , Humanos , Área Bajo la Curva , Piperidinas/efectos adversos , Piridinas/efectos adversos , Trastornos Migrañosos/tratamiento farmacológicoRESUMEN
BACKGROUND: Rimegepant is an oral, small molecule calcitonin gene-related peptide receptor antagonist for acute treatment of migraine and migraine prevention. METHODS: This was a single-site, placebo-controlled, sequential, single and multiple ascending dose study in healthy males and females, aged 18-55 years, with no clinically significant medical history. The objectives were to assess the safety, tolerability, and pharmacokinetics of the oral capsule free-base formulation. Single oral doses of rimegepant from 25-1500 mg were evaluated in the single ascending dose phase, and 75-600 mg/day doses administered for 14 days were evaluated in the multiple ascending dose phase. RESULTS: No dose-related trends were observed in orthostatic systolic and diastolic blood pressure or heart rate after rimegepant administration. Rimegepant was rapidly absorbed with the median time of maximum observed plasma concentration from 1-3.5 hours. Rimegepant showed a more than dose-proportional increase in exposure from 25-1500 mg following a single dose and from 75-600 mg/day following multiple doses. CONCLUSIONS: Rimegepant was safe and generally well tolerated at single oral doses up to 1500 mg and multiple doses up to 600 mg/day for 14 days in healthy participants in this study. Median terminal half-life ranged from 8-12 hours across the wide range of single doses studied.
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Trastornos Migrañosos , Masculino , Femenino , Humanos , Voluntarios Sanos , Método Doble Ciego , Relación Dosis-Respuesta a Droga , Administración Oral , Trastornos Migrañosos/tratamiento farmacológicoRESUMEN
OBJECTIVE: To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non-menopausal females with tubal ligation. BACKGROUND: Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti-migraine medications and contraceptives. Rimegepant, a calcitonin gene-related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. METHODS: This open-label, single-center, phase 1, drug-drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non-menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration-time curve for 1 dosing interval (AUC0-τ,ss ) and maximum observed concentration (Css[max] ). RESULTS: The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co-administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01-1.06; and GMR, 1.16; 90% CI, 1.13-1.20, respectively). After 8 days of co-administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0-τ,ss and Css(max) , increased by 20% (GMR, 1.20; 90% CI, 1.16-1.25) and 34% (GMR, 1.34; 90% CI, 1.23-1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39-1.52) and 40% (GMR, 1.40; 90% CI, 1.30-1.51), respectively. CONCLUSIONS: The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine.
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Anticonceptivos Orales Combinados , Etinilestradiol , Femenino , Humanos , Anticonceptivos Orales Combinados/efectos adversos , Anticonceptivos Orales Combinados/farmacocinética , Etinilestradiol/farmacocinética , PiridinasRESUMEN
Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist (gepant) with demonstrated efficacy and safety in the acute and preventive treatment of migraine. Here, we report the pharmacokinetics and safety of a single 75-mg oral dose of rimegepant in subjects with severe, moderate, or mild hepatic impairment and matched healthy subjects from an open-label, single-dose, 4-group phase 1 study. Thirty-six subjects aged 41-71 years were enrolled, including 6 each with severe, moderate, or mild hepatic impairment and 18 healthy subjects. All subjects completed the study. A <20% increase in total and unbound pharmacokinetics was observed in subjects with mild hepatic impairment and ≤65% increase with moderate hepatic impairment versus matched healthy controls. Total and unbound systemic exposure increased 2.0- and 3.9-fold in the severe hepatic impairment group. In subjects with severe hepatic impairment, geometric mean ratios (severe impairment/controls) for total concentrations were 202.2% for area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, 202.2% for area under the plasma concentration-time curve from time 0 to infinity, and 189.1% for maximum observed plasma concentration. Corresponding geometric mean ratios using unbound concentrations were 388.8% and 388.7%, respectively. Three (8.3%) subjects reported 4 treatment-emergent adverse events. Rimegepant is not recommended for use in adults with severe hepatic impairment.
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Hepatopatías , Adulto , Humanos , Área Bajo la Curva , Hepatopatías/tratamiento farmacológico , Piperidinas/efectos adversosRESUMEN
BACKGROUND: This post-hoc analysis from three phase 3 treatment trials of rimegepant 75 mg - an oral small molecule calcitonin gene-related peptide receptor antagonist for acute and preventive treatment of migraine - assessed efficacy in adults with migraine based on triptan treatment experience. METHODS: Participants were assigned to one of four groups based on triptan treatment experience: insufficient response (e.g. lack of efficacy and/or poor tolerability) to 1 triptan, insufficient response to ≥2 triptans, current triptan users, and triptan-naïve participants. The co-primary efficacy endpoints were pain freedom and most bothersome symptom freedom at two hours postdose. RESULTS: In the three trials (N = 3507; rimegepant n = 1749, placebo n = 1758), 1235 (35.2%) participants had a history of insufficient response to 1 triptan (n = 910 [25.9%]) or ≥2 triptans (n = 325 [9.3%]), and 2272 (64.8%) had no history of insufficient response to triptans (current use = 595 [17.0%], naïve = 1677 [47.8%]). Rimegepant was effective on the co-primary endpoints in all subgroups (p ≤ 0.013), except for freedom from the most bothersome symptom in the triptan-naïve group (p = 0.06). No differences on co-primary endpoints were found in pairwise comparisons of rimegepant-treated participants. CONCLUSIONS: Rimegepant was effective for the acute treatment of migraine in adults with a history of insufficient response to 1 or ≥2 triptans and in current triptan users. Efficacy on co-primary endpoints did not differ based on the number of insufficient triptan responses.Trial registration: Clinicaltrials.gov: NCT03235479, NCT03237845, NCT03461757.
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Trastornos Migrañosos , Triptaminas , Adulto , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Piperidinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Triptaminas/uso terapéutico , Ensayos Clínicos Fase III como AsuntoRESUMEN
We report a fatal infection in a 65-year-old immunocompromised male patient caused by pan-triazole-resistant Aspergillus fumigatus containing a TR34/L98H genetic mutation linked to agricultural fungicide use. Clinical and environmental surveillance of triazole-resistant A. fumigatus is needed in the United States to prevent spread and guide healthcare and agricultural practices.
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Aspergillus fumigatus , Fungicidas Industriales , Anciano , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Aspergillus fumigatus/genética , Azoles , Sistema Enzimático del Citocromo P-450/genética , Farmacorresistencia Fúngica/genética , Proteínas Fúngicas/genética , Fungicidas Industriales/farmacología , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Pennsylvania , Triazoles/farmacologíaRESUMEN
BACKGROUND: High rates of asymptomatic infections with COVID-19 have been reported. OBJECTIVE: We aimed to describe an asymptomatic COVID-19 testing protocol in a pediatric emergency department (ED). METHODS: This was a retrospective cohort study of pediatric patients (younger than 18 years) who were tested for COVID-19 via the asymptomatic testing protocol at a single urban pediatric ED between May 2020 and January 2021. This included all pediatric patients undergoing admission, urgent procedures, and psychiatric facility placement. The primary outcome was the percentage of positive COVID-19 tests. COVID-19 testing was performed via real-time polymerase chain reaction RNA assay testing. County-level COVID-19 data were used to estimate local daily COVID-19 cases/100,000 individuals (from all ages). Data were described with simple descriptive statistics. RESULTS: There were 1459 children tested for COVID-19 under the asymptomatic protocol. Mean ± standard deviation age was 8.2 ± 5.8 years. Two tests were inconclusive and 29 (2.0%; 95% confidence interval [CI] 1.3-2.8%) were positive. Of the 29 positive cases, 14 (48%; 95% CI 29-67%) had abnormal vital signs or signs and symptoms of COVID-19, on retrospective review. A total of 15 truly asymptomatic infections were identified. On the days that asymptomatic cases were identified, the lowest average daily community rate was 7.67 cases/100,000 individuals. CONCLUSIONS: Asymptomatic COVID-19 positivity rates in the pediatric ED were low when the average daily community rate was fewer than 7.5 cases/100,000 individuals. In the current pandemic, ED clinicians should assess for signs and symptoms of COVID-19, even when children present to the ED with unrelated chief symptoms.
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COVID-19 , Humanos , Niño , Preescolar , Adolescente , COVID-19/diagnóstico , Prueba de COVID-19 , Infecciones Asintomáticas/epidemiología , SARS-CoV-2 , Estudios Retrospectivos , Servicio de Urgencia en HospitalRESUMEN
OBJECTIVES: To explore patients' experiences of living with inflammatory bowel disease (IBD) with a focus on their information and support needs. METHODS: Qualitative interview study involving adults diagnosed with IBD recruited through social media. Interviews were audio recorded, transcribed and data were analysed thematically. RESULTS: Interviews with 15 patients (9 females, 6 males) highlighted how misdiagnosis or hesitation to diagnose had caused frustration and anxiety. Once diagnosed, only a few participants received detailed information about IBD from their doctor. Negative experiences shared on social media caused initial anxiety, as individuals assumed that they may have a similar experience, yet online communities enabled insights into the experiences of others, helping patients adjust to living with IBD. Participants described both positive and negative impacts of living with IBD, including improved confidence and periods of anxiety.Discussion: Our findings highlight the importance of clear information and support from health professionals, as well as the benefits of online communities for ongoing support. At the point of diagnosis, patients would benefit from information about what IBD is, as well as how it may impact day to day life from doctors so that social media is not the only source of initial information about IBD.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Medios de Comunicación Sociales , Adulto , Enfermedad Crónica , Femenino , Humanos , Masculino , Investigación Cualitativa , Apoyo SocialRESUMEN
BACKGROUND: Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment. METHODS: In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered. RESULTS: A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection. CONCLUSIONS: Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).
Asunto(s)
Analgésicos/uso terapéutico , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Piperidinas/uso terapéutico , Piridinas/uso terapéutico , Administración Oral , Adulto , Analgésicos/efectos adversos , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/complicaciones , Náusea/inducido químicamente , Piperidinas/efectos adversos , Placebos/uso terapéutico , Piridinas/efectos adversosRESUMEN
STUDY OBJECTIVE: We evaluate the effect of decreasing county mental health services on the emergency department (ED). METHODS: This is a retrospective before-and-after study at a Level I academic university hospital adjacent to the county mental health treatment center. On October 1, 2009, the county decreased its inpatient psychiatric unit from 100 to 50 beds and closed its outpatient unit. Electronic health record data were collected for ED visits for the 8 months before the decrease in county services (October 2008 to May 2009) and the 8 months after the decrease (October 2009 to May 2010). Data for all adult patients (≥18 years) evaluated for a psychiatric consultation by a licensed clinical social worker were included. Outcome measures included the number of patients evaluated and the ED length of stay for those patients. RESULTS: One thousand three hundred ninety-two patient visits included a psychiatry consultation for the study period. The median age was 38 years (interquartile range [IQR] 27, 49), with no difference in age between periods. The mean number of daily psychiatry consultations increased from 1.3 (95% confidence interval [CI] 1.2 to 1.5) before closure to 4.4 (95% CI 4.1 to 4.7) afterward, with a difference in means of 3.0 visits (95% CI 2.7 to 3.3 visits). Average ED length of stay for psychiatry consultation patients was 14.1 hours (95% CI 13.1 to 15.0 hours) before closure and 21.9 hours (95% CI 20.7 to 23.2 hours) afterward, with a difference in means of 7.9 hours (95% CI 5.5 to 10.2 hours). CONCLUSION: The number of visits and length of stay for patients undergoing psychiatric consultation in the ED increased significantly after a decrease in county mental health services. This phenomenon has important implications for future policy to address the challenges of caring for patients with psychiatric needs in our communities.