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1.
Sleep Med ; 80: 100-104, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33588260

RESUMO

Patients with delayed sleep-wake phase disorder (DSWPD) suffer from difficulties in sleep initiation at night, difficulties in waking up at the socially required time, and daytime somnolence. About half of the patients resist conventional light therapy and melatonin therapy. Therapy using hypnotics is not recommended due to its adverse effects. Recently, suvorexant, an orexin receptor antagonist, has become available for clinical use. The drug is relatively safer than traditional hypnotics such as benzodiazepines. We report three DSWPD patients who were successfully treated by the combination therapy of suvorexant and ramelteon. The first case was a 19-year-old woman who was experiencing difficulties in sleep initiation, difficulty in waking up in the morning, and daytime somnolence. She showed a prompt response to the combination therapy of suvorexant and ramelteon. Her sleep phase advanced, and her daytime somnolence reduced. The second and third cases were 21-year-old and 17-year-old men, respectively, who also showed significant sleep phase advances. Although case 2 was resistant to ramelteon treatment, his sleep phase advanced after suvorexant started. His difficulty in falling asleep and his habit of daytime napping disappeared after the combination therapy of suvorexant and ramelteon was started. Case 3 also showed a prompt response. His difficulties in falling asleep and waking up in the morning were ameliorated immediately after suvorexant with ramelteon was started. No obvious side effects were observed. Therapy using the combination therapy of suvorexant and ramelteon might be a reasonable option for DSWPD patients.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Distúrbios do Início e da Manutenção do Sono , Adulto , Azepinas/efeitos adversos , Feminino , Humanos , Indenos , Masculino , Sono , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis , Adulto Jovem
3.
Br J Cancer ; 124(4): 744-753, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33311588

RESUMO

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. METHODS: We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. RESULTS: Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. CONCLUSIONS: This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. CLINICAL TRIALS REGISTRATION: NCT01987362.


Assuntos
Azepinas/administração & dosagem , Azepinas/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Proteínas Nucleares/metabolismo , Proteínas/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Azepinas/sangue , Azepinas/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Linfoma Difuso de Grandes Células B/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/efeitos adversos , Bibliotecas de Moléculas Pequenas/farmacocinética
4.
Cochrane Database Syst Rev ; 11: CD009178, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33189083

RESUMO

BACKGROUND: Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering, and daytime sleepiness are common clinical problems in dementia, and are associated with significant carer distress, increased healthcare costs, and institutionalisation. Although non-drug interventions are recommended as the first-line approach to managing these problems, drug treatment is often sought and used. However, there is significant uncertainty about the efficacy and adverse effects of the various hypnotic drugs in this clinically vulnerable population. OBJECTIVES: To assess the effects, including common adverse effects, of any drug treatment versus placebo for sleep disorders in people with dementia. SEARCH METHODS: We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, on 19 February 2020, using the terms: sleep, insomnia, circadian, hypersomnia, parasomnia, somnolence, rest-activity, and sundowning. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared a drug with placebo, and that had the primary aim of improving sleep in people with dementia who had an identified sleep disturbance at baseline. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on study design, risk of bias, and results. We used the mean difference (MD) or risk ratio (RR) with 95% confidence intervals (CI) as the measures of treatment effect, and where possible, synthesised results using a fixed-effect model. Key outcomes to be included in our summary tables were chosen with the help of a panel of carers. We used GRADE methods to rate the certainty of the evidence. MAIN RESULTS: We found nine eligible RCTs investigating: melatonin (5 studies, n = 222, five studies, but only two yielded data on our primary sleep outcomes suitable for meta-analysis), the sedative antidepressant trazodone (1 study, n = 30), the melatonin-receptor agonist ramelteon (1 study, n = 74, no peer-reviewed publication), and the orexin antagonists suvorexant and lemborexant (2 studies, n = 323). Participants in the trazodone study and most participants in the melatonin studies had moderate-to-severe dementia due to Alzheimer's disease (AD); those in the ramelteon study and the orexin antagonist studies had mild-to-moderate AD. Participants had a variety of common sleep problems at baseline. Primary sleep outcomes were measured using actigraphy or polysomnography. In one study, melatonin treatment was combined with light therapy. Only four studies systematically assessed adverse effects. Overall, we considered the studies to be at low or unclear risk of bias. We found low-certainty evidence that melatonin doses up to 10 mg may have little or no effect on any major sleep outcome over eight to 10 weeks in people with AD and sleep disturbances. We could synthesise data for two of our primary sleep outcomes: total nocturnal sleep time (TNST) (MD 10.68 minutes, 95% CI -16.22 to 37.59; 2 studies, n = 184), and the ratio of day-time to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03; 2 studies; n = 184). From single studies, we found no evidence of an effect of melatonin on sleep efficiency, time awake after sleep onset, number of night-time awakenings, or mean duration of sleep bouts. There were no serious adverse effects of melatonin reported. We found low-certainty evidence that trazodone 50 mg for two weeks may improve TNST (MD 42.46 minutes, 95% CI 0.9 to 84.0; 1 study, n = 30), and sleep efficiency (MD 8.53%, 95% CI 1.9 to 15.1; 1 study, n = 30) in people with moderate-to-severe AD. The effect on time awake after sleep onset was uncertain due to very serious imprecision (MD -20.41 minutes, 95% CI -60.4 to 19.6; 1 study, n = 30). There may be little or no effect on number of night-time awakenings (MD -3.71, 95% CI -8.2 to 0.8; 1 study, n = 30) or time asleep in the day (MD 5.12 minutes, 95% CI -28.2 to 38.4). There were no serious adverse effects of trazodone reported. The small (n = 74), phase 2 trial investigating ramelteon 8 mg was reported only in summary form on the sponsor's website. We considered the certainty of the evidence to be low. There was no evidence of any important effect of ramelteon on any nocturnal sleep outcomes. There were no serious adverse effects. We found moderate-certainty evidence that an orexin antagonist taken for four weeks by people with mild-to-moderate AD probably increases TNST (MD 28.2 minutes, 95% CI 11.1 to 45.3; 1 study, n = 274) and decreases time awake after sleep onset (MD -15.7 minutes, 95% CI -28.1 to -3.3: 1 study, n = 274) but has little or no effect on number of awakenings (MD 0.0, 95% CI -0.5 to 0.5; 1 study, n = 274). It may be associated with a small increase in sleep efficiency (MD 4.26%, 95% CI 1.26 to 7.26; 2 studies, n = 312), has no clear effect on sleep latency (MD -12.1 minutes, 95% CI -25.9 to 1.7; 1 study, n = 274), and may have little or no effect on the mean duration of sleep bouts (MD -2.42 minutes, 95% CI -5.53 to 0.7; 1 study, n = 38). Adverse events were probably no more common among participants taking orexin antagonists than those taking placebo (RR 1.29, 95% CI 0.83 to 1.99; 2 studies, n = 323). AUTHORS' CONCLUSIONS: We discovered a distinct lack of evidence to guide decisions about drug treatment of sleep problems in dementia. In particular, we found no RCTs of many widely prescribed drugs, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks for these common treatments. We found no evidence for beneficial effects of melatonin (up to 10 mg) or a melatonin receptor agonist. There was evidence of some beneficial effects on sleep outcomes from trazodone and orexin antagonists and no evidence of harmful effects in these small trials, although larger trials in a broader range of participants are needed to allow more definitive conclusions to be reached. Systematic assessment of adverse effects in future trials is essential.


Assuntos
Doença de Alzheimer/complicações , Transtornos do Sono-Vigília/tratamento farmacológico , Azepinas/efeitos adversos , Azepinas/uso terapêutico , Fardo do Cuidador/tratamento farmacológico , Cognição/efeitos dos fármacos , Humanos , Indenos/efeitos adversos , Indenos/uso terapêutico , Melatonina/efeitos adversos , Melatonina/uso terapêutico , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sono/efeitos dos fármacos , Sono/fisiologia , Transtornos do Sono-Vigília/etiologia , Fatores de Tempo , Trazodona/efeitos adversos , Trazodona/uso terapêutico , Triazóis/efeitos adversos , Triazóis/uso terapêutico
5.
PLoS One ; 15(9): e0238723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32916693

RESUMO

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.


Assuntos
Acidentes por Quedas , Azepinas/efeitos adversos , Indenos/efeitos adversos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Azepinas/administração & dosagem , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Estudos Cross-Over , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Indenos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sono/efeitos dos fármacos , Sono/fisiologia , Triazóis/administração & dosagem
6.
Medicine (Baltimore) ; 99(30): e21043, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791676

RESUMO

BACKGROUND: Delirium is a frequently encountered complication, which is associated with increased mortality. Suvorexant, an approved agent for the treatment of insomnia, is recently suggested to be also effective for prevention of delirium by some authors. However, a consensus has yet to be reached. The goal of this study was to perform a meta-analysis to overall estimate the effectiveness of suvorexant in preventing delirium and its related consequences. METHODS: Eligible studies were identified by searching online databases of PubMed, EMBASE, and Cochrane Library. The pooled OR was calculated for binary outcomes (e.g., the incidence of delirium, mortality, or adverse events), while standardized mean difference (SMD) were expressed for continuous outcomes (e.g., time to delirium onset, length of stay in hospital and ICU, time on ventilation). RESULTS: Seven studies which comprised 402 suvorexant treatment patients and 487 patients with control treatment were included in this meta-analysis. Overall, pooled analysis indicated the incidence of delirium could be significantly reduced (OR, 0.30; P < .001) and time to delirium onset was significantly lengthened (SMD, 0.44; P = .006) in patients undergoing suvorexant treatment compared with controls. Suvorexant had no beneficial effects on the secondary outcomes [length of stay in hospital (SMD, -0.65; P = .161) and ICU (SMD, 0.34; P = .297), time on ventilation (SMD, 1.09; P = .318), drug-related adverse events (OR, drug-related adverse events (OR, 1.66; P = .319) and mortality (OR, 2.21; P = .261)]. Subgroup analysis also confirmed the benefit of suvorexant on the development of delirium, which was significant in any subgroup. CONCLUSION: Suvorexant should be recommended for the prevention of delirium in clinic.


Assuntos
Azepinas/uso terapêutico , Delírio/prevenção & controle , Medicamentos Indutores do Sono/uso terapêutico , Triazóis/uso terapêutico , Azepinas/efeitos adversos , Humanos , Tempo de Internação , Mortalidade , Respiração Artificial , Medicamentos Indutores do Sono/efeitos adversos , Fatores de Tempo , Triazóis/efeitos adversos
7.
J Crit Care ; 59: 1-5, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32480359

RESUMO

PURPOSE: To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization. MATERIALS AND METHODS: Pubmed (1946 to December 2019) and Embase (1947 to December 2019) were queried using the search term combination: delirium, confusion, cognitive defect, encephalopathy, critically ill patient, critical illness, or hospitalization and suvorexant or orexin receptor antagonist. Studies analyzed for relevance evaluated clinical outcomes of patients treated with suvorexant for prevention of delirium. Studies appropriate to the objective were evaluated, including two randomized controlled trials and four retrospective studies. RESULTS: In acutely hospitalized patients, treatment with suvorexant 15 to 20 mg alone or in combination with ramelteon resulted in a reduction in development of delirium, time until delirium onset, and length of hospital stay. When assessed, suvorexant was well tolerated and adverse effects were no worse than placebo. CONCLUSION: Based on the reviewed literature, suvorexant has shown positive outcomes in the prevention of delirium during an acute hospitalization. Larger trials comparing the efficacy of suvorexant to other sleep modulating options are necessary to further delineate its role for the prevention of delirium.


Assuntos
Azepinas/administração & dosagem , Azepinas/efeitos adversos , Cuidados Críticos/métodos , Delírio/prevenção & controle , Tempo de Internação , Antagonistas dos Receptores de Orexina/administração & dosagem , Antagonistas dos Receptores de Orexina/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Quimioterapia Combinada , Feminino , Humanos , Indenos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Estudos Retrospectivos , Sono/efeitos dos fármacos , Resultado do Tratamento
8.
Biol Pharm Bull ; 43(6): 925-931, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32475914

RESUMO

We investigated whether use of hypnotic drugs, including benzodiazepine receptor agonists, as well as ramelteon and suvorexant are associated with fall incidents in elderly inpatients aged no less than 75 years, who were hospitalized at an acute care general hospital in Japan, between November 1st, 2016 and October 31st, 2017. Multivariate analysis results were reported as odds ratio (OR) with 95% confidence interval (CI). Following to a case-crossover study protocol, the time windows of the case and the control days were assigned to the day or the days, which are one day or 2-8 d before the fall incidents, respectively. In the enrolled 111 patients, the accumulated total available numbers of the cases and the control days were 111 and 554 patient days, respectively. Hypnotic drug use was significantly associated with fall incidents (OR: 2.85, 95% CI: 1.03-7.90, p = 0.04). Especially benzodiazepine receptor agonists (OR: 5.79, 95% CI: 1.52-22.1, p = 0.01) showed statistically significant association with fall incidents. In contrast, neither ramelteon (OR: 7.95, 95% CI: 0.72-87.9, p = 0.09) nor suvorexant (OR: 0.25, 95% CI: 0.06-1.06, p = 0.06) were significantly associated with fall incidents. Thus, benzodiazepine receptor agonists, but not ramelteon or suvorexant, showed significant association with fall incidents. Therefore, special care should be taken especially when benzodiazepine receptor agonists are administrated to elderly subjects. In contrast, fall risk may be much less in patients treated with ramelteon or suvorexant. These results could help us to conduct safer drug treatment for insomnia patients aged no less than 75 years.


Assuntos
Acidentes por Quedas , Azepinas/efeitos adversos , Agonistas de Receptores de GABA-A/efeitos adversos , Hipnóticos e Sedativos/efeitos adversos , Indenos/efeitos adversos , Triazóis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Feminino , Hospitalização , Humanos , Japão , Masculino , Receptores de GABA-A , Fatores de Risco
9.
Curr Med Res Opin ; 36(3): 465-471, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31793350

RESUMO

Objective: Global Phase III trials of suvorexant showed no obvious differences in the safety and efficacy profile of suvorexant between elderly and non-elderly patients. However, the clinical profile of suvorexant in elderly patients with comorbidities in a real-world setting was not evaluated. To further understand the safety and efficacy profile of suvorexant in elderly patients with insomnia in a daily clinical practice setting, we conducted a sub-group analysis of the post-marketing drug-use results survey.Methods: Patients with insomnia who were treated with suvorexant for the first time were divided into three groups: group-1 (<65 years, N = 1490), group-2 (≥65 years and <75 years, N = 730), and group-3 (≥75 years, N = 1028).Results: The incidence of overall adverse drug reactions (ADRs) were 11.28% (N = 168), 8.63% (N = 63), and 8.17% (N = 84) in group-1, -2, and -3, respectively. The ADRs most commonly observed in this survey were somnolence, insomnia, and dizziness, with no new safety concerns or differences in safety issues found. The numbers of patients in group-1, -2, and -3 who visited internal medicine departments were: 690 patients (46.3%), 521 patients (71.4%), and 793 patients (77.1%), respectively. The percentage of patients who were deemed to have "improved", based on the patient's self-assessment and their physician's assessment, was 70-75% of patients in all groups.Conclusion: These results reveal the safety and efficacy profile of suvorexant in elderly patients who often have various and multiple comorbidities and were treated in a daily clinical practice setting.


Assuntos
Azepinas/administração & dosagem , Vigilância de Produtos Comercializados , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/administração & dosagem , Idoso , Azepinas/efeitos adversos , Tontura/induzido quimicamente , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Triazóis/efeitos adversos
10.
Lancet Haematol ; 7(2): e122-e133, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837959

RESUMO

BACKGROUND: Increased aurora A kinase (AAK) expression occurs in acute myeloid leukaemia; AAK inhibition is a promising therapeutic target in this disease. We therefore aimed to assess the activity of alisertib combined with 7 + 3 induction chemotherapy in previously untreated patients with high-risk acute myeloid leukaemia. METHODS: We did a single-arm, phase 2 trial of patients recruited from the Dana-Farber/Harvard Cancer Center in the USA. Eligible patients had previously untreated acute myeloid leukaemia, an Eastern Cooperative Oncology Group performance status of 0-2, and were at high risk of disease as defined by the presence of an adverse-risk karyotype, the presence of secondary acute myeloid leukaemia arising from previous myelodysplastic syndrome or myeloproliferative neoplasm, the presence of therapy-related acute myeloid leukaemia, or being 65 years or older. Enrolled patients received 7 + 3 induction chemotherapy of continuous infusion of cytarabine (100 mg/m2 per day on days 1-7) and intravenous bolus of idarubicin (12 mg/m2 per day on days 1-3). Oral alisertib (30 mg) was given twice per day on days 8-15. Patients could receive up to four consolidation cycles with cytarabine and alisertib, and alisertib maintenance for 12 months. The primary endpoint was a composite including the proportion of patients achieving complete remission and those with a complete remission with incomplete neutrophil or platelet count recovery. Analyses were per-protocol. This study is registered with Clinicaltrials.gov, number NCT02560025, and has completed enrolment. FINDINGS: Between Dec 31, 2015, and Aug 1, 2017, we enrolled a total of 39 eligible patients. 19 (49%) of 39 patients had secondary acute myeloid leukaemia and three (8%) had therapy-related acute myeloid leukaemia. At mid-induction, 33 (85%) of 39 patients showed marrow aplasia, six (15%) received re-induction. The median follow-up was 13·7 months (IQR 12·7-14·4). Composite remission was 64% (two-stage 95% CI 48-79), with 20 (51%) of 39 patients achieving complete remission and five (13%) achieving complete remission with incomplete neutrophil or platelet count recovery. The most common grade 3 or 4 adverse events included febrile neutropenia (16 [41%] of 39), neutropenia (12 [31%]), thrombocytopenia (13 [33%]), anaemia (11 [28%]), anorexia (nine [23%]), and oral mucositis (four [10%]). No treatment-related deaths were observed. INTERPRETATION: These results suggest that alisertib combined with induction chemotherapy is active and safe in previously untreated patients with high-risk acute myeloid leukaemia. This study met criteria to move forward to a future randomised trial. FUNDING: Millennium Pharmaceuticals.


Assuntos
Azepinas/administração & dosagem , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Pirimidinas/administração & dosagem , Idoso , Azepinas/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Seguimentos , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Fatores de Risco
13.
Expert Opin Drug Saf ; 18(11): 1109-1118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478753

RESUMO

Objectives: Suvorexant is a dual orexin receptor antagonist used for treating insomnia. The authors elucidated the safety profiles and clinical course of insomnia therapy with suvorexant under different initial treatment status seen in daily routine practice. Methods: Subgroup analysis of a post-marketing survey (PMS; 2015-2017) divided patients based on their initial treatment status with suvorexant into 'hypnotic-naïve (Group N)', 'switching from a prior sleep medication (Group S),' 'add-on therapy (Group A),' and 'others (Group O).' Results: Among 3248 patients analyzed in the PMS, the number of patients in Groups N, S, A, and O was 1946 (59.9%), 703 (21.6%), 536 (16.5%), and 63 (1.9%), respectively. The incidence of insomnia-related adverse drug reactions (ADRs) in Group S (5.3%) tended to be higher than that in Groups N (0.46%) and A (1.5%). Discontinuation rate due to an inadequate effect at 6 months in Group S (14.9%) tended to be higher than that in Groups N (9.6%) and A (10.4%). Conclusion: The results suggest that initiating suvorexant treatment after switching from other insomnia medication must require careful monitoring of insomnia-related ADRs, which might be due to abrupt discontinuation of the prior insomnia medication use.


Assuntos
Azepinas/uso terapêutico , Antagonistas dos Receptores de Orexina/uso terapêutico , Medicamentos Indutores do Sono/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/uso terapêutico , Idoso , Azepinas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Vigilância de Produtos Comercializados , Estudos Prospectivos , Medicamentos Indutores do Sono/efeitos adversos , Inquéritos e Questionários , Resultado do Tratamento , Triazóis/efeitos adversos
14.
Adv Ther ; 36(9): 2450-2462, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31267367

RESUMO

INTRODUCTION: Hepatitis B viral capsid assembly is an attractive target for new antiviral treatments. JNJ-56136379 (JNJ-6379) is a potent capsid assembly modulator in vitro with a dual mode of action. In Part 1 of this first-in-human study in healthy adults, the pharmacokinetics (PK), safety and tolerability of JNJ-6379 were evaluated following single ascending and multiple oral doses. METHODS: This was a double-blind, randomized, placebo-controlled study in 30 healthy adults. Eighteen subjects were randomized to receive single doses of JNJ-6379 (25 to 600 mg) or placebo. Twelve subjects were randomized to receive 150 mg JNJ-6379 or placebo twice daily for 2 days, followed by 100 mg JNJ-6379 or placebo daily for 10 days. RESULTS: The maximum observed plasma concentration and the area under the curve increased dose proportionally from 25 to 300 mg JNJ-6379. Following multiple dosing, steady-state conditions were achieved on day 8. Steady-state clearance was similar following single and multiple dosing, suggesting time-linear PK. All adverse events (AEs) reported were mild to moderate in severity. There were no serious AEs or dose-limiting toxicities and no apparent relationship to dose for any AE. CONCLUSION: JNJ-6379 was well tolerated in this study. Based on the safety profile and plasma exposures of JNJ-6379 in healthy subjects, a dosing regimen was selected for Part 2 of this study in patients with chronic hepatitis B. This is anticipated to achieve trough plasma exposures of JNJ-6379 at steady state of more than three times the 90% effective concentration of viral replication determined in vitro. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02662712. FUNDING: Janssen Pharmaceutica.


Assuntos
Antivirais/administração & dosagem , Azepinas/farmacologia , Capsídeo/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Piperidinas/farmacologia , Adulto , Área Sob a Curva , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos
15.
Neuropsychopharmacol Rep ; 39(3): 252-255, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31283862

RESUMO

AIM: There have been no previous reports on the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders. METHODS: This one-week, prospective, single-arm, clinical trial of fixed dose of suvorexant (20 mg if ages 18-64 or 15 mg if age ≥ 65 years) for insomnia included 57 patients with psychiatric disorders who had experienced any of the following insomnia symptoms for four or more nights during the week prior to the start of the study: total sleep time (TST) <6 hours, time to sleep onset (TSO) ≥30 minutes, or two or more episodes of wake after sleep onset. RESULTS: The mean age of the patients was 49.4 ± 17.3 years; 54.4% were women, 49.1% had a major depressive disorder, and 77.2% completed the trial. Compared with the baseline scores (the mean scores for the two days before the start of the study), taking suvorexant was associated with significant improvements in TST, TSO, wake time after sleep onset, and the patients' sleep satisfaction level at week 1. Adverse events included at least one adverse event (43.9%), sleepiness (28.8%), fatigue (11.5%), nightmares (5.8%), headache (3.8%), dizziness (3.8%), and vomiting (1.9%). CONCLUSION: Suvorexant was beneficial for the treatment of insomnia in people with psychiatric disorders. However, this study was of short duration and included only a relatively small number of patients. A larger, long-term study is needed to investigate the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders.


Assuntos
Azepinas/uso terapêutico , Transtornos Mentais/complicações , Medicamentos Indutores do Sono/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/uso terapêutico , Adulto , Idoso , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/complicações , Triazóis/administração & dosagem , Triazóis/efeitos adversos
16.
J Clin Hypertens (Greenwich) ; 21(7): 896-903, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30874378

RESUMO

Orexins are neuropeptides that play a role in maintaining wakefulness and contribute to central regulation of cardiovascular function. This first multicenter, randomized, double-blind study investigated the effects of suvorexant, a reversible dual orexin receptor antagonist, on nighttime blood pressure (BP) in patients with insomnia and hypertension. After a 4-week run-in period, adult outpatients (n = 82) with treated hypertension (clinic SBP <160 mm Hg) and insomnia were treated with suvorexant 20 mg/d or placebo before bedtime for 2 weeks. Twenty-four-hour ambulatory BP monitoring was performed at baseline and the end of treatment, and home BP measurements (morning and evening) were taken daily. Nighttime systolic BP (SBP), the primary endpoint, decreased slightly from baseline to week 2 in both the suvorexant and placebo groups (-4.4 vs -1.8 mm Hg; P = 0.494). Clinic, 24-hour, daytime and morning SBP (ambulatory blood pressure monitoring) also decreased slightly and similarly from baseline in both groups. In this study, suvorexant had no overall effect on BP in patients with insomnia and treated hypertension.


Assuntos
Azepinas , Monitorização Ambulatorial da Pressão Arterial/métodos , Hipertensão , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis , Anti-Hipertensivos/uso terapêutico , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/administração & dosagem , Antagonistas dos Receptores de Orexina/efeitos adversos , Medicamentos Indutores do Sono/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/efeitos adversos
17.
Drug Des Devel Ther ; 13: 809-816, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880914

RESUMO

Purpose: Although patients with suspected obstructive sleep apnea (OSA) might suffer difficulty in falling asleep during overnight polysomnography (PSG), standard hypnotics to obtain sleep during PSG have not been established. The aim of this study was to investigate the safety and efficacy of a new hypnotic agent, suvorexant, a dual orexin receptor antagonist, for insomnia in suspected OSA patients during in-laboratory PSG. Patients and methods: An observational study was conducted during PSG for 149 patients with suspected OSA who had no insomnia at home. Patients with difficulty in falling asleep during PSG were optionally permitted to take single-use suvorexant. Patients with residual severe insomnia (>1 hour) after taking suvorexant were permitted to take an add-on use zolpidem. Clinical data and sleep questionnaire results were analyzed between a no insomnia group (without hypnotics) and an insomnia group (treated with suvorexant). Results: Among 84 patients who experienced insomnia during PSG and required hypnotics (the insomnia group; treated with suvorexant), 44 (52.4%) achieved sufficient subjective sleep with single-use of suvorexant, while the other 40 (47.6%) required suvorexant plus zolpidem. An apnea hypopnea index (AHI) of ≥5 was observed in 144 out of 149 patients with predominantly obstructive respiratory events. Among those patients, 70.8% in the no insomnia group and 63.1% in the insomnia group had severe OSA. Regarding both subjective sleep time and morning mood, significant differences between the no insomnia group and the insomnia group were not observed. No patient taking suvorexant had an adverse event, such as delirium or falling. Conclusion: Single-use suvorexant seems to be a safe and effective (but mild) hypnotic agent for suspected OSA patients with insomnia during in-laboratory PSG.


Assuntos
Azepinas/administração & dosagem , Azepinas/uso terapêutico , Polissonografia/métodos , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/uso terapêutico , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Azepinas/efeitos adversos , Humanos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos
18.
J Clin Oncol ; 37(8): 613-623, 2019 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-30707661

RESUMO

PURPOSE: The aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS: Adult patients with relapsed/refractory PTCL-one or more prior therapy-were randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m2 (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m2 or intravenous romidepsin 14 mg/m2 (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned. RESULTS: Between May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm. CONCLUSION: In patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm.


Assuntos
Antineoplásicos/uso terapêutico , Aurora Quinase A/antagonistas & inibidores , Azepinas/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Aurora Quinase A/metabolismo , Azepinas/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/enzimologia , Linfoma de Células T Periférico/mortalidade , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Recidiva , Fatores de Tempo , Adulto Jovem
19.
Clin Cancer Res ; 25(11): 3229-3238, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777875

RESUMO

PURPOSE: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). PATIENTS AND METHODS: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. RESULTS: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 µmol/L, exceeding the 1 µmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. CONCLUSIONS: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.


Assuntos
Antineoplásicos/uso terapêutico , Azepinas/uso terapêutico , Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Azepinas/farmacocinética , Biomarcadores Tumorais , Criança , Pré-Escolar , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Leucemia/diagnóstico , Leucemia/mortalidade , Masculino , Camundongos , Imagem Multimodal , Neoplasias/diagnóstico , Neoplasias/mortalidade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Recidiva , Retratamento , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
20.
Ann Thorac Cardiovasc Surg ; 25(1): 26-31, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30089761

RESUMO

OBJECTIVE: Suvorexant is an orexin receptor antagonist and is effective in inducing sleep. We hypothesized that Suvorexant would reduce the incidence of postoperative delirium (POD) after coronary artery bypass grafting (CABG). METHODS: We reviewed 88 patients (12 women, mean age: 69.3 ± 2.5 years) who were undergone CABG alone. Patients were divided into two groups; patients received Suvorexant (S group, n = 36), patients not received Suvorexant (N group, n = 52), and the following data were analyzed and compared between two groups. RESULTS: Intensive Care Unit Delirium Screening Checklist Score was significantly lower in S group compared with N group (N:S = 2.0 ± 1.7:0.8 ± 1.0, p = 0.0003). Although POD was present in 11 of 52 patients (21.2%) in N group, one patient (2.8%) developed in S group (p = 0.008). In S group, both intensive care unit stay (N:S = median 6:5 days, p = 0.001) and hospital stay (N:S = median 23:20 days, p = 0.035) were significantly shorter than in N group. CONCLUSIONS: Suvorexant might reduce incidence of POD in patients undergone CABG.


Assuntos
Azepinas/administração & dosagem , Ponte de Artéria Coronária/efeitos adversos , Delírio/prevenção & controle , Antagonistas dos Receptores de Orexina/administração & dosagem , Triazóis/administração & dosagem , Idoso , Azepinas/efeitos adversos , Lista de Checagem , Delírio/diagnóstico , Delírio/psicologia , Esquema de Medicação , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Triazóis/efeitos adversos
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