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2.
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
4.
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
5.
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
6.
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
7.
Invest New Drugs ; 37(4): 666-673, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30397836

RESUMO

Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [14C]-alisertib oral solution (~80 µCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography-tandem mass spectrometry, and mass balance/recovery of [14C]-radioactivity in urine and feces by liquid scintillation counting. Part B; patients received non-radiolabeled alisertib 50 mg as enteric-coated tablets twice-daily for 7 days in 21-day cycles. Results In part A, absorption was fast (median plasma Tmax, 1 h) for alisertib and TRA. Mean plasma t1/2 for alisertib and TRA were 23.4 and 42.0 h, respectively. Mean plasma alisertib/TRA AUC0-inf ratio was 0.45, indicating presence of alisertib metabolites in circulation. Mean TRA blood/plasma AUC0-last ratio was 0.60, indicating preferential distribution of drug-related material in plasma. On average, 87.8% and 2.7% of administered radioactivity was recovered in feces and urine, respectively (total recovery, 90.5% by 14 days post-dose). In part B, patients received a median 3 cycles of alisertib. The most common any-grade adverse events were fatigue and alopecia. Conclusions Findings suggest that alisertib is eliminated mainly via feces, consistent with hepatic metabolism and biliary excretion of drug-related material. Further investigation of alisertib pharmacokinetics in patients with moderate-severe hepatic impairment is warranted to inform dosing recommendations in these patient populations.


Assuntos
Antineoplásicos/farmacocinética , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacocinética , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/urina , Azepinas/efeitos adversos , Azepinas/sangue , Azepinas/urina , Fezes/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/urina , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/urina
8.
JAMA Oncol ; 5(1): e183773, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347019

RESUMO

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azepinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azepinas/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Europa (Continente) , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Pirimidinas/efeitos adversos , Fatores de Tempo , Estados Unidos
9.
Clin Cancer Res ; 25(1): 43-51, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30232224

RESUMO

PURPOSE: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. PATIENTS AND METHODS: Sixty men were treated with alisertib 50 mg twice daily for 7 days every 21 days. Eligibility included metastatic prostate cancer and at least one: small-cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; or elevated serum neuroendocrine markers. The primary endpoint was 6-month radiographic progression-free survival (rPFS). Pretreatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed. RESULTS: Median PSA was 1.13 ng/mL (0.01-514.2), number of prior therapies was 3, and 68% had visceral metastases. Genomic alterations involved RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%), and AR (27%), and there was a range of androgen receptor signaling and NEPC marker expression. Six-month rPFS was 13.4% and median overall survival was 9.5 months (7.3-13). Exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity. Patient organoids exhibited concordant responses to alisertib and allowed for the dynamic testing of Aurora-N-myc complex disruption. CONCLUSIONS: Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.


Assuntos
Aurora Quinase A/genética , Azepinas/administração & dosagem , Carcinoma Neuroendócrino/tratamento farmacológico , Proteína Proto-Oncogênica N-Myc/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirimidinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Aurora Quinase A/antagonistas & inibidores , Azepinas/efeitos adversos , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Orquiectomia , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Pirimidinas/efeitos adversos , Receptores Androgênicos/genética , Transdução de Sinais/efeitos dos fármacos
10.
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
12.
Clin Drug Investig ; 38(7): 631-638, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29705869

RESUMO

BACKGROUND AND OBJECTIVES: Suvorexant (MK-4305) is an orexin receptor antagonist approved for the treatment of insomnia in the USA and other regions. This randomized, double-blind, placebo-controlled, sequential-panel, Phase 1 trial assessed the safety, tolerability, and pharmacokinetic data following single and multiple dosing of suvorexant in healthy men (aged 18-45 years). METHODS: Within allocated panels, subjects (n = 8) were randomized to receive nightly doses of suvorexant (10, 20, 40, 80, and 100 mg) administered orally for 14 days, or placebo. Safety assessments included daily adverse event (AE) monitoring; pharmacokinetic data were obtained through periodic sampling. RESULTS: Of 40 subjects randomized, 39 completed the trial. The incidence of any AEs in the 10 and 20 mg groups was 67 and 83%, respectively, while 100% of subjects reported AEs in the dose groups of 40, 80, and 100 mg and the placebo group. The most frequently reported AEs were somnolence (n = 19 subjects), fatigue (n = 17), and headache (n = 15). Following single and multiple dosing, median time to reach maximum observed concentration ranged from 1.5 to 4.0 h and the apparent terminal half-life ranged from 7.7 to 14.5 h. Across the investigated doses, accumulation ratios for the area under the concentration-time curve and the maximum observed concentration were independent of dose and ranged from 1.21 to 1.60 and 1.00 to 1.46, respectively. CONCLUSIONS: Suvorexant was generally well tolerated after single and multiple dosing for 14 days. The findings support the once-nightly dosing regimen.


Assuntos
Azepinas/administração & dosagem , Azepinas/farmacocinética , Antagonistas dos Receptores de Orexina/administração & dosagem , Antagonistas dos Receptores de Orexina/farmacologia , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/farmacocinética , Triazóis/administração & dosagem , Triazóis/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Azepinas/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Fadiga/induzido quimicamente , Cefaleia/induzido quimicamente , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos , Adulto Jovem
14.
Eur J Clin Pharmacol ; 74(7): 939-943, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29568975

RESUMO

PURPOSE: The objective of this study was to evaluate the safety of brotizolam in hospitalized patients. METHODS: A single-center, comparative retrospective cohort analysis of patients hospitalized in internal medicine wards. Patients treated with brotizolam were compared to patients not treated with any benzodiazepines during hospitalization. Primary outcome was any of the following safety events: mechanical ventilation, delirium, and falls. RESULTS: Six hundred patients were included after exclusion in the final analysis; 300 treated with brotizolam (treatment) and 300 not treated with any benzodiazepines (comparator). The brotizolam-treated patients were older with more comorbidities and psychotropic medications. After adjustment using multivariate logistic regression analysis with propensity score, the primary outcomes occurred at significantly higher rates in treated patients than in untreated patients (17 vs. 2 events; OR = 7.33). Any psychotropic medication administered during hospitalization was found by logistic regression to be the main independent risk factor for the studied safety outcomes while age, comorbidities, and the cause of hospitalization were not. CONCLUSIONS: Treatment with brotizolam during hospitalization in internal medicine wards is linked to a higher risk of respiratory deterioration, delirium, and falls. Use of psychotropic medications during hospitalization is the main independent risk factor of safety outcomes. Further research is needed to fully evaluate the risks and benefits of sleep induction medications in hospitals.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Azepinas/efeitos adversos , Delírio/induzido quimicamente , Hospitalização/estatística & dados numéricos , Hipnóticos e Sedativos/efeitos adversos , Respiração Artificial/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
15.
J Psychiatr Pract ; 24(2): 104-110, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29509180

RESUMO

This column is the fifth in a series examining the advances being made in central nervous system drug development because of advances in molecular pharmacology and an improved understanding of the neurobiology underlying disturbances in brain function including psychiatric illnesses. This column covers the special animal and human studies conducted as part of the development of suvorexant, which is the first in the class of dual orexin 1 and 2 receptor antagonists to be approved; it has an indication for the treatment of disturbances in sleep onset and maintenance. The animal studies included determination of the therapeutic index of the drug (ie, lethal dose 50 which is the dose at which 50% of animals die following administration of the drug), adverse effects on fertility, teratogenicity, carcinogenicity, and ability to cause narcolepsy. The human studies included investigation of the effects of the drug on balance, memory, driving performance, and propensity to cause respiratory depression in normal volunteers and individuals with mild to moderate chronic obstructive pulmonary disorder or mild to moderate obstructive sleep apnea. This column illustrates how targeting the drug to one mechanism out of hundreds yields increased safety and highlights the importance of the package insert which summarizes the results of all of the studies from the drug's development program.


Assuntos
Azepinas/efeitos adversos , Fármacos do Sistema Nervoso Central/efeitos adversos , Aprovação de Drogas , Desenvolvimento de Medicamentos/métodos , Triazóis/efeitos adversos , Animais , Desenvolvimento de Medicamentos/normas , Feminino , Humanos , Masculino , Gravidez
16.
Psychogeriatrics ; 18(3): 209-215, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29423967

RESUMO

BACKGROUND: Benzodiazepine use is a risk factor for the development of delirium in adult intensive care unit (ICU) patients. Suvorexant is an alternative to benzodiazepines to induce sleep, but the incidence of delirium in critically ill patients is unknown. We undertook this retrospective study to investigate the incidence of delirium in patients who receive suvorexant in the ICU. METHODS: This retrospective cohort study was conducted in a closed 12-bed ICU at a tertiary teaching hospital. Patients admitted to the ICU for 72 h or longer between January and June 2015 were evaluated for delirium using the Confusion Assessment Method for the Intensive Care Unit tool. We evaluated the incidence of delirium in patients who received suvorexant and those who did not. To adjust for confounding factors, multivariable logistic regression analysis was conducted. RESULTS: Study subjects included 118 patients, with a median age of 72 years and a median Acute Physiology and Chronic Health Evaluation II score of 18 points. Eighty-two patients (69.5%) were admitted after cardiovascular surgery. In the suvorexant group, there were fewer post-cardiovascular surgical patients and more medical patients. The duration of mechanical ventilation during ICU stay was longer in the suvorexant group, and sedatives and sleep inducers other than suvorexant were used more frequently in the suvorexant group. The incidence of delirium was 43.8% in the suvorexant group and 58.8% in the non-suvorexant group (P = 0.149). After adjustment for risk factors using multivariable logistic regression analysis, suvorexant was associated with a lower incidence of delirium (odds ratio = 0.23, 95% confidence interval: 0.07-0.73; P = 0.012). CONCLUSIONS: Suvorexant was associated with decreased odds of transitioning to delirium in critically ill patients. The use of suvorexant may lower the incidence of delirium in ICU patients. Future prospective studies are warranted.


Assuntos
Azepinas/administração & dosagem , Delírio/induzido quimicamente , Unidades de Terapia Intensiva/estatística & dados numéricos , Antagonistas dos Receptores de Orexina/administração & dosagem , Medicamentos Indutores do Sono/administração & dosagem , Triazóis/administração & dosagem , Idoso , Azepinas/efeitos adversos , Ocupação de Leitos , Cuidados Críticos , Delírio/epidemiologia , Feminino , Humanos , Incidência , Japão/epidemiologia , Tempo de Internação , Masculino , Antagonistas dos Receptores de Orexina/efeitos adversos , Estudos Retrospectivos , Medicamentos Indutores do Sono/efeitos adversos , Resultado do Tratamento , Triazóis/efeitos adversos
17.
Breast Cancer Res Treat ; 168(3): 639-647, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29289986

RESUMO

PURPOSE: In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC). METHODS: In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant. RESULTS: Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3-not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0-87.2%). CONCLUSIONS: In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1-3, 8-10, and 15-17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.


Assuntos
Azepinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Pirimidinas/administração & dosagem , Idoso , Antineoplásicos Hormonais , Azepinas/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Receptor alfa de Estrogênio/genética , Feminino , Fulvestranto/administração & dosagem , Fulvestranto/efeitos adversos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Pós-Menopausa , Pirimidinas/efeitos adversos
18.
Expert Opin Investig Drugs ; 27(1): 105-112, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29260599

RESUMO

INTRODUCTION: Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Alisertib is an oral aurora kinase inhibitor which has been shown to induce cell-cycle arrest and apoptosis in preclinical studies. It is currently under investigation for a wide variety of malignancies including hematologic (specifically Non-Hodgkin's lymphoma) and solid tumors. Areas covered: A PubMed search was performed to identify clinical studies reporting outcomes with alisertib. Promising results are notable in patients with peripheral T cell lymphoma in particular, forming the basis for the first phase 3 randomized trial of alisertib. Although it did show encouraging response rates, it failed to demonstrate superiority over the comparator arm at an interim analysis, halting further enrollment. Expert opinion: Despite disappointing early results, alisertib remains under investigation in a number of cancer types both as monotherapy and in combination with traditional cytotoxic chemotherapy, with encouraging results. Most common toxicities in early trials include myelosuppression alopecia, mucositis and fatigue. The relatively manageable toxicity profile of alisertib along with ease of dosing may allow it to be combined with other oral agents or traditional chemotherapy across a wide variety of malignancy types.


Assuntos
Azepinas/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Aurora Quinase A/antagonistas & inibidores , Azepinas/efeitos adversos , Azepinas/farmacocinética , Humanos , Linfoma não Hodgkin/patologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto
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