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1.
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
2.
Nat Biotechnol ; 38(3): 303-308, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31959954

RESUMO

Monitoring drug-target interactions with methods such as the cellular thermal-shift assay (CETSA) is well established for simple cell systems but remains challenging in vivo. Here we introduce tissue thermal proteome profiling (tissue-TPP), which measures binding of small-molecule drugs to proteins in tissue samples from drug-treated animals by detecting changes in protein thermal stability using quantitative mass spectrometry. We report organ-specific, proteome-wide thermal stability maps and derive target profiles of the non-covalent histone deacetylase inhibitor panobinostat in rat liver, lung, kidney and spleen and of the B-Raf inhibitor vemurafenib in mouse testis. In addition, we devised blood-CETSA and blood-TPP and applied it to measure target and off-target engagement of panobinostat and the BET family inhibitor JQ1 directly in whole blood. Blood-TPP analysis of panobinostat confirmed its binding to known targets and also revealed thermal stabilization of the zinc-finger transcription factor ZNF512. These methods will help to elucidate the mechanisms of drug action in vivo.


Assuntos
Sangue/metabolismo , Proteoma/química , Proteoma/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Azepinas/administração & dosagem , Azepinas/farmacologia , Células Hep G2 , Humanos , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Pulmão/química , Pulmão/metabolismo , Masculino , Espectrometria de Massas , Camundongos , Especificidade de Órgãos , Panobinostat/administração & dosagem , Panobinostat/farmacologia , Estabilidade Proteica , Ratos , Bibliotecas de Moléculas Pequenas/farmacologia , Baço/química , Baço/metabolismo , Testículo/química , Testículo/metabolismo , Termodinâmica , Triazóis/administração & dosagem , Triazóis/farmacologia , Vemurafenib/administração & dosagem , Vemurafenib/farmacologia
3.
Alzheimers Dement ; 16(3): 541-551, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944580

RESUMO

INTRODUCTION: We evaluated the clinical profile of the orexin receptor antagonist suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia. METHODS: Randomized, double-blind, 4-week trial of suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4. RESULTS: Of 285 participants randomized (suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients. DISCUSSION: Suvorexant improved TST in patients with probable AD dementia and insomnia.


Assuntos
Doença de Alzheimer/psicologia , Azepinas/administração & dosagem , Polissonografia , Medicamentos Indutores do Sono/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Triazóis/administração & dosagem , Idoso , Feminino , Humanos , Masculino
4.
Int J Pharm ; 575: 118920, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31863880

RESUMO

The hypothesis for the investigation was that the overall mechanism of action of skin penetration enhancers is best explained by the Solubility-Physicochemical-Thermodynamic (SPT) theory. To our knowledge, this is the first report of the application of SPT theory in transdermal/topical/enhancer research. The SPT theory puts forward the concept that the mode of action of enhancers is related to solubility parameters, physicochemical interactions and thermodynamic activity. This paper discusses these concepts by using experimentally derived permeation data, various physicochemical and solubility parameters (ingredient active gap (IAG), ingredient skin gap (ISG), solubility of active in the formulation (SolV) and the formulation solubility in the skin (SolS)) generated by using FFE (Formulating for Efficacy™ - ACT Solutions Corp) software. These studies suggest that there is an inverse relationship between measured flux and IAG values given that there is an optimum ingredient skin gap, SolV and SolS ratio. The study demonstrated that the flux is actually proportional to a gradient of thermodynamic activity rather than the concentration and maximum skin penetration and deposition can be achieved when the drug is at its highest thermodynamic activity.


Assuntos
Benzoquinonas/administração & dosagem , Excipientes/administração & dosagem , Nicotina/administração & dosagem , Absorção Cutânea , Administração Cutânea , Azepinas/administração & dosagem , Azepinas/química , Benzoquinonas/química , Eucaliptol/administração & dosagem , Eucaliptol/química , Excipientes/química , Humanos , Técnicas In Vitro , Modelos Teóricos , Nicotina/química , Ácido Oleico/administração & dosagem , Ácido Oleico/química , Polissorbatos/administração & dosagem , Polissorbatos/química , Propilenoglicol/administração & dosagem , Propilenoglicol/química , Pirrolidinonas/administração & dosagem , Pirrolidinonas/química , Pele/metabolismo , Software , Solubilidade , Termodinâmica
5.
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
7.
Int J Pharm ; 572: 118800, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678378

RESUMO

The aim of the present work was to develop compound transdermal patch containing teriflunomide (TEF) and ketoprofen (KTP) using permeation enhancement strategy; reveal the molecular mechanism by which Azone (AZ) promoted transdermal absorption of compound patch through the enhancement of drug-drug intermolecular interaction. The formulation was optimized using in vitro skin permeation study and confirmed with pharmacodynamics study, anti-inflammatory study and analgesics study. Enhanced drug-drug interaction by AZ was characterized using FT-IR, 13C NMR, molecular modeling and thermal analysis. The optimized formulation was composed of TEF (3%), KTP (2%), AZ (10%) and DURO-TAK® 87-4098 as adhesive matrix. The skin permeation amount of TEF-KTP combination was promoted by AZ about 1.9 times (594.2 ±â€¯46.8 µg/cm2) and 1.2 times (502.92 ±â€¯24.0 µg/cm2) compared with TEF-AZ and KTP-AZ individual patch. It was proved that the interaction between TEF and KTP via hydrogen bonding was further enhanced by AZ due to the increased molecular mobility of acrylate polymer (ΔTg = -17.7 °C), which was proved by FTIR and 13C NMR spectra. The enhanced drug-drug intermolecular interaction increased drug dispersed status and decreased the quantity of drug's hydrogen bonding site, thus increasing the drug release amount significantly. In conclusion, a compound transdermal patch containing KTP and TEF was developed successfully and a novel enhancement mechanism was clarified at molecular level, which provided reference for the development of novel compound transdermal patch.


Assuntos
Analgésicos/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Experimental/prevenção & controle , Azepinas/administração & dosagem , Crotonatos/administração & dosagem , Cetoprofeno/administração & dosagem , Dor/prevenção & controle , Absorção Cutânea/efeitos dos fármacos , Toluidinas/administração & dosagem , Adesivo Transdérmico , Ácido Acético , Administração Cutânea , Analgésicos/química , Analgésicos/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Experimental/induzido quimicamente , Azepinas/química , Crotonatos/química , Crotonatos/farmacocinética , Combinação de Medicamentos , Composição de Medicamentos , Interações Medicamentosas , Liberação Controlada de Fármacos , Adjuvante de Freund , Ligação de Hidrogênio , Cetoprofeno/química , Cetoprofeno/farmacocinética , Masculino , Camundongos , Dor/induzido quimicamente , Permeabilidade , Coelhos , Ratos , Toluidinas/química , Toluidinas/farmacocinética
8.
PLoS One ; 14(11): e0225774, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31774882

RESUMO

Human papilloma virus (HPV) is the main culprit in cervical cancers. Although the HPV vaccine is now available, the slow and gradual process for HPV cancers to form means little will change, even for vaccinated individuals. This warrants the development of new therapeutic strategies in both the newly diagnosed and recurrent patients. We have previously shown that Alisertib (MLN8237), an Aurora A kinase inhibitor, potently and selectively kills HPV-positive cervical cancer cells. However, Alisertib is known for its unfavorable side effects when administered systemically. A targeted delivery approach is therefore warranted. The topical delivery of drugs to the cervix for the treatment of cervical cancer is an underexplored area of research that has the potential to significantly improve therapeutic outcome. Here, we design a novel topical drug delivery system for localized delivery in the vaginal tract using intravaginal silicone rings loaded with Alisertib. We assessed the suitability of the drug for the application and delivery method and develop a high-performance liquid chromatography method, then show that the vaginal rings were effective at releasing Alisertib over an extended period of time. Furthermore, we showed that Alisertib-loaded vaginal rings did not induce overt inflammation in the mouse vaginal tract. Our work has major translational implications for the future development of vaginal ring devices for the topical treatment of cervical cancer.


Assuntos
Administração Intravaginal , Administração Tópica , Aurora Quinase A/antagonistas & inibidores , Azepinas/administração & dosagem , Pirimidinas/administração & dosagem , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Azepinas/farmacologia , Feminino , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cell Death Dis ; 10(12): 881, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754113

RESUMO

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aurora Quinase A/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Proteína Proto-Oncogênica N-Myc/genética , Proteínas/antagonistas & inibidores , Adulto , Idoso , Azepinas/administração & dosagem , Azepinas/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Proto-Oncogênica N-Myc/biossíntese , Proteína Proto-Oncogênica N-Myc/metabolismo , Temozolomida/administração & dosagem , Temozolomida/farmacologia , Triazóis/administração & dosagem , Triazóis/farmacologia
10.
Head Neck ; 41(12): 4069-4075, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31497919

RESUMO

BACKGROUND: Schwann cells (SC) may play an important role in perineural invasion (PNI) by promoting cancer cell dispersion. Brain-derived neurotrophic factor (BDNF) may contribute to these cellular events by activating tropomyosine receptor kinase B (TrkB). This study examines the effect of TrkB inhibition on SC migration and oral cancer cell dispersion in vitro. METHODS: Human tongue squamous cell carcinoma (SCC-9) and human SCs were cocultured in three different conditioned mediums: control, BDNF, and TrkB inhibitor. Cell migration, cancer cell dispersion, and SC dedifferentiation were measured on time-lapse and immunofluorescence images. RESULTS: Cancer cell migration exceeded SC migration in all conditions. TrkB inhibition promoted SC dedifferentiation and significantly increased SC migration, when compared to BDNF conditions. TrkB inhibition also reduced cancer cell dispersion, when compared to control and BDNF-treated cultures. CONCLUSION: SCs may have importance in the pathophysiology of PNI. TrkB inhibition may be a potential avenue for therapeutic intervention.


Assuntos
Carcinoma de Células Escamosas/patologia , Movimento Celular/efeitos dos fármacos , Glicoproteínas de Membrana/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Células de Schwann/metabolismo , Neoplasias da Língua/patologia , Azepinas/administração & dosagem , Benzamidas/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma de Células Escamosas/metabolismo , Desdiferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Cocultura , Humanos , Glicoproteínas de Membrana/metabolismo , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Invasividade Neoplásica/patologia , Receptor trkB/metabolismo , Neoplasias da Língua/metabolismo
11.
Int J Oncol ; 55(4): 879-895, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485609

RESUMO

Bromodomain and extraterminal domain proteins, especially bromodomain­containing protein 4 (Brd4), have recently emerged as therapeutic targets for several cancers, although the role and mechanism of Brd4 in glioblastoma multiforme (GBM) are unclear. In this study, we aimed to explore the underlying mechanisms of the anti­tumor effects of Brd4 and the bromodomain inhibitor JQ1 on glioma stem cells (GSCs). In vitro, JQ1 and small interfering RNAs targeting Brd4 (siBrd4) inhibited the proliferation and self­renewal of GSCs. In vivo, JQ1 significantly inhibited the growth of xenograft GSCs tumors. The RNA­seq analysis revealed that the PI3K­AKT pathway played an important role in GBM. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 phosphorylation was downregulated by exposure to JQ1 in GSCs, thereby reducing PI3K and AKT activity. In addition, treatment with JQ1 inhibited MMP expression, thereby inhibiting degradation of the extracellular matrix by MMP and angiogenesis in GBM tumors. Suppression of AKT phosphorylation inhibited the expression of the retinoblastoma/E2F1 complex, resulting in cell cycle arrest. In addition, treatment with siBrd4 or JQ1 induced apoptosis by activating AKT downstream target genes involved in apoptosis. In conclusion, these results suggest that Brd4 has great potential as a therapeutic target, and JQ1 has notable anti­tumor effects against GBM which may be mediated via the VEGF/PI3K/AKT signaling pathway.


Assuntos
Azepinas/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Glioma/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Triazóis/administração & dosagem , Animais , Azepinas/farmacologia , Neoplasias Encefálicas/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/metabolismo , Humanos , Masculino , Camundongos , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triazóis/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
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
13.
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
14.
J Pharm Sci ; 108(10): 3302-3311, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31152746

RESUMO

Tuberculosis (TB) remains the single most serious infectious disease attributable to a single-causative organism. A variety of drugs have been evaluated for pulmonary delivery as dry powders: capreomycin sulfate has shown efficacy and was safely delivered by inhalation at high doses to human volunteers, whereas CPZEN-45 is a new drug that has also been shown to kill resistant TB. The studies here combine these drugs-acting by different mechanisms-as components of single particles by spray-drying, yielding a new combination drug therapy. The spray-dried combination powder was prepared in an aerodynamic particle size range suitable for pulmonary delivery. Physicochemical storage stability was demonstrated for a period of 6 months. The spray-dried combination powders of capreomycin and CPZEN-45 have only moderate affinity for mucin, indicating that delivered drug will not be bound by these mucins in the lung and available for microbicidal effects. The pharmacokinetics of disposition in guinea pigs demonstrated high local concentrations of drug following direct administration to the lungs and subsequent systemic bioavailability. Further studies are required to demonstrate the in vivo efficacy of the combination to confirm the therapeutic potential of this novel combination.


Assuntos
Antituberculosos/química , Azepinas/química , Capreomicina/química , Tuberculose/tratamento farmacológico , Administração por Inalação , Aerossóis/administração & dosagem , Aerossóis/química , Animais , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/química , Antituberculosos/administração & dosagem , Azepinas/administração & dosagem , Química Farmacêutica/métodos , Inaladores de Pó Seco/métodos , Cobaias , Pulmão/efeitos dos fármacos , Masculino , Tamanho da Partícula , Pós/administração & dosagem , Pós/química
15.
Cancer Med ; 8(10): 4792-4805, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31250978

RESUMO

AIM: JQ1, a BET bromodomain inhibitor, is a promising therapeutic approach for bladder cancer (BC). Our study aimed to determine whether autophagy is induced by JQ1 and its potential role toward proliferation in BC. METHODS: Cell proliferation was determined by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, cell counting assay, and colony formation assay. Autophagosomes and autolysosomes were observed by transmission electron microscopy and mRFP-EGFP-LC3 fluorescence assay. 3-MA, BAFA1, NH4 Cl, and siATG5 were used to inhibit autophagy. AMPK siRNA was used to knock down AMPK. T24 xenograft model in mice was chosen to perform in vivo studies. Autophagy markers LC-3B and p62, p-AMPKα, p-ACC, p-ULK1, p-mTOR and p-LKB1 were determined by western blot in vitro studies and by immunohistochemistry (IHC) in vivo specimens. RESULTS: We found that BC cell proliferation was suppressed by JQ1; moreover, JQ1 induced the accumulation of autophagosomes and autolysosomes, and autophagy flux, and the growth suppression capacity of JQ1 was attenuated by autophagy inhibitors. Furthermore, we found that JQ1 induced the phosphorylation of AMPKα, and AMPKα knockdown attenuated autophagy induction and anti-proliferation effect induced by JQ1 in BC cells, indicating that autophagy induced by JQ1 is dependent on AMPKα. Through endogenous immunoprecipitation analysis, we found that JQ1 dramatically increased the interaction between LKB1 and AMPKα, which may lead to more AMPK activation. Proliferation inhibition, autophagy induction, and LKB1/AMPK activation capacities of JQ1 were further confirmed in vivo. CONCLUSIONS: Taken together, our results demonstrate that autophagy is induced by JQ1 through activation of LKB1/AMPK pathway, and the autophagy induced by JQ1 positively contributes to the inhibition of BC cell proliferation. These findings provide a novel point of view to understand the mechanism of how targeting BET bromodomain suppress cancer cell growth and suggest that targeting BET bromodomain might be a potential approach to treat BC in the future.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Azepinas/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Triazóis/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/genética , Animais , Autofagia , Azepinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Fosforilação , Triazóis/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Theranostics ; 9(6): 1777-1793, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037138

RESUMO

The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Proteínas de Ciclo Celular/análise , Neoplasias de Cabeça e Pescoço/patologia , Fatores de Transcrição/análise , Animais , Azepinas/administração & dosagem , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Imuno-Histoquímica , Camundongos SCID , Fatores de Transcrição/antagonistas & inibidores , Transplante Heterólogo , Resultado do Tratamento , Triazóis/administração & dosagem
17.
Psychopharmacology (Berl) ; 236(9): 2797-2810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31049607

RESUMO

RATIONALE: Previous studies have demonstrated that repeated social defeat (RSD) stress only induces cognitive deficits when experienced during adulthood. However, RSD increases cocaine-rewarding effects in adult and adolescent mice, inducing different expressions of proBDNF in the ventral tegmental area. OBJECTIVE: The aim of the present study was to evaluate the effect of cocaine administration in socially defeated adult or adolescent mice on learning, memory, and anxiety. Additionally, the role of BDNF was also studied. METHODS: Adolescent and young adult mice were exposed to four episodes of social defeat or exploration (control), being treated with a daily injection of four doses of saline or 1 mg/kg of cocaine 3 weeks after the last social defeat. Other groups were treated with the TrkB receptor antagonist ANA-12 during this 21-day period. After this treatment, their cognitive and anxiogenic profiles were evaluated, along with the expression of BDNF, pCREB, and pERK1/2 in the dentate gyrus (DG) and basolateral amygdala (BLA). RESULTS: Cocaine induced an increased expression of pCREB and BDNF in the DG and BLA only in defeated animals. Although RSD did not affect memory, the administration of cocaine induced memory impairments only in defeated animals. Defeated adult mice needed more time to complete the mazes, and this effect was counteracted by cocaine administration. RSD induced anxiogenic effects only when experienced during adulthood and cocaine induced a general anxiolytic effect. Blockade of Trkb decreased memory retention without affecting spatial learning and modified anxiety on non-stressed mice depending on their age. CONCLUSION: Our results demonstrate that the long-lasting effects of social defeat on anxiety and cognition are modulated by cocaine administration. Our results highlight that the BDNF signaling pathway could be a target to counteract the effects of cocaine on socially stressed subjects.


Assuntos
Azepinas/administração & dosagem , Benzamidas/administração & dosagem , Cocaína/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Comportamento Social , Estresse Psicológico/psicologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Camundongos Endogâmicos , Receptor trkB/antagonistas & inibidores , Estresse Psicológico/tratamento farmacológico
18.
J Neurooncol ; 143(2): 231-240, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31011934

RESUMO

INTRODUCTION: Glioblastoma remains difficult to treat and patients whose tumors express high levels of O6-methylguanine DNA methyltransferase (MGMT) usually respond poorly to standard temozolomide chemotherapy. We have previously shown that the selective AURKA inhibitor alisertib potently inhibits growth of glioblastoma cells. METHODS: We used colony formation assays, annexin V binding, and western blotting to examine the effects of alisertib on the antiproliferative capabilities of carboplatin and irinotecan in glioblastoma cells. RESULTS: In colony formation assays, alisertib potentiated the antiproliferative effects of both carboplatin and irinotecan, often synergistically, including against glioblastoma tumor stem-like cells, as demonstrated by Chou-Talalay and Bliss statistical analyses. Western blotting showed that high MGMT expression in cell lines correlated with more pronounced potentiation of carboplatin's growth inhibitory effects by alisertib, while low MGMT expression correlated with stronger potentiation of irinotecan by alisertib. This pattern was also observed when these drug combinations were tested for their ability to induce apoptosis via annexin V binding assays. MGMT knockdown increased apoptosis caused by combined alisertib and irinotecan, while exogenous MGMT overexpression increased apoptosis from alisertib and carboplatin combination treatment. CONCLUSIONS: These results suggest that tumor MGMT expression levels may be predictive of patient response to these drug combinations, and importantly that the combination of alisertib and carboplatin may be selectively effective in glioblastoma patients with high tumor MGMT who are resistant to standard therapy. Since clinical experience with alisertib, carboplatin and irinotecan as single agents already exists, these findings may provide rationale for the design of clinical trials for their use in combination treatment regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Sinergismo Farmacológico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Proteínas Supressoras de Tumor/metabolismo , Azepinas/administração & dosagem , Carboplatina/administração & dosagem , Metilases de Modificação do DNA/antagonistas & inibidores , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/genética , Glioblastoma/metabolismo , Humanos , Irinotecano/administração & dosagem , Pirimidinas/administração & dosagem , RNA Interferente Pequeno/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética
19.
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
20.
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
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