Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.782
Filtrar
1.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200955

RESUMO

Nanocarriers are delivery platforms of drugs, peptides, nucleic acids and other therapeutic molecules that are indicated for severe human diseases. Gliomas are the most frequent type of brain tumor, with glioblastoma being the most common and malignant type. The current state of glioma treatment requires innovative approaches that will lead to efficient and safe therapies. Advanced nanosystems and stimuli-responsive materials are available and well-studied technologies that may contribute to this effort. The present study deals with the development of functional chimeric nanocarriers composed of a phospholipid and a diblock copolymer, for the incorporation, delivery and pH-responsive release of the antiglioma agent TRAM-34 inside glioblastoma cells. Nanocarrier analysis included light scattering, protein incubation and electron microscopy, and fluorescence anisotropy and thermal analysis techniques were also applied. Biological assays were carried out in order to evaluate the nanocarrier nanotoxicity in vitro and in vivo, as well as to evaluate antiglioma activity. The nanosystems were able to successfully manifest functional properties under pH conditions, and their biocompatibility and cellular internalization were also evident. The chimeric nanoplatforms presented herein have shown promise for biomedical applications so far and should be further studied in terms of their ability to deliver TRAM-34 and other therapeutic molecules to glioblastoma cells.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Lipossomos/administração & dosagem , Nanopartículas/administração & dosagem , Polímeros/química , Pirazóis/administração & dosagem , Apoptose , Proliferação de Células , Glioma/metabolismo , Glioma/patologia , Humanos , Concentração de Íons de Hidrogênio , Lipossomos/química , Nanopartículas/química , Células Tumorais Cultivadas
2.
Isr Med Assoc J ; 23(6): 353-358, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34155848

RESUMO

BACKGROUND: Real-world information regarding the use of direct oral anticoagulants therapy and the outcome in patients with renal dysfunction is limited. OBJECTIVES: To evaluate the clinical characteristics and outcomes of patients with atrial fibrillation (AF) and severe renal dysfunction who are treated with apixaban. METHODS: A sub-analysis was conducted within a multicenter prospective cohort study. The study included consecutive eligible apixaban- or warfarin-treated patients with non-valvular AF and renal impairment (estimated glomerular filtration rate [eGFR] modification of diet in renal disease [MDRD] < 60 ml/min/BSA) were registered. All patients were prospectively followed for clinical events and over a mean period of 1 year. Our sub-analysis included the patients with 15 < eGFR MDRD < 30 ml/min/BSA. The primary outcomes at 1 year were recorded. They included mortality, stroke or systemic embolism, major bleeding, and myocardial infarction as well as their composite occurrence. RESULTS: The sub-analysis included 155 warfarin-treated patients and 97 apixaban-treated ones. All had 15 < eGFR MDRD < 30 ml/min/BSA. When comparing outcomes for propensity matched groups (n=76 per group) of patients treated by reduced dose apixaban or warfarin, the rates of the 1-year composite endpoint as well as mortality alone were higher among the warfarin group (30 [39.5%] vs. 14 [18.4%], P = 0.007 and 28 [36.8%] vs.12 [15.8%], P = 0.006), respectively. There was no significant difference in the rates of stroke, systemic embolism, or major bleeding. CONCLUSIONS: Apixaban might be a reasonable alternative to warfarin in patients with severe renal impairment.


Assuntos
Fibrilação Atrial , Hemorragia , Infarto do Miocárdio , Insuficiência Renal , Acidente Vascular Cerebral , Varfarina , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/mortalidade , Estudos de Coortes , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Israel/epidemiologia , Testes de Função Renal/métodos , Testes de Função Renal/estatística & dados numéricos , Masculino , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Avaliação de Resultados em Cuidados de Saúde , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Insuficiência Renal/complicações , Insuficiência Renal/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Análise de Sobrevida , Varfarina/administração & dosagem , Varfarina/efeitos adversos
3.
Medicine (Baltimore) ; 100(23): e26272, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115024

RESUMO

ABSTRACT: East Asians are reportedly at high risk of anticoagulant-related bleeding; therefore, some physicians prefer to prescribe low-dose direct oral anticoagulants (DOACs). Little is known about the therapeutic effectiveness and safety of off-label reduced-dose apixaban in East Asians with nonvalvular atrial fibrillation (AF). We aimed to investigate the effectiveness and safety of off-label reduced-dose apixaban in Taiwanese patients with nonvalvular AF.This retrospective cohort study enrolled 1073 patients with nonvalvular AF who took apixaban between July 2014 and October 2018 from 4 medical centers in southern Taiwan. The primary outcomes included thromboembolic events (stroke/transient ischemic attack or systemic embolism), major bleeding, and all-cause mortality.Among all patients, 826 (77%) patients were classified as the "per-label adequate-dose" treatment group (i.e., consistent with the Food and Drug Administration label recommendations) while 247 (23%) patients were the "off-label reduced-dose" treatment group. The mean follow-up period was 17.5 ±â€Š13 months. The "off-label reduced-dose" group did not have a lower major bleeding rate than the "per-label adequate-dose" group (4.8% vs 3.8%, adjusted hazard ratio [HR] 1.20, 95% confidence interval [CI] 0.69-2.09), but had a nonsignificantly higher incidence of thromboembolic events (4.23% vs 3.05%, adjusted HR: 1.29, 95% CI: 0.71-2.34).An off-label reduced-dose apixaban treatment strategy may not provide incremental benefits or safety for Taiwanese patients with nonvalvular AF.


Assuntos
Fibrilação Atrial , Hemorragia , Uso Off-Label/estatística & dados numéricos , Pirazóis , Piridonas , Tromboembolia , Anticoagulantes , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Hemorragia/diagnóstico , Hemorragia/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Taiwan/epidemiologia , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Tromboembolia/prevenção & controle
4.
Medicine (Baltimore) ; 100(22): e26211, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087896

RESUMO

BACKGROUND: Riociguat is a novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH. METHODS: Randomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test. RESULTS: Four studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = -0.24, 95%CI -0.35 to -0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = -0.31, 95%CI -0.51 to -0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=-0.23, 95%CI -0.42 to -0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = -0.24, 95%CI -0.61 to -0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed. CONCLUSIONS: We confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.


Assuntos
Ativadores de Enzimas/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Embolia Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Doença Crônica , Gerenciamento de Dados , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/efeitos adversos , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Hipertensão Arterial Pulmonar/complicações , Embolia Pulmonar/complicações , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Guanilil Ciclase Solúvel/efeitos dos fármacos , Resultado do Tratamento
5.
Gene ; 794: 145746, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34062258

RESUMO

The expression of HOXB2, a homeobox transcription factor, is altered in a variety of solid tumors. Using an in vivo screen to identify regulators of breast tumor growth in murine mammary fat pads, Boimel and co-workers recently identified HOXB2 as a tumor suppressor. However, the mechanistic underpinnings of its role in breast cancer is not understood. Given the emerging interaction of estrogen-regulated gene expression and altered HOX gene expression network in the pathophysiology of breast cancer, this study addressed the relationship between estrogen signaling and HOXB2 expression. Using a mouse model and human breast cancer cell lines, we show that estrogen suppresses HOXB2 expression. Suppression of HOXB2 by PPT, a known ERα agonist, in MCF-7 and T47D cells indicated the involvement of ERα, which was confirmed by siRNA-mediated ERα knockdown experiments. In-silico analysis of the upstream promoter region revealed the presence of three putative EREs. Chromatin immunoprecipitation experiments showed that upon estrogen binding, ERα engaged with EREs in the 5' upstream region of HOXB2 in MCF-7 and T47D cells. Future investigations should address the implications of estrogen-mediated suppression on the proposed tumor suppressor function of HOXB2.


Assuntos
Neoplasias da Mama/genética , Regulação para Baixo , Receptor alfa de Estrogênio/genética , Proteínas de Homeodomínio/genética , Fenóis/administração & dosagem , Pirazóis/administração & dosagem , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Transplante de Neoplasias , Fenóis/farmacologia , Regiões Promotoras Genéticas , Pirazóis/farmacologia
6.
Life Sci ; 279: 119655, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34043988

RESUMO

Psoriasis is a chronic inflammatory disorder of the skin and is characterized by hyper-dividing keratinocytes. This hyper-proliferation of keratinocytes is due to the high level of inflammatory cytokines. In this study, we evaluated the effect of topically applied Baricitinib, JAK1/2 inhibitor on chronic 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced psoriasis model in mice. To our knowledge, this is the first report evaluating the topical route of administration of Baricitinib in the context of psoriasis in vivo. TPA-induced inflammation was induced by the topical application of TPA in both ears. Thirty minutes before the application of TPA, the inner and outer surface of each ear was treated with Baricitinib for 6 days. Topical application of Baricitinib inhibited the expression of inflammation markers up-regulated by TPA. Besides, Baricitinib substantially reduced ear swelling, infiltration of leukocytes, the proliferation of epidermal cells, and angiogenesis of the dermal layer. The results suggest that Baricitinib significantly reduced phosphorylation of STAT3 and STAT1 levels in turn attenuating the downstream expression of inflammatory cytokines. Collectively, these results suggest that Baricitinib can be a potential therapeutic through topical route for psoriasis progresses.


Assuntos
Azetidinas/administração & dosagem , Inflamação/prevenção & controle , Psoríase/prevenção & controle , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Pele/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Acetato de Tetradecanoilforbol/toxicidade , Administração Tópica , Animais , Carcinógenos/toxicidade , Inflamação/induzido quimicamente , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/induzido quimicamente , Psoríase/patologia , Pele/patologia
7.
BMC Infect Dis ; 21(1): 427, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962573

RESUMO

PURPOSE: Hyperinflammation in severe COVID-19 infection increases the risk of respiratory failure and one of the cogent reasons of mortality associated with COVID-19. Baricitinib, a janus kinases inhibitor, can potentially suppress inflammatory cascades in severe COVID-19 pneumonia. METHODS: The objective of this study was to compare the clinical outcomes of high dose of baricitinib with its usual dose in patients with severe COVID-19 pneumonia. This prospective cohort study was conducted on 238 adult patients with severe COVID-19 pneumonia. Eight milligram and 4 mg of baricitinib was given orally to 122 patients in the high dose (HD) group and 116 patients the usual dose (UD) group, respectively daily for 14 days, and clinical outcomes were compared among the groups. RESULTS: Blood oxygen saturation level was stabilized (≥94% on room air) earlier in the HD group compared to the UD group [5 (IQR: 4-5)/8 (IQR: 6-9), P < 0.05]. Patients in the HD group required intensive care unit (ICU) and intubation supports more in the UD group than that in patients of the HD group [17.2%/9%, P < 0.05; 11.2%/4.1%, P > 0.05; N = 116/122, respectively]. The 30-day mortality and 60-day rehospitalization rate were higher in the UD group than the HD group [6%/3.3%, P < 0.01; 11.9%/7.6%, P > 0.05; N = 116/122, respectively]. CONCLUSION: The daily high dose of baricitinib in severe COVID-19 results in early stabilization of the respiratory functions, declined requirements of critical care supports, reduced rehospitalization with mortality rate compared to its daily usual dose.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Azetidinas/administração & dosagem , COVID-19/tratamento farmacológico , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Azetidinas/uso terapêutico , Bangladesh , COVID-19/mortalidade , Comorbidade , Cuidados Críticos , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Estudos Prospectivos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
8.
Neurologist ; 26(3): 108-111, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33942794

RESUMO

INTRODUCTION: The coronavirus disease 2019 (COVID-19) has been associated with a hypercoagulable state, increasing the risk for ischemic stroke. In select cases, patients are already on anticoagulation therapy. Such examples highlight the severity of COVID-19's hyperthrombotic state, and raise questions regarding optimal stroke prevention in these patients. CASE REPORT: An 84-year-ool male with past medical history of chronic obstructive pulmonary disease, hypertension, and paroxysmal atrial fibrillation was admitted for respiratory failure secondary to COVID-19 pneumonia. He was continued on his home apixaban 5 mg twice daily. On day 2 of admission, he developed a new aphasia, and right-sided facial droop. Computed tomography (CT) head was unrevealing. CT angiography did not show large vessel occlusion. CT perfusion demonstrated a left middle cerebral artery ischemic penumbra, without core. He was not eligible for thrombolysis or thrombectomy interventions. Later CT head confirmed L middle cerebral artery infarct. The patient's D-dimer was 1,184 ng/mL on day 1 of admission, and increased to 111,574 by day 4. His hypoxia worsened, requiring intubation and transfer to the ICU. He experienced further clinical decline and eventual demise. CONCLUSION: Ischemic stroke in anticoagulated patients with COVID-19 has been previously reported. Such cases emphasize the severity of the coronavirus virus associated hypercoagulable state. A majority of reported cases have occurred in patients continuing their ambulatory therapy. Overall, such cases are likely underreported. There are current trials comparing therapeutic versus prophylactic dose anticoagulation in patients with COVID-19. There are no studies specifically addressing anticoagulation agent failure in these patients. Further research is required this area to determine the optimal therapy for patients with COVID-19.


Assuntos
COVID-19/complicações , Inibidores do Fator Xa/administração & dosagem , AVC Isquêmico/etiologia , Idoso de 80 Anos ou mais , Fibrilação Atrial/tratamento farmacológico , Evolução Fatal , Humanos , Hipertensão/tratamento farmacológico , Masculino , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirazóis/administração & dosagem , Piridonas/administração & dosagem
9.
AAPS PharmSciTech ; 22(4): 147, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33948767

RESUMO

The present study was conducted to formulate ethosomal thermoreversible in situ gel of apixaban, an anticoagulant drug, for nasal delivery. Ethosomes were formed, of lecithin, cholesterol, and ethanol, by using thin-film hydration method. The prepared ethosomes were characterized by Zetasizer, transmission electron microscope, entrapment efficiency, and in vitro study. The selected ethosomal formula (API-ETHO2) was incorporated in gel using P407 and P188 as thermoreversible agents and carbopol 934 as mucoadhesive agent. Box-Behnken design was used to study the effect of independent variables (concentration of P407, P188, and carbopol 934) on gelation temperature, mucoadhesive strength, and in vitro cumulative percent drug released at 12h (response variables). The optimized formulation was subjected to compatibility study, ex vivo permeation, histopathological examination for the nasal mucosa, and in vivo study. API-ETHO2 was spherical with an average size of 145.1±12.3 nm, zeta potential of -20±4 mV, entrapment efficiency of 67.11%±3.26, and in vitro % release of 79.54%±4.1. All gel formulations exhibited an acceptable pH and drug content. The optimum gel offered 32.3°C, 1226.3 dyne/cm2, and 53.50% for gelation temperature, mucoadhesive strength, and in vitro percent released, respectively. Apixaban ethosomal in situ gel evolved higher ex vivo permeation (1.499±0.11 µg/cm2h) through the nasal mucosa than pure apixaban gel. Histopathological study assured that there is no necrosis or tearing of the nasal mucosa happened by ethosomal gel. The pharmacokinetic parameters in rabbit plasma showed that intranasal administration of optimized API-ethosomal in situ gel achieved higher Cmax and AUC0-∞ than unprocessed API nasal gel, nasal suspension, and oral suspension. The ethosomal thermoreversible nasal gel established its potential to improve nasal permeation and prolong anticoagulant effect of apixaban.


Assuntos
Géis/administração & dosagem , Géis/síntese química , Nanosferas/química , Mucosa Nasal/metabolismo , Pirazóis/administração & dosagem , Pirazóis/síntese química , Piridonas/administração & dosagem , Piridonas/síntese química , Administração Intranasal , Animais , Búfalos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/síntese química , Inibidores do Fator Xa/farmacocinética , Géis/farmacocinética , Nanosferas/administração & dosagem , Mucosa Nasal/efeitos dos fármacos , Pirazóis/farmacocinética , Piridonas/farmacocinética , Coelhos
10.
J Urol ; 206(2): 298-307, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33818140

RESUMO

PURPOSE: No published head-to-head randomized trials have compared the safety and efficacy of darolutamide vs apalutamide or enzalutamide in nonmetastatic castration-resistant prostate cancer. This study compares prespecified adverse events and metastasis-free survival associated with darolutamide vs apalutamide, and darolutamide vs enzalutamide, via matching-adjusted indirect comparisons. MATERIALS AND METHODS: Individual patient data from the phase III ARAMIS trial (NPLACEBO=553; NDAROLUTAMIDE=943) were selected and reweighted to match the inclusion criteria and baseline characteristics published for the phase III SPARTAN (NPLACEBO=401; NAPALUTAMIDE=806) and PROSPER (NPLACEBO=468; NENZALUTAMIDE=933) trials. Only baseline factors consistently reported across trials were included as matching covariates. Both indirect comparisons matched on age, prostate specific antigen level and doubling time, Eastern Cooperative Oncology Group performance status, Gleason score, and bone-sparing agent use. Darolutamide vs apalutamide also matched on prior surgery and darolutamide vs enzalutamide also matched on region. Risk differences and odds ratios were calculated for adverse events and hazard ratios for metastasis-free survival. RESULTS: No differences in metastasis-free survival hazard ratios were found after matching in either comparison. However, fall, fracture and rash rates were statistically significantly lower in favor of darolutamide vs apalutamide. Fall, dizziness, mental impairment, fatigue and severe fatigue rates were statistically significantly lower in favor of darolutamide vs enzalutamide. CONCLUSIONS: While metastasis-free survival did not differ across drugs in these cross-trial indirect comparisons, darolutamide showed a favorable safety and tolerability profile in prespecified adverse events vs apalutamide and enzalutamide. Consideration of these adverse events is important in clinical decision-making and treatment selection in nonmetastatic castration-resistant prostate cancer.


Assuntos
Benzamidas/efeitos adversos , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/efeitos adversos , Tioidantoínas/efeitos adversos , Acidentes por Quedas/estatística & dados numéricos , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Benzamidas/administração & dosagem , Disfunção Cognitiva/induzido quimicamente , Tontura/induzido quimicamente , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Fraturas Espontâneas/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/mortalidade , Pirazóis/administração & dosagem , Tioidantoínas/administração & dosagem
11.
Cancer Med ; 10(9): 3059-3067, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33811482

RESUMO

BACKGROUND: Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-ß signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF-targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC). METHODS: This is a multicenter, open-label, phase 1b study of galunisertib, an inhibitor of TGF-ß receptor 1, and ramucirumab, an anti-VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha-fetoprotein and TGF-ß kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1-14 of a 28-day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks. RESULTS: Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose-limiting toxicities were observed. Treatment-related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment-related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose-proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively. CONCLUSION: Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFß signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pirazóis/administração & dosagem , Quinolinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Estudos Prospectivos , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Critérios de Avaliação de Resposta em Tumores Sólidos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Vômito/induzido quimicamente , alfa-Fetoproteínas/análise
12.
Ned Tijdschr Geneeskd ; 1642021 04 26.
Artigo em Holandês | MEDLINE | ID: mdl-33914427

RESUMO

Real-world evidence is accumulating to support the idea that there are differences among the direct oral anticoagulants (DOACs). The results of the study, discussed elsewhere in the NTvG, add to the growing body of evidence that while there is almost no difference in efficacy in prevention of the thromboembolic complications of non-valvular atrial fibrillation there are significant differences in safety. Apixaban is safer than rivaroxaban, with significantly less major bleeding, any bleeding or gastro-intestinal bleeding. Apixaban is probably the safest DOAC of the four available. These differences between DOACs with almost equal half-life are probably partly due to the differences in dosing interval: twice a day (BID) versus once a day (QD).


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Administração Oral , Idoso , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Dabigatrana/efeitos adversos , Esquema de Medicação , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Rivaroxabana/efeitos adversos , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Resultado do Tratamento
13.
BMC Cancer ; 21(1): 291, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33740926

RESUMO

BACKGROUND: Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). METHODS: This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan-Meier survival curves were compared by Cox regression. RESULTS: Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan-Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. CONCLUSIONS: In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. TRIAL REGISTRATION: The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirróis/administração & dosagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Triazinas/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirróis/efeitos adversos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Estudos Retrospectivos , Triazinas/efeitos adversos
15.
Medicine (Baltimore) ; 100(11): e25188, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33726009

RESUMO

RATIONALE: The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH). PATIENT CONCERNS: A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. DIAGNOSIS: Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level. INTERVENTION: This patient was treated with ruxolitinib and the HLH-94 protocol. OUTCOMES: The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve. LESSONS: This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.


Assuntos
Infecções por Vírus Epstein-Barr/tratamento farmacológico , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Pirazóis/administração & dosagem , Adolescente , Protocolos Clínicos , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Quimioterapia Combinada , Infecções por Vírus Epstein-Barr/complicações , Etoposídeo/administração & dosagem , Evolução Fatal , Feminino , Humanos , Quimioterapia de Indução , Unidades de Terapia Intensiva , Linfo-Histiocitose Hemofagocítica/virologia , Metilprednisolona/administração & dosagem , Polietilenoglicóis/administração & dosagem , Resultado do Tratamento
16.
Clin Drug Investig ; 41(4): 353-369, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33677803

RESUMO

BACKGROUND AND OBJECTIVE: Rivaroxaban and apixaban are direct oral anticoagulants increasing in popularity as convenient alternatives to warfarin. However, current guidelines recommend against use in patients with a BMI > 40 kg/m2 or bodyweight > 120 kg unless drug-specific levels are measured, which may not be feasible across all clinical practices. Accordingly, the objective of this study was to broadly examine literature evaluating the clinical outcomes of rivaroxaban and/or apixaban in patients with increased body mass. METHODS: A systematic literature review (guided by PRISMA) was performed through January 27, 2021 using PubMed, Embase, and Scopus. Key search term clusters included drug and weight-related concepts (overweight/obese, body mass index [BMI], waist circumference). DistillerSR was utilized to review and process search results. Studies met inclusion if they analyzed the risk of bleeding and/or thrombosis in patients with increased body mass (i.e., via BMI or other criteria) receiving rivaroxaban or apixaban. Clinical guidelines, case reports/series, pharmacokinetic/dynamic analyses, and commentaries were excluded. Bias was examined qualitatively across studies. RESULTS: After duplicates were removed, the original search rendered 1822 abstracts and 200 full-texts for screening, ultimately providing a final set of 24 studies for qualitative review. Of these studies, 13 (54.2%) enabled comparisons between patients of increased versus normal body mass, while 11 (45.8%) reported outcomes only for patients of increased body mass. The working definition of 'increased body mass' varied amongst the studies, including 11 (45.8%) studies that utilized BMI, seven (29.2%) with a combination of BMI and body measurement, two (8.3%) that relied on body weight alone, and four (16.7%) that identified obesity-related ICD codes. All 13 comparative studies found similar or reduced rates of safety and efficacy outcomes with rivaroxaban and apixaban. CONCLUSION: The literature reports similar or lower bleeding and thrombotic risk for rivaroxaban and apixaban in patients of increased body mass compared to patients of normal body mass. Future prospective controlled studies are needed to further define guidelines for use in this population.


Assuntos
Anticoagulantes/uso terapêutico , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/uso terapêutico , Administração Oral , Fibrilação Atrial/tratamento farmacológico , Índice de Massa Corporal , Hemorragia/induzido quimicamente , Humanos , Varfarina/uso terapêutico
17.
Expert Rev Clin Pharmacol ; 14(5): 535-544, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33685318

RESUMO

Introduction: Important changes in the treatment of prostate cancer have taken place in recent years. Non-metastatic castration-resistant prostate cancer (nmCRPC) has been clinically delineated. In this setting, three drugs have been approved in high-risk disease: apalutamide, enzalutamide and darolutamide.Areas covered:This manuscript aims to profile darolutamide, its clinical development, pharmacologic properties, efficacy and safety. We presented the results of published clinical studies, but we also investigated ongoing ones.Expert opinion: An indirect comparison with the other two aforementioned drugs emerged. While the clinical efficacy is comparable, the toxicity profile is different for darolutamide, resulting in greater tolerance. We must wait for the results of the trials that study darolutamide in hormone-sensitive disease, both in the metastatic phase and in the localized phase. Clinical experience will also be important to determine ever more personalized treatments for patients.


Assuntos
Antagonistas de Receptores de Andrógenos/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Humanos , Masculino , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Nitrilas/farmacologia , Feniltioidantoína/administração & dosagem , Feniltioidantoína/efeitos adversos , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/patologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Tioidantoínas/administração & dosagem , Tioidantoínas/efeitos adversos , Tioidantoínas/farmacologia
18.
Clin Drug Investig ; 41(3): 255-267, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33587284

RESUMO

BACKGROUND AND OBJECTIVE: The increasing availability of real-world evidence (RWE) about safety and effectiveness of direct non-vitamin K oral anticoagulants (DOACs) for the management of atrial fibrillation (AF) offers the opportunity to better understand the clinical and economic implications of DOACs versus vitamin K antagonists (VKAs). The objective of this study was to compare the economic implications of DOACs and VKAs using data from real-world evidence in patients with AF. METHODS: A Markov model simulating the lifetime course of patients diagnosed with non-valvular AF was used to evaluate the cost-effectiveness of DOACs (i.e., rivaroxaban, dabigatran and apixaban) versus VKAs from the Italian National Health System (INHS) perspective. The model was made up of data from the literature and a meta-analysis of RWE on the incidence of stroke/systemic embolism (SE), major bleeding (MB), intracranial haemorrhage (ICH) and all-cause mortality (ACM); direct costs included drug costs, costs for drug monitoring, and management of events from official national lists. One-way and probabilistic sensitivity analyses (PSA) were used to assess the robustness of the results. RESULTS: Results from the meta-analysis showed that apixaban had a high probability of being the most effective for stroke/SE, MB and ACM. Despite their higher acquisition costs, the cost-effectiveness analysis showed all DOACs involved a saving when compared with VKAs, with per-patient savings ranging between €4647 (rivaroxaban) to €6086 (apixaban). Moreover, all DOACs indicated a gain both in quality-adjusted life-years and life-years. According to PSA, findings related to apixaban were consistent, while for dabigatran and rivaroxaban PSA revealed a higher degree of uncertainty. CONCLUSIONS: The beneficial effect of DOACs on containing events showed in RWE had the potential to offset drug-related costs, thus improving the sustainability of treatment for non-valvular AF in daily clinical practice.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Administração Oral , Análise Custo-Benefício , Dabigatrana/uso terapêutico , Feminino , Hemorragia/induzido quimicamente , Humanos , Itália , Masculino , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/epidemiologia
19.
J Wildl Dis ; 57(2): 434-438, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631008

RESUMO

In western North America, sylvatic plague (a flea-borne disease) poses a significant risk to endangered black-footed ferrets (Mustela nigripes) and their primary prey, prairie dogs (Cynomys spp.). Pulicides (flea-killing agents) can be used to suppress fleas and thereby manage plague. In South Dakota, US, we tested edible "FipBit" pellets, each containing 0.84 mg fipronil, on free-living black-tailed prairie dogs (Cynomys ludivicianus). FipBits were applied along transects at 125 per ha and nearly eliminated fleas for 2 mo. From 9-14 mo post-treatment, we found only 10 fleas on FipBit sites versus 1,266 fleas on nontreated sites. This degree and duration of flea control should suppress plague transmission. FipBits are effective, inexpensive, and easily distributed but require federal approval for operational use.


Assuntos
Furões , Infestações por Pulgas/veterinária , Peste/veterinária , Pirazóis/farmacologia , Sciuridae/parasitologia , Sifonápteros/efeitos dos fármacos , Animais , Infestações por Pulgas/prevenção & controle , Inseticidas/administração & dosagem , Inseticidas/farmacologia , Peste/prevenção & controle , Pirazóis/administração & dosagem
20.
Eur J Med Chem ; 214: 113189, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33540354

RESUMO

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized. A promising, pyrazole-containing new chemotype with good physicochemical and in vitro parameters was identified. Retrospective analysis based on homology modeling was also carried out. Besides its favorable in vitro characteristics, the most advanced derivative 69 also showed in vivo efficacy in a rodent model of cognition (scopolamine-induced amnesia in the mouse place recognition test) and acceptable pharmacokinetic properties. Based on the in vivo data, the resulting molecule with advanced drug-like characteristics has the possibility to improve cognitive performance in a biologically relevant dose range, further strengthening the view of the supportive role of α7 nACh receptors in the cognitive processes.


Assuntos
Descoberta de Drogas , Agonistas Nicotínicos/farmacologia , Pirazóis/farmacologia , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Amnésia/metabolismo , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/metabolismo , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Ratos , Ratos Wistar , Escopolamina , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...