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1.
Nihon Koshu Eisei Zasshi ; 67(8): 501-508, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879236

RESUMO

Objectives Medical expenses for diabetes differ between Japan's 47 prefectures. The medical care expenditure regulation plan aims to reduce regional differences in outpatient medical costs through prevention of severe diabetes, promotion of specific health checkups and specific health guidance, promotion of generic drugs, and proper use of medicines. To achieve this goal, we need to conduct an in-depth analysis of inter-prefecture differences in diabetes care expenses. This study analyzed regional differences in prescription fees for dipeptidyl peptidase-4 (DPP-4) inhibitors and the use of generic sulfonylureas (SUs), glinides, biguanides, α-glucosidase inhibitors (α-GIs), and thiazoline derivatives, using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB). Furthermore, we analyzed regional differences in consultancy fees for dialysis prevention.Methods We analyzed the 2nd NDB Open Data Japan website of the Ministry of Health, Labor, and Welfare. Pearson's correlation coefficient (r) was used to evaluate the relationship between the medical costs of diabetes and each factor. The correlation coefficient was analyzed with Student's t-test, and a P-value<0.05 was considered statistically significant.Results Regarding oral hypoglycemic drugs, prefectures with a large number of DPP-4 inhibitors tended to have higher medical costs of diabetes (r=0.40, P=0.0048). Furthermore, such expenses tended to be low in prefectures where the use of generic SU drugs was high (r=-0.43, P=0.0023).Conclusions In conclusion, the results revealed regional differences in the use of DPP-4 inhibitors and generic SU drugs, which may contribute to the regional differences in medical expenses for diabetes. This study suggests that NDB open data are useful for policy making to reduce regional differences in outpatient medical costs of diabetes.


Assuntos
Serviços de Saúde Comunitária/economia , Efeitos Psicossociais da Doença , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/economia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/economia , Custos de Cuidados de Saúde , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/economia , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/economia , Análise de Dados , Diabetes Mellitus/prevenção & controle , Dipeptidil Peptidase 4 , Humanos , Japão , Honorários por Prescrição de Medicamentos , Encaminhamento e Consulta/economia
2.
Lancet Diabetes Endocrinol ; 8(9): 762-772, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32822600

RESUMO

BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression. FUNDING: European Commission Seventh Framework Programme.


Assuntos
Alcaptonúria/tratamento farmacológico , Alcaptonúria/metabolismo , Cicloexanonas/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Internacionalidade , Nitrobenzoatos/administração & dosagem , Adulto , Idoso , Alcaptonúria/diagnóstico , Esquema de Medicação , Feminino , Ácido Homogentísico/metabolismo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Resultado do Tratamento
3.
Isr Med Assoc J ; 7(22): 338-342, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32692493

RESUMO

BACKGROUND: Methylene blue (MB), an inhibitor of nitric oxide synthesis and its effects is a potentially effective treatment against distributive shock states such as septic shock and vasoplegic syndrome. MB has been shown to alleviate vasoplegia and promote an increase in blood pressure. It may reduce mortality. However, in the pediatric population, there are few case reports and only one controlled study on administration of MB use for vasoplegia, sepsis, or shock in general. OBJECTIVES: To summarize the experience of administering MB for vasoplegic shock in a tertiary care pediatric intensive care unit. METHODS: A retrospective chart review of seven pediatric cases treated with MB for vasoplegic shock was conducted. MB was administered as a bolus followed by continuous infusion. The authors measured blood pressure, vasopressor, and inotropic support. Patient outcome was monitored. RESULTS: The authors observed a favorable hemodynamic response with an increase in blood pressure and a reduction in vasopressor and inotropic support needed following MB administration in six patients. No side effects were observed. Three patients eventually died one to two days later, secondary to their underlying disease. CONCLUSIONS: This case series adds to the small body of evidence in the pediatric population supporting the use of MB for distributive shock states and emphasizes the need for larger, randomized trials evaluating its role in vasoplegic shock treatment.


Assuntos
Hemodinâmica/efeitos dos fármacos , Azul de Metileno/administração & dosagem , Choque Séptico/tratamento farmacológico , Vasoplegia/tratamento farmacológico , Pré-Escolar , Estado Terminal , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica , Masculino , Estudos Retrospectivos , Resultado do Tratamento
4.
PLoS One ; 15(7): e0236159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702053

RESUMO

Asthma is a common chronic inflammatory disease. Although effective asthma therapies are available, part of asthmatic population do not respond to these treatment options. In this work we present the result of development of CPL302-253 molecule, a selective PI3Kδ inhibitor. This molecule is intended to be a preclinical candidate for dry powder inhalation in asthma treatment. Studies we performed showed that this molecule is safe and effective PI3Kδ inhibitor that can impact many immune functions. We developed a short, 15-day HDM induced asthma mouse model, in which we showed that CPL302-253 is able to block inflammatory processes leading to asthma development in vivo.


Assuntos
Antiasmáticos/administração & dosagem , Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Asma/prevenção & controle , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Administração por Inalação , Animais , Antiasmáticos/uso terapêutico , Linhagem Celular , Inaladores de Pó Seco , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Camundongos
5.
PLoS One ; 15(6): e0234493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520953

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination and inflammation. Dysregulated lipid metabolism and mitochondrial dysfunction are hypothesized to play a key role in MS. Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting enzyme for beta-oxidation of fatty acids in mitochondria. The therapeutic effect of pharmacological CPT1 inhibition with etomoxir was investigated in rodent models of myelin oligodendrocyte glycoprotein- and myelin basic protein-induced experimental autoimmune encephalitis (EAE). Mice receiving etomoxir showed lower clinical score compared to placebo, however this was not significant. Rats receiving etomoxir revealed significantly lower clinical score and lower body weight compared to placebo group. When comparing etomoxir with interferon-ß (IFN-ß), IFN-ß had no significant therapeutic effects, whereas etomoxir treatment starting at day 1 and 5 significantly improved the clinical scores compared to the IFN-ß and the placebo group. Immunohistochemistry and image assessments of brain sections from rats with EAE showed higher myelination intensity and decreased expression of CPT1A in etomoxir-treated rats compared to placebo group. Moreover, etomoxir mediated increased interleukin-4 production and decreased interleukin-17α production in activated T cells. In conclusion, CPT1 is a key protein in the pathogenesis of EAE and MS and a crucial therapeutic target for the treatment.


Assuntos
Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Feminino , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Ratos , Ratos Endogâmicos Lew
6.
Medicine (Baltimore) ; 99(26): e20719, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590747

RESUMO

BACKGROUND: Regorafenib, a multitargeted tyrosine kinase inhibitor, proved to be active in patients with soft tissue sarcomas (STS). METHODS: We conducted an open-label, non-randomized, single-center phase II study in advanced pretreated STS patients. Patients received regorafenib 160 mg daily on days 1 enrule 21 of a 28-day cycle. The primary endpoint was the progression-free survival (PFS) at 8 weeks. Toxicity was registered. RESULTS: Between April 2015 and November 2016, 21 patients were enrolled in the trial. A total of 13 out of 21 evaluable patients (61.9%) were progression-free at 8 weeks. Median PFS was 3.8 months (95% CI: 2.1-9.4). Median overall survival was 14.8 months (95% CI: 7.7-27.8). In the intention-to-treat population, we reported a PFS of 66.7% at 3 months (95% CI: 40.4-83.4) and 16.7% at 12 months (95% CI: 4.1-36.5). As per the RECIST criteria, the response rate was 4.7% (1 partial response out of 21 evaluable patients) with a clinical benefit rate of 61.9%; no complete response was observed. Treatment was well tolerated. CONCLUSION: Regorafenib shows signs of clinical activity in patients with advanced STS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02307500.


Assuntos
Neoplasias Ovarianas , Neoplasias Pancreáticas , Compostos de Fenilureia , Piridinas , Sarcoma , Timoma , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Monitoramento de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Timoma/tratamento farmacológico , Timoma/patologia , Resultado do Tratamento
7.
Am J Physiol Heart Circ Physiol ; 319(2): H271-H281, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32559139

RESUMO

The purpose of this study was to investigate the effect of race and subclinical elevations in blood pressure (i.e., prehypertension) on cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation. We recruited participants who self-identified as either non-Hispanic black (n = 16) or non-Hispanic white (n = 16). Within each group, participants were subdivided as either normotensive (n = 8 per group) or prehypertensive (n = 8 per group). Each participant was instrumented with four intradermal microdialysis fibers: 1) control (lactated Ringer's), 2) 5% lidocaine (sensory nerve inhibition), 3) 20 mM Nω-nitro-l-arginine methyl ester (l-NAME) (NO synthase inhibition), and 4) lidocaine + l-NAME. Skin blood flow was assessed via laser-Doppler flowmetry, and each site underwent local heating from 33°C to 39°C. At the plateau, 20 mM l-NAME were infused at control and lidocaine sites to quantify NO-dependent vasodilation. Maximal vasodilation was induced via 54 mM sodium nitroprusside and local heating to 43°C. Data are means ± SD. Sensory nerve-mediated cutaneous vasodilation was reduced in prehypertensive non-Hispanic white (34 ± 7%) and both non-Hispanic black groups (normotensive, 20 ± 9%, prehypertensive, 24 ± 15%) relative to normotensive non-Hispanic whites (54 ± 12%). NO-dependent vasodilation was also reduced in prehypertensive non-Hispanic white (41 ± 7%) and both non-Hispanic black groups (normotensive, 44 ± 7%, prehypertensive, 19 ± 7%) relative to normotensive non-Hispanic whites (60 ± 11%). The decrease in NO-dependent vasodilation in prehypertensive non-Hispanic blacks was further reduced relative to all other groups. These data suggest subclinical increases in blood pressure adversely affect sensory-mediated and NO-dependent vasodilation in both non-Hispanic blacks and whites.NEW & NOTEWORTHY Overt hypertension is known to reduce cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation, but the effect of subclinical increases in blood pressure (i.e., prehypertension) is unknown. The combined effect of race and prehypertension is also unknown. In this study, we found that prehypertension reduces cutaneous sensory nerve-mediated and NO-dependent vasodilation in both non-Hispanic white and black populations, with the greatest reductions observed in prehypertensive non-Hispanic blacks.


Assuntos
Pressão Sanguínea , Vasos Sanguíneos/inervação , Vasos Sanguíneos/metabolismo , Células Endoteliais/metabolismo , Óxido Nítrico/metabolismo , Pré-Hipertensão/fisiopatologia , Células Receptoras Sensoriais , Pele/irrigação sanguínea , Vasodilatação , Administração Cutânea , Adolescente , Adulto , Afro-Americanos , Anestésicos Locais/administração & dosagem , Vasos Sanguíneos/efeitos dos fármacos , Estudos de Casos e Controles , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Grupo com Ancestrais do Continente Europeu , Feminino , Georgia/epidemiologia , Humanos , Masculino , Microdiálise , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Pré-Hipertensão/diagnóstico , Pré-Hipertensão/etnologia , Pré-Hipertensão/metabolismo , Fatores Raciais , Células Receptoras Sensoriais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adulto Jovem
10.
Lancet Oncol ; 21(6): 796-807, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32416072

RESUMO

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. FINDINGS: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. INTERPRETATION: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. FUNDING: Agios Pharmaceuticals.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/administração & dosagem , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Mutação , Piridinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/enzimologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Progressão da Doença , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Europa (Continente) , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridinas/efeitos adversos , República da Coreia , Fatores de Tempo , Estados Unidos
11.
Proc Natl Acad Sci U S A ; 117(24): 13670-13679, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32471953

RESUMO

Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Inibidores Enzimáticos/administração & dosagem , Histona Desmetilases/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Receptores de Fator Estimulador de Colônias/genética , Fatores de Transcrição STAT/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Feminino , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Fator Estimulador de Colônias/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Transdução de Sinais/efeitos dos fármacos
12.
Am J Cardiol ; 128: 147-150, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32425199

RESUMO

Coronavirus disease 2019 (COVID-19) has become a global pandemic. It is still uncontrolled in most countries and no therapies are currently available. Various drugs are under investigation for its treatment. The disease is known to have worse outcomes in patients who have underlying cardiovascular disease. Chloroquine/hydroxychloroquine, azithromycin, remdesivir and lopinavir/ritonavir are currently being studied in trials and show some promise. Conduction disorders, heart failure, and mortality have been reported with the use of these drugs. It is important to have knowledge of potential cardiotoxic effects of these drugs before using them for COVID-19 patients for better allocation of healthcare resources and improvement in clinical outcomes.


Assuntos
Anti-Infecciosos/efeitos adversos , Betacoronavirus , Doenças Cardiovasculares/induzido quimicamente , Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Anti-Infecciosos/administração & dosagem , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Combinação de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Lopinavir/uso terapêutico , Pandemias , Ritonavir/uso terapêutico
13.
Libyan J Med ; 15(1): 1753943, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32281500

RESUMO

Knee Osteoarthritis is a considerable public health concern, both in terms of life quality and treatment financial impacts. To investigate this disease, animal models are deemed a promising alternative. In fact, although a perfect model is generally farfetched, the creation of models that simulate human disease as accurately as possible remains an important research stake. This study aims to highlight the usefulness of the model induced by injected Mono-Iodo-Acetate and to standardize it for the rabbit species. Osteoarthritis was induced by an infra-patellar injection of 0.2 ml of an MIA solution in the left knee of 24 female New Zealand rabbits. The right knee served as a control by receiving an injection of physiological serum. The rabbits were divided into 4 groups of 6 individuals each according to the dose of MIA received per knee. All rabbits were euthanized 30 days after the injection. After sacrifice, the knees were carefully dissected and macroscopic and microscopic scores of cartilage, meniscal and synovial lesions were attributed to each group. Our study followed the laboratory animal care and management guideline published in 2017 by the Canadian Council of Animal Care. The control knees of all rabbits showed no macroscopic or microscopic lesions. The macroscopic lesions: osteophytes, meniscal lesions, fibrillation and erosion of the cartilage and microscopic lesions: disorganization of the chondrocytes, decrease in proteoglycans and synovial inflammation clinically diagnosed in human pathology were all detected and were similarly reproducible among the knees of the same group. Through this work, we highlighted the merits of the arthritis model induced by MIA, namely its simulation of several aspects of human pathology. Further advantages are low cost, speed, reproducibility. This model notably avoids delicate and risky surgical operations.


Assuntos
Inibidores Enzimáticos/administração & dosagem , Ácido Iodoacético/administração & dosagem , Osteoartrite do Joelho/induzido quimicamente , Animais , Bolsa Sinovial/patologia , Bolsa Sinovial/ultraestrutura , Canadá/epidemiologia , Cartilagem/patologia , Cartilagem/ultraestrutura , Condrócitos/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Injeções/métodos , Ácido Iodoacético/efeitos adversos , Menisco/patologia , Menisco/ultraestrutura , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/veterinária , Proteoglicanas/metabolismo , Coelhos , Reprodutibilidade dos Testes
14.
Biochem Pharmacol ; 175: 113914, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173363

RESUMO

Transcriptional coactivators p300 and CBP catalyze the acetylation of lysine residues in histone proteins. Upregulation of p300 and CBP has been associated with lung, colorectal and hepatocellular cancer, indicating an important role of p300 and CBP in tumorigenesis. Recently, the novel p300 and CBP-selective inhibitor A485 became available, which was shown to inhibit proliferation of 124 different cancer cell lines. Here, we found that downregulation of EP300 or CREBBP enhances apoptosis upon TRAIL stimulation in non-small-cell lung cancer (NSCLC) cells. A485 upregulates pro- and anti-apoptotic genes at the mRNA level, implying an apoptosis-modulating effect in NSCLC cells. However, A485 alone does not induce apoptosis. Interestingly, we observed that the number of apoptotic cells increases upon combined treatment with A485 and TRAIL. Therefore, A485, as a TRAIL-sensitizer, was used in combination with TRAIL in wild type of NSCLC cell lines (HCC827 and H1650) and cells with acquired erlotinib resistance (HCC827-ER and H1650-ER). Our results show that the combination of A485 and TRAIL synergistically increases cell death and inhibits long-term cell proliferation. Furthermore, this combination inhibits the growth of 3D spheroids of EGFR-TKI-resistant cells. Taken together, we demonstrate a successful combination of A485 and TRAIL in EGFR-TKI-sensitive and resistant NSCLC cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Inibidores Enzimáticos/administração & dosagem , Histona Acetiltransferases/antagonistas & inibidores , Neoplasias Pulmonares/enzimologia , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Histona Acetiltransferases/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
15.
J Med Chem ; 63(8): 4183-4204, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202790

RESUMO

Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/ß-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and ß-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Desenho de Fármacos , Descoberta de Drogas/métodos , Inibidores Enzimáticos/administração & dosagem , Tanquirases/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/enzimologia , Inibidores Enzimáticos/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Terciária de Proteína , Ratos , Tanquirases/química , Tanquirases/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Biochem J ; 477(5): 985-1008, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32168372

RESUMO

Fatty acids (FAs) are stored safely in the form of triacylglycerol (TAG) in lipid droplet (LD) organelles by professional storage cells called adipocytes. These lipids are mobilized during adipocyte lipolysis, the fundamental process of hydrolyzing TAG to FAs for internal or systemic energy use. Our understanding of adipocyte lipolysis has greatly increased over the past 50 years from a basic enzymatic process to a dynamic regulatory one, involving the assembly and disassembly of protein complexes on the surface of LDs. These dynamic interactions are regulated by hormonal signals such as catecholamines and insulin which have opposing effects on lipolysis. Upon stimulation, patatin-like phospholipase domain containing 2 (PNPLA2)/adipocyte triglyceride lipase (ATGL), the rate limiting enzyme for TAG hydrolysis, is activated by the interaction with its co-activator, alpha/beta hydrolase domain-containing protein 5 (ABHD5), which is normally bound to perilipin 1 (PLIN1). Recently identified negative regulators of lipolysis include G0/G1 switch gene 2 (G0S2) and PNPLA3 which interact with PNPLA2 and ABHD5, respectively. This review focuses on the dynamic protein-protein interactions involved in lipolysis and discusses some of the emerging concepts in the control of lipolysis that include allosteric regulation and protein turnover. Furthermore, recent research demonstrates that many of the proteins involved in adipocyte lipolysis are multifunctional enzymes and that lipolysis can mediate homeostatic metabolic signals at both the cellular and whole-body level to promote inter-organ communication. Finally, adipocyte lipolysis is involved in various diseases such as cancer, type 2 diabetes and fatty liver disease, and targeting adipocyte lipolysis is of therapeutic interest.


Assuntos
Adipócitos/metabolismo , Metabolismo Energético/fisiologia , Lipólise/fisiologia , Domínios e Motivos de Interação entre Proteínas/fisiologia , Adipócitos/efeitos dos fármacos , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Humanos , Lipólise/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos
17.
J Med Chem ; 63(7): 3634-3664, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32176488

RESUMO

Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg-1, 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.


Assuntos
Ceramidase Ácida/antagonistas & inibidores , Benzoxazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Administração Oral , Animais , Benzoxazóis/administração & dosagem , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Encéfalo/metabolismo , Linhagem Celular Tumoral , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Feminino , Doença de Gaucher/enzimologia , Doença de Gaucher/metabolismo , Humanos , Leucodistrofia de Células Globoides/enzimologia , Leucodistrofia de Células Globoides/metabolismo , Masculino , Camundongos , Estrutura Molecular , Psicosina/análogos & derivados , Psicosina/metabolismo , Relação Estrutura-Atividade
18.
Braz J Med Biol Res ; 53(3): e8853, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130289

RESUMO

Anaphylactic shock can be defined as an acute syndrome, and it is the most severe clinical manifestation of allergic diseases. Anaphylactoid reactions are similar to anaphylactic events but differ in the pathophysiological mechanism. Nitric oxide (NO) inhibitors during anaphylaxis suggest that NO might decrease the signs and symptoms of anaphylaxis but exacerbate associated vasodilation. Therefore, blocking the effects of NO on vascular smooth muscle by inhibiting the guanylate cyclase (GC) would be a reasonable strategy. This study aimed to investigate the effects of NO/cGMP pathway inhibitors methylene blue (MB), Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), and indigo carmine (IC) in shock induced by compound 48/80 (C48/80) in rats. The effect was assessed by invasive blood pressure measurement. Shock was initiated by C48/80 intravenous bolus injection 5 min before (prophylactic) or after (treatment) the administration of the inhibitors MB (3 mg/kg), L-NAME (1 mg/kg), and IC (3 mg/kg). Of the groups that received drugs as prophylaxis for shock, only the IC group did not present the final systolic blood pressure (SBP) better than the C48/80 group. Regarding shock treatment with the drugs tested, all groups had the final SBP similar to the C48/80group. Altogether, our results suggested that inhibition of GC and NO synthase in NO production pathway was not sufficient to revert hypotension or significantly improve survival.


Assuntos
Anafilaxia/tratamento farmacológico , GMP Cíclico/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Índigo Carmim/administração & dosagem , Masculino , Azul de Metileno/administração & dosagem , NG-Nitroarginina Metil Éster/administração & dosagem , Ratos , Ratos Wistar
19.
Braz J Med Biol Res ; 53(3): e8761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32159612

RESUMO

Nitric oxide (NO) inhibition by high-dose NG-nitro-L-arginine methyl ester (L-NAME) is associated with several detrimental effects on the cardiovascular system. However, low-dose L-NAME increases NO synthesis, which in turn induces physiological cardiovascular benefits, probably by activating a protective negative feedback mechanism. Aerobic exercise, likewise, improves several cardiovascular functions in healthy hearts, but its effects are not known when chronically associated with low-dose L-NAME. Thus, we tested whether the association between low-dose L-NAME administration and chronic aerobic exercise promotes beneficial effects to the cardiovascular system, evaluating the cardiac remodeling process. Male Wistar rats were randomly assigned to control (C), L-NAME (L), chronic aerobic exercise (Ex), and chronic aerobic exercise associated to L-NAME (ExL). Aerobic training was performed with progressive intensity for 12 weeks; L-NAME (1.5 mg·kg-1·day-1) was administered by orogastric gavage. Low-dose L-NAME alone did not change systolic blood pressure (SBP), but ExL significantly increased SBP at week 8 with normalization after 12 weeks. Furthermore, ExL promoted the elevation of left ventricle (LV) end-diastolic pressure without the presence of cardiac hypertrophy and fibrosis. Time to 50% shortening and relaxation were reduced in ExL, suggesting a cardiomyocyte contractile improvement. In addition, the time to 50% Ca2+ peak was increased without alterations in Ca2+ amplitude and time to 50% Ca2+ decay. In conclusion, the association of chronic aerobic exercise and low-dose L-NAME prevented cardiac pathological remodeling and induced cardiomyocyte contractile function improvement; however, it did not alter myocyte affinity and sensitivity to intracellular Ca2+ handling.


Assuntos
Cálcio/análise , Inibidores Enzimáticos/farmacologia , Contração Miocárdica/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Adiposidade , Animais , Peso Corporal/fisiologia , Inibidores Enzimáticos/administração & dosagem , Hemodinâmica , Masculino , Modelos Animais , Atividade Motora/fisiologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico Sintase/metabolismo , Ratos Wistar , Pressão Ventricular/efeitos dos fármacos
20.
AAPS PharmSciTech ; 21(3): 98, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32128656

RESUMO

Oseltamivir is a neuraminidase inhibitor widely used to treat and prevent influenza A and B infections, although its safety and pharmacokinetics have not been evaluated in patients with severe hepatic impairment. A physiologically based pharmacokinetic (PBPK) model of the prodrug oseltamivir and its active metabolite, oseltamivir carboxylate (OC), was established and validated to simulate their disposition in adults and predict the exposure in patients with Child-Pugh C cirrhosis (CP-C). The simulated results from PBPK modeling and the observed data after oral administration of various oseltamivir regimens were consistent according to the fold error values of less than 2. Furthermore, the clinical observations published in the literature were comparable with our pharmacokinetic predictions. In patients with CP-C, the oseltamivir Cmax was approximately 2-fold increased, and its AUC was approximately 6-fold higher compared with those in normal subjects. In contrast, the AUC of OC in CP-C patients did not differ significantly from that in normal subjects, whereas its Cmax was reduced by approximately 30% in the patients. Examination of drug exposure in different health conditions indicated that the oseltamivir exposure was significantly increased in conditions with elevated cirrhosis severity, which might be associated with a higher risk of adverse drug effects, e.g., neuropsychiatric adverse events (NPAEs). In conclusion, the pharmacokinetics of oseltamivir and OC were correctly predicted by PBPK modeling. The model further predicted that the pharmacokinetics of oseltamivir might be altered in liver cirrhosis, depending on the degree of severity.


Assuntos
Antivirais/farmacocinética , Simulação por Computador , Cirrose Hepática/metabolismo , Modelos Biológicos , Oseltamivir/análogos & derivados , Oseltamivir/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Cirrose Hepática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Oseltamivir/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Adulto Jovem
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