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1.
Drugs ; 79(12): 1287-1304, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313099

RESUMO

Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Aprovação de Drogas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Terapia de Alvo Molecular , Nitrofenóis/uso terapêutico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Estados Unidos , United States Food and Drug Administration
2.
Orthop Nurs ; 38(4): 273-277, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343633

RESUMO

The treatment of hepatitis C virus (HCV) has evolved significantly, marked by the approval of combination, direct-acting antiviral medications, which have improved the tolerability and efficacy of therapy. As the number of patients engaged in HCV treatment increases, it is important that all members of the healthcare team remain current on treatment options and equipped with the knowledge to educate patients. Nursing staff play a critical role in understanding the role of new medications in treatment, significant drug interactions, and patient counseling points on administration, potential adverse reactions, and the importance of adherence.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Educação de Pacientes como Assunto/métodos , Quinoxalinas/uso terapêutico , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do Tratamento
3.
Medicine (Baltimore) ; 98(30): e16524, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348267

RESUMO

Anti-hepatitis C virus (HCV) treatment for human immunodeficiency virus (HIV)/HCV co-positive patients with hemophilia A presents numerous problems in terms of safety and effectiveness. The emergence of direct-acting antiviral (DAA) regimens has led to tremendous changes in the management of HIV/HCV co-infection over the past few years, but the application of DAA in patients with hemophilia complicated with HIV/HCV co-infection has rarely been reported.We retrospectively analyzed the clinical course and outcome of hemophilia A patients with HIV/HCV co-infection receiving DAA with a focus on the virological response, changes in cluster of differentiation 4 lymphocyte (CD4) count, side effects, and impact on bleeding before and after DAA therapy.A total of 12 hemophilia A patients with HIV/HCV co-infection were included, 9 of which were severe. All the patients were in stable states with CD4 counts >200/mm and plasma HIV ribonucleic acid (RNA) suppressed (<40 IU/mL) while taking the antiretroviral regimen. Majority of the patients (n = 9, 75.0%) were infected with HCV genotype (GT) 1b, while 2 and 1 was infected with HCV GT 2i and HCV GT 3, respectively.After 12 weeks of DAA treatment, 11 patients (91.7%) obtained sustained virologic response within 24 weeks of discontinuation of treatment (SVR24), except 1 patient who was treated with sofosbuvir (SOF) + pegylated interferon + ribavirin (PR), which was then switched to daclatasvir (DCV) + asunaprevir (ASV) for 12 weeks; this patient then achieved SVR24. During DAA treatment, HIV RNA in all the patients was constantly suppressed, while CD4 counts showed no obvious change.The most common treatment-emergent adverse events were weakness and loss of appetite (generally mild). There was no evidence of an increased tendency of bleeding, and changes in response to replacement.DAA therapy offered a safe and well-tolerated management strategy for HIV/HCV co-infected patients with hemophilia A. An awareness of the potential drug-drug interactions (DDI) between DAA and combination antiretroviral therapy (cART) by clinicians is important for optimal management of co-infected patients.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hemofilia A/tratamento farmacológico , Hepatite C/tratamento farmacológico , Adulto , Contagem de Linfócito CD4 , Coinfecção/imunologia , Coinfecção/virologia , Quimioterapia Combinada , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1 , Hemofilia A/imunologia , Hemofilia A/virologia , Hepacivirus , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Imidazóis/uso terapêutico , Interferons/uso terapêutico , Isoquinolinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada
4.
J Enzyme Inhib Med Chem ; 34(1): 1186-1192, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282228

RESUMO

A series of sixteen benzenesulfonamide derivatives has been synthesised and tested as inhibitors of Vibrio cholerae carbonic anhydrase (CA) enzymes, belonging to α-CA, ß-CA, and γ-CA classes (VchCAα, VchCAß, and VchCAγ). The determined Ki values were compared to those of selected human CA isoforms (hCA I and hCA II). Structure-affinity relationship analysis highlighted that all tested compounds proved to be active inhibitors of VchCAα at nanomolar concentration. The VchCAß activity was lower to respect inhibitory efficacy toward VchCAα, whereas, these benzenesulfonamide derivatives failed to inhibit VchCAγ. Interestingly, compound 7e combined the best activity toward VchCAα and VchCAß. In order to obtain a model for binding mode of our inhibitors toward bacterial CAs, we carried out docking simulations by using the available crystal structures of VchCAß.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Cólera/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Inibidores da Anidrase Carbônica/química , Cólera/enzimologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Vibrio cholerae/enzimologia
5.
Ann Hematol ; 98(8): 1927-1932, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187237

RESUMO

Patients with acute myeloid leukemia (AML) who progress after exposure to hypomethylating agents (HMA) have a dismal prognosis. We hypothesized that the addition of venetoclax, a BCL-2 inhibitor, to AML patients who previously failed HMA might overcome resistance. Adult patients (≥ 18 years) with AML were eligible if leukemia relapsed after, or was refractory to HMA. In general, in addition to venetoclax, patients continued HMA or other low-intensity therapies. Patients who previously underwent allogeneic hematopoietic cell transplantation (HCT) were also eligible. Data were analyzed in November 2018. Twenty-three patients were treated between October 2016 and October 2018 and were eligible for this study. Median age was 76 years and 6 patients had leukemia that relapsed post allogeneic HCT. None of the patients experienced tumor lysis syndrome and toxicities were as expected and manageable. Febrile neutropenia was the most common toxicity (78% of patients). Median hospitalization time was 13 days. Forty-three percent of the patients achieved CR/CRi. Overall survival (OS) was 74% at 6 months and median OS in patients who achieved remission was 10.8 months. Higher number of blasts in both bone marrow and peripheral blood was associated with lower chances of CR, while higher WBC, LDH, and bone marrow or peripheral blasts were associated with increased mortality rate. The addition of venetoclax to patients with HMA-refractory AML may result in a substantial anti-leukemic activity, specifically in those achieving complete remission. This should be further tested in a well-designed prospective trial.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/administração & dosagem , Neutropenia Febril Induzida por Quimioterapia/etiologia , Neutropenia Febril Induzida por Quimioterapia/mortalidade , Decitabina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , Transplante Homólogo
6.
Nat Commun ; 10(1): 2385, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160589

RESUMO

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.


Assuntos
Antineoplásicos/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/metabolismo , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cristalização , Cristalografia por Raios X , Humanos , Mutação , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Ressonância de Plasmônio de Superfície
7.
Medicine (Baltimore) ; 98(24): e15860, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192917

RESUMO

BACKGROUND: Vonoprazan, a novel potassium-competitive acid blocking agent, has been used in the management of endoscopic submucosal dissection (ESD)-induced artificial ulcers. This study aimed to perform a systematic review and meta-analysis for the comparison of the effects of vonoprazan and proton pump inhibitors (PPIs) in treating ESD-induced artificial ulcers and preventing delayed bleeding in randomized controlled trial and cohort studies. METHODS: We searched OVID-MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, and clinical trial registries in April 2018 to identify all studies that assess and compare the effects of vonoprazan and PPI in treating ESD-induced artificial ulcers and preventing delayed bleeding. Primary outcome of ulcer healing rate and secondary outcomes of shrinkage rate, ulcer size, and delayed bleeding were studied. RESULTS: A total of 1265 patients from 12 studies were included in the final analysis. Healing rate at 4 weeks post-ESD was significantly higher in the vonoprazan group than in the PPI group (relative ratio [RR] 1.20 [1.03-1.40]). However, healing rate at 8 weeks post-ESD was significantly higher in the PPI group than in the vonoprazan group (RR 0.68 [0.48-0.97]).There was no evidence of significant difference between groups in shrinkage rate at 4 weeks post-ESD, shrinkage rate at 8 weeks post-ESD, delayed bleeding, ulcer size at 0 weeks post-ESD, and ulcer size at 8 weeks post-ESD. CONCLUSIONS: There was no substantial difference in ulcer healing and post-ESD bleeding between vonoprazan and PPIs. However, vonoprazan more rapidly and effectively treated artificial ulcers after ESD than did PPIs.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Ressecção Endoscópica de Mucosa/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Úlcera/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Úlcera/etiologia
8.
Dtsch Med Wochenschr ; 144(11): 748-752, 2019 06.
Artigo em Alemão | MEDLINE | ID: mdl-31163474

RESUMO

In Germany, baricitinib and tofacitinib have been approved for the treatment of at least moderately active rheumatoid arthritis after the failure of conventional disease modifying anti-rheumatic drugs in 2017, and tofacitinib also for psoriatic arthritis and ulcerative colitis. Both baricitinib and tofacitinib can be taken orally and reversibly inhibit Janus kinases (JAK) and therefore the signaling of a large number of cytokines via the JAK/STAT pathway. JAK inhibitors have been shown to be at least as efficacious in rheumatoid arthritis as adalimumab and tofacitinib was also efficacious in psoriatic arthritis. Since they inhibit many cytokines, it is likely that in the future they will be applied for the treatment of further chronic inflammatory disorder such as connective tissue diseases and vasculitis. The adverse events of JAK inhibitors are comparable to those observed with biologicals, only herpes zoster is slightly more common. In the placebo-controlled trials, venous thromboembolic events (VTE) were more common in the baricitinib treated patients. The VTE rate does not appear to be elevated in baricitinib treated patients compared to RA cohorts however.In conclusion, JAK inhibitors are a powerful new treatment of RA and likely many other rheumatic diseases and fulfill an unmet need since they may be taken orally.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Azetidinas/uso terapêutico , Alemanha , Humanos , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico
9.
Value Health ; 22(6): 693-703, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31198187

RESUMO

BACKGROUND: Direct-acting antivirals are successful in curing hepatitis C virus infection in more than 95% of patients treated for 12 weeks, but they are expensive. Shortened treatment durations, which may have lower cure rates, have been proposed to reduce costs. OBJECTIVES: To evaluate the lifetime cost-effectiveness of different shortened treatment durations for genotype 1 noncirrhotic treatment-naive patients. METHODS: Assuming a UK National Health Service perspective, we used a probabilistic decision tree and Markov model to compare 3 unstratified shortened treatment durations (8, 6, and 4 weeks) against a standard 12-week treatment duration. Patients failing shortened first-line treatment were re-treated with a 12-week treatment regimen. Parameter inputs were taken from published studies. RESULTS: The 8-week treatment duration had an expected incremental net monetary benefit of £7737 (95% confidence interval £3242-£11 819) versus the standard 12-week treatment, per 1000 patients. The 6-week treatment had a positive incremental net monetary benefit, although some uncertainty was observed. The probability that the 8- and 6-week treatments were the most cost-effective was 56% and 25%, respectively, whereas that for the 4-week treatment was 17%. Results were generally robust to sensitivity analyses, including a threshold analysis that showed that the 8-week treatment was the most cost-effective at all drug prices lower than £40 000 per 12-week course. CONCLUSIONS: Shortening treatments licensed for 12 weeks to 8 weeks is cost-effective in genotype 1 noncirrhotic treatment-naive patients. There was considerable uncertainty in the estimates for 6- and 4-week treatments, with some indication that the 6-week treatment may be cost-effective.


Assuntos
Antivirais/economia , Hepatite C Crônica/tratamento farmacológico , Antivirais/uso terapêutico , Carbamatos/economia , Carbamatos/uso terapêutico , Análise Custo-Benefício , Árvores de Decisões , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Compostos Heterocíclicos de 4 ou mais Anéis/economia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Compostos Macrocíclicos/economia , Compostos Macrocíclicos/uso terapêutico , Cadeias de Markov , Sofosbuvir/economia , Sofosbuvir/uso terapêutico , Medicina Estatal/organização & administração , Medicina Estatal/estatística & dados numéricos , Sulfonamidas/economia , Sulfonamidas/uso terapêutico , Reino Unido
10.
Chem Biol Interact ; 309: 108723, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31228469

RESUMO

Ischemic preconditioning and pharmacological preconditioning are common strategies to prevent lethal myocardial injury, especially nutritional preconditioning (NPC). In this study, we investigated the effects of astragaloside IV (Ast), as an NPC agent, on myocardium suffered anoxia/reoxygenation (A/R) injury. Rats received 5 mg/kg Ast daily for 3 weeks by intragastric administration. Then, hearts were harvested and underwent A/R treatment using a Langendorff apparatus. Ast- pretreatment significantly promoted functional recovery of the myocardium, reduced infarct size, and oxidative stress, and decreased the apoptotic index. Similar findings were demonstrated in H9c2 cardiomyocytes that were pretreated with Ast for 24 h. Moreover, Ast-pretreatment significantly upregulated Bcl-2 expression, especially in mitochondria. The effects of Ast treatment against A/R injury were also reflected by increased antioxidant potential, inhibited reactive oxygen species (ROS) burst, increased oxygen consumption rate, maintained mitochondrial membrane potential (MMP), inhibited mitochondrial permeability transition pore (mPTP) opening, and prevented apoptosis. Selective inhibition of Bcl-2 by ABT-737 decreased myocardial injury protection of Ast. Ast-pretreatment resulted in NPC- related effects against A/R, and mitochondria may be the target of a cascade of events elicited by upregulating Bcl-2 expression, promoting translocation of Bcl-2 into mitochondria, maintaining MMP, inhibiting ROS bursts, thereby leading to recovery of mitochondrial respiration, preventing mPTP opening, decreasing cytochrome C release, preventing apoptosis, and ultimately alleviating myocardial injury.


Assuntos
Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nitrofenóis/farmacologia , Nitrofenóis/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Superóxido Dismutase/metabolismo
11.
Nat Cell Biol ; 21(6): 778-790, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160710

RESUMO

Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAFV600E tumours, we found mechanisms of intrinsic resistance to BRAFV600E-targeted therapy in colorectal cancer, including targetable parallel activation of PDPK1 and PRKCA. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identifies RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAFV600E patients. The results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for precision medicine.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Neoplasias Colorretais/tratamento farmacológico , Melanoma/tratamento farmacológico , Proteína Quinase C-alfa/genética , Proteínas Proto-Oncogênicas c-pim-1/genética , Adulto , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/química , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/genética , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/uso terapêutico , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico
12.
BMC Infect Dis ; 19(1): 378, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053098

RESUMO

BACKGROUND: Treatments for Hepatitis C virus (HCV) infection have vastly improved over the past few decades with current regimens now offering pangenotypic activity with excellent cure rates reported in clinical trials, including in the HIV-HCV coinfected population. However, there is some concern that stringent inclusion and exclusion criteria in the trials may lead to results that are not achievable in real-world populations. METHODS: Our study evaluated a real-world HIV-HCV coinfected population and compared them to the eligibility criteria for trials of two of the most recent approved HCV agents; sofosbuvir/velpatasvir and glecaprevir/pibrentasvir. RESULTS: Our study included 219 HIV-HCV coinfected patients and found that 89% met exclusion criteria for the sofosbuvir/velpatasvir trial and 90% met exclusion criteria for the glecaprevir/pibrentasvir trial. The majority of patients met more than one exclusion criteria with the most frequent criteria for exclusion being a non-approved ART regimen (58 and 47% respectively), having a psychiatric disorder (52%), active alcohol or injection drug use (27%), having an HIV viral load > 50 copies/ml (15%), a CrCl < 60 ml/min (13%) and a history of decompensated cirrhosis (13%). CONCLUSION: Although the newer Hepatitis C treatments are very effective, the real world HIV-HCV coinfected population often have comorbidities and other characteristics that make them ineligible for clinical trials, such that they are barriers to treatment. These barriers need to be recognized and addressed in order to optimize treatment outcomes in the HIV patient population.


Assuntos
Antivirais/uso terapêutico , Coinfecção/diagnóstico , Infecções por HIV/diagnóstico , Hepatite C/tratamento farmacológico , Adulto , Idoso , Antirretrovirais/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Interações de Medicamentos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Quinoxalinas/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do Tratamento , Carga Viral
13.
Medicine (Baltimore) ; 98(20): e15632, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096477

RESUMO

BACKGROUND: It is commonly reported a limitation of therapeutic strategy in Eisenmenger syndrome (ES) historically. This qualitative systematic review is conducted to evaluate the safety and efficacy of pulmonary arterial hypertension-specific drug therapy (PAH-SDT) for ES patients for a clinical therapeutic strategy based on evidence. METHODS: PubMed, EMBASE, and the Cochrane Library databases have been systematically reviewed up to January 2019. Two reviewers independently conducted a literature search, quality evaluation, and data extraction. The occurrence of death, deterioration, and adverse events (AEs) has respectively been described as a count or percentage. Meta-analysis was conducted by Stata 15.1, and weighted mean differences (WMD) with 95% confidence intervals (CI) were recorded for continuous data. Randomized-effect model or fixed-effect model was applied according to the heterogeneity test. RESULTS: Fifteen citations recruiting 456 patients associated with ES were eventually pooled, which involved 4 RCTs, 6 prospective studies, and 5 retrospective studies. Within the first year, it indicated PAH-SDT significantly ameliorated exercise capacity in 6-minute walk distance (6MWD) (I = 60.5%; WMD: 53.86 m, 95% CI [36.59, 71.13], P < .001), functional class (FC) (WMD = -0.71, 95% CI [-0.98, -0.44], P < .001) and Borg dyspnea index (WMD = -1.28, 95% CI [-1.86, -0.70], P < .001), in addition to hemodynamics, especially mean pulmonary arterial pressure by 5.70 mmHg (WMD = -5.70 mmHg, 95% CI [-8.19, -3.22], P < .001) and pulmonary vascular resistance by 4.20 wood U (WMD: -4.20, 95% CI [-7.32, -1.09], P = .008), but unsatisfactory effects in oxygen saturation at exercise (P = .747). In a prolonged medication, bosentan, a dual ERA, has been proved acting an important role in improving exercise tolerance of patients with ES (6MWD: I = 47.5%; WMD: 88.68 m, 95% CI [54.05, 123.3], P < .001; FC: I = 0.0%; WMD = -0.65, 95% CI [-1.10, -0.19], P = .006). While a nonsignificant change of 6MWD was noted in a long-term therapy of ambrisentan (P = .385). There existed rare evidence about the efficacy and safety of macitentan, phosphodiesterase-5 inhibitors (PDE5i), and prostanoids in a prolonged medication. Most AEs were recorded as mild to moderate with PAH-SDT, but about 4.3% individuals treated with endothelin receptor antagonists (ERAs) suffered from serious ones, and 3.9% suffered from death. CONCLUSIONS: This systematic review and meta-analysis proved PAH-SDT as a safe and effective role in ES in an early stage. However, in a long-term treatment, bosentan has been supported for a lasting effect on exercise tolerance. A further multicenter research with a large sample about pharmacotherapy of ES is necessary.


Assuntos
Anti-Hipertensivos/uso terapêutico , Complexo de Eisenmenger/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostaglandinas/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/efeitos adversos , Tolerância ao Exercício/efeitos dos fármacos , Hemodinâmica , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Oxigênio/sangue , Fenilpropionatos/uso terapêutico , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/efeitos adversos , Prostaglandinas/administração & dosagem , Prostaglandinas/efeitos adversos , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico
14.
Medicine (Baltimore) ; 98(20): e15701, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096515

RESUMO

BACKGROUND: Endoscopic submucosal dissection (ESD) is a standard procedure for treating gastric neoplasms. However, ESD causes larger artificial ulcers other than mucosal resection methods. We conducted this prospective randomized controlled study to evaluate the effect of stronger acid suppression on ESD ulcers caused by doubling the proton pump inhibitor (PPI) dose and compare the effects of 20-mg (standard dose) and 40-mg (double dose) esomeprazole (EswonampTM, Daewon Pharmaceutical Co., Ltd., Seoul, Korea) on ulcer healing. METHODS: One hundred ninety-seven patients who underwent gastric ESD from July 2017 to December 2017 at Pusan National University Yangsan Hospital were enrolled and randomly assigned to the standard or double-dose group. Change in ulcer size from the day of ESD to 4 weeks after ESD and the scar-change rate were compared between the groups. RESULTS: There were no significant differences in ulcer contraction (84.5% in 20 mg group vs 86.3% in 40 mg group, P = .91) or scar-change rate (30.9% vs 30.6%, P > .99) between the groups. In a multivariate analysis, initial ulcer size [odds ratio (OR) 0.24; 95% confidence interval (CI) 0.11-0.50] and early gastric cancer (OR 0.22, 95% CI 0.08-0.58) were significantly associated with delayed ulcer healing. CONCLUSIONS: Both 40 and 20-mg esomeprazole have similar effects on ESD-induced ulcer area reduction, suggesting that strong acid suppression does not necessarily result in rapid artificial ulcer healing. TRIAL REGISTRATION NUMBER: RCT no.: KCT0002885.


Assuntos
Ressecção Endoscópica de Mucosa/efeitos adversos , Esomeprazol/uso terapêutico , Neoplasias Gástricas/cirurgia , Úlcera Gástrica/tratamento farmacológico , Ressecção Endoscópica de Mucosa/métodos , Esomeprazol/administração & dosagem , Feminino , Humanos , Masculino , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/administração & dosagem , Pirróis/uso terapêutico , República da Coreia/epidemiologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/patologia , Úlcera Gástrica/patologia , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Úlcera/tratamento farmacológico , Úlcera/patologia , Cicatrização/efeitos dos fármacos
15.
Drugs Today (Barc) ; 55(4): 247-264, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31050693

RESUMO

BRAF is a constituent of the mitogen-activated protein kinase (MAPK) signaling pathway, which serves to activate downstream MEK, and is one of the most commonly mutated oncogenes in human tumors. Indeed, BRAF V600 mutations are present in approximately 40% of metastatic melanoma tumors. Encorafenib (LGX-818, Braftovi) and binimetinib (MEK-162, Mektovi) are small-molecule inhibitors of BRAF and MEK, respectively. BRAF and MEK inhibitors have been shown to improve overall and progression-free survival among patients with metastatic melanoma. Of these inhibitors, encorafenib and binimetinib are the newest combination, which received approval by the Food and Drug Administration (FDA) for the treatment of BRAF V600E/K-mutated melanoma in June 2018. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of encorafenib and binimetinib in BRAF V600-mutated melanoma.


Assuntos
Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/uso terapêutico , Humanos , Melanoma/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
16.
BMC Vet Res ; 15(1): 137, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068210

RESUMO

BACKGROUND: Oclacitinib is a Janus kinase (JAK) 1 enzyme inhibitor and blocks JAK1-dependent cytokines and is used to control pruritus. Studies available in cats are very limited and as there is a potential role for oclacitinib in the control of pruritus in this specie, the aim of this study was to evaluate the safety and clinical effects of oral oclacitinib maleate in healthy cats. RESULTS: Thirty mixed-breed cats weighing from 2.1 to 5.3 kg each were randomly allocated to three treatment groups of 10 animals each. Cats in two groups received oclacitinib at 1 mg/kg or 2 mg/kg q 12 h orally for 28 days. Cats in the third group were given placebo tablets (cornstarch) q 12 h orally for 28 days. Oclacitinib maleate was well tolerated during the study and few adverse events were observed in treated cats. Clinical signs of toxicity were not observed in any animals treated at 1 mg/kg. Gastrointestinal clinical signs observed in the 2 mg/kg group included vomiting in two of the 10 cats and soft stools in two cats. One cat treated with placebo also exhibited soft stools. No significant differences were observed between the groups for hematologic analyses performed during the study. There was a slight increase in neutrophils and monocytes and a decrease in eosinophil mean counts in treated cats. Mean renal and liver enzymes remained normal throughout the entire study. A small, but significant increase in fructosamine levels was observed for both treated groups compared with placebo; however, values remained within the normal reference range. There were no significant difference between treated groups and the placebo group for urine specific gravity, pH, or urine protein to creatinine ratio mean values. CONCLUSIONS: Oclacitinib maleate was well tolerated by cats at 1 mg/kg and 2 mg/kg and appeared to be safe for this species when administered orally twice daily for 28 days. More studies would be needed to demonstrate if oclacitinib maleate may be a suitable alternative to treat pruritic cats.


Assuntos
Doenças do Gato/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Gatos , Feminino , Masculino , Pirimidinas/efeitos adversos , Distribuição Aleatória , Sulfonamidas/efeitos adversos
17.
Eur J Med Chem ; 177: 188-197, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136893

RESUMO

Carbonic Anhydrases have been recently validated as novel therapeutic targets in neuropathic pain. In this study, we combine the anticonvulsant propriety of spyrohydantoin and the CA inhibitor moiety of benzenesulfonamide to synthesize a novel series of spyrohydantoin bearing sulfonamides with strong activity against hCA II and VII. These isoforms are present in the nervous system and largely expressed both at the central as well as at peripheral level and can be modulated for pain relief. The crystal structures of hCA II in complex with selected compounds 5a-c demonstrate the importance of the tail in the binding modes within the isoform. Finally, in vivo, in an animal model of oxaliplatin induced neuropathy, compounds with organoselenium tails (8b-c) showed potent neuropathic pain attenuating effects. Taken together, these data strongly suggest the translational utility of these inhibitors as novel pain relievers.


Assuntos
Analgésicos/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Hidantoínas/uso terapêutico , Neuralgia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Cristalografia por Raios X , Desenho de Drogas , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
18.
Georgian Med News ; (288): 77-81, 2019 Mar.
Artigo em Russo | MEDLINE | ID: mdl-31101781

RESUMO

The aim of this study was to investigate the efficacy and safety of the ombitasvir/ paritaprevir/ ritonavir and dasabuvir in patients with HCV, genotype-1b, in real clinical practice in Ukraine. The study included a total of 50 HCV infection genotype 1b patients receiving ombitasvir/ paritaprevir/ ritonavir and dasabuvir for 12 weeks. The patients were evaluated in respect of demographic, clinical and virological data, sustained virologic response (SVR) and adverse events. The mean age of patients was 52 years (40-60), 42% men, 20% treatment experienced, 42% with compensated cirrhosis. The SVR12 rate of all HCV genotype 1b patients was 96% (95%CI:86,3-99,5%). The most common adverse events were fatigue in 14 (28%) patients, diarrhea in 10 (20%) and headache in 12 (24%). In our study, the real world clinical practice data shows that ombitasvir/ paritaprevir/ ritonavir and dasabuvir for 12 weeks in HCV genotype 1b patients was well tolerated and resulted in 96% SVR12 regardless of previous treatment status and liver fibrosis stage.


Assuntos
Antivirais , Hepatite C Crônica , Adulto , Anilidas/uso terapêutico , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Humanos , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ribavirina , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do Tratamento , Ucrânia , Uracila/análogos & derivados , Uracila/uso terapêutico
19.
Expert Opin Investig Drugs ; 28(6): 505-511, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31010343

RESUMO

Introduction: Liposarcomas (LPS) are a heterogeneous group of adipocytic soft tissue sarcomas with limited treatment options in the advanced/metastatic setting. Pazopanib is a multi-target tyrosine kinase inhibitor (TKI) with anti-angiogenic and antitumorigenic properties. Whilst targeted agents including TKIs have been extensively studied in other solid tumors and the sarcoma subtype gastrointestinal stromal tumor (GIST), we currently lack effective treatments for the liposarcoma subtype. Several phase II and III studies of oral TKIs in soft tissue sarcomas have excluded liposarcoma because of a reported lack of activity following the EORTC 62043 study. Areas: We review the use of pazopanib in advanced intermediate and high-grade liposarcomas where complete surgical resection is not possible. Expert opinion: The current clinical and pharmacological data demonstrate the efficacy of pazopanib in soft tissue sarcomas, but new data suggest that anti-angiogenic agents may have limited activity in liposarcoma. Anti-angiogenic TKIs are generally well tolerated and liposarcomas vary in their response to systemic chemotherapy; hence, there is a role for further exploration of the efficacy of this treatment amongst the histological subtypes of liposarcoma. This affords further understanding of biomarkers which may be associated with response to pazopanib and other anti-angiogenic TKI treatments.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Lipossarcoma/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Humanos , Lipossarcoma/patologia , Gradação de Tumores , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Resultado do Tratamento
20.
Medicine (Baltimore) ; 98(15): e15170, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985700

RESUMO

Atrial remodeling plays a significant role during the progression of atrial fibrillation (AF). Left atrial wall thickness (LAT) is a subjective and easily acquirable indicator referring to structural remodeling. Therefore, we aimed to investigate the association between LAT and atrial remodeling substrate, and to explore the predictive role of LAT about strong maintenance substrate and poor response to catheter ablation.LAT was measured by cardiac computed tomography in 2 selected locations (roof and floor) in 100 persistent AF patients. Then the low-dose-ibutilide-facilitated catheter ablation was performed and atrial maintenance substrate was categorized as weak, mild, and strong, based on the response to circumferential pulmonary vein isolation or complex fractionated atrial electrograms ablation. During follow-up, the success rate was evaluated. LAT showed a progressive thickening tendency from weak, mild, to strong maintenance substrate (roof: 2.2 mm vs. 2.6 mm vs. 3.9 mm, P < .0001; floor: 1.7 mm vs. 2.0 mm vs. 2.5 mm, P < .0001). During follow-up, the success rate of ablation was decreased with the maintenance substrate strengthening (weak 80%, mild 64.53%, strong 31.43%, P = .009). LA roof thickness >3.10 mm might be the predictor to strong atrial maintenance substrate and poor response to ablation.LAT was associated with the remodeling extent of atrial maintenance substrate and might predict the response to catheter ablation. These findings could help the clinicians to select the appropriate ablative strategy and predict the complexity and prognosis before catheter ablation.


Assuntos
Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Idoso , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/terapia , Ablação por Cateter , Meios de Contraste , Feminino , Seguimentos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Estudos Prospectivos , Sulfonamidas/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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