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1.
Arq Gastroenterol ; 57(1): 39-44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294734

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is the most common hepatotropic viral infection affecting the patients on maintenance hemodialysis. Treatment of chronic HCV infection in stage 4 and 5 CKD includes a combination of elbasvir/grazoprevir and glecaprevir/pibrentasvir, which are not available in many countries. OBJECTIVE: Hence, we have conducted this study to look for the safety and efficacy of sofosbuvir combination therapy in this difficult to treat population. METHODS: We conducted a single-center, prospective, open-label study in which Stage 5 CKD patients on maintenance hemodialysis with HCV infection. Total of 18 patients was included. sofosbuvir with daclatasvir or ledipasvir was used according to genotype for 12 weeks. HCV RNA, genotype, transient elastography (TE) was considered for every patient. HCV RNA was quantified at 4th week, 12th week and 12 weeks post-treatment to look for sustained virologic response (SVR 12). RESULTS: Infection due to genotype 1 was seen in 12 (66.7%) patients followed by genotype 3 in 4 (22.3%) with each patient of genotype 2 and 5. The median value of HCV RNA was 2,35,000 IU/mL. On TE, all had liver stiffness of <9.4 KPa. All patients had HCV RNA of <15 IU/mL at 4th and 12th week of treatment and 12 weeks post-treatment. No significant change in hemoglobin, eGFR and liver stiffness was observed. CONCLUSION: Full dose sofosbuvir i.e. 400 mg, in combination with NS5A inhibitors daclatasvir or ledipasvir is found to be safe and effective in patients with end stage renal disease, who are on maintenance hemodialysis.


Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Sofosbuvir/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral , Diálise Renal , Índice de Gravidade de Doença , Resposta Viral Sustentada , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(11): e19140, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176039

RESUMO

Treatment of hepatitis C virus (HCV) infection for patients with human immunodeficiency virus (HIV) has improved with direct acting antivirals. However, outcomes among Black persons treated with ledipasvir/sofosbuvir (LDV/SOF) may be inferior to non-Blacks. We assessed responses to LDV/SOF in a cohort of Black HIV/HCV coinfected persons.Retrospective chart reviews were conducted for Black, genotype 1 (GT1), HIV/HCV coinfected patients treated with LDV/SOF at 3 hospitals in Newark, NJ between January 2014 and July 2016. Data collected included demographics, HCV treatment history, treatment duration, and response.One hundred seventeen HIV/HCV coinfected Black patients started treatment with LDV/SOF but 5 had no follow-up data and 5 prematurely discontinued treatment (1 due to side effects). We included 107 HIV/HCV coinfected patients who completed LDV/SOF at all 3 sites. The study population was 65% male, median age 58 years, 26% had cirrhosis, and 78% had GT1a. Thirty-one percent were treatment experienced but none with prior NS5a treatment. At baseline, median CD4 count was 680 cells/mm, HIV viral load (VL) was <40 copies/mL in 94% and median HCV VL was 2,257,403 IU/mL. Twenty-nine percent of patients changed antiretroviral treatment before LDV/SOF treatment due to drug interactions. Six, 89, and 12 patients completed 8, 12, and 24 weeks of LDV/SOF, respectively. Overall sustained virologic response rate was 93% with 7 relapses.In this real-world cohort of Black, GT1, HIV/HCV coinfected patients, LDV/SOF had high sustained virologic response 12 weeks post completion of treatment rate of 93%. This data supports the overall high efficacy of LDV/SOF in a historically difficult-to-treat patient population.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Coinfecção/tratamento farmacológico , Fluorenos/uso terapêutico , Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepatite C/complicações , Uridina Monofosfato/análogos & derivados , Afro-Americanos/estatística & dados numéricos , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Coinfecção/virologia , Feminino , Fluorenos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , New Jersey , Estudos Retrospectivos , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/uso terapêutico
3.
Artigo em Inglês | MEDLINE | ID: mdl-32004940

RESUMO

Flibanserin (FLB) is the first FDA approved drug showed to have significant activity against sexual desire disorder of premenopausal and postmenopausal women. Unfortunately, FLB is used as an adulterant in dietary supplement products as a performance enhancer in sports. Identification of FLB and its metabolites in the biological samples requires an authenticated analytical technique. The aim of this study was to identify N-oxide metabolite of FLB in microsomal and S9 human liver enzyme fractions, rat urine and feces. There are several N-oxide reported as genotoxic impurity or reactive metabolites based on position of N-oxide in piperazine ring. This study also describes the strategy to utilize degradation chemistry for isolation of N-oxide and its step-wise characterization. An LC-MS method has been developed and employed for identifying the N-oxide metabolite of FLB. The targeted N-oxide metabolite in the extracted ion chromatogram of the in vitro and in vivo samples has been confirmed by analyzing the changes in observed mass at m/z 407.1693. Major distinguished abundant ions at m/z 243.1104, 190.0974, 161.0705, 119.0601 confirmed the structure of the metabolite. This study will help to understand the oxidative potential of FLB in toxicokinetic study. The developed method can be useful to identify FLB or its N-oxide metabolite in dope testing in future. This is the first time to report a strategy to utilize degradation chemistry for N-oxide metabolite characterization. In this study, isolated N-oxidative degradation product was used to confirm N-oxide metabolite which was characterized by LC-MS through H/D exchange and structure was ensured by NMR spectroscopy (1H, COSY).


Assuntos
Benzimidazóis , Medição da Troca de Deutério/métodos , Fezes/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/análise , Benzimidazóis/química , Benzimidazóis/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley
4.
PLoS One ; 15(2): e0229517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106270

RESUMO

AIMS: To analyze the efficacy and safety of sofosbuvir (SOF)-based regimens in Thai patients with chronic hepatitis C virus infection who had pre-existing significant liver fibrosis. PATIENTS AND METHODS: This was a retrospective cohort study, conducted between 1 June 2018 and 31 May 2019 at Rajavithi Hospital, Bangkok, Thailand. All patients completed 12 weeks of SOF-based regimens and had follow-up for at least 12 weeks after therapy discontinuation. The primary outcome was sustained virological response (SVR) 12 weeks after the end of therapy. RESULT: A total of 185 patients were included, with 52, 63 and 70 taking SOF+Ledipasvir (SOF+LDV), SOF+LDV+ribavirin (RBV) and SOF+Pegylated interferon (Peg-IFN)+RBV (SOF+Peg-IFN+RBV) respectively. Genotype (GT) 1 was predominant at 40.0%, followed by GT3 at 37.8%, and GT6 at 22.2%. Overall 95.1% of patients in this study achieved SVR (n = 176/185), and the only factor associated with SVR was HCV genotype (p = 0.001). GT6 patients had lower SVR rates compared to GT1 and GT3 patients (82.9%, 98.6%, and 98.6% respectively) while there was no association between SVR and other factors (p >0.05) such as gender, age, BMI, underlying cirrhosis, baseline HCV viral load, or prior treatment history. No serious adverse events were reported in the present study. CONCLUSION: Sofosbuvir-based regimens in the treatment of patients with chronic HCV infection were highly efficacious with excellent safety and tolerability profiles in a real-world setting; however, further research is required to establish whether or not such a regimen is an adequate treatment for all genotype 6 patients.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Estudos de Coortes , Quimioterapia Combinada , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2/administração & dosagem , Interferon alfa-2/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Tailândia , Fatores de Tempo , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/análogos & derivados
5.
PLoS One ; 15(1): e0224875, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995556

RESUMO

INTRODUCTION: Guidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.gov/ct2/show/NCT02707601) was to evaluate the safety/efficacy of ledipasvir/sofosbuvir (LDV/SOF) co-administered with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/F/TAF (R/F/TAF) in HIV-1/HCV co-infected participants. METHODS: Participants with HIV-1 RNA <50 copies/mL and chronic HCV-genotype (GT) 1 (HCV treatment-naïve ± compensated cirrhosis or HCV treatment-experienced non-cirrhotic) were randomized 1:1 to switch to E/C/F/TAF or R/F/TAF. If HIV suppression was maintained at Week 8, participants received 12 weeks of LDV/SOF. The primary endpoint was sustained HCV virologic response 12 weeks after LDV/SOF completion (SVR12). RESULTS: Of 150 participants, 148 received ≥1 dose of HIV study drug and 144 received LDV/SOF (72 in each F/TAF group; 83% GT1a, 94% HCV treatment-naïve, 12% cirrhotic). Overall, SVR12 was 97% (95% confidence interval: 93-99%). Black race did not affect SVR12. Of four participants not achieving SVR12, one had HCV relapse, one had HCV virologic non-response due to non-adherence, and two missed the post-HCV Week 12 visit. Of 148 participants, 96% receiving E/C/F/TAF and 95% receiving R/F/TAF maintained HIV suppression at Week 24; no HIV resistance was detected. No participant discontinued LDV/SOF or E/C/F/TAF due to adverse events; one participant discontinued R/F/TAF due to worsening of pre-existing hypercholesterolemia. Renal toxicity was not observed in either F/TAF regimen during LDV/SOF co-administration. In conclusion, high rates of HCV SVR12 and maintenance of HIV suppression were achieved with LDV/SOF and F/TAF-based regimens. CONCLUSION: This study supports LDV/SOF co-administered with an F/TAF-based regimen in HIV-1/HCV-GT1 co-infected patients.


Assuntos
Coinfecção/tratamento farmacológico , Combinação de Medicamentos , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Idoso , Benzimidazóis/administração & dosagem , Coinfecção/virologia , Farmacorresistência Viral/efeitos dos fármacos , Emtricitabina/administração & dosagem , Feminino , Fluorenos/administração & dosagem , Infecções por HIV/complicações , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Hepacivirus/patogenicidade , Hepatite C/complicações , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/isolamento & purificação , Sofosbuvir/administração & dosagem , Tenofovir/administração & dosagem
6.
Gynecol Oncol ; 156(1): 13-22, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708167

RESUMO

BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles. FINDINGS: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID. INTERPRETATION: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651). FUNDING: National Cancer Institute.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Epitelial do Ovário/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Peritoneais/patologia , Intervalo Livre de Progressão
7.
Eur J Med Chem ; 185: 111848, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732254

RESUMO

Protein neddylation is a posttranslational modification of conjugating the neuronal precursor cell-expressed developmentally down-regulated protein 8 (Nedd8) to substrates. Our previous work revealed that neddylation pathway is overactivated in various human lung cancers and correlates with the disease progression, whereas pharmacologically targeting this pathway has emerged as an attractive therapeutic strategy. As a follow-up research, 1331 approved drugs were investigated the inhibitory activities of cullin1 neddylation for screening the hit compounds via an improved enzyme-based assay. An antihypertensive agent, candesartan cilexetic (CDC), was identified as a novel neddylation inhibitor that ATP-competitively suppressing Nedd8-activating enzyme (NAE, E1) in mechanism, which inhibited the cullins neddylation superior than two representative non-covalent NAE inhibitors, M22 and mitoxantrone. Following with the findings such as apoptotic induction and tumor growth suppression in human lung cancer A549 in vitro and in vivo, CDC represents a potential anticancer lead compound with promising neddylation inhibitory activity.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Descoberta de Drogas , Tetrazóis/farmacologia , Células A549 , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzimidazóis/administração & dosagem , Benzimidazóis/química , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Injeções Intraperitoneais , Injeções Subcutâneas , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Tetrazóis/administração & dosagem , Tetrazóis/química
8.
Expert Opin Drug Saf ; 19(1): 1-8, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31855607

RESUMO

Introduction: Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual dysfunction in women, previously managed with off-label therapies. Indicated for premenopausal women, flibanserin is the first FDA-approved medication to treat HSDD.Areas covered: This review summarizes flibanserin's pharmacokinetics, proposed mechanism of action, and safety data in clinical trials with a focus on sedation- and hypotension-related adverse events, and drug interactions with alcohol and antidepressants. Sources included peer-reviewed publications and internal data from the manufacturer.Expert opinion: Flibanserin is a well-tolerated and effective treatment that decreases distress and restores sexual desire to a level that is normative for the individual patient with HSDD. Simplification of a risk mitigation program for flibanserin in the US is likely to increase the number of prescribing clinicians if accompanied with educational efforts to clarify flibanserin's risk-benefit profile. As flibanserin is dosed daily and may be used for a decade or more in the typical premenopausal patient, long-term pharmacovigilance data will be essential. Over time, HSDD will be treated by more nonspecialist health care professionals and flibanserin will likely become established as a significant treatment option along with other medications approved for this indication in the context of a holistic biopsychosocial treatment paradigm.


Assuntos
Benzimidazóis/administração & dosagem , Pré-Menopausa , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Benzimidazóis/efeitos adversos , Interações Medicamentosas , Humanos , Hipotensão/induzido quimicamente , Hipotensão/epidemiologia
9.
Yakugaku Zasshi ; 139(11): 1427-1434, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685739

RESUMO

Recently, a clinical study using a Chronic Liver Disease Questionnaire (CLDQ) showed that ledipasvir/sofosbuvir (LDV/SOF)-treated patients' QOL was more favorable than that of IFN/ribavirin (RBV)-treated patients. However, no study has reported QOL assessment in clinical practice. In this study, we compared the QOL between patients treated with LDV/SOF and those treated with simeprevir (SMV)/peginterferon (Peg-IFN)/RBV to provide QOL information in clinical practice. The subjects were 169 patients with type I chronic hepatitis C or compensated cirrhosis C (Child-Pugh Grade A) who were treated with SMV/Peg-IFN/RBV or LDV/SOF in Hitachi General Hospital. The QOL was assessed ≥2 weeks after the start of administration using the Japanese version of the CLDQ (Kida et al., 2008 version). The total CLDQ score in the LDV/SOF group was significantly higher than in the SMV/Peg-IFN/RBV group (6.59 vs. 6.38, respectively, p=0.007). In particular, the scores for 4 domains (abdominal symptoms, systemic symptoms, activity, and emotional function) in the former were significantly higher than in the latter (p<0.05). Furthermore, the rates of patients scoring 7 (no symptom) on 8 items in the former were significantly higher than in the latter (p<0.05). In clinical practice, LDV/SOF-treated patients' QOL was more favorable than that of those receiving conventional treatment with IFN and RBV. This study may make it possible for health care professionals to provide clinical QOL information on LDV/SOF therapy to patients. Furthermore, QOL information may promote decision-making for treatment, leading to effective treatment.


Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/psicologia , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Qualidade de Vida , Ribavirina/administração & dosagem , Simeprevir/administração & dosagem , Sofosbuvir/administração & dosagem , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem
10.
N Engl J Med ; 381(17): 1632-1643, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31566309

RESUMO

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Progressão da Doença , Eletrocorticografia , Feminino , Humanos , Análise de Intenção de Tratamento , Irinotecano/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
11.
Medicine (Baltimore) ; 98(36): e17050, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490400

RESUMO

BACKGROUND: Hypertension is one of the most common chronic diseases and an increasingly public-health challenge worldwide. Previous meta-analyses evaluated the effects of azilsartan medoxomil compared to placebo or other antihypertensive drugs in patients with hypertension. However, it is still unclear which dose of azilsartan is optimal. This study will perform a network meta-analysis to assess the efficacy and safety of different doses of azilsartan medoxomil in patients with hypertension. METHODS: PubMed, EMBASE.com, the Cochrane library, Scopus, and Web of Science were searched from inception to May 2019. Randomized controlled trials reporting efficacy and safety of different doses of azilsartan medoxomil on hypertension will be included if they compared 1 dose of azilsartan medoxomil with another dose of azilsartan medoxomil or with a placebo. Risk of bias of the included trials will be evaluated according to the Cochrane Handbook 5.1.0. NMA will be performed in a Bayesian hierarchical framework using WinBUGS 14. RESULTS: The results will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will summarize all the available data to provide reliable evidence of the value of different doses of azilsartan medoxomil for the treatment of hypertension. PROSPERO REGISTRATION NUMBER: CRD42019136882.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Benzimidazóis/administração & dosagem , Hipertensão/tratamento farmacológico , Oxidiazóis/administração & dosagem , Humanos , Metanálise em Rede
12.
J Neurooncol ; 144(3): 583-589, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31399935

RESUMO

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors are becoming increasingly utilized in the setting of advanced, hormone receptor (HR+) positive breast cancer. Pre-clinical data suggests a potential synergy between radiation therapy (RT) and CDK4/6 inhibitors. We assessed clinical outcomes of patients treated at our institution with the use of CDK4/6 inhibitors and stereotactic radiation in the management of HR+ breast brain metastases. METHODS: A retrospective analysis of patients who received stereotactic radiotherapy for HR+ brain metastases within 6 months of CDK4/6 inhibitor administration was performed. The primary endpoint was neurotoxicity during or after stereotactic radiation. Secondary endpoints were local brain control, distant brain control, and overall survival (OS). RESULTS: A total of 42 lesions treated with stereotactic radiation in 15 patients were identified. Patients received either palbociclib (n = 10; 67%) or abemaciclib (n = 5; 33%). RT was delivered concurrently, before, or after CDK4/6 inhibitors in 18 (43%), 9 (21%), and 15 (36%) lesions, respectively. Median follow-up following stereotactic radiation was 9 months. Two lesions (5%) developed radionecrosis, both of which received four prior RT courses to the affected lesion prior to onset of radionecrosis and subsequently managed with steroids and bevacizumab. Six- and 12-month local control of treated lesions was 88% and 88%, while 6- and 12-month distant brain control was 61% and 39%, respectively. Median OS was 36.7 months from the date of brain metastases diagnosis. CONCLUSIONS: Stereotactic radiation to breast brain metastases was well tolerated alongside CDK4/6 inhibitors. Compared to historical data, brain metastases control rates are similar whereas survival appears prolonged.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Neoplasias da Mama/terapia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Radiocirurgia/mortalidade , Adulto , Idoso , Aminopiridinas/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Terapia Combinada , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Prognóstico , Piridinas/administração & dosagem , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
13.
Pan Afr Med J ; 33: 26, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384341

RESUMO

Introduction: approximately eighty million people around the world are living with hepatitis C, and 700,000 people die every year, due to hepatitis C related complications. In Seychelles, a total of 777 cases of hepatitis C were reported from 2002 to 2016, but up to mid of 2016, the cases were not being treated. Treatment with Harvoni, a combination of sofosbuvir and ledipasvir (SOF/LDV), is now being offered on the condition that the patient does not, or has stopped, injecting drugs. This paper is the first to establish the cost effectiveness of treating all cases of hepatitis C in Seychelles with Harvoni, as compared to no treatment. Methods: data extracted from literature was used to populate an economic model to calculate cost-effectiveness from Seychelles' government perspective. The model structure was also informed by the systematic review and an accompanying grading of economic models using the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) checklist. A Markov model was developed, employing a lifetime horizon and costs and benefits were analysed from a payer's perspective and combined into incremental cost effectiveness ratios (ICERs). Results: the direct-acting antiviral (DAA), Harvoni, was found to be cost-saving in Seychelles hepatitis C virus (HCV) cohort, as compared to no treatment, with an ICER of € 753.65/QALY. The treatment was also cost-saving when stratified by gender, with the ICER of male and female being € 783.74/QALY and € 635.20/QALY, respectively. Moreover, the results obtained from acceptability curves showed that treating patients with Harvoni is the most cost-effective option, even for low thresholds. Conclusion: treating hepatitis C cases in Seychelles is cost-saving. It is worth developing a treatment programme to include all cases of hepatitis C, regardless of status of drug injection.


Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Uridina Monofosfato/análogos & derivados , Antivirais/economia , Benzimidazóis/economia , Análise Custo-Benefício , Feminino , Fluorenos/economia , Hepatite C Crônica/economia , Humanos , Masculino , Cadeias de Markov , Anos de Vida Ajustados por Qualidade de Vida , Fatores Sexuais , Seicheles , Abuso de Substâncias por Via Intravenosa/epidemiologia , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/economia
14.
Pak J Pharm Sci ; 32(3): 1019-1024, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278715

RESUMO

To compare the pharmacokinetics of candesartan cilexetil in healthy male and female volunteers in order to identify possible influence of gender and to improve therapeutic outcomes, an HPLC method for the quantification of candesartan cilexetil was developed and validated. Total of 16 volunteers (8 male and 8 female) were registered. Candesartan cilexetil 16 mg was administered orally to all the volunteers and blood samples were collected at different time intervals between 0-72 hours. Plasma was separated and analysed by HPLC method. Pharmacokinetic parameters were calculated by using APO software MW/PHARM version 3.02 and compared in male and female volunteers. The developed HPLC method fulfils the criteria for linearity, accuracy and precision described in EMA guideline. The values for absorption rate constant (Ka), maximum plasma concentration (Cmax), volume of distribution (Vd) and Clearance (CL) were similar in male and female volunteers. No influence of gender was observed on overall pharmacokinetics of candesartan cilexetil. Therefore, no need for dose optimization while administering candesartan cilexetil in male and female patients was found based on the results of this study.


Assuntos
Anti-Hipertensivos/sangue , Anti-Hipertensivos/farmacocinética , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Tetrazóis/sangue , Tetrazóis/farmacocinética , Adolescente , Adulto , Anti-Hipertensivos/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Cromatografia de Fase Reversa/métodos , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Fatores Sexuais , Tetrazóis/administração & dosagem , Adulto Jovem
15.
Biomed Res Int ; 2019: 9584748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360729

RESUMO

Background: The effect of ramosetron on the analgesic action of tramadol is not well known when ramosetron is added to intravenous-tramadol patient-controlled analgesia (PCA) and infused continuously. The aim of this randomized noninferiority study was to evaluate the effects of ramosetron on the analgesic action of tramadol when it is administered simultaneously in women undergoing laparoscopic gynecology who are receiving tramadol via IV PCA. Method: This study used a prospective, randomized, controlled, noninferiority clinical trial design and compared the analgesic effect of tramadol plus ramosetron with that of tramadol only. A total of 110 postoperative patients, who were using IV PCA tramadol, were randomly assigned either to a group receiving ramosetron (group R, n=49) or to a group that received the same volume of normal saline continuously (group N, n=51). Observation time points for cumulative tramadol consumption were the first hour, and every 4 h up to 12 h and then 24 h after surgery. Pain intensity at rest and during movement, coughing, and nausea scores, the analgesic and antiemetic doses used, side effects, and patient satisfaction were evaluated 1 and 24 h after surgery. Results: Groups R and N received, respectively, 88 ± 55 vs. 79 ± 42 mg tramadol (P=0.511) after 1 h, 211 ± 122 vs. 198 ± 109 mg cumulative tramadol (P=0.610) after 4 h, 244 ± 150 vs. 231 ± 134 mg cumulative tramadol (P= 0.793) after 8 h, 250 ± 156 vs. 247 ± 153 mg cumulative tramadol (P=0.972) after 12 h, and 294 ± 190 vs. 284 ± 178 mg cumulative tramadol (P=0.791) after 24 h, postsurgery. Tramadol plus ramosetron was shown to be not significantly inferior to tramadol alone in alleviating the postoperative pain. Conclusions: The analgesic effect of tramadol combined with ramosetron was found to be noninferior to tramadol alone for postoperative PCA after laparoscopic gynecologic surgery.


Assuntos
Benzimidazóis/administração & dosagem , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Tramadol/administração & dosagem , Administração Intravenosa , Adulto , Benzimidazóis/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Dor Pós-Operatória/patologia , Tramadol/efeitos adversos
16.
PLoS One ; 14(6): e0217471, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31158245

RESUMO

AIMS: The advent of direct-acting antivirals for hepatitis C virus (HCV) and limited effectiveness of prevention have generated interest in "Treatment as Prevention" (TasP), in which those most likely to transmit HCV (i.e. people who inject drugs [PWID]) are treated to reduced secondary transmission. However, there are scant data regarding the feasibility of treating PWID at high risk for secondary transmission or the optimal approach to treatment delivery. METHODS: We conducted a 2:1 randomized trial of modified directly-observed (mDOT) versus unobserved HCV treatment with ledipasvir-sofosbuvir daily for 8 weeks among PWID with 36 weeks of follow-up in San Francisco from 2015-2017. We evaluated recruitment-enrollment, treatment completion, end-of-treatment and 12-week response, and reinfection rate. RESULTS: Of 83 individuals eligible for screening, 72 (87.6%) attended the screening visit, 33 were eligible, and 31 enrolled; mean age was 42 years, 81% were male, 74% white. All but one participant (in the mDOT arm) completed treatment and 89.4% of mDOT and 96.6% of unobserved arm visits were attended. HCV was undetectable for 96.8% (30/31) at end of treatment and 89.7% (26/29) 12 weeks later (1 relapse, 1 reinfection), with no differences by arm. Two additional reinfections were subsequently identified, for a reinfection rate of 16.3 (95% CI 5.3-50.5) per 100 person-years of observation. CONCLUSIONS: It was feasible to recruit active PWID for HCV treatment and achieve high retention, viral response, and satisfaction with either mDOT or unobserved protocols, supporting treatment of PWID at risk of transmitting HCV to others. The reinfection rate suggests we successfully reached a high-risk population and that successful HCV TasP initiatives may aim to be sufficient in scope to significantly lower prevalence in the community. TRIAL REGISTRATION: clinicaltrials.gov NCT02609893.


Assuntos
Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepatite C , Abuso de Substâncias por Via Intravenosa , Uridina Monofosfato/análogos & derivados , Adulto , Feminino , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , São Francisco/epidemiologia , Abuso de Substâncias por Via Intravenosa/tratamento farmacológico , Abuso de Substâncias por Via Intravenosa/epidemiologia , Uridina Monofosfato/administração & dosagem
17.
Int J Clin Pharmacol Ther ; 57(8): 420-428, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31232274

RESUMO

OBJECTIVE: To investigate the bioequivalence, safety, and tolerability of single-dose nifedipine gastrointestinal therapeutic system (GITS) and candesartan as a fixed-dose combination (FDC) relative to the loose combination in healthy males under fed conditions. MATERIALS AND METHODS: A total of 48 subjects received nifedipine GITS 60 mg and candesartan 32 mg as an FDC or loose combination in an open-label, 2-way crossover, 2-treatment sequence design, with a washout of at least 5 days between treatments. Study medications were administered following an overnight fast of at least 10 hours, and 30 minutes after ingestion of a high-fat test meal. Plasma samples were collected at intervals over a 48-hour period post-dosing. Safety and tolerability parameters were documented throughout the study. RESULTS: For nifedipine, 90% confidence intervals (CIs) for the ratios of FDC/loose combination were within acceptance limits of bioequivalence (i.e., 80 - 125%) for both AUC0-tlast (91.36%; 111.5%) and Cmax (87.93%; 100.5%). For candesartan, 90% CIs for the ratios of FDC/loose combination were within acceptance limits for AUC0-tlast (112.8%; 124.4%), but not for Cmax (120.5%; 137.8%). There were no serious adverse events (AEs) or AEs leading to treatment discontinuation and no clinically relevant changes in vital signs or laboratory parameters. CONCLUSION: A single dose of the FDC-containing nifedipine GITS 60 mg and candesartan 32 mg, when compared to the corresponding loose combination under fed conditions, met the criterion for bioequivalence based on AUC0-tlast, while the slightly higher Cmax for candesartan is not considered clinically relevant. The FDC displayed safety and tolerability profiles similar to the loose combination.


Assuntos
Benzimidazóis/administração & dosagem , Nifedipino/administração & dosagem , Tetrazóis/administração & dosagem , Área Sob a Curva , Estudos Cross-Over , Combinação de Medicamentos , Humanos , Masculino , Comprimidos , Equivalência Terapêutica
18.
J Pharmacol Sci ; 140(2): 193-196, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31235271

RESUMO

We tested whether NNC 55-0396 (NNC), a T-type calcium channel (T-channel) blocker, reduces the brain injury caused by middle cerebral artery occlusion and reperfusion (MCAO/R) in mice. NNC, administered i.c.v. before the occlusion, greatly reduced the MCAO/R-induced brain infarct and neurological dysfunctions, although it, given toward the end of occlusion, was less effective. Systemic administration of NNC before the occlusion also attenuated the infarct and neurological dysfunctions. Our data imply that blood-brain-barrier-permeable T-channel blockers such as NNC are capable of reducing MCAO/R-induced brain damage, and that T-channels are involved in neuronal damage induced by ischemia rather than reperfusion.


Assuntos
Benzimidazóis/administração & dosagem , Lesões Encefálicas/etiologia , Lesões Encefálicas/prevenção & controle , Bloqueadores dos Canais de Cálcio/administração & dosagem , Ciclopropanos/administração & dosagem , Infarto da Artéria Cerebral Média/complicações , Naftalenos/administração & dosagem , Traumatismo por Reperfusão/complicações , Animais , Benzimidazóis/metabolismo , Barreira Hematoencefálica/metabolismo , Bloqueadores dos Canais de Cálcio/metabolismo , Canais de Cálcio Tipo T/fisiologia , Ciclopropanos/metabolismo , Infusões Intraventriculares , Infusões Parenterais , Masculino , Camundongos Endogâmicos , Naftalenos/metabolismo , Fatores de Tempo
19.
Rev Esp Quimioter ; 32(4): 296-302, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31232572

RESUMO

OBJECTIVE: The efficacy of ledipasvir/sofosbuvir (LDV/SOF) have been demonstrated in randomized controlled trials, however,there is an unmet need for real-world effectiveness data. It is important to gather data regarding potential predictors of treatment failure with (LDV/SOF). Predictors of sustained virologic response (SVR) to all-oral HCV regimens can inform nuanced treatment decisions. The objectives of this study were to evaluate the effectiveness of LDV/SOF, SVR12 as main endpoint and SVR24 as second endpoint, and identify predictors of treatment failure. METHODS: Retrospective and observational study carried out from April 2015 to January 2016. Inclusion criteria: patients with HCV infection treated with LDV/SOF for 12 weeks during study period. The patients that were treated during 24 weeks were excluded as well as those treated with peg-interferon. Binary logistic regression was used to predict what variable was associated with treatment failure. RESULTS: A total of 122 patients were analyzed achieving SVR12 91.80% (112/122) of them. The patients with HCV genotype (GT) 1a or GT1b or GT4 achieved SVR12. Only one pre-treated non-cirrhotic HCV GT1 patients relapsed to treatment. The lowest SVR12 were obtained for GT3, 43.75%, (7/16). Everybody that got SVR12 achieved SVR24. None of the variables analyzed significantly influenced the SVR12, except GT (p=0.001). Almost all the relapses occurred in GT3. CONCLUSIONS: LDV/SOF combination has been very effective to treat GT1 and GT4 infected patients, however, has constituted a suboptimal therapeutic option for those patients infected with GT3, regardless of the rest of the variables analyzed.


Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Sofosbuvir/administração & dosagem , Resposta Viral Sustentada , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Hepatite C/virologia , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Análise de Regressão , Estudos Retrospectivos , Falha de Tratamento
20.
Z Gastroenterol ; 57(5): 584-592, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083746

RESUMO

BACKGROUND: The urgent need in HCV-infected patients with liver disease mandated the rapid implementation of IFN-free DAA combination therapies following their regulatory approval in 2014 and 2015 without full knowledge of the optimal combinations and regimens. Investigating the evolution of the DAA utilization patterns and treatment outcomes could provide learnings for future situations. METHODS: This was an analysis of a prospective observational database from the German Hepatitis C Registry (DHC-R) covering a period from May 2014 to September 2015. Adult patients had evidence of chronic HCV GT1 or GT4 infection and were treated with an IFN-free combination regimen of simeprevir (SMV) + sofosbuvir (SOF) or other IFN-free regimens: daclatasvir + sofosbuvir (DCV + SOF), ledipasvir/sofosbuvir (SOF/LDV), paritaprevir/r + ombitasvir ± dasabuvir (PrOD), with or without ribavirine (R). RESULTS: A total of 5496 subjects were followed during the period. During this period, clinical recommendations and treatment patterns evolved rapidly in response to new evidence from clinical trials and clinical routine and regulatory approval of additional regimens. High SVR12 rates were seen in this cohort, even in hard-to-treat patient subgroups. In the multivariate analysis, gender, age, advanced cirrhosis, and intensified treatment for cirrhotics were associated with treatment outcome. CONCLUSION: Despite limited knowledge of the optimal utilization of the newly approved DAA combinations and treatment durations as well as their comparative efficacy and safety profiles, high SVR rates were achieved regardless of the DAA combination. These outcomes were facilitated by the rapid adaptation of clinical recommendations. Future situations with high unmet medical need may follow a similar approach.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Hepatite C/tratamento farmacológico , Adulto , Antivirais/uso terapêutico , Benzimidazóis/administração & dosagem , Combinação de Medicamentos , Quimioterapia Combinada , Fluorenos/administração & dosagem , Hepacivirus/genética , Hepatite C/virologia , Hepatite C Crônica/virologia , Humanos , Estudos Prospectivos , Sistema de Registros , Sofosbuvir/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento
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