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1.
BMC Cancer ; 19(1): 1253, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31881856

RESUMO

BACKGROUND: A previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings. METHODS: Records of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution. RESULTS: Totally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3-5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8-2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48-0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥ 3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444). CONCLUSIONS: In real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities. TRIAL REGISTRATION: Retrospectively registered.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Uracila/uso terapêutico , Adulto Jovem
2.
Lancet ; 394(10213): 2012-2024, 2019 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-31727409

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-ß agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. METHODS: MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260. FINDINGS: 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (-32·9% resmetirom vs -10·4% placebo; least squares mean difference -22·5%, 95% CI -32·9 to -12·2; p<0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom. INTERPRETATION: Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging. FUNDING: Madrigal Pharmaceuticals.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piridazinas/uso terapêutico , Receptores beta dos Hormônios Tireóideos/agonistas , Uracila/análogos & derivados , Adulto , Alanina Transaminase/sangue , Biomarcadores/sangue , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Inflamação/patologia , Lipídeos/sangue , Fígado/diagnóstico por imagem , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Piridazinas/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico
3.
Am J Health Syst Pharm ; 76(6): 339-348, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31361848

RESUMO

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, dosing, and place in therapy of trifluridine-tipiracil are reviewed. SUMMARY: Trifluridine-tipiracil is an oral antineoplastic agent consisting of trifluridine (a trifluorothymidine, a thymidine-based nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor), at a molar ratio of 1:0.5. Tipiracil blocks the degradation of trifluridine by thymidine phosphorylase, which improves the bioavailability of trifluridine and allows for oral administration. A Phase III study comparing trifluridine-tipiracil versus placebo in metastatic colorectal cancer (mCRC) patients refractory to or intolerant of standard therapy (n = 800) showed a benefit in overall survival (the primary endpoint) and progression-free survival compared with placebo. The most common grade ≥ 3 adverse events in trifluridine-tipiracil groups in Phase II and III trials were neutropenia, anemia, and leukopenia. The recommended dose of trifluridine-tipiracil is 35 mg/m2 twice a day after meals in a 28-day cycle comprising 2 weeks of 5 days of treatment and 2 days of rest (days 1-5 and 8-12 [every] 28 days), followed by 2 weeks of rest. Trifluridine-tipiracil is approved for the treatment of patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antivascular endothelial growth factor biological therapy and, if RAS wild-type, an antiepidermal growth factor receptor therapy. CONCLUSION: Trifluridine-tipiracil is a new treatment option for patients with mCRC who have received at least 2 prior lines of standard chemotherapy (including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an antiepidermal growth factor receptor antibody in patients with KRAS wild-type tumors). Ongoing trials are investigating trifluridine/tipiracil in combination with other anticancer agents for mCRC and its use in other malignancies, such as metastatic gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/farmacologia , Trifluridina/farmacologia , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Humanos , Intervalo Livre de Progressão , Pirrolidinas/uso terapêutico , Timidina Fosforilase/antagonistas & inibidores , Timidina Fosforilase/metabolismo , Trifluridina/uso terapêutico , Uracila/farmacologia , Uracila/uso terapêutico
4.
J Cancer Res Clin Oncol ; 145(8): 2157-2166, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273512

RESUMO

PURPOSE: Adjuvant chemotherapy for gastric cancer, particularly stage III, improves survival after curative D2 gastrectomy. We investigated the clinical value of the lymph-node ratio (LNR; number of metastatic lymph nodes/number of lymph nodes examined) for selecting the appropriate adjuvant chemotherapy regimen in patients with D2-resected stage II/III gastric cancer. METHODS: We reviewed the data of 819 patients who underwent curative D2 gastrectomy followed by adjuvant chemotherapy. Of them, 353 patients received platinum-based chemotherapy and 466 received TS-1. The patients were categorized into three groups according to their LNR (LNR 1, 0-0.1; LNR 2, > 0.1-0.25; and LNR 3, > 0.25), and their disease-free survival (DFS) was evaluated. RESULTS: The DFS curves of the patients were well separated according to stage and LNR. In multivariate analyses, an LNR > 0.1 was strongly associated with the 3-year DFS (hazard ratio 2.402, 95% confidence interval 1.607-3.590, P < 0.001). Platinum-based chemotherapy improved the 3-year DFS compared to TS-1 in patients with LNR 3 group in stage III gastric cancer (platinum vs. TS-1, median DFS 26.87 vs. 16.27 months, P = 0.028). An LNR > 0.1 was associated with benefiting from platinum-based adjuvant chemotherapy in stage III gastric cancer patients with lymphovascular invasion (platinum vs. TS-1, median DFS 47.57 vs. 21.77 months, P = 0.011). CONCLUSIONS: The LNR can be used to select the appropriate adjuvant chemotherapy regimen for patients with D2-resected gastric cancer, particularly in stage III.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Comportamento de Escolha , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Gastrectomia , Linfonodos/patologia , Neoplasias Gástricas/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/classificação , Cisplatino/uso terapêutico , Terapia Combinada , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Gastrectomia/métodos , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Tegafur/uso terapêutico , Uracila/uso terapêutico
5.
Expert Opin Pharmacother ; 20(14): 1679-1687, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31335214

RESUMO

Introduction: A growth in the market for anti-diabetic drugs, along with an ever-increasing population suffering from type 2 diabetes mellitus (T2DM), requires a critical re-evaluation of anti-diabetic drugs used for a long time, in order to provide up-to-date practical prescribing information for clinicians. Alogliptin benzoate was firstly approved in 2010 in Japan for T2DM, both as a monotherapy or in combination with other anti-diabetic drugs. Areas covered: This article provides a comprehensive review of the latest data on alogliptin benzoate, including hypoglycemic activity and safety. Expert opinion: The cumulative evidence for alogliptin benzoate is robust with regards to glycemic efficacy and safety. Low hypoglycemia risks and weight changes support its consideration as a first-line medication for T2DM, either as a monotherapy or in combination therapy with other anti-diabetic drugs such as metformin. Ongoing trials will look to better analyze and address its safety and efficacy in pediatric patients and expand our clinical knowledge of this medication.


Assuntos
Benzoatos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Piperidinas/uso terapêutico , Uracila/análogos & derivados , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Meia-Vida , Humanos , Hipoglicemia/patologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Uracila/efeitos adversos , Uracila/farmacocinética , Uracila/uso terapêutico
6.
Diabetes Res Clin Pract ; 153: 41-48, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31150724

RESUMO

AIMS: The changes in patients' satisfaction with the treatment, medication adherence and unused drugs before and after switching from daily DPP-4 inhibitors to once-weekly trelagliptin administration were prospectively investigated in patients with type 2 diabetes. METHODS: After excluding 46 patients who declined to switch from daily DPP-4 inhibitors, 79 subjects were included in the present study. The clinical parameters and results of questionnaire surveys regarding satisfaction with treatment as well as impressions of the amount of medicine/number of doses, medication adherence, and unused drug were examined at the baseline and 3 months after switching from daily DPP-4 inhibitors to trelagliptin in 75 patients with type 2 diabetes. RESULTS: Although the value of HbA1c did not change (7.0% ±â€¯0.5% to 7.0% ±â€¯0.6%), the scores representing satisfaction with the treatment (25.2 ±â€¯6.4 to 26.4 ±â€¯6.0), impression of the amount of medicine (-0.3 ±â€¯1.0 to 0.3 ±â€¯1.0) and number of doses (0.3 ±â€¯1.0 to 0.8 ±â€¯0.6), and medication adherence (0.8 ±â€¯0.4 to 0.9 ±â€¯0.3) as assessed by the questionnaire surveys were significantly improved after switching from DPP-4 inhibitors. The self-reported amount of unused drugs was significantly reduced after switching. CONCLUSIONS: Switching from daily DPP-4 inhibitors to once-weekly trelagliptin improved the satisfaction with the treatment, impression of the prescribed medicine and medication adherence in the type 2 diabetic patients who expresses a desire to reduce their prescription medicines. In such patients, improvements in the glycemic control and long-term prognosis might be expected through the reduction of unused drugs.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Uracila/análogos & derivados , Idoso , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Humanos , Hipoglicemiantes/farmacologia , Masculino , Estudos Prospectivos , Uracila/farmacologia , Uracila/uso terapêutico
7.
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
8.
Neuropharmacology ; 155: 131-141, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132435

RESUMO

Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5 mg/kg, i.p) and donepezil (0.75 mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/dietoterapia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/metabolismo , Donepezila/metabolismo , Desenvolvimento de Medicamentos/tendências , Uracila/análogos & derivados , Animais , Sítios de Ligação/fisiologia , Células CHO , Inibidores da Colinesterase/uso terapêutico , Cricetinae , Cricetulus , Donepezila/uso terapêutico , Humanos , Camundongos , Camundongos Transgênicos , Distribuição Aleatória , Resultado do Tratamento , Uracila/química , Uracila/metabolismo , Uracila/uso terapêutico
9.
Anticancer Res ; 39(4): 2139-2144, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952760

RESUMO

We report a 64-year-old woman with a 9-cm liver tumor in the left lateral section. The patient had neither hepatitis B or C virus infection, nor cirrhosis. Carbohydrate antigen 19-9 (CA 19-9) level was 1,889 U/ml. We also suspected bulky hilar lymph node metastasis, and a left lateral sectionectomy without lymph node dissection (R2) was performed. The pathological findings led to diagnosis of combined hepatocellular and cholangiocarcinoma. Three weeks post-operation, the patient underwent hepatic arterial infusion chemotherapy with cisplatin, fluorouracil, and mitomycin C. In addition, a total dose of 45 Gy of irradiation for the hilar lymph node was performed; while oral tegafur-uracil (UFT) has been administered for 10 years at a dose of 400 mg/day. The CA19-9 level of the patient was normalized after hepatectomy, hepatic arterial infusion, irradiation for hilar lymph node, and oral UFT administration. Currently, the patient is alive without any relapse for 12 years post-operation.


Assuntos
Neoplasias dos Ductos Biliares/terapia , Carcinoma Hepatocelular/terapia , Colangiocarcinoma/terapia , Neoplasias Hepáticas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Carcinoma Hepatocelular/diagnóstico por imagem , Colangiocarcinoma/diagnóstico por imagem , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Raios gama/uso terapêutico , Hepatectomia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Pessoa de Meia-Idade , Mitomicina/uso terapêutico , Tegafur/uso terapêutico , Uracila/uso terapêutico
10.
Acta Oncol ; 58(8): 1149-1157, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31002008

RESUMO

Background: The treatment options for patients with therapy refractory metastatic colorectal cancer (mCRC) are sparse. TAS-102 (FTD/TPI) is a new oral anti-tumour agent composed of a nucleoside analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil, indicated for patients with mCRC who are refractory to standard therapies. This study summarizes published and unpublished experience with FTD/TPI in clinical practice settings. Patients and methods: The Medline/PubMed, Embase and Cochrane Library databases were searched to identify observational studies on FTD/TPI monotherapy for mCRC. Papers describing use of FTD/TPI monotherapy outside clinical trials in series of patients evaluable for effectiveness were eligible. The outcomes of interest were median progression free survival (mPFS), median overall survival (mOS) as well as mean PFS time restricted to six months (PFS6m) and mean OS time restricted to one year (OS1y). Results of the pooled analyses of observational studies were compared to the results of the Japanese phase II trial and the two phase III trials, RECOURSE and TERRA. Results: Seven published and two unpublished studies with 1008 patients from 64 centres were included for analysis. The pooled mPFS was 2.2 months (95% CI 2.1 to 2.3 months), and the pooled mOS was 6.6 months (95% CI 6.1 to 7.1 months). PFS6m was 2.9 months (95% CI 2.6 to 3.1 months) and OS1y was 6.8 (95% CI 6.0 to 7.5) months. While these results all reflect RECOURSE, the pooled mOS is lower than in the phase II trial and the OS1y is inferior to both the phase II trial and TERRA. Conclusion: This systematic review and a meta-analysis indicates that in real life settings, the survival benefit of FTD/TPI monotherapy in patients with therapy refractory mCRC reflects the outcomes in RECOURSE but is inferior to outcomes in the two Asian efficacy trials. What is already known TAS 102 (Lonsurf) is an oral fixed dose combination of trifluridine (FTD) and tipiracil (TPI) indicated as salvage-line treatment in patients with therapy refractory metastatic colorectal cancer (mCRC). A Japanese phase II trial and two phase III trials, RECOURSE and TERRA, demonstrated that FTD/TPI prolonged overall survival. What this study adds This systematic review and meta-analysis of real life data from 64 sites indicates that the effectiveness in daily clinical practice settings of FTD/TPI monotherapy in late stage mCRC reflects the outcomes in RECOURCE but is inferior to the outcomes in the Japanese phase II trial and TERRA.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Administração Oral , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Estudos Observacionais como Assunto , Intervalo Livre de Progressão , Uracila/uso terapêutico
11.
Ann Intern Med ; 170(11): 741-748, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31035291

RESUMO

Background: Mavacamten, an orally administered, small-molecule modulator of cardiac myosin, targets underlying biomechanical abnormalities in obstructive hypertrophic cardiomyopathy (oHCM). Objective: To characterize the effect of mavacamten on left ventricular outflow tract (LVOT) gradient. Design: Open-label, nonrandomized, phase 2 trial. (ClinicalTrials.gov: NCT02842242). Setting: 5 academic centers. Participants: 21 symptomatic patients with oHCM. Intervention: Patients in cohort A received mavacamten, 10 to 20 mg/d, without background medications. Those in cohort B received mavacamten, 2 to 5 mg/d, with ß-blockers allowed. Measurements: The primary end point was change in postexercise LVOT gradient at 12 weeks. Secondary end points included changes in peak oxygen consumption (pVO2), resting and Valsalva LVOT gradients, left ventricular ejection fraction (LVEF), and numerical rating scale dyspnea score. Results: In cohort A, mavacamten reduced mean postexercise LVOT gradient from 103 mm Hg (SD, 50) at baseline to 19 mm Hg (SD, 13) at 12 weeks (mean change, -89.5 mm Hg [95% CI, -138.3 to -40.7 mm Hg]; P = 0.008). Resting LVEF was also reduced (mean change, -15% [CI, -23% to -6%]). Peak VO2 increased by a mean of 3.5 mL/kg/min (CI, 1.2 to 5.9 mL/kg/min). In cohort B, the mean postexercise LVOT gradient decreased from 86 mm Hg (SD, 43) to 64 mm Hg (SD, 26) (mean change, -25.0 mm Hg [CI, -47.1 to -3.0 mm Hg]; P = 0.020), and mean change in resting LVEF was -6% (CI, -10% to -1%). Peak VO2 increased by a mean of 1.7 mL/kg/min (SD, 2.3) (CI, 0.03 to 3.3 mL/kg/min). Dyspnea scores improved in both cohorts. Mavacamten was well tolerated, with mostly mild (80%), moderate (19%), and unrelated (79%) adverse events. The most common adverse events definitely or possibly related to mavacamten were decreased LVEF at higher plasma concentrations and atrial fibrillation. Limitation: Small size; open-label design. Conclusion: Mavacamten can reduce LVOT obstruction and improve exercise capacity and symptoms in patients with oHCM. Primary Funding Source: MyoKardia.


Assuntos
Benzilaminas/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Uracila/análogos & derivados , Função Ventricular Esquerda/efeitos dos fármacos , Administração Oral , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Benzilaminas/efeitos adversos , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Tolerância ao Exercício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos , Estudos Prospectivos , Volume Sistólico/efeitos dos fármacos , Uracila/efeitos adversos , Uracila/uso terapêutico , Adulto Jovem
12.
J Pharmacol Exp Ther ; 370(1): 84-91, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31010842

RESUMO

The illicit use of γ-hydroxybutyric acid (GHB), and its prodrug, γ-butyrolactone (GBL), results in severe adverse effects including sedation, coma, respiratory depression, and death. Current treatment of GHB/GBL overdose is limited to supportive care. Recent reports indicate that GHB-related deaths are on the rise; a specific treatment may reduce lethality associated with GHB/GBL. Pretreatment with inhibitors of monocarboxylate transporter 1 (MCT1), a transporter that mediates many of the processes involved in the absorption, distribution (including brain uptake), and elimination of GHB/GBL, has been shown to prevent GHB-induced respiratory depression by increasing the renal clearance of GHB. To identify whether MCT1 inhibition is an effective treatment of GHB overdose, the impact of two MCT1 inhibitors, (S)-5-(4-hydroxy-4-methylisoxazolidine-2-carbonyl)-1-isopropyl-3-methyl-6-((3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thieno[2,3-day]pyrimidine-2,4(1H,3H)-dione (AZD3965) and 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-day]pyrimidine2,4(1H,3H)-dione (AR-C155858), on the toxicokinetics and toxicodynamics of GHB/GBL was assessed when the administration of the inhibitor was delayed 60 and 120 minutes (post-treatment) after administration of GHB/GBL. AR-C155858 and AZD3965 reduced the toxicodynamic effects of GHB when GHB was administered intravenously, orally, or orally as the prodrug GBL. The impact of these inhibitors on GHB toxicokinetics was dependent on the route of GHB administration and the delay between GHB/GBL administration and administration of the MCT1 inhibitor. The reduction in GHB plasma exposure did not explain the observed effect of MCT1 inhibition on GHB-induced respiratory depression. The efficacy of MCT1 inhibition on GHB toxicodynamics is likely driven by the pronounced reduction in GHB brain concentrations. Overall, this study indicates that inhibition of MCT1 is an effective treatment of GHB/GBL overdose.


Assuntos
4-Butirolactona/toxicidade , Overdose de Drogas/tratamento farmacológico , Hidroxibutiratos/toxicidade , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Pró-Fármacos/farmacologia , Pirimidinonas/farmacologia , Simportadores/antagonistas & inibidores , Tiofenos/farmacologia , Uracila/análogos & derivados , 4-Butirolactona/administração & dosagem , Administração Intravenosa , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Overdose de Drogas/sangue , Overdose de Drogas/metabolismo , Hidroxibutiratos/administração & dosagem , Hidroxibutiratos/sangue , Hidroxibutiratos/farmacocinética , Masculino , Pirimidinonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tiofenos/uso terapêutico , Uracila/farmacologia , Uracila/uso terapêutico
13.
Exp Clin Transplant ; 17(1): 52-58, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30719954

RESUMO

OBJECTIVES: The introduction of direct-acting antiviral agents has allowed significant chances for treatment for difficult-to-treat populations. This study aimed to investigate the efficacy, tolerability, and safety of these therapies in both patients with end-stage renal disease and kidney transplant recipients with chronic hepatitis C virus infection. MATERIALS AND METHODS: This study was a retrospective analysis with prospective follow-up of patients. The antiviral combination of ombitasvir 25 mg, paritaprevir 75 mg, ritonavir 50 mg, and dasabuvir 50 mg was prescribed to patients with end-stage renal disease or kidney transplant recipients with noncirrhotic or compensated cirrhotic liver disease. The other antiviral combination consisted of sofosbuvir 400 mg and ledipasvir 90 mg, which was recommended to patients with decompensated cirrhosis or those who could not tolerate the first combination regimen. Ribavirin was given to all patients with genotype 1a hepatitis C virus infection. All clinical and laboratory data were recorded at week 4, at end of the treatment, and at 12 weeks after completion of treatment. RESULTS: In terms of efficacy, sustained virologic response at 12 weeks was achieved in 94% of patients in the end-stage renal disease group and 92% of patients in the kidney transplant group. In terms of tolerability, antiviral treatment was well tolerated in both groups. Cardiac arrest and cerebrovascular accident were seen in the end-stage renal disease group; severe mucositis and glossitis were seen in the kidney transplant group. Hospitalization was needed in 2 patients for treatment of drug interactions with tacrolimus and sirolimus. Renal allograft function worsened in 2 patients, with 1 patient having biopsyproven antibody-mediated rejection. CONCLUSIONS: We observed great efficacy and safety in both kidney transplant recipients and patients with end-stage renal disease with these agents in treatment of chronic hepatitis C. However, clinicians should remain aware of drug interactions and adverse events in this fragile patient population.


Assuntos
Anilidas/uso terapêutico , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Falência Renal Crônica/complicações , Falência Renal Crônica/cirurgia , Transplante de Rim , Compostos Macrocíclicos/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Anilidas/efeitos adversos , Antivirais/efeitos adversos , Carbamatos/efeitos adversos , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/virologia , Humanos , Imunossupressores/efeitos adversos , Falência Renal Crônica/diagnóstico , Transplante de Rim/efeitos adversos , Compostos Macrocíclicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Ribavirina/uso terapêutico , Fatores de Risco , Ritonavir/efeitos adversos , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Uracila/efeitos adversos , Uracila/uso terapêutico
14.
Biochem Biophys Res Commun ; 511(2): 387-393, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30797555

RESUMO

Liver fibrosis occurs in most types of chronic liver diseases. The understanding of the pathogenesis of liver fibrosis has grown considerably, but the effective treatments are still lacking. Alogliptin, a classical Dipeptidyl peptidase-4 (DPP4) inhibitor with great effects on type 2 diabetes, has shown the potential to protect liver, but its effects on the progression of liver fibrosis have not been clarified. Herein, we explored the anti-fibrosis effects of alogliptin. In vitro, we demonstrated that alogliptin suppressed the activation of LX-2 upon transforming growth factor-ß (TGF-ß) challenge. In vivo, chronic treatment with alogliptin alleviated hepatic steatosis and protected from the liver injury in ob/ob mice, which delayed the progression of liver fibrosis. Furthermore, alogliptin significantly relieved the hepatic fibrosis in CCl4-induced liver fibrosis mouse model. In conclusion, our results demonstrate that negatively modulation of alogliptin on hepatic stellate cell (HSC) activation might contribute to liver fibrosis alleviation. Our research provides the potential possibility of alogliptin on the application for liver fibrosis therapy and suggests that DPP4 may be a novel target for liver fibrosis therapy.


Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Piperidinas/uso terapêutico , Uracila/análogos & derivados , Animais , Linhagem Celular , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta/metabolismo , Uracila/uso terapêutico
15.
Eur J Gastroenterol Hepatol ; 31(4): 534-539, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30672829

RESUMO

INTRODUCTION: Both hepatitis C virus infection (HCV) and chronic kidney disease (CKD) have been comorbid illnesses with increasing morbidity and mortality. The present study was conducted to present real-life experiences about treatment of HCV and CKD with a fixed-dose combination of paritaprevir 150 mg/day, ritonavir 100 mg/day as a booster, ombitasvir 25 mg/day, and dasabuvir 250 mg twice/day, the PROD regimen. PATIENTS AND METHODS: This was a multicenter, retrospective cohort study. Seventy-five patients with both HCV and CKD were treated with a PROD-based regimen with or without ribavirin. Fifty-three of 75 patients were on maintenance hemodialysis program. Seven patients had compensated liver cirrhosis. The patients with genotype 1a or compensated liver cirrhosis were treated with the PROD regimen and ribavirin in a dose of 200 mg every other day for 12 weeks. The patients with genotype 1b were treated with PROD for 12 weeks. The patients with genotype 4 were treated with a combination of paritaprevir, ritonavir, ombitasvir, and ribavirin 200 mg every other day. RESULTS: All patients except one were HCV-RNA negative (98.6%) at the end of treatment. One patient had decompensated after the fourth day of therapy. She stopped the treatment, and she was exitus after 2 months. Two patients died of reasons not related to the drugs 2 months after negativity of HCV-RNA. Sustained viral rate 12 weeks after treatment was found in 96% of the patients. CONCLUSION: The PROD regimen was very effective and safe for treatment in patients with HCV and CKD who were in stages 4 and 5.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Antivirais/administração & dosagem , Carbamatos/administração & dosagem , Carbamatos/uso terapêutico , Quimioterapia Combinada , Feminino , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Uracila/administração & dosagem , Uracila/análogos & derivados , Uracila/uso terapêutico
16.
Bioorg Med Chem ; 27(4): 644-654, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30642693

RESUMO

Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S2' site, a series of novel uracil derivatives 1a-l and 2a-i incorporating benzoic acid moieties at the N3 position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC50 = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 µM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.


Assuntos
Benzoatos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/farmacologia , Uracila/análogos & derivados , Uracila/uso terapêutico , Animais , Benzoatos/síntese química , Benzoatos/toxicidade , Domínio Catalítico , Linhagem Celular , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/toxicidade , Desenho de Fármacos , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/toxicidade , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Uracila/toxicidade
17.
Virol J ; 16(1): 11, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30654809

RESUMO

BACKGROUND: Data on the treatment of patients with hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection remains limited. A comprehensive analysis was performed to evaluate the efficacy and safety of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir(r) ± dasabuvir (DSV) ± ribavirin (RBV) for treatment in HCV/HIV coinfected patients. METHODS: We systematically searched and included studies that enrolled patients with HIV/HCV coinfection using the OBV/PTV/r ± DSV ± RBV regimens and reported sustained virological response after 12 weeks (SVR12) end-of-treatment. Heterogeneity of results was assessed and pooled SVR rates were computed with 95% confidence intervals (95%CI). Subgroup analysis and assessment of publication bias through Egger's test were further performed. RESULTS: Ten studies containing 1358 coinfected patients were included in this study. The pooled estimate of SVR12 was 96.3% (95%CI: 95.1-97.4). Subgroup analysis showed that pooled SVR12 rate was 96.2% (95% CI: 94.8-97.4) for patients with genotype (GT) 1 and 98.8% (95% CI: 95.1-100.0) for those with GT4. The SVR12 rates for the treatment-naïve (TN) and treatment-experienced (TE) patients were 96.8% (95% CI, 94.8-98.5) and 98.9% (95% CI, 96.4-100.0), respectively. Pooled SVR12 rate was 97.8(95%CI: 94.6-99.8) for patients with cirrhosis and 96.7% (95%CI: 95.3-97.8) without cirrhosis. The pooled incidence of any adverse events (AEs) and serious adverse events (SAEs) was 73.9% (95%CI: 38.1-97.6) and 2.7% (95%CI: 0.0-9.5). Publication bias did not exist in this study. CONCLUSIONS: The comprehensive analysis showed high efficacy for the OBV/PTV/r ± DSV ± RBV regimen in patients coinfected with HIV and HCV, regardless of genotypes, history of treatment and the presence or absence of cirrhosis.


Assuntos
Anilidas/uso terapêutico , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Coinfecção/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Compostos Macrocíclicos/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , Adulto , Ensaios Clínicos como Assunto , Coinfecção/virologia , Quimioterapia Combinada , Feminino , HIV , Infecções por HIV/virologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Resposta Viral Sustentada , Uracila/uso terapêutico
18.
Gastroenterol Hepatol ; 42(3): 164-170, 2019 Mar.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30293914

RESUMO

INTRODUCTION: In the interferon era, the treatment of hepatitis C virus (HCV) infection in patients on haemodialysis (HD) was limited due to the significant number of treatment-related adverse events (AEs). Direct-acting antivirals (DAAs) have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis. The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs, and to assess the impact of HCV elimination on clinical and analytical outcomes. PATIENTS AND METHODS: This is a prospective, interventional, single-center study at Hospital Clínic de Barcelona. All HCV-RNA positive patients who received antiviral therapy with DAAs within a 3-year period (2014-2017) were analyzed (n=20). Data on virologic response, adverse events, and biochemical and hematological parameters during and after DAA therapy were analyzed. RESULTS: All patients achieved sustained virologic response (SVR) and only 40% of patients presented with mild AEs. None of the patients presented with HCV reinfection after a 1-year follow-up period, and thus HCV was eliminated from our HD unit. SVR was associated with a significant increase in hemoglobin and hematocrit, and a tendency toward the need for lower doses of iron supplementation with no changes in darbepoetin dose. CONCLUSION: HCV infection can be safely eliminated from HD units with the use of DAAs, preventing new infections in patients and healthcare staff. In the short term, the achievement of SVR is associated with an improvement in the control of anemia.


Assuntos
Anemia/tratamento farmacológico , Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Diálise Renal , Insuficiência Renal Crônica/terapia , Resposta Viral Sustentada , Anemia/etiologia , Anilidas , Carbamatos , Darbepoetina alfa/administração & dosagem , Feminino , Hematínicos/administração & dosagem , Hematócrito , Hemoglobina A , Humanos , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , Uracila/uso terapêutico
19.
Surgery ; 165(3): 586-592, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30314724

RESUMO

BACKGROUND: Lateral lymph node dissection has been 1 of the standard treatments for mid and ow rectal cancer in Japan. The aim of this ad-hoc analysis was to evaluate the impact of lateral lymph node dissection on outcomes in the randomized clinical trial, referred to as the Adjuvant Chemotherapy for Stage II/III Rectal Cancer trial. METHODS: The Adjuvant Chemotherapy for Stage II/III Rectal Cancer trial was a randomized, phase III trial of adjuvant chemotherapy of 2 different oral fluoropyrimidines; 445 patients with lower rectal cancer were studied in this ad-hoc analysis out of 959 patients in total, 215 of whom underwent lateral lymph node dissection and 230 did not. RESULTS: There were no significant differences in background characteristics of the patients in the group, except for in age and number of dissected lymph nodes, between the lateral lymph node dissection and without lateral lymph node dissection groups. The age of the younger patients was often used to select candidates for lateral lymph node dissection (lateral lymph node dissection versus non-lateral lymph node dissection; 63.5 ± 8.9 vs 60.7 ± 9.4 [P = .0017]). Lateral lymph node dissection had no impact on relapse-free survival (hazard ratio = 0.941, 95% confidence interval: 0.696-1.271) or overall survival (hazard ratio = 0.858, 95% confidence interval: 0.601-1.224) in all patients with mid and low rectal cancer. In subset analysis, lateral lymph node dissection improved relapse-free survival in female patients and in patients with stage B/C or N3/4 disease. For cumulative recurrence across all patients, the proportion of patients with distant recurrence was slightly greater in the lateral lymph node dissection group but there was no difference in local recurrence. CONCLUSION: This exploratory analysis did not show that lateral lymph node dissection improves relapse-free survival and overall survival in patients with mid and low rectal cancer. Lateral lymph node dissection may, however, have a prognostic impact on patients with highly invasive rectal cancer.


Assuntos
Excisão de Linfonodo/métodos , Linfonodos/patologia , Estadiamento de Neoplasias , Neoplasias Retais/secundário , Abdome , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Colonoscopia , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/diagnóstico , Neoplasias Retais/terapia , Estudos Retrospectivos , Tegafur/uso terapêutico , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Uracila/uso terapêutico , Adulto Jovem
20.
J Diabetes Investig ; 10(3): 723-730, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30156056

RESUMO

AIMS/INTRODUCTION: The aim of the present study was to investigate the effects of metformin and a dipeptidyl peptidase-4 inhibitor, alogliptin, on body composition in a 12-week randomized add-on trial in Japanese participants with type 2 diabetes. MATERIALS AND METHODS: A total of 84 participants with poorly controlled type 2 diabetes undergoing antidiabetic therapy were randomly assigned to receive alogliptin (25 mg, once daily) or metformin (1,000 mg, twice daily) for 12 weeks. The primary efficacy end-point was body composition. The secondary end-points included factors associated with decreased bodyweight. RESULTS: Compared with the baseline values, alogliptin significantly increased bodyweight (66.5 ± 19.2 to 67.6 ± 19.3 kg), body mass index (BMI; 25.4 ± 6.1 to 25.8 ± 6.3 kg/m2 ) and fat mass (20.3 ± 12.8 to 21.8 ± 14.5 kg), whereas metformin had no significant effect on body composition. Alogliptin was inferior to metformin in reducing bodyweight (0.84 ± 1.57 vs -0.35 ± 1.53 kg, P = 0.002), BMI (0.34 ± 0.69 to -0.15 ± 0.56 kg/m2 , P = 0.002) and fat mass (1.49 ± 5.06 vs -0.04 ± 1.81 kg, P = 0.042). BMI at baseline was associated with changes in bodyweight negatively in the metformin group and positively in the alogliptin group. CONCLUSIONS: Metformin and alogliptin exert opposite effects on bodyweight in type 2 diabetes patients who are overweight. The higher the BMI, the more metformin reduces bodyweight and alogliptin increases weight.


Assuntos
Composição Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Piperidinas/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Glicemia/análise , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Uracila/uso terapêutico , Adulto Jovem
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