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1.
Anticancer Res ; 41(4): 2157-2163, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813427

RESUMO

BACKGROUND: This study assessed the efficacy and safety of biweekly trifluridine and tipiracil hydrochloride (TAS-102) with bevacizumab combination therapy for patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We included 19 patients with mCRC who received TAS-102 and bevacizumab combination therapy biweekly as third-line chemotherapy. The primary endpoint was progression-free survival. RESULTS: Patients had a median age of 73 years and most (73.4%) were men. The median progression-free and overall survival were 5.6 and 11.5 months, respectively. Five (26.3%) patients achieved a response and the disease control rate was 12/19 (63.1%). One patient (5.2%) experienced neutropenia grade 3 or more. The median time from baseline performance status 0/1 to worsening to 2 or more was 10.3 months. CONCLUSION: Biweekly TAS-102 plus bevacizumab facilitates tumor shrinkage by reducing the incidence of grade 3 or more neutropenia, improving survival, and maintaining performance status. This combination may represent a treatment option for patients with late-stage mCRC receiving third- or later-line therapy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neutropenia Febril Induzida por Quimioterapia/etiologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirrolidinas/efeitos adversos , Análise de Sobrevida , Timina/efeitos adversos , Resultado do Tratamento , Trifluridina/efeitos adversos
2.
Medicine (Baltimore) ; 100(5): e23171, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592817

RESUMO

BACKGROUND: Vibegron is a new ß3-adrenergic receptor agonist which has been demonstrated for the treatment of overactive bladder (OAB). We carried out meta-analysis to evaluate the efficiency of vibegron vs antimuscarinic monotherapy for treating OAB. METHODS: Randomized controlled trials (RCTs) of Vibegron vs antimuscarinic monotherapy for OAB were searched systematically by using EMBASE, MEDLINE, and the Cochrane Controlled Trials Register. The RevMan version 5.3.0. was used to analysis the data. RESULTS: Three RCTs involving a total of 1751 patients were studied in the Systematic review and Meta-analysis. Efficacy end points: the mean number of micturitions episodes/d (P = .16); the mean number of urgency episodes/d (P = .05); mean number of urgency incontinence episodes/d (P = .11) and mean number of incontinence episodes/d (P = .14) indicated that vibegron and antimuscarinic had no significant differences in terms of OAB treatment. Mean volume voided/micturition showed a distinct difference in the two groups (P = .009). With regard to dry mouth and drug related treatment-emergent adverse event (TEAE), vibegron showed better tolerance than antimuscarinic. Serious adverse event (SAE) and discontinuations due to adverse event (AE) did not show a significant difference between the two groups. CONCLUSIONS: The therapeutic effect of vibegron is similar to that of antimuscarinic, but vibegron does not increase the risk of AE.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Pirimidinonas/uso terapêutico , Pirrolidinas/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Humanos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Lancet Gastroenterol Hepatol ; 6(3): 209-217, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33508242

RESUMO

BACKGROUND: Findings of preclinical and clinical trials in colorectal cancer have shown promising antitumour effects of the co-formulation trifluridine/tipiracil and VEGF inhibition. We aimed to investigate the safety and activity of trifluridine/tipiracil and ramucirumab for previously treated advanced gastric cancer. METHODS: We did an open-label, single-arm, two-cohort, phase 2 study at eight centres in Japan. We enrolled patients with unresectable advanced gastric cancer or gastro-oesophageal junction adenocarcinoma. Cohort A included patients previously treated with one line of chemotherapy without ramucirumab and cohort B included patients previously treated with two to four lines of chemotherapy, including ramucirumab. Patients received trifluridine/tipiracil (35 mg/m2) orally twice daily on days 1-5 and days 8-12 of each 28-day treatment cycle, plus intravenous ramucirumab (8 mg/kg) on days 1 and 15. The primary endpoint was the disease control rate, assessed by investigators and defined as the proportion of patients with a confirmed best overall response, according to Response Evaluation Criteria in Solid Tumors version 1.1. This trial is registered on JapicCTI (JapicCTI-194596) and is ongoing but not recruiting. FINDINGS: Between April 8 and Oct 11, 2019, 64 patients were enrolled and included in the safety and activity analyses, 33 in cohort A and 31 in cohort B. In cohort A, the disease control rate was 85% (95% CI 68-95; 28 of 33 patients) and in cohort B it was 77% (59-90; 24 of 31 patients). Common treatment-related adverse events of grade 3 or worse were neutrophil count decreased (27 [82%] in cohort A and 23 [74%] in cohort B), white blood cell count decreased (eight [24%] and seven [23%]), and platelet count decreased (eight [24%] and four [13%]). Serious treatment-related adverse events were recorded in three patients in cohort A (fatigue and neutrophil count decreased; large intestine perforation; and febrile neutropenia, platelet count decreased, and anaemia). No patients in cohort B had a serious treatment-related adverse event, and no treatment-related deaths were reported in either cohort. INTERPRETATION: Trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure. FUNDING: Taiho Pharmaceutical and Eli Lilly.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Pirrolidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Timina/uso terapêutico , Trifluridina/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Administração Intravenosa , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Combinação de Medicamentos , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Segurança , Timina/administração & dosagem , Timina/efeitos adversos , Trifluridina/administração & dosagem , Trifluridina/efeitos adversos
4.
Anticancer Res ; 41(2): 1055-1062, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517315

RESUMO

BACKGROUND/AIM: This study aimed to describe the chemotherapy effects after trifluridine/tipiracil (TFTD) and/or regorafenib treatment in colorectal cancer (CRC) patients. PATIENTS AND METHODS: Patients receiving regorafenib or TFTD for metastatic CRC during 2013-2018 were selected and divided into two groups: one with additional chemotherapy after regorafenib or TFTD (CTX group) and one without additional chemotherapy (Non-CTX group). Patients were followed up from a landmark point (90 days from the last day of administration of regorafenib or TFTD). We compared overall survival (OS) between the groups. RESULTS: The median OS was 7.7 months in the CTX group and 4.1 months in the non-CTX groups. Several sensitivity analyses did not negate the survival advantage detected in the CTX group. CONCLUSION: The chemotherapy after regorafenib or TFTD was associated with prolonged OS in advanced CRC patients. Further study is required to determine appropriate treatment choice.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/mortalidade , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Estudos Retrospectivos , Terapia de Salvação , Análise de Sobrevida , Timina/uso terapêutico , Resultado do Tratamento , Trifluridina/uso terapêutico
5.
J Antimicrob Chemother ; 76(3): 753-757, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33338232

RESUMO

INTRODUCTION: Effective treatments are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). This trial aims to evaluate sofosbuvir and daclatasvir versus standard care for outpatients with mild COVID-19 infection. METHODS: This was a randomized controlled clinical trial in outpatients with mild COVID-19. Patients were randomized into a treatment arm receiving sofosbuvir/daclatasvir plus hydroxychloroquine or a control arm receiving hydroxychloroquine alone. The primary endpoint of the trial was symptom alleviation after 7 days of follow-up. The secondary endpoint of the trial was hospital admission. Fatigue, dyspnoea and loss of appetite were investigated after 1 month of follow-up. This study is registered with the IRCT.ir under registration number IRCT20200403046926N1. RESULTS: Between 8 April 2020 and 19 May 2020, 55 patients were recruited and allocated to either the sofosbuvir/daclatasvir treatment arm (n = 27) or the control arm (n = 28). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms at Day 7. One patient was admitted to hospital in the sofosbuvir/daclatasvir arm and four in the control arm, but the difference was not significant. After 1 month of follow-up, two patients reported fatigue in the sofosbuvir/daclatasvir arm and 16 in the control arm; P < 0.001. CONCLUSIONS: In this study, sofosbuvir/daclatasvir did not significantly alleviate symptoms after 7 days of treatment compared with control. Although fewer hospitalizations were observed in the sofosbuvir/daclatasvir arm, this was not statistically significant. Sofosbuvir/daclatasvir significantly reduced the number of patients with fatigue and dyspnoea after 1 month. Larger, well-designed trials are warranted.


Assuntos
Assistência Ambulatorial/métodos , Antivirais/administração & dosagem , /tratamento farmacológico , Carbamatos/administração & dosagem , Imidazóis/administração & dosagem , Pirrolidinas/administração & dosagem , Sofosbuvir/administração & dosagem , Valina/análogos & derivados , Adulto , Assistência Ambulatorial/tendências , Antimaláricos/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hidroxicloroquina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Valina/administração & dosagem
6.
Cochrane Database Syst Rev ; 12: CD012980, 2020 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-33341943

RESUMO

BACKGROUND: Frostbite is a thermal injury caused when tissue is exposed to sub-zero temperatures (in degrees Celsius) long enough for ice crystals to form in the affected tissue. Depending on the degree of tissue damage, thrombosis, ischaemia, necrosis (tissue death), gangrene and ultimately amputation may occur. Several interventions for frostbite injuries have been proposed, such as hyperbaric oxygen therapy, sympathectomy (nerve block), thrombolytic (blood-thinning) therapy and vasodilating agents such as iloprost, reserpine, pentoxifylline and buflomedil, but the benefits and harms of these interventions are unclear. OBJECTIVES: To assess the benefits and harms of the different management options for frostbite injuries. SEARCH METHODS: On 25 February 2020, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase (OvidSP), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index-Science (CPCI-S), as well as trials registers. Shortly before publication, we searched Clinicaltrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, OpenGrey and GreyLit (9 November 2020) again. We investigated references from relevant articles, and corresponded with a trial author. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any medical intervention, e.g. pharmacological therapy, topical treatments or rewarming techniques, for frostbite injuries to another treatment, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. We used Review Manager 5 for statistical analysis of dichotomous data with risk ratio (RR) with 95% confidence intervals (CIs). We used the Cochrane 'Risk of bias' tool to assess bias in the included trial. We assessed incidence of amputations, rates of serious and non-serious adverse events, acute pain, chronic pain, ability to perform activities of daily living, quality of life, withdrawal rate from medical therapy due to adverse events, occupational effects and mortality. We used GRADE to assess the quality of the evidence. MAIN RESULTS: We included one, open-label randomised trial involving 47 participants with severe frostbite injuries. We judged this trial to be at high risk of bias for performance bias, and uncertain risk for attrition bias; all other risk of bias domains we judged as low. All participants underwent rapid rewarming, received 250 mg of aspirin and 400 mg intravascular (IV) buflomedil (since withdrawn from practice), and were then randomised to one of three treatment groups for the following eight days. Group 1 received additional IV buflomedil 400 mg for one hour per day. Group 2 received the prostacyclin, iloprost, 0.5 ng to 2 ng/kg/min IV for six hours per day. Group 3 received IV iloprost 2 ng/kg/min for six hours per day plus fibrinolysis with 100 mg recombinant tissue plasminogen activator (rtPA) for the first day only. The results suggest that iloprost and iloprost plus rtPA may reduce the rate of amputations in people with severe frostbite compared to buflomedil alone, RR 0.05 (95% CI 0.00 to 0.78; P = 0.03; very low-quality evidence) and RR 0.31 (95% CI 0.10 to 0.94; P = 0.04; very low-quality evidence), respectively. Iloprost may be as effective as iloprost plus rtPA at reducing the amputation rate, RR 0.14 (95% CI 0.01 to 2.56; P = 0.19; very low-quality evidence). There were no reported deaths or withdrawals due to adverse events in any of the groups; we assessed evidence for both outcomes as being of very low quality. Adverse events (including flushing, nausea, palpitations and vomiting) were common, but not reported separately by comparator arm (very low-quality evidence). The included study did not measure the outcomes of acute pain, chronic pain, ability to perform activities of daily living, quality of life or occupational effects. AUTHORS' CONCLUSIONS: There is a paucity of evidence regarding interventions for frostbite injuries. Very low-quality evidence from a single small trial indicates that iloprost, and iloprost plus rtPA, in combination with buflomedil may reduce the need for amputation in people with severe frostbite compared to buflomedil alone. However, buflomedil has been withdrawn from use. High quality randomised trials are needed to establish firm evidence for the treatment of frostbite injuries.


Assuntos
Congelamento das Extremidades/terapia , Amputação/estatística & dados numéricos , Aspirina/administração & dosagem , Viés , Quimioterapia Combinada/métodos , Epoprostenol/administração & dosagem , Fibrinolíticos/administração & dosagem , Humanos , Iloprosta/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Pirrolidinas/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Reaquecimento/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Vasodilatadores/administração & dosagem
7.
Medicine (Baltimore) ; 99(43): e22780, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120790

RESUMO

RATIONALE: Currently, the 5-year survival rate remains poor for patients with metastatic colorectal cancer (mCRC), and the purpose of therapy is to prolong survival while maintaining the quality of life. Trifluridine/tipiracil, an oral drug combining trifluorothymidine and a thymidine phosphorylase inhibitor, is indicated as salvage therapy for mCRC patients who have progressed after all available regimens. Combination of local treatments with systemic therapy such as trifluridine/tipiracil represents an apt management strategy for mCRC patients. PATIENT CONCERNS: A 72-year-old man diagnosed with stage IV rectal adenocarcinoma (KRAS mutation) with peritoneal carcinomatosis and liver metastases developed resistance to 2 lines of treatment (bevacizumab/irinotecan/S-1 and bevacizumab/oxaliplatin/HDFL [high-dose 24-hour infusion of 5-fluorouracil and leucovorin regimen]) within 5 months. DIAGNOSIS: Refractory stage IV rectal adenocarcinoma. INTERVENTIONS: Systemic treatment of trifluridine/tipiracil has been given for approximately 15 months in addition to radiotherapy, Yttrium-90 radioembolization, and trans-arterial chemoembolization for peritoneal and liver metastases. OUTCOMES: After 15 months, the patient was still taking trifluridine/tipiracil for disease control with a good quality of life. LESSONS: Trifluridine/tipiracil plus other appropriate local therapy may significantly prolong patients survival with a satisfactory quality of life for patients with refractory mCRC. The favorable safety profile of trifluridine/tipiracil renders it a suitable option to be combined with other local therapies for metastatic lesions.


Assuntos
Adenocarcinoma/tratamento farmacológico , Pirrolidinas/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Timina/uso terapêutico , Trifluridina/uso terapêutico , Adenocarcinoma/patologia , Idoso , Combinação de Medicamentos , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Masculino , Estadiamento de Neoplasias , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Pirrolidinas/administração & dosagem , Qualidade de Vida , Neoplasias Retais/patologia , Terapia de Salvação , Timina/administração & dosagem , Trifluridina/administração & dosagem
8.
Nat Commun ; 11(1): 4659, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938936

RESUMO

The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.


Assuntos
Butiratos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Administração por Inalação , Animais , Antígenos de Neoplasias/metabolismo , Bleomicina/toxicidade , Butiratos/administração & dosagem , Butiratos/metabolismo , Butiratos/farmacocinética , Colágeno/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Integrinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Naftiridinas/administração & dosagem , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Fator de Crescimento Transformador beta/metabolismo , Pesquisa Médica Translacional
9.
J Nanosci Nanotechnol ; 20(12): 7311-7323, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32711596

RESUMO

We started a study on the molecular docking of six potential pharmacologically active inhibitors compounds that can be used clinically against the COVID-19 virus, in this case, remdesivir, ribavirin, favipiravir, galidesivir, hydroxychloroquine and chloroquine interacting with the main COVID-19 protease in complex with a COVID-19 N3 protease inhibitor. The highest values of affinity energy found in order from highest to lowest were chloroquine (CHL), hydroxychloroquine (HYC), favipiravir (FAV), galidesivir (GAL), remdesivir (REM) and ribavirin (RIB). The possible formation of hydrogen bonds, associations through London forces and permanent electric dipole were analyzed. The values of affinity energy obtained for the hydroxychloroquine ligands was -9.9 kcal/mol and for the chloroquine of -10.8 kcal/mol which indicate that the coupling contributes to an effective improvement of the affinity energies with the protease. Indicating that, the position chosen to make the substitutions may be a pharmacophoric group, and cause changes in the protease.


Assuntos
Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Adenina/administração & dosagem , Adenina/análogos & derivados , Adenina/química , Adenina/farmacologia , Adenosina/análogos & derivados , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Amidas/administração & dosagem , Amidas/química , Amidas/farmacologia , Antivirais/administração & dosagem , Sítios de Ligação , Cloroquina/administração & dosagem , Cloroquina/química , Cloroquina/farmacologia , Interações Medicamentosas , Humanos , Ligação de Hidrogênio , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/química , Hidroxicloroquina/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Nanotecnologia , Pandemias , Inibidores de Proteases/administração & dosagem , Pirazinas/administração & dosagem , Pirazinas/química , Pirazinas/farmacologia , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Pirrolidinas/farmacologia , Ribavirina/administração & dosagem , Ribavirina/química , Ribavirina/farmacologia , Eletricidade Estática
10.
J Cancer Res Clin Oncol ; 146(10): 2575-2587, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32715436

RESUMO

BACKGROUND: Limited treatment options are available in chemotherapy-refractory metastatic colorectal cancer (mCRC). The objective was to conduct a systematic literature review (SLR) and exploratory network meta-analysis (NMA) to compare the tolerability and effectiveness of SIRT with Y-90 resin microspheres, regorafenib, TAS-102 (trifluridine/tipiracil), and best supportive care (BSC) as third-line treatment in patients with mCRC. METHODS: An SLR was conducted to identify studies comparing two or more of the treatments and reporting overall survival (OS), progression-free survival, tumor response, or adverse event (AE) incidence. An exploratory NMA was conducted to compare hazard ratios (HRs) for OS using Markov chain Monte Carlo (MCMC) techniques. RESULTS: Seven studies were identified in the SLR: two double-blind randomized-controlled trials (RCT) for each drug, one open-label RCT, and two non-randomized comparative studies for SIRT. Patient selection criteria differed between studies, with SIRT studies including patients with liver-dominant colorectal metastases. Nausea and vomiting were more frequent with TAS-102 than regorafenib or SIRT; diarrhea was more common with TAS-102 and regorafenib than SIRT. The exploratory NMA suggested that all active treatments improved OS, with HRs of 0.48 (95% CrI 0.30-0.78) for SIRT with Y-90 resin microspheres, 0.63 (0.38-1.03) for TAS-102, and 0.67 (0.40-1.08) for regorafenib each compared to BSC. CONCLUSIONS: Regorafenib, TAS-102 and SIRT using Y-90 resin microspheres are more effective than BSC in third-line treatment of mCRC; however, study heterogeneity made comparisons between active treatments challenging. SIRT is a viable treatment for third-line mCRC and its favorable AE profile should be considered in the therapeutic decision-making process.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia/métodos , Neoplasias Colorretais/dietoterapia , Neoplasias Colorretais/radioterapia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Radioisótopos de Ítrio/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Microesferas , Metástase Neoplásica , Metanálise em Rede , Cuidados Paliativos/métodos , Compostos de Fenilureia/administração & dosagem , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Timina , Trifluridina/administração & dosagem , Uracila/administração & dosagem , Uracila/uso terapêutico
11.
Lancet Gastroenterol Hepatol ; 5(9): 839-849, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32682494

RESUMO

BACKGROUND: Glecaprevir-pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data for glecaprevir-pibrentasvir in non-Japanese Asian patients have been minimal. The aim of these studies was to assess the efficacy and safety of glecaprevir-pibrentasvir in treatment-naive and treatment-experienced Asian patients with chronic HCV genotype 1-6 infection without cirrhosis (VOYAGE-1) and with compensated cirrhosis (VOYAGE-2). METHODS: We did two phase 3 studies in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection. VOYAGE-1 was a randomised, double-blind, placebo-controlled study that recruited patients without cirrhosis at 47 sites across China, South Korea, and Singapore. Randomisation was 2:1 with a fixed block size of three and stratified by geographical region and HCV genotype. Investigators, study site personnel, the study sponsor, and patients were masked to treatment allocation. VOYAGE-2 was a single-arm, open-label study that recruited patients with compensated cirrhosis at 34 sites across China and South Korea. Glecaprevir (300 mg) and pibrentasvir (120 mg) or placebo (VOYAGE-1, 2:1 ratio), administered as three tablets daily, was given for 8 weeks in patients without cirrhosis and for 12 weeks in those with cirrhosis (and for 16 weeks in treatment-experienced patients with genotype 3). The primary efficacy endpoint was the proportion of patients with a sustained virological response, defined as HCV RNA below the lower limit of quantification 12 weeks after the last dose of glecaprevir-pibrentasvir. We analysed efficacy and safety in all patients who received at least one dose of the study drug. These trials are registered with ClinicalTrials.gov, NCT03222583 (VOYAGE-1) and NCT03235349 (VOYAGE-2); both trials have been completed. This Article reports the results of the primary analysis for each study, undertaken when all patients who received glecaprevir-pibrentasvir (during the double-blind period in VOYAGE-1) had been followed up for 12 weeks following their last dose of study drug. Data from the double-blind period for placebo patients in VOYAGE-1 are also summarised. FINDINGS: Between Oct 4, 2017, and April 20, 2018, 546 patients with chronic HCV without cirrhosis were randomly assigned to treatment (363 to glecaprevir-pibrentasvir, 183 to placebo) in VOYAGE-1. One patient withdrew consent and did not receive treatment with glecaprevir-pibrentasvir. 352 of 362 patients who received glecaprevir-pibrentasvir achieved SVR12 (97·2% [95% CI 95·5-98·9]). Of 160 patients with compensated cirrhosis who were enrolled in VOYAGE-2 between Sept 29, 2017, and June 14, 2018, 159 of 160 achieved SVR12 (99·4%, 95% CI 98·2-100·0). 20 patients with HCV genotype 3b across both trials received glecaprevir-pibrentasvir; six of these patients were among the 11 patients who did not achieve SVR12. Upper respiratory tract infection was the most common adverse event (35 [10%] of 362 receiving glecaprevir-pibrentasvir and 18 [10%] of 183 receiving placebo in VOYAGE-1; 19 [12%] of 160 in VOYAGE-2). For patients receiving glecaprevir-pibrentasvir, serious adverse events occurred in three (<1%) of 362 patients in VOYAGE-1 and five (3%) of 160 patients in VOYAGE-2. Grade 3-4 adverse events in patients receiving glecaprevir-pibrentasvir occurred in five (1%) of 362 patients in VOYAGE-1 and six (4%) of 160 patients in VOYAGE-2; each type of event was experienced by at most one patient within a study. One patient with cirrhosis discontinued study drug because of an adverse event. INTERPRETATION: Glecaprevir-pibrentasvir showed high efficacy and an acceptable safety profile in these studies although responses were less common in the few patients with HCV genotype 3b. The results support the use of glecaprevir-pibrentasvir in these Asian populations. FUNDING: AbbVie.


Assuntos
Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Ásia/epidemiologia , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Estudos de Casos e Controles , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/epidemiologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Prevalência , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Infecções Respiratórias/induzido quimicamente , Infecções Respiratórias/epidemiologia , Segurança , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Resultado do Tratamento
12.
Oncology ; 98(9): 630-636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428899

RESUMO

OBJECTIVE: Nivolumab is recommended as a third-line treatment in patients with unresectable advanced or recurrent gastric cancer. Although recent studies have demonstrated the prognostic impact of salvage chemotherapy after immune checkpoint inhibitors in several malignancies, its clinical significance remains unclear in patients with gastric cancer. This study aimed to investigate tumor response to subsequent chemotherapy after nivolumab in patients with advanced gastric cancer and assess the prognostic effect of salvage chemotherapy. METHODS: We retrospectively enrolled 31 patients with unresectable advanced or recurrent gastric cancer receiving nivolumab. RESULTS: Twenty-two and nine patients received nivolumab as third-line and fourth- to sixth-line treatments, respectively. The objective response rate (ORR) and disease control rate (DCR) to nivolumab were 20.0% (4/20) and 55.0% (11/20), respectively. Eleven patients received salvage chemotherapy after nivolumab. The ORR and DCR to salvage chemotherapy were 37.5% (3/8) and 75.0% (6/8), respectively. The median progression-free survival and overall survival following salvage chemotherapy were 285 and 360 days, respectively. CONCLUSION: Our preliminary study indicates that nivolumab exposure may enhance subsequent chemosensitivity in patients with advanced gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Nivolumabe/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Feminino , Humanos , Irinotecano/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Prognóstico , Intervalo Livre de Progressão , Pirrolidinas/administração & dosagem , Estudos Retrospectivos , Terapia de Salvação/métodos , Neoplasias Gástricas/diagnóstico por imagem , Timina/administração & dosagem
13.
Lancet Gastroenterol Hepatol ; 5(7): 649-657, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389183

RESUMO

BACKGROUND: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors. METHODS: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log10IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV. INTERPRETATION: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors. FUNDING: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ezetimiba/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Canadá/epidemiologia , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Quinoxalinas/uso terapêutico , Vírus de RNA/genética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Doadores de Tecidos/estatística & dados numéricos , Transplantados/estatística & dados numéricos , Transplantes/virologia , Carga Viral/estatística & dados numéricos
14.
J Bone Miner Metab ; 38(5): 687-694, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32274572

RESUMO

INTRODUCTION: Primary hyperparathyroidism (PHPT) is caused by parathyroid adenoma, primary parathyroid hyperplasia, or parathyroid carcinoma. For some patients with PHPT controlling serum calcium levels is critical. MATERIALS AND METHODS: We conducted an open-label, single-arm, 52-week, phase III study in Japanese patients with hypercalcemia due to PHPT to demonstrate efficacy and safety of evocalcet, a new calcimimetic. Patients with intractable PHPT (n = 13), postsurgical recurrence (n = 2), and parathyroid carcinoma (n = 3) were enrolled. Evocalcet administration started at a dose of 2 mg once or twice daily and was titrated to achieve the target serum corrected calcium (cCa) concentration (≤ 10.3 mg/dL) for two consecutive weeks (maximal dose 24 mg/day). RESULTS: Fourteen patients achieved the target (77.8%; 95% confidence interval [CI] 52.4-93.6). The lower limit of 95% CI exceeded the predetermined reference limit (11%), and thus, efficacy was confirmed. Of 18 patients, 12 (66.7%; 95% CI 41.0-86.7) showed decreased serum cCa of ≥ 1.0 mg/dL from the baseline for two consecutive weeks during the titration phase. Sixteen patients entered the maintenance phase, and 15 patients completed the study. Treatment-emergent adverse events (TEAEs) were recorded in 18/18 patients (100%) and drug-related TEAEs in 8/18 (44.4%). The most commonly observed drug-related TEAE was nausea (2/18 patients). No unexpected drug-related TEAEs were observed. All drug-related TEAEs were mild in severity. No patient discontinued the study because of drug-related TEAEs. CONCLUSION: Evocalcet demonstrated long-term effectiveness in reducing serum cCa concentrations and safety without any unexpected drug-related TEAEs in PHPT patients.


Assuntos
Hiperparatireoidismo Primário/tratamento farmacológico , Naftalenos/uso terapêutico , Pirrolidinas/uso terapêutico , Cálcio/sangue , Creatinina/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Hiperparatireoidismo Primário/sangue , Masculino , Pessoa de Meia-Idade , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Naftalenos/farmacologia , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacologia
15.
Sci Rep ; 10(1): 6852, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321982

RESUMO

Postoperative atrial fibrillation (POAF) is one of the most frequent complications after cardiothoracic surgery and a predictor for postoperative mortality and prolonged ICU-stay. Current guidelines suggest the multi-channel inhibitor Vernakalant as a treatment option for rhythm control. However, rare cases of severe hypotension and cardiogenic shock following drug administration have been reported. To elucidate the impact of Vernakalant on hemodynamics, we included ten ICU patients developing POAF after elective cardiac surgery, all of them awake and breathing spontaneously, in this prospective trial. Patients received the recommended dosage of Vernakalant and were clinically observed and monitored (heart rate, invasive blood pressure, pulse oximetry, central venous pressure) in 1-minute-intervals for 20 minutes before- and 120 minutes after the first dose of Vernakalant. The median time from the end of surgery until occurrence of POAF amounted up to 52.8 [45.9-77.4] hours, it took 3.5 [1.2-10.1] hours from occurrence of POAF until the first application of Vernakalant. All patients received catecholamine support with epinephrine that was held steady and not dynamic throughout the observational phase. We noted stable hemodynamic conditions, with a trend towards a reduction in heart rate throughout the 120 minutes after drug administration. In 7 patients (70%), conversion to sustained sinus rhythm (SR) occurred within 8.0 minutes [6.0-9.0]. No serious adverse events (SAEs) were noted during the observation period. In this prospective trial in ICU-patients showing POAF after cardiac surgery, intravenous Vernakalant did not induce clinically relevant negative effects on patients' hemodynamics but resulted in conversion to sustained SR after a median of 8.0 minutes in 7 out of ten patients.


Assuntos
Anisóis/administração & dosagem , Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Hemodinâmica/efeitos dos fármacos , Unidades de Terapia Intensiva , Complicações Pós-Operatórias , Pirrolidinas/administração & dosagem , Idoso , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/fisiopatologia
16.
Cancer Chemother Pharmacol ; 85(5): 995-1001, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32318809

RESUMO

PURPOSE: Fedratinib, an oral, selective Janus kinase 2 inhibitor with activity against both wild-type and mutant Janus kinase 2, has pH-dependent solubility, with free solubility at pH 1. Concomitant administration of drugs that reduce gastric acid secretion, such as pantoprazole, may decrease the absorption of fedratinib and affect patient outcomes. The aim of this study was to evaluate the impact of 7-day repeated 40-mg doses of pantoprazole on the pharmacokinetic (PK) properties of a single 500-mg dose of fedratinib in healthy male subjects. METHODS: In this phase I, single-center, open-label, two-period, two-treatment, fixed-sequence crossover study, healthy male subjects were administered a single dose of fedratinib 500 mg on day 1 in Period 1, followed by pantoprazole 40 mg daily for 7 days (day 1 to day 7) and a single dose of fedratinib 500 mg on day 7 in Period 2. After the discontinuation of nine subjects due to vomiting, the protocol was amended to provide ondansetron as antiemetic prophylaxis to an additional ten enrolled subjects. RESULTS: Twenty-six subjects were included. Repeated doses of pantoprazole 40 mg resulted in clinically insignificant increases in fedratinib exposure. Maximum plasma concentration increased by 1.09-fold and area under the plasma concentration-time curve from time 0 to infinity increased by 1.15-fold. All treatment-emergent adverse events were mild or moderate, except for one instance of neutropenia, which was considered unrelated to study intervention. CONCLUSION: Coadministration with pantoprazole did not have clinically meaningful effects on fedratinib PK. No new or unexpected safety signals were observed with fedratinib.


Assuntos
Interações Medicamentosas , Janus Quinase 2/antagonistas & inibidores , Pantoprazol , Pirrolidinas , Sulfonamidas , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Pantoprazol/administração & dosagem , Pantoprazol/efeitos adversos , Pantoprazol/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Resultado do Tratamento
17.
Am J Hematol ; 95(6): 594-603, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32129512

RESUMO

Fedratinib is an oral, selective Janus kinase 2 (JAK2) inhibitor. The phase II JAKARTA2 study assessed fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) who were resistant or intolerant to prior ruxolitinib per investigator assessment. Patients received fedratinib 400 mg/day in 28-day cycles. The JAKARTA2 outcomes were initially reported using a last-observation-carried forward (LOCF) analysis in a "Per Protocol" population. This updated analysis of JAKARTA2 employs intention-to-treat analysis principles without LOCF for all treated patients (ITT Population; N = 97), and for a patient subgroup who met more stringent definitions of prior ruxolitinib failure (Stringent Criteria Cohort; n = 79). Median duration of prior ruxolitinib exposure was 10.7 months. The primary endpoint was spleen volume response rate (SVRR; ≥35% spleen volume decrease from baseline to end of cycle 6 [EOC6]). The SVRR was 31% in the ITT Population and 30% in the Stringent Criteria Cohort. Median duration of spleen volume response was not reached. Symptom response rate (≥50% reduction from baseline to EOC6 in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) was 27%. Grade 3-4 anemia and thrombocytopenia rates were 38% and 22%, respectively. Patients with advanced MF substantially pretreated with ruxolitinib attained robust spleen responses and reduced symptom burden with fedratinib.


Assuntos
Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/patologia , Pirrolidinas/administração & dosagem , Baço/patologia , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Pirazóis/administração & dosagem
18.
PLoS One ; 15(3): e0229239, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155165

RESUMO

BACKGROUND: Directly acting antivirals (DAA) against hepatitis C virus (HCV) infection have facilitated sustained virologic response (SVR) rates >90% in clinical studies. Yet, real life data regarding DAA treatment in people who inject drugs (PWIDs) are scarce. We evaluated the effectiveness of glecaprevir/pibrentasvir (G/P) in difficult-to-treat PWIDs with presumed high risk of non-adherence to DAA therapy using the concept of directly observed therapy involving their opioid substitution therapy (OST) facility. METHODS: N = 145 patients (m/f: 91/54; median age: 41.1 (IQR 19.5) years; HCV-genotype (GT) 1/2/3/4: 82/1/56/5, GT3: 38.6%; cirrhosis: n = 6; 4.1%) treated with G/P were included. PWIDs at high risk for non-adherence to DAA therapy received HCV treatment together with their OST under the supervision of medical staff ("directly observed therapy", DOT). The effectiveness of G/P given as DOT in PWIDs with presumed high risk of non-adherence to DAA therapy was compared to patients with suspected "excellent compliance" in the "standard setting" (SS) of G/P prescription at a tertiary care center and self-managed G/P intake at home. Treatment duration was 8-16 weeks according to the G/P drug label. RESULTS: DOT-patients (n = 74/145; 51.0%) were younger than SS-patients (median 38.7, IQR 12.5 vs. median 50.6, IQR 20.3 years), all had psychiatric co-morbidities and most had a poor socioeconomic status. 50/74 (67.6%) reported ongoing intravenous drug use (IDU). SVR was achieved in n = 70/74 (94.6%) patients with n = 3 being lost to follow-up (FU) and n = 1 showing nonresponse to therapy. SS-patients achieved SVR in 97.2% (69/71) with n = 1 patient being lost to FU and n = 1 patient with GT3 showing HCV relapse. CONCLUSION: G/P given as DOT along with OST in PWIDs with high risk of non-adherence to DAA therapy resulted in similarly high SVR rates (94.6%) as in patients with presumed "excellent compliance" under standard drug intake.


Assuntos
Benzimidazóis/administração & dosagem , Terapia Diretamente Observada/métodos , Hepatite C Crônica/tratamento farmacológico , Tratamento de Substituição de Opiáceos/métodos , Pirrolidinas/administração & dosagem , Quinoxalinas/administração & dosagem , Abuso de Substâncias por Via Intravenosa/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adulto , Idoso , Áustria , Benzimidazóis/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Cooperação do Paciente , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Classe Social , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Adulto Jovem
19.
Curr Med Sci ; 40(1): 35-47, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166663

RESUMO

Type 1 diabetes mellitus (T1DM) is associated with an increased risk of diabetic cardiomyopathy (DCM). Nuclear factor kappa B (NF-κB) and Wnt/ß-catenin/GSK3ß have been demonstrated to play pathogenic roles in diabetes. In this study, we evaluated the roles of these two pathways in T1DM-induced cardiomyopathy in rats. Streptozotocin (STZ)-induced type 1 diabetic rats were treated with pyrrolidine dithiocarbamate (PDTC) or meisoindigo (Me) to inhibit NF-κB and Wnt/ß-catenm/GSK3ß respectively for 4 or 8 weeks. As compared with untreated diabetic rats, treatment with either PDTC or Me partly attenuated the myocardial hypertrophy and interstitial fibrosis, improved cardiac function, and exhibited reduction in inflammatory reaction. In addition, we found that inhibiting NF-κB and Wnt/ß-catenin/GSK3ß pathways could regulate glucose and lipid metabolism. The effects were associated with the decrease of NF-κB activity and the downregulation of some proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-2. Our data suggested that the activities of NF-κB and Wnt/ß-catenin/GSK3ß pathways were both increased and inhibiting NF-κB and Wnt/ß-catenin/GSK3ß signaling pathways might improve myocardial injury in T1DM rats.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Pirrolidinas/administração & dosagem , Tiocarbamatos/administração & dosagem , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Indóis/administração & dosagem , Indóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , Pirrolidinas/farmacologia , Ratos , Estreptozocina , Tiocarbamatos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
20.
Respir Res ; 21(1): 75, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216814

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.


Assuntos
Butiratos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/uso terapêutico , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Volume de Ventilação Pulmonar/efeitos dos fármacos , Administração por Inalação , Idoso , Antígenos de Neoplasias , Teorema de Bayes , Butiratos/administração & dosagem , Butiratos/farmacocinética , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Nebulizadores e Vaporizadores , Tomografia por Emissão de Pósitrons , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Resultado do Tratamento
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