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1.
Expert Opin Ther Pat ; 30(1): 27-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31771391

RESUMO

Introduction: The activation of free fatty acid receptor 1 (FFAR1) induces insulin secretion in a glucose-dependent manner, and thereby is considered as an attractive anti-diabetic target. The clinical studies provided a lot of evidence that FFAR1 agonists improved glucose control in T2DM without the risk of hypoglycemia. The field of FFAR1 agonists is extremely competitive with many patent applications filed in recent years identifying potent candidates.Area covered: The present review summarizes patent applications (2016-2019) filing for FFAR1 modulators, including FFAR1 partial/full agonists, atypical agonists, and multiple target agonists, along with in vitro and in vivo evaluation.Expert opinion: The clinical studies of FFAR1 agonists have proved their potential for the improvement of glucose control. However, there are a few issues still to be solved in this field since TAK-875 terminated in Phase III studies due to liver toxicity. The biggest challenge on the development of FFAR1 agonists may not be the identification of a highly potent compound, but finding out the exact mechanisms of hepatotoxicity and avoid it. Moreover, the further exploration of chemical spaces on FFAR1 full agonists and multi-targeted agonists, as well as corresponding clinical studies, will be expected and might open up new directions in this field.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Benzofuranos/efeitos adversos , Benzofuranos/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Patentes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Sulfonas/efeitos adversos , Sulfonas/farmacologia
2.
Environ Int ; 129: 59-67, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31121516

RESUMO

Bisphenol analogues including bisphenol A (BPA), bisphenol AF (BPAF), bisphenol F (BPF), and bisphenol S (BPS) share similar chemical structures and endocrine disrupting effects. Their effects on metabolisms, however, are so far only marginally understood. In this study, NMR-based metabonomic profiles of HepG2 cell culture media and PCR array were used to assess the metabolomics disturbances and gene expression levels of HepG2 in response to four BPs (BPA, BPAF, BPF, and BPS). The results indicated that BP analogues resulted in disturbances in 7-15 metabolites that were classified as amino acid (alanine, glutamine, glutamate), intermediates and end-products in the glycolysis (pyruvate) and the tricarboxylic acid cycle (acetate, lactate). Their rank in order according to the number of metabolites and pathways was BPF > BPA > BPAF > BPS. The common disrupted pathways (pyruvate metabolism; alanine, aspartate, and glutamate metabolism) indicated enhanced glycolysis. The following glucometabolic PCR array analysis suggested that although four BPs shared the capability of disrupting glucose metabolism, they may act through different mechanisms: BPAF has increased the pyruvate kinase (PKLR) expression level, which implied enhanced glycolysis that was agreed with NMR results. The other three BP analogues, however, decreased the expression level of glucokinase (GCK) that indicated glucose sensing impairment. Our results demonstrated the potential for using metabolomic and PCR array to understand the underlying action of mechanisms and identify the potential targets for future targeted risk assessment.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Poluentes Ambientais/efeitos adversos , Metaboloma/efeitos dos fármacos , Fenóis/efeitos adversos , Sulfonas/efeitos adversos , Transcriptoma/efeitos dos fármacos , Células Hep G2 , Humanos
3.
Drugs Aging ; 36(Suppl 1): 25-44, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31073922

RESUMO

OBJECTIVE: Our aim was to assess the safety of cyclooxygenase-2 (COX-2) inhibitors in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials. METHODS: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL) and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with COX-2 inhibitors in patients with OA were eligible for inclusion. Two authors appraised titles, abstracts and full-text papers for suitability and then assessed the studies for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective outcomes reporting. The primary outcomes of interest were gastrointestinal disorders, cardiac disorders, vascular disorders, nervous system disorders, skin and subcutaneous tissue disorders, hepatobiliary disorders, renal and urinary disorders, as well as overall severe and serious AEs, drug-related AEs and mortality. Secondary outcomes were withdrawals due to AEs (i.e. the number of participants who stopped the treatment due to an AE) and total number of AEs (i.e. the number of patients who experienced any AE at least once). RESULTS: Database searches identified 2149 records from which, after exclusions, 40 trials were included in the meta-analysis. The use of COX-2 inhibitors in OA was associated with a significant increased risk of drug-related AEs compared with placebo (relative risk (RR) 1.26, 95% CI 1.09-1.46; I2 = 24%). The risk of upper gastrointestinal complications (including dyspepsia, gastritis and heartburn) was significantly increased with COX-2 inhibitors versus placebo (RR 1.19, 95% CI 1.03-1.38; I2 = 0%), particularly for abdominal pain, which increased by 40% with COX-2 inhibitors (RR 1.40, 95% CI 1.08-1.80; I2 = 0%). The risk of hypertension increased by 45% overall (RR 1.45, 95% CI 1.01-2.10; I2 = 25%); however, when rofecoxib was removed from the analysis the risk of hypertension in the COX-2 inhibitor group was no longer significant (RR 1.21, 95% CI 0.80-1.83; I2 = 20%). The overall risk of heart failure and edema was increased by nearly 70% with COX-2 inhibitors versus placebo (RR 1.68, 95% CI 1.22-2.31; 0%) and this level of risk did not change appreciably when rofecoxib was excluded (RR 1.67, 95% CI 1.21-2.29; 0%). CONCLUSIONS: In our analysis, COX-2 inhibitors were associated with an increased risk of upper gastrointestinal AEs, especially abdominal pain. We also found an increased risk of cardiovascular AEs with COX-2 inhibitors, namely hypertension, heart failure and edema.


Assuntos
Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Lactonas/efeitos adversos , Osteoartrite/tratamento farmacológico , Sulfonas/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , Lactonas/administração & dosagem , Lactonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonas/administração & dosagem , Sulfonas/uso terapêutico , Resultado do Tratamento
4.
Cancer Treat Res Commun ; 20: 100149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075537

RESUMO

Anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) is diagnosed in up to 126,000 patients worldwide annually. Ceritinib is a next-generation ALK-targeted tyrosine kinase inhibitor that is approved for the treatment of patients with metastatic ALK+ NSCLC. In December 2017, the US Food and Drug Administration-approved dose of ceritinib was changed from 750 mg/day under fasting conditions to 450 mg/day taken with food for the treatment of patients with ALK+ NSCLC. This change was implemented on the basis of data from studies designed to investigate ways to reduce the frequency of gastrointestinal adverse events noted in patients enrolled in several ASCEND clinical trials that evaluated a ceritinib 750-mg fasted dose as either first- or second/third-line treatment. This review highlights and discusses published findings from the ASCEND-8 food-effect trial and includes commentary from physicians regarding their own clinical cases of patients who were enrolled in the trial and treated with either the 750-mg fasted or 450-mg fed dose of ceritinib. The review also discusses the implications of using the recently approved ceritinib 450-mg dose in the clinical setting.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonas/administração & dosagem , Administração Oral , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Sulfonas/efeitos adversos , Resultado do Tratamento
5.
Oncol Res Treat ; 42(5): 275-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30955009

RESUMO

BACKGROUND: Little is known regarding the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) efficacy and safety in the elderly. OBJECTIVES AND METHODS: Consecutive patients (n = 53) with ALK-positive advanced non-small cell lung cancer treated with an ALK TKI were identified through internal databases of three cancer centers and divided into groups A (< 65 years old; n = 34) and B (≥65 years old; n = 19). Progression-free survival (PFS), ALK TKI safety and overall survival (OS) were assessed. Uni- and multivariate PFS and OS analyses were performed. RESULTS: Crizotinib, ceritinib, and alectinib were administered in 94 and 100%, 35 and 31%, 38 and 52% of patients in groups A and B, respectively. The median PFS (months) was 5.4 (95% CI, 3.4-12.4) and 5.6 (95% CI, 2.5-14.7) with crizotinib (log-rank 0.0009, p = 0.9), 4.7 (95% CI, 1.0-11.5) and 23.0 (95% CI, 0.8-27.7) with ceritinib (log-rank 0.44, p = 0.5), and 21.2 (95% CI, 1.2 to not reached, NR) and 5.6 (95% CI, 0.5 to NR) with alectinib (log-rank 0.53, p = 0.5) in groups A and B, respectively. The median OS (months) comprised 29.8 (95% CI, 21.0 to NR) and 25.1 (95% CI, 10.8-53.6) in groups A and B, respectively (log-rank 0.57, p = 0.4). Age affected neither PFS nor OS. 19 and 37%, 50 and 40%, and 0 and 0% of patients in groups A and B, treated with crizotinib, ceritinib, and alectinib, respectively, developed high-grade adverse events. The treatment discontinuation rate was 9 and 21%, 16 and 60%, 0 and 0% with crizotinib, ceritinib, and alectinib in groups A and B, respectively. CONCLUSIONS: In the elderly, crizotinib, ceritinib, and alectinib treatments are associated with similar efficacy but different safety profiles; alectinib is associated with a lower rate of high-grade adverse events and a lower treatment discontinuation rate.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Carbazóis/efeitos adversos , Carbazóis/uso terapêutico , Crizotinibe/efeitos adversos , Crizotinibe/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Sulfonas/efeitos adversos , Sulfonas/uso terapêutico , Adulto Jovem
6.
Pulm Pharmacol Ther ; 56: 86-93, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30917927

RESUMO

BACKGROUND: There are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Human neutrophil elastase (HNE) is a mediator of tissue destruction in non-CF BE. BAY 85-8501, a selective and reversible HNE inhibitor, could represent a new treatment option for this disease. METHODS: This was a phase 2a, randomized, placebo-controlled, double-blind, parallel-group study. The primary objective was to assess the safety and tolerability of 1 mg BAY 85-8501 once daily (OD) for 28 days compared with placebo in patients with non-CF BE. Secondary objectives were to investigate the effects of 4 weeks of treatment with BAY 85-8501 on health-related quality of life, pulmonary function, and inflammatory and tissue damage biomarkers in sputum, blood and/or urine, and to evaluate the pharmacokinetics of BAY 85-8501. RESULTS: Overall, 94 patients (mean age, 66 years; 53% male) were randomized (n = 47 per group), and 82 completed the study (BAY 85-8501, n = 37; placebo, n = 45). Treatment-emergent adverse events (TEAEs) occurred in 31 patients (66%) taking BAY 85-8501 and in 36 patients (77%) taking placebo, and were mostly mild or moderate. The serious TEAEs (BAY 85-8501, n = 3; placebo, n = 1) were not considered to be study-drug related. There were no changes in pulmonary function parameters from baseline to end of treatment, and health-related quality of life did not improve in any group. HNE activity in blood after zymosan challenge decreased significantly with BAY 85-8501 treatment (P = 0.0250 versus placebo). There were no significant differences in other biomarkers between treatment groups, with the exception of a small increase in interleukin-8 levels in sputum in the BAY 85-8501 group. Trough plasma concentrations of BAY 85-8501 plateaued after 2 weeks. CONCLUSIONS: 1 mg BAY 85-8501 OD had a favourable safety and tolerability profile when administered for 28 days to patients with non-CF BE. Further studies with a longer treatment duration are needed to evaluate the potential clinical efficacy in this study population.


Assuntos
Bronquiectasia/tratamento farmacológico , Elastase de Leucócito/antagonistas & inibidores , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Pirimidinonas/uso terapêutico , Sulfonas/uso terapêutico , Idoso , Bronquiectasia/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Secretadas Inibidoras de Proteinases/efeitos adversos , Proteínas Secretadas Inibidoras de Proteinases/farmacocinética , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Qualidade de Vida , Escarro/metabolismo , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Resultado do Tratamento
7.
Drugs ; 79(4): 477-481, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30806972

RESUMO

Esaxerenone (MINNEBRO™)-a novel oral, non-steroidal, selective mineralocorticoid receptor blocker-is being developed by Daiichi Sankyo for the treatment of hypertension and diabetic nephropathies. In January 2019, based on positive results from a phase III trial conducted in Japan in patients with essential hypertension, esaxerenone received marketing approval in Japan for the treatment of hypertension. This article summarizes the milestones in the development of esaxerenone leading to this first global approval for the treatment of hypertension.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pirróis/uso terapêutico , Sulfonas/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Aprovação de Drogas , Humanos , Japão , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Estrutura Molecular , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Mineralocorticoides/metabolismo , Sulfonas/efeitos adversos
8.
Drug Metab Dispos ; 47(5): 525-534, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30765394

RESUMO

Fasiglifam, a potent and highly selective agonist of G protein-coupled receptor 40, was developed for the treatment of type 2 diabetes mellitus. However, phase III clinical programs were terminated owing to liver safety concerns. Fasiglifam-related liver toxicity was also observed in repeat-dose dog toxicology studies, characterized by granulomatous inflammation with crystal formation in the liver and/or bile ducts. These histopathological changes were not observed in rat toxicology studies. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of dog liver sections obtained from a repeat-dose toxicology study indicated that the crystalline material in the affected dog liver contained fasiglifam and fasiglifam glucuronide (fasiglifam-G). Nonclinical mechanistic studies indicated that after 14 days of repeated oral dosing with [14C]fasiglifam at 200 mg/kg per day to dogs, the concentrations of fasiglifam and fasiglifam-G in the bile exceeded the solubility limit of these compounds in the bile (approximately 3000 µg/ml). After single oral 2- and 200-mg/kg doses administered to rats and dogs, fasiglifam and fasiglifam-G concentrations in dog bile were 5- to 10-fold higher than those in rat bile for the same dose of fasiglifam, while the bile flow rate adjusted by body weight was 4- to 8-fold lower in dogs than in rats. High fasiglifam and fasiglifam-G concentrations in dog bile together with lower bile flow rate could cause crystal formation in dog bile, resulting in secondary granulomatous inflammation in the dog liver.


Assuntos
Benzofuranos/efeitos adversos , Benzofuranos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado/efeitos dos fármacos , Sulfonas/efeitos adversos , Sulfonas/metabolismo , Animais , Bile/metabolismo , Cães , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
9.
Mol Cell Endocrinol ; 483: 64-73, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30654004

RESUMO

The use of Bisphenol S (BPS) was proposed as an alternative to Bisphenol A (BPA), a chemical employed in the production of polycarbonate plastics and epoxy resins. BPA is a xenoestrogen that affects normal physiology in several species. It was reported that BPS may also act as a xenoestrogen with harmful effects in the reproductive system. Here we studied the effects of BPS during the induction of a polycystic ovarian syndrome (PCOS)-like condition in rats. Animals were injected daily with vehicle, DHEA 60 mg/kg, BPS 1 µg/kg and DHEA-BPS, for 20 days. Cell apoptosis, cell proliferation, and EZRIN expression were analyzed by immunohistochemistry. We found an increase in PCNA expression, which correlates with cytoplasmic accumulation of the polarization marker, EZRIN, in the BPS treated groups. Additionally, the administration of BPS in the DHEA treated group augmented the stratification and number of "intraepithelial lumina" in the endometrial surface epithelium.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Desidroepiandrosterona/administração & dosagem , Endométrio/citologia , Fenóis/administração & dosagem , Síndrome do Ovário Policístico/metabolismo , Sulfonas/administração & dosagem , Regulação para Cima , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desidroepiandrosterona/efeitos adversos , Modelos Animais de Doenças , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Tamanho do Órgão/efeitos dos fármacos , Fenóis/efeitos adversos , Síndrome do Ovário Policístico/induzido quimicamente , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Sulfonas/efeitos adversos
10.
Drug Saf ; 42(2): 199-209, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30649741

RESUMO

The chimeric protein echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, resulting from the rearrangement of the homonym genes, is one of the currently targetable oncogenic drivers in anaplastic lymphoma kinase-positive non-small-cell lung cancer. In fact, four first- and second-generation anaplastic lymphoma kinase tyrosine kinase inhibitors, crizotinib (PF-02341066), ceritinib (LDK378), alectinib (CH5424802), and brigatinib (AP26113), are presently approved for clinical practice; however, these agents are not devoid of complications and thus should be administered meaningfully. Furthermore, third-generation inhibitors are currently under development to overcome acquired resistance mechanisms inevitably resulting from treatment with first- and second-generation tyrosine kinase inhibitors. Therefore, this article aims to provide a comprehensive state-of-the-art review about the pharmacodynamics, pharmacokinetics, safety, and tolerability profiles of currently available and promising under-development anaplastic lymphoma kinase tyrosine kinase inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinase do Linfoma Anaplásico/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/diagnóstico , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Sulfonas/efeitos adversos , Sulfonas/farmacologia , Sulfonas/uso terapêutico
11.
Artigo em Inglês | MEDLINE | ID: mdl-30670439

RESUMO

Fexinidazole is a novel oral treatment for human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT). Fexinidazole also has activity against T. cruzi, the causative agent of Chagas disease. During the course of a dose ranging assessment in patients with chronic indeterminate Chagas disease, delayed neutropenia and significant increases in hepatic transaminases were observed and clinical investigations were suspended. We retrospectively analyzed all available pharmacokinetic and pharmacodynamic data on fexinidazole in normal healthy volunteers and in patients with Chagas disease and g-HAT to assess the determinants of toxicity. A population pharmacokinetic model was fitted to plasma concentrations (n = 4,549) of the bioactive fexinidazole sulfone metabolite, accounting for the majority of the bioactive exposure, from three phase 1 studies, two g-HAT phase 2/3 field trials, and one Chagas disease phase 2 field trial (n = 462 individuals in total). Bayesian exposure-response models were then fitted to hematological and liver-related pharmacodynamic outcomes in Chagas disease patients. Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found to be exposure dependent and, thus, dose dependent in patients with Chagas disease. Clinically insignificant transient reductions in neutrophil and platelet counts consistent with these exposure-response relationships were observed in patients with g-HAT. In contrast, no evidence of hepatotoxicity was observed in patients with g-HAT. Fexinidazole treatment results in a dose-dependent liver toxicity and transient bone marrow suppression in Chagas disease patients. Regimens of shorter duration should be evaluated in clinical trials with patients with Chagas disease. The currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety margin for bone marrow suppression and does not cause hepatotoxicity.


Assuntos
Medula Óssea/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nitroimidazóis/efeitos adversos , Nitroimidazóis/farmacocinética , Tripanossomicidas/efeitos adversos , Tripanossomicidas/farmacocinética , Administração Oral , Animais , Teorema de Bayes , Medula Óssea/metabolismo , Doença de Chagas/tratamento farmacológico , Doença de Chagas/metabolismo , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Método Duplo-Cego , Humanos , Fígado/metabolismo , Masculino , Nitroimidazóis/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Sulfonas/farmacologia , Resultado do Tratamento , Tripanossomicidas/farmacologia , Trypanosoma brucei gambiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/metabolismo
12.
Medicine (Baltimore) ; 98(1): e13726, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30608384

RESUMO

AIM: Activation of the anaplastic lymphoma kinase (ALK) gene has been found in several human cancers, including non-small-cell lung cancer (NSCLC). Currently, novel drugs targeting ALK gene have been extensively investigated in NSCLC. However, concerns about ALK inhibitors-induced liver toxicities have been increasing. MATERIALS AND METHODS: Eligible prospective clinical studies have been searched in several databases. Primary outcomes of interest were incidence rates of liver toxicities, relative risks (RRs), and 95% confidence intervals (CIs). RESULTS: Data from 2418 patients (1873 in the experimental arm; 545 in the control arm) were included. The incidences of all-grade alanine transaminase (ALT) and aspartate aminotransferase (AST) elevation were 26.0% (95% CI: 17.4%-37%), and 23.2% (95% CI, 16.7%-31.4%), respectively. The incidences of high-grade ALT and AST elevation were 8.4% (95% CI, 5.1%-13.4% and 7.0% (95% CI: 5.4%-9.0%), respectively. Sub-group analysis according to the ALK inhibitors found that pooled incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK inhibitors significantly increased the all-grade and high-grade ALT elevation (RR 2.37, 95% CI, 1.97-2.86; P < .001; RR 7.34, 95% CI, 3.95-13.63; P < .001) and AST elevation (RR 3.27, 95% CI, 2.47-4.34; P < .001; RR 11.54, 95% CI, 4.33-30.7; P < .001), respectively. No publication bias was detected for RR of ALT and AST. CONCLUSIONS: The findings of the present study offer substantial evidence that ALK inhibitors treatment in advanced NSCLC significantly increases the risk of developing all-grade and high-grade liver toxicities in comparison with controls. Clinicians should recognize liver toxicities promptly as early interventions may alleviate future complications.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Carbazóis/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ensaios Clínicos como Assunto , Crizotinibe/efeitos adversos , Feminino , Humanos , Incidência , Fígado/efeitos dos fármacos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Estudos Prospectivos , Pirimidinas/efeitos adversos , Fatores de Risco , Sulfonas/efeitos adversos
13.
Eur J Ophthalmol ; 29(4): 394-401, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30112930

RESUMO

PURPOSE: Characterize the safety and tolerability of lifitegrast ophthalmic solution 5.0% for the treatment of dry eye disease. METHODS: Pooled data from five randomized controlled trials were analyzed. Key inclusion criteria were adults with dry eye disease (Schirmer tear test score ⩾1 and ⩽10 mm, eye dryness score ⩾40 (visual analog scale 0-100), corneal staining score ⩾2.0 (0-4 scale)). Participants were randomized to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 or 360 days. Treatment-emergent adverse events and drop comfort scores were assessed. RESULTS: Overall, 2464 participants (lifitegrast, n = 1287; placebo, n = 1177) were included. Ocular treatment-emergent adverse events occurring in >5% in either group were instillation site irritation (lifitegrast, 15.2%; placebo, 2.8%), instillation site reaction (lifitegrast, 12.3%; placebo, 2.3%), and instillation site pain (lifitegrast, 9.8%; placebo, 2.1%); the most common (> 5%) nonocular treatment-emergent adverse event was dysgeusia (lifitegrast, 14.5%; placebo, 0.3%). The majority of treatment-emergent adverse events were mild to moderate in severity. Discontinuation due to treatment-emergent adverse events occurred in 7.0% (lifitegrast) versus 2.6% (placebo) of participants (ocular: 5.5% vs 1.5%; nonocular: 1.9% vs 1.1%). Drop comfort scores with lifitegrast improved within 3 min of instillation and the score at 3 min improved across visits (12-week trials (both eyes, day 84 vs 0): 2.0 vs 3.3; SONATA (day 360 vs 0): right eye, 1.2 vs 1.7; left eye, 1.2 vs 1.8). CONCLUSION: Lifitegrast ophthalmic solution 5.0% appeared to be safe and well tolerated for the treatment of dry eye disease. Drop comfort with lifitegrast improved within 3 min of instillation.


Assuntos
Síndromes do Olho Seco/tratamento farmacológico , Soluções Oftálmicas/uso terapêutico , Fenilalanina/análogos & derivados , Sulfonas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico , Estudos Prospectivos , Sulfonas/efeitos adversos , Resultado do Tratamento , Escala Visual Analógica
14.
Intern Med ; 58(6): 817-820, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30449809

RESUMO

We herein report a 75-year-old woman with insulin-treated diabetes and metastatic anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who received ceritinib, a second-generation ALK inhibitor, and achieved dramatic tumor reduction. However, her fasting blood glucose increased, particularly markedly in the first two weeks after ceritinib administration, and did not normalize even increasing the total insulin dose. After discontinuing ceritinib, her glucose levels rapidly reduced. Ceritinib can aggravate hyperglycemia in patients with diabetes who lack compensatory insulin secretion, due to its inhibitory effects on the insulin receptor. Careful monitoring for ceritinib-induced hyperglycemia should be performed, especially in the first two weeks after ceritinib administration.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas/efeitos adversos , Sulfonas/efeitos adversos , Idoso , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Biomarcadores Tumorais/metabolismo , Glicemia/metabolismo , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hipoglicemiantes/uso terapêutico , Insulinas/uso terapêutico , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Pirimidinas/uso terapêutico , Sulfonas/uso terapêutico
15.
Chemosphere ; 217: 629-635, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30447611

RESUMO

As an alternate of bisphenol A (BPA), bisphenol S (BPS) is now widely used to produce our daily consumer goods. Some studies have shown that BPS has the potential to disrupt the reproduction and glucose homeostasis. However, the impact of BPS on the nervous system remains unclear. The purpose of this study is to investigate the impact of BPS on the nervous systems of zebrafish in their early growing stages. The 96 h-LC50 value of BPS to zebrafish larvae was 323 mg/L (95%CI: 308-339 mg/L). Zebrafish embryos were exposed to BPS at concentrations of 0, 0.03, 0.3 and 3.0 mg/L until 6 days postfertilization. Our results showed that 0.3 and 3.0 mg/L BPS exposure markedly decreased locomotor behavior, accompany by the increased oxidative stress, promoted apoptosis and altered retinal structure in zebrafish. In addition, the expression levels of six neurodevelopment genes (α1-tubulin, elavl3, gap43, mbp, syn2a and gfap) were downregulated after 3.0 mg/L BPS treatment. In conclusion, BPS may affect locomotor behavior and alter retinal structure in zebrafish larvae partially by increasing oxidative stress, and by suppressing the expression levels of neurodevelopment genes.


Assuntos
Larva/efeitos dos fármacos , Fenóis/efeitos adversos , Sulfonas/efeitos adversos , Poluentes Químicos da Água/efeitos adversos , Peixe-Zebra/fisiologia , Animais , Regulação da Expressão Gênica no Desenvolvimento , Locomoção/efeitos dos fármacos , Sistema Nervoso/crescimento & desenvolvimento , Estresse Oxidativo
17.
PLoS One ; 13(12): e0208357, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30533010

RESUMO

Vascular cognitive impairment dementia (VCID) is a major cause of cognitive loss in the elderly. Matrix metalloproteinases (MMPs) are a family of proteases involved in remodeling the extracellular matrix in development, injury and repair. Blood-brain barrier (BBB) disruption due to inflammation mediated by MMPs is a mechanism of white matter injury. Currently there are no treatments besides the control of vascular risk factors. We tested two MMP-9 inhibitors that improved outcome in acute stroke: DP-460 and SB-3CT. We hypothesized that these inhibitors would have a beneficial effect in chronic stroke by reducing edema in white matter and improving behavioral outcomes. Spontaneously hypertensive stroke-prone rats (SHRSPs) with unilateral carotid artery occlusion (UCAO) fed a Japanese Permissive Diet (JPD) were used as a model of VCID. JPD was begun in the 12th week of life. Rats were treated with DP-460 (500 mg/kg) for 4 weeks, or SB-3CT (10 mg/kg) for 8 weeks, beginning at the UCAO/JPD onset. Rats treated with a dextrose or DMSO solution served as vehicle controls. Naïve SHRSPs on a standard diet served as sham control. Magnetic resonance imaging (MRI) analyses of the corpus callosum, external capsule, hippocampus and Morris water maze behavioral tests were conducted. We found an increase in body weight (p = 0.004) and blood pressure (p = 0.007) at 15 weeks with the DP-460 drug. SB-3CT increased body weight at 14 weeks (p = 0.015) and had significant but variable effects on blood pressure. Neither drug affected imaging parameters. Behavioral studies showed an impaired ability to learn with DP-460 (p<0.001) and no effect on learning with SB-3CT. Unchanged MMP-9 levels were detected in DP-460-treated rats via gel zymography. Our findings suggest that MMPs are not major factors in white matter damage in the SHRSP model of VCID and that drugs that are relatively selective for MMP-9 can interfere with learning.


Assuntos
Ácido Egtázico/análogos & derivados , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Aprendizagem/classificação , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/efeitos adversos , Sulfonas/efeitos adversos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Ácido Egtázico/efeitos adversos , Masculino , Ratos , Ratos Endogâmicos SHR
18.
Diabetes Care ; 41(12): 2603-2609, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30459247

RESUMO

OBJECTIVE: To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. RESULTS: The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ≥3-5 × upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ≥3 × ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, P < 0.001, and the incidence for ≥10 × ULN was 0.31% vs. 0.06%, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63). CONCLUSIONS: Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.


Assuntos
Benzofuranos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Sulfonas/efeitos adversos , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
19.
PLoS One ; 13(11): e0204746, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383755

RESUMO

BACKGROUND: Use of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used. OBJECTIVES: To estimate the risk of AMI for individual NSAIDs. METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) matching cases to a maximum of 100 controls on database, sex, age, and calendar time. Data were retrieved from six healthcare databases. Adjusted odds ratios (ORs) of current use of individual NSAIDs compared to past use were estimated per database. Pooling was done by two-stage pooling using a random effects model (ORmeta) and by one-stage pooling (ORpool). RESULTS: Among 8.5 million new NSAID users, 79,553 AMI cases were identified. The risk was elevated for current use of ketorolac (ORmeta 2.06;95%CI 1.83-2.32, ORpool 1.80; 1.49-2.18) followed, in descending order of point estimate, by indometacin, etoricoxib, rofecoxib, diclofenac, fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen (ORmeta 1.12; 1.03-1.22, ORpool 1.00;0.86-1.16). Higher doses showed higher risk estimates than lower doses. CONCLUSIONS: The relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diclofenaco/efeitos adversos , Etoricoxib/efeitos adversos , Feminino , Humanos , Indometacina/efeitos adversos , Cetorolaco/efeitos adversos , Lactonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Sulfonas/efeitos adversos
20.
BMC Cancer ; 18(1): 995, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30340555

RESUMO

BACKGROUND: Ceritinib demonstrated a statistically significant effect on the progression-free survival versus chemotherapy in patients with advanced anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) as the first therapy or after previous treatment with crizotinib and one or two prior chemotherapy regimens in global phase 3 studies. However, some serious adverse effects related to ceritinib therapy were reported across these clinical studies. Among them, a grade 3 and 4 increase in hepatobiliary enzymes was one of the common adverse events related to treatment with ceritinib. However, the pathology remains unclear. Previously, increased Interleukin (IL)-18 was observed in both biliary duct disease and liver disease. Therefore, we hypothesized that IL-18 is involved in the pathology of hepatobiliary adverse effects related to treatment with ceritinib and evaluated the serum IL-18. CASE PRESENTATION: The patient was a 53-year-old Japanese woman that we previously reported as having severe hepatobiliary adverse effects related to ceritinib therapy. Laboratory data, CT and MRI were obtained at each time point. IL-18 was evaluated by ELISA method at each time point. Immunochemical staining of liver tissue was performed as a standard protocol using antibodies against IL-18. Our records showed that the levels of serum IL-18 increased from the early stage of hepatobiliary adverse effects related to the treatment with ceritinib and were became worse with an increase in hepatobiliary enzymes and the progression of imaging abnormalities in the bile duct. Furthermore, IL-18 positive cells were detected in the inflammatory sites around the interlobular bile duct of the liver tissue. CONCLUSION: Our case report shows that the increase of serum IL-18 had a positive correlation with the progression of severe hepatobiliary adverse effects related to treatment with ceritinib and the involvement of IL-18 in the hepatobiliary inflammation by pathological evaluation. These results suggest that IL-18 could be a useful surrogate marker for the hepatobiliary toxicity of ceritinib. However, this is only one case report and further prospective observations will complement our data in the future.


Assuntos
Antineoplásicos/efeitos adversos , Doenças Biliares/sangue , Doenças Biliares/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/sangue , Interleucina-18/sangue , Pirimidinas/efeitos adversos , Sulfonas/efeitos adversos , Doenças Biliares/diagnóstico , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento
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