RESUMO
Binding affinity prediction by means of computer simulation has been increasingly incorporated in drug discovery projects. Its wide application, however, is limited by the prediction accuracy of the free energy calculations. The main error sources are force fields used to describe molecular interactions and incomplete sampling of the configurational space. Organic host-guest systems have been used to address force field quality because they share similar interactions found in ligands and receptors, and their rigidity facilitates configurational sampling. Here, we test the binding free energy prediction accuracy for 14 guests with an aromatic or adamantane core and the CB7 host using molecular electron density derived nonbonded force field parameters. We developed a computational workflow written in Python to derive atomic charges and Lennard-Jones parameters with the Minimal Basis Iterative Stockholder method using the polarized electron density of several configurations of each guest in the bound and unbound states. The resulting nonbonded force field parameters improve binding affinity prediction, especially for guests with an adamantane core in which repulsive exchange and dispersion interactions to the host dominate.
Assuntos
Adamantano , Elétrons , Adamantano/química , Simulação por Computador , Ligantes , TermodinâmicaRESUMO
Pancreatic cancer is one of the most lethal human neoplasms, and despite advances in the understanding of the molecular complexity involved in the development and progression of this disease, little of this new information has been translated into improvements in therapy and prognosis. Ezrin (EZR) is a protein that regulates multiple cellular functions, including cell proliferation, survival, morphogenesis, adhesion, and motility. In pancreatic cancer, EZR is highly expressed and reflects an unfavorable prognosis, whereas EZR silencing ameliorates the malignant phenotype of pancreatic cancer cells. NSC305787 was identified as a pharmacological EZR inhibitor with favorable pharmacokinetics and antineoplastic activity. Here, we endeavored to investigate the impact of EZR expression on survival outcomes and its associations with molecular and biological characteristics in The Cancer Genome Atlas pancreatic adenocarcinoma cohort. We also assessed the potential antineoplastic effects of NSC305787 in pancreatic cancer cell lines. High EZR expression was an independent predictor of worse survival outcomes. Functional genomics analysis indicated that EZR contributes to multiple cancer-related pathways, including PI3K/AKT/mTOR signaling, NOTCH signaling, estrogen-mediated signaling, and apoptosis. In pancreatic cells, NSC305787 reduced cell viability, clonal growth, and migration. Our exploratory molecular studies identified that NSC305787 modulates the expression and activation of key regulators of the cell cycle, proliferation, DNA damage, and apoptosis, favoring a tumor-suppressive molecular network. In conclusion, EZR expression is an independent prognosis marker in pancreatic cancer. Our study identifies a novel molecular axis underlying the antineoplastic activity of NSC305787 and provides insights into the development of therapeutic strategies for pancreatic cancer.
Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias Pancreáticas , Adamantano/análogos & derivados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Proteínas do Citoesqueleto , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases , Quinolinas , Neoplasias PancreáticasRESUMO
PURPOSE: Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML. METHODS: Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays. RESULTS: High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p < 0.05). Functional genomics analyses suggested that EZR contributes to responses to stimuli and signal transduction pathways in leukemia cells. EZR pharmacological inhibition with NSC305787 and NSC668394 reduced viability, proliferation, autonomous clonal growth, and cell cycle progression in AML cells (p < 0.05). NSC305787 had a greater potency and efficiency than NSC668394 in leukemia models. At the molecular level, EZR inhibitors reduced EZR, S6 ribosomal protein and 4EBP1 phosphorylation, and induced PARP1 cleavage in AML cells. NSC305787, but not NSC668394, favored a gene network involving cell cycle arrest and apoptosis in Kasumi 1 AML cells. CONCLUSIONS: From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs.
Assuntos
Biomarcadores Tumorais/genética , Proteínas do Citoesqueleto/genética , Citoesqueleto/metabolismo , Regulação Leucêmica da Expressão Gênica , Genes Reguladores/genética , Leucemia Mieloide/genética , Doença Aguda , Adamantano/análogos & derivados , Adamantano/farmacologia , Adulto , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/metabolismo , Intervalo Livre de Doença , Feminino , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/metabolismo , Masculino , Fenóis/farmacologia , Prognóstico , Quinolinas/farmacologia , Quinolonas/farmacologia , Células THP-1 , Células U937RESUMO
The objective of this work, is to study adamantanes and to tune their bandgap, since pure adamantane is considered as an insulator due to its high bandgap energy. For this, we doped adamantane with oxygen and sulfur atoms, thus obtaining 730 different structures with double bonds and 730 different structures with single bonds, for a total of 1460 structures, and compared their properties. Among all, 31 molecules were selected that best represented the reduced bandgap behavior. The calculations with greater precision in its results were made using the Local Density Approximation (LDA), in the Density-Functional Theory (DFT) formalism, with PWC functional and TNP basis set. The electronic and optical properties were analyzed, by calculating the energy gap and absorption spectrum. Importantly, we observed that molecules doped with sulfur atoms (double bonds) had their energy gap reduced significantly compared to molecules doped with sulfur and/or oxygen atom with single bonds and pristine adamantane. It was found that in the absorption spectrum, the sulfur-doped structures had their spectrum shifted to the visible region, a fact that becomes relevant for potential dyes and optoelectronic applications. From the seven selected functionalized adamantanes (ADD-04, ADD-05, ADD-07, ADD-19, ADD-20, ADD-41, and ADD-48), any of these could be used as a dye. However, the ADD-20 molecule in particular, which presented optical absorption near (RGB) primary colors, could indicate a potential quantum dot material for application in developing screens of various electronic devices.
Assuntos
Adamantano , Oxigênio , EnxofreRESUMO
Peficitinib hydrobromide is a small Janus kinase inhibitor (JAK1, JAK2, JAK3 and TYK2) molecule for the treatment of rheumatoid arthritis (RA). Phase II and phase III clinical trials and extension studies with different doses have been conducted to assess the drug's efficacy and safety with substantially improved outcomes observed in RA. This JAK inhibitor oral drug demonstrated clinical response as once-daily monotherapy in patients with moderate to severe RA, also in combination with methotrexate (MTX), who had an inadequate response to MTX. The findings from studies of this new JAK inhibitor have shown that, both in monotherapy as well as in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), it has efficacy, safety and tolerability in RA patients.
Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Adamantano/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Janus Quinases/antagonistas & inibidores , Niacinamida/uso terapêutico , Resultado do TratamentoRESUMO
Introducción: El hidrocloruro de amantadina (I) es conocido como un medicamento antiviral utilizado para prevenir y tratar las infecciones por influenza A. También se utiliza para aliviar los síntomas de la enfermedad de Parkinson en el período inicial. Se han informado varios métodos para la preparación de (I). Estos procedimientos comienzan con adamantano (II) en cuatro o tres pasos de reacción, para producir hidrocloruro de amantadina con rendimientos globales que van del 45 por ciento al 58 por ciento. Objetivo: Mejorar el método para la síntesis de hidrocloruro de amantadina, que puede introducirse a escala industrial. Métodos: La optimización paso a paso para reducir el uso de reactivos, disolventes, así como las condiciones de cada paso, se seleccionaron para ser menos agresivas y más amigables con el medio ambiente. Resultados: Todos los factores relacionados con el rendimiento de la reacción para sintetizar los compuestos intermedios y finales se seleccionaron para obtener el mayor rendimiento de cada etapa. Finalmente, se estableció un procedimiento de dos pasos para la síntesis de (I) a partir de (II), a través de N- (1-adamantil) formamida (III), con un rendimiento global mejorado del 78 por ciento y una pureza del 99,2 por ciento. Se confirmó la estructura del producto por 1H-NMR, 13C-NMR, IR y MS. La síntesis de N- (1-adamantil) formamida (VI) a partir de (II) también se logró con éxito en un solo paso. Este método evita el uso de bromo líquido o ácido sulfúrico gaseoso como reactivos. La conversión posterior de (VI) a (I) se llevó a cabo bajo condiciones de reacción, más suaves sin usar solventes peligrosos. Conclusiones: Se logró la síntesis mejorada del clorhidrato de amantadina (I). Este resultado puede utilizarse en una producción industrialmente conveniente. Las materias primas y reactivos utilizados en esta investigación son baratas y están disponibles. El tiempo total de preparación se redujo significativamente, con ahorro de energía y mano de obra(AU)
Introduction: Amantadine hydrochloride (I) was well-known as an antiviral drug used to prevent and treat influenza A infections. Besides, it also was used to relieve the symptoms of Parkinson's disease in the early period. Several methods for the preparation of I have been reported. These procedures started with adamantane (II) in four or three reaction steps to produce amantadine hydrochloride with overall yields ranging from 45 percent to 58 percent. Objectives: Improving method for synthesis of amantadine hydrochloride could introduce to industrial scale. Methods: Step-by-step optimization to reduce the use of reagents, solvents, as well as the conditions of each step were screened to be milder and more environment-friendly. Results: All factors related to the yield of reaction to synthesize the intermediate and final compounds were screened to give the highest yield of each step. Finally, a two-step procedure for the synthesis of (I) from (II) via N-(1-adamantyl) formamide (III) with improving overall yield of 78 percent and a purity of 99.2 percent was established, and the structure of the product was confirmed by 1H-NMR,13C-NMR, IR and MS. The synthesis of N-(1-adamantyl) formamide (VI) from (II) also was successfully accomplished within only one step. This method avoided the use of liquid bromine or fuming sulfuric acid as reactants. The subsequent conversion of (VI) to (I) was carried out under milder reaction conditions without using hazardous solvents. Conclusions: An improved synthesis for amantadine hydrochloride (I) have been provided. This research can be an industrially convenient production of amantadine hydrochloride. Because the raw materials and reagents used in this research are cheap and available which also were screened to save their use. Moreover, the total preparation time was significantly reduced to save energy as well as labor(AU)
Assuntos
Humanos , Masculino , Feminino , Pesquisa , Adamantano , Preparações Farmacêuticas , Espectroscopia de Ressonância Magnética , Amantadina , Indicadores e ReagentesRESUMO
Leishmania donovani is the causative agent of visceral leishmaniasis. Annually, 500 million new cases of infection are reported mainly in poor communities, decreasing the interest of the pharmaceutical industries. Therefore, the repositioning of new drugs is an ideal strategy to fight against these parasites. SQ109, a compound in phase IIb/III of clinical trials to treat resistant Mycobacterium tuberculosis, has a potent effect against Trypanosoma cruzi, responsible for Chagas' disease, and on Leishmania mexicana, the causative agent of cutaneous and muco-cutaneous leishmaniasis. In the latter, the toxic dose against intramacrophagic amastigotes is very low (IC50 ~ 11 nM). The proposed mechanism of action on L. mexicana involves the disruption of the parasite intracellular Ca2+ homeostasis through the collapse of the mitochondrial electrochemical potential (ΔΨm). In the present work, we show a potent effect of SQ109 on L. donovani, the parasite responsible for visceral leishmaniasis, the more severe and uniquely lethal form of these infections, obtaining a toxic effect on amastigotes inside macrophages even lower to that obtained in L. mexicana (IC50 of 7.17 ± 0.09 nM) and with a selectivity index > 800, even higher than in L. mexicana. We also demonstrated for first time that SQ109, besides collapsing ΔΨm of the parasite, induced a very rapid damage to the parasite acidocalcisomes, essential organelles involved in the bioenergetics and many other important functions, including Ca2+ homeostasis. Both effects of the drug on these organelles generated a dramatic increase in the intracellular Ca2+ concentration, causing parasite death.
Assuntos
Adamantano/análogos & derivados , Etilenodiaminas/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Adamantano/farmacologia , Animais , Proliferação de Células , Doença de Chagas/tratamento farmacológico , Citoplasma , Humanos , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/parasitologia , Macrófagos/parasitologia , Mitocôndrias , Trypanosoma cruzi/efeitos dos fármacosRESUMO
BACKGROUND: Extracellular vesicles (EVs) are promising therapeutics for cardiovascular disease, but poorly-timed delivery might hinder efficacy. We characterized the time-dependent response to endothelial progenitor cell (EPC)-EVs within an injectable shear-thinning hydrogel (STG+EV) post-myocardial infarction (MI) to identify when an optimal response is achieved. METHODS: The angiogenic effects of prolonged hypoxia on cell response to EPC-EV therapy and EV uptake affinity were tested in vitro. A rat model of acute MI via left anterior descending artery ligation was created and STG+EV was delivered via intramyocardial injections into the infarct border zone at time points corresponding to phases of post-MI inflammation: 0 hours (immediate), 3 hours (acute inflammation), 4 days (proliferative), and 2 weeks (fibrosis). Hemodynamics 4 weeks post-treatment were compared across treatment and control groups (phosphate buffered saline [PBS], shear-thinning gel). Scar thickness and ventricular diameter were assessed histologically. The primary hemodynamic end point was end systolic elastance. The secondary end point was scar thickness. RESULTS: EPC-EVs incubated with chronically versus acutely hypoxic human umbilical vein endothelial cells resulted in a 2.56 ± 0.53 versus 1.65 ± 0.15-fold increase (P = .05) in a number of vascular meshes and higher uptake of EVs over 14 hours. End systolic elastance improved with STG+EV therapy at 4 days (0.54 ± 0.08) versus PBS or shear-thinning gel (0.26 ± 0.03 [P = .02]; 0.23 ± 0.02 [P = .01]). Preservation of ventricular diameter (6.20 ± 0.73 mm vs 8.58 ± 0.38 mm [P = .04]; 9.13 ± 0.25 mm [P = .01]) and scar thickness (0.89 ± 0.05 mm vs 0.62 ± 0.03 mm [P < .0001] and 0.58 ± 0.05 mm [P < .0001]) was significantly greater at 4 days, compared wit PBS and shear-thinning gel controls. CONCLUSIONS: Delivery of STG+EV 4 days post-MI improved left ventricular contractility and preserved global ventricular geometry, compared with controls and immediate therapy post-MI. These findings suggest other cell-derived therapies can be optimized by strategic timing of therapeutic intervention.
Assuntos
Células Progenitoras Endoteliais/transplante , Vesículas Extracelulares/transplante , Hemodinâmica , Infarto do Miocárdio/cirurgia , Miocárdio/patologia , Neovascularização Fisiológica , Tempo para o Tratamento , Adamantano/química , Animais , Hipóxia Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Células Progenitoras Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Fibrose , Géis , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Ácido Hialurônico/química , Mediadores da Inflamação/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Ratos Wistar , Fatores de Tempo , beta-Ciclodextrinas/químicaRESUMO
Synthesis of dinuclear oxadiazole-adamantane platinum(II) and palladium(II) complexes (PtO, PdO) and mononuclear thiazolidine derivative complexes (PtT, PdT) was described. Characterization was performed by elemental analysis, infrared, UV-visible, 1H, 13C, 195Pt NMR spectra, MS spectroscopy and single crystal X-ray diffraction. The cytotoxicity by MTT assay against tumor and normal cell lines with or without extracellular GSH was also investigated. In general, mononuclear complexes containing thiazolidine-adamantane ligands were more cytotoxic than oxadiazole-adamantane derivatives. PtT complex proved to be as active as cisplatin. Dinuclear compounds were considered inactive to cells in evaluated conditions, due to their high stability with ligands in a chelated and bridged way. Results suggest that GSH cannot be considered a target. DNA- and BSA-binding interactions were evaluated using UV-visible and fluorescence spectroscopy, intercalating dyes and molecular docking. Upon coordination to platinum(II), the cytotoxic effect was appreciably improved against tested cell lines, in comparison to free thiazolidine ligand. Comparing thiazolidine derivatives, it is noticeable that the less active compound (PdT) presents stronger interaction with BSA, while PtT has the weaker interaction with BSA and relatively strong binding to isolated DNA, resulting in the most cytotoxic complex. This work shows that the presence of metal is significant but it should be available for interaction. The high lability of palladium complex made this stay retainable in BSA and two metal atoms do not increase activity if it is not able to do any interaction.
Assuntos
Adamantano/química , Azóis/química , DNA/metabolismo , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Paládio/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cricetinae , DNA/química , Humanos , Lignanas , Camundongos , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Compostos Organoplatínicos/metabolismoRESUMO
Phospholipids are the main component of membranes and are responsible for cell integrity. Alkylphospholipid analogues (APs) were first designed as antitumoral agents and were later tested against different cell types. Trypanosoma cruzi, the Chagas disease etiological agent, is sensitive to APs (edelfosine, miltefosine and ilmofosine) in vitro. We investigated the effect of synthetic ring substituted AP against epimastigotes, amastigotes and trypomastigotes. TCAN26, could inhibit the in vitro growth of epimastigotes and amastigotes with the 50% inhibitory concentrations (IC50) in the nanomolar range. Trypomastigotes lysis was also induced with 24-h treatment and a LC50 of 2.3⯵M. Ultrastructural analysis by electron microscopy demonstrated that TCAN26 mainly affected the parasite's membranes leading to mitochondrial and Golgi cisternae swelling, membrane blebs, and autophagic figures in the different parasite developmental stages. While the Golgi of the parasites was significantly affected, the Golgi complex of the host cells remained normal suggesting a specific mechanism of action. In summary, our results suggest that TCAN 26 is a potent and selective inhibitor of T. cruzi growth probably due to disturbances of phospholipid biosynthesis.
Assuntos
Adamantano/farmacologia , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Adamantano/química , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Autofagia/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Relação Dose-Resposta a Droga , Citometria de Fluxo , Complexo de Golgi/efeitos dos fármacos , Concentração Inibidora 50 , Dose Letal Mediana , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Microscopia Imunoeletrônica , Mitocôndrias/efeitos dos fármacos , Fosforilcolina/química , Tripanossomicidas/química , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestruturaRESUMO
In late 2016, an H7N6 low pathogenic avian influenza virus outbreak occurred in domestic turkeys in Central Chile. We characterized the genetic and antigenic properties of the outbreak virus and its experimental transmission in chickens. Our studies demonstrate that the outbreak virus is a reassortment of genes identified from Chilean wild bird viruses between 2013 and 2017 and displays molecular adaptations to poultry and antiviral resistance to adamantanes. Further, these wild bird viruses are also able to transmit in experimentally infected chickens highlighting the need for continued surveillance and improvement of biosecurity in poultry farms.
Assuntos
Surtos de Doenças , Vírus da Influenza A/classificação , Vírus da Influenza A/isolamento & purificação , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Vírus Reordenados/classificação , Vírus Reordenados/isolamento & purificação , Adamantano/farmacologia , Adaptação Biológica , Animais , Animais Domésticos , Antivirais/farmacologia , Chile/epidemiologia , Farmacorresistência Viral , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Vírus Reordenados/genética , Vírus Reordenados/imunologia , PerusAssuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Glicemia/efeitos dos fármacos , Canagliflozina/uso terapêutico , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/uso terapêutico , Quimioterapia Combinada , Glucosídeos/uso terapêutico , Hemoglobinas Glicadas/efeitos dos fármacos , Glicosídeos/uso terapêutico , Humanos , Hipoglicemia/induzido quimicamente , Insulina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the clinical efficacy and the possible mechanisms of saxagliptin in the treatment of type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD). METHODS: A total of 95 T2DM and NAFLD patients were randomly divided into group A (saxagliptin group), group B (glimepiride group), and group C (glimepiride combined with polyene phosphatidylcholine group). RESULTS: After intervention treatment for 24 w, body mass index (BMI), waist-to-hip ratio (WHR), glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), interleukin-6 (IL-6), triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), and quantitative detection of liver steatosis of study subjects were observed, the action of liver steatosis in subjects of groups A and C were significantly different from those of group B; however, there were no differences between groups A and C. The FINS, HOMA-IR, and IL-6 of subjects in group A was lower than those in groups B and C; however, there were no significant differences between the latter two groups. CONCLUSION: For T2DM combined with NAFLD patients, the saxagliptin treatment could not only effectively control blood glucose but also attenuate insulin resistance and inflammatory injury of the liver to improve fatty liver further.
Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fosfatidilcolinas/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Adamantano/administração & dosagem , Glicemia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Resultado do TratamentoRESUMO
SUMMARY OBJECTIVE To investigate the clinical efficacy and the possible mechanisms of saxagliptin in the treatment of type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD). METHODS A total of 95 T2DM and NAFLD patients were randomly divided into group A (saxagliptin group), group B (glimepiride group), and group C (glimepiride combined with polyene phosphatidylcholine group). RESULTS After intervention treatment for 24 w, body mass index (BMI), waist-to-hip ratio (WHR), glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), interleukin-6 (IL-6), triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), and quantitative detection of liver steatosis of study subjects were observed, the action of liver steatosis in subjects of groups A and C were significantly different from those of group B; however, there were no differences between groups A and C. The FINS, HOMA-IR, and IL-6 of subjects in group A was lower than those in groups B and C; however, there were no significant differences between the latter two groups. CONCLUSION For T2DM combined with NAFLD patients, the saxagliptin treatment could not only effectively control blood glucose but also attenuate insulin resistance and inflammatory injury of the liver to improve fatty liver further.
RESUMO OBJETIVO Investigar a eficácia clínica e os possíveis mecanismos da saxagliptina no tratamento do diabetes mellitus tipo 2 (DM2) associado à doença hepática gordurosa não alcoólica (DHGNA). MÉTODOS Um total de 95 DM2 combinados com pacientes com DHGNA foram aleatoriamente divididos em grupo A (grupo saxagliptina), grupo B (grupo glimepirida) e grupo C (glimepirida combinado com grupo fosfatidilcolina polienizada). RESULTADOS Após a intervenção tratamento por 24 w, índice de massa corporal (IMC), relação cintura-quadril (RCQ), hemoglobina glicada (HbA1c), glicemia de jejum (FPG), insulina de jejum (Fins), avaliação do modelo homeostático de insulina resistência (Homa-IR), interleucina-6 (IL-6), triglicérides (TG), colesterol total (CT), alanina aminotransferase (ALT), aspartato aminotransferase (AST), γ-glutamiltransferase (γ-GT) e detecção de esteatose hepática dos sujeitos do estudo foram observados. Ação de esteatose hepática de indivíduos nos grupos A e C foram significativamente diferentes do grupo B; no entanto, não houve diferenças entre os grupos A e C. Os grupos Fins, Homa-IR e IL-6 dos participantes do grupo A foram menores que os dos grupos B e C; no entanto, não houve diferenças significativas entre os dois últimos grupos. CONCLUSÃO Para o DM2 combinado com pacientes com DHGNA, o tratamento com saxagliptina pode não apenas controlar efetivamente a glicemia, mas também atenuar a resistência à insulina e a lesão inflamatória do fígado para melhorar ainda mais o fígado gorduroso.
Assuntos
Humanos , Masculino , Feminino , Fosfatidilcolinas/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Glicemia , Resistência à Insulina , Adamantano/administração & dosagem , Índice de Massa Corporal , Resultado do Tratamento , Diabetes Mellitus Tipo 2/complicações , Dipeptídeos/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/complicações , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. MATERIALS AND METHODS: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. RESULTS: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: -0.32% [-0.54, -0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, -0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, -1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, -1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. CONCLUSION: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.
Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Transportador 2 de Glucose-Sódio/uso terapêutico , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada/métodos , Feminino , Glucosídeos/efeitos adversos , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Infecções do Sistema Genital/induzido quimicamente , Transportador 2 de Glucose-Sódio/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose , Resultado do TratamentoRESUMO
ABSTRACT Objective: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. Materials and methods: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. Results: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: −0.32% [-0.54, −0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, −0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, −1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, −1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. Conclusion: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Compostos Benzidrílicos/uso terapêutico , Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Método Duplo-Cego , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/efeitos adversos , Transportador 2 de Glucose-Sódio/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêuticoRESUMO
AIMS: To evaluate the glucose variability, oxidative stress, metabolic and cardiovascular responses after an aerobic exercise session in diabetic patients on treatment with metformin plus vildagliptin or glibenclamide. METHODS: Parallel clinical trial including patients with type 2 diabetes treated with metformin plus vildagliptin or glibenclamide for 12â¯weeks. Glucose variability, oxidative stress, metabolic (plasma glucose, insulin and glucagon-like-peptide-1) and cardiovascular responses were evaluated at rest, during and after a 30â¯min aerobic exercise session (70% of the peak heart rate). RESULTS: Thirteen patients were included, seven in vildagliptin group (METV) and six in glibenclamide group (METG), baseline glycated hemoglobin (HbA1c) 8.8⯱â¯0.3%. Treatment reduced HbA1c (1.2% and 1.5% for METV and METG, respectively). The aerobic exercise session did not change glucose variability in both groups. A decrease in glucose during exercise recovery was found, with area under the curve lower in the METG vs. METV (pâ¯=â¯0.04). After the intervention, systolic blood pressure (SBP) decreased in both groups. Patients treated with vildagliptin showed lower SBP variability compared to those treated with glibenclamide. CONCLUSIONS: Besides improvement in glucose control and reduction of SBP obtained by both treatments, lower blood pressure variability was observed in patients receiving vildagliptin. Glucose variability remained unaffected by both interventions and the exercise session.
Assuntos
Adamantano/análogos & derivados , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Exercício Físico/fisiologia , Glucose/metabolismo , Glibureto/uso terapêutico , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Adamantano/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , VildagliptinaRESUMO
OBJECTIVES: To determine whether the drug saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor which is utilized for the treatment of Diabetes Mellitus, has neuroprotective effects in the animal model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) in rats. METHODS: Male Wistar rats (weighing 280-300 g) received a bilateral infusion of 6-OHDA in the substantia nigra. Twenty-four hours later, they were treated with saxagliptin (1 mg/kg, p.o) once daily, for 21 days. The motor function was evaluated using the open field and rotarod (RT) tests. In addition, cognition was assessed with the novel object recognition test (ORT). After the evaluation of the behavioural tests, the animals were transcardially perfused to perform immunohistochemistry staining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc). KEY FINDINGS: Saxagliptin impaired the memory of animals in the sham group. CONCLUSIONS: Saxagliptin treatment did not exhibit neuroprotection and it did not improve the cognitive and motor deficits in the 6-OHDA model of PD. Interestingly, when saxagliptin was administered to the sham animals, a cognitive decline was observed. Therefore, this drug should be investigated as a possible treatment for PTSD.
Assuntos
Adamantano/análogos & derivados , Comportamento Animal/efeitos dos fármacos , Dipeptídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Adamantano/administração & dosagem , Adamantano/uso terapêutico , Animais , Dipeptídeos/administração & dosagem , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Masculino , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Ratos Wistar , Resultado do TratamentoRESUMO
AIMS: This study aims to evaluate whether there is a difference between the effects of vildagliptin and gliclazide MR (modified release) on glycemic variability (GV) in women with type 2 diabetes (T2DM) as evaluated by continuous glucose monitoring (CGM). METHODS: An open-label, randomized study was conducted in T2DM women on steady-dose metformin monotherapy which were treated with 50â¯mg vildagliptin twice daily or 60-120â¯mg of gliclazide MR once daily. CGM and GV indices calculation were performed at baseline and after 24â¯weeks. RESULTS: In total, 42 patients (age: 61.9⯱â¯5.9â¯years, baseline glycated hemoglobin (HbA1c): 7.3⯱â¯0.56) were selected and 37 completed the 24-week protocol. Vildagliptin and gliclazide MR reduced GV, as measured by the mean amplitude of glycemic excursions (MAGE, pâ¯=â¯0.007 and 0.034, respectively). The difference between the groups did not reach statistical significance. Vildagliptin also significantly decreased the standard deviation of the mean glucose (SD) and the mean of the daily differences (MODD) (pâ¯=â¯0.007 and 0.030). CONCLUSIONS: Vildagliptin and gliclazide MR similarly reduced the MAGE in women with T2DM after 24â¯weeks of treatment. Further studies are required to attest differences between vildagliptin and gliclazide MR regarding glycemic variability.
Assuntos
Adamantano/análogos & derivados , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliclazida/administração & dosagem , Hipoglicemiantes/administração & dosagem , Nitrilas/administração & dosagem , Pirrolidinas/administração & dosagem , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adulto , Idoso , Glicemia/efeitos dos fármacos , Automonitorização da Glicemia , Brasil/epidemiologia , Preparações de Ação Retardada/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Gliclazida/efeitos adversos , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/efeitos adversos , Metformina/uso terapêutico , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Pirrolidinas/efeitos adversos , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/efeitos adversos , Resultado do Tratamento , VildagliptinaRESUMO
INTRODUCTION: Vildagliptin is an inhibitor of the enzyme dipeptidyl peptidase 4, indicated for the treatment of type 2 diabetes mellitus, combined or not with metformin. This study aims to evaluate the cost-effectiveness of vildagliptin in the Brazilian context. Areas covered: Using MEDLINE, Cochrane Library, Lilacs and CRD, six studies were selected for the economic models. This study utilised cost data in the Brazilian health system to provide the context. Expert commentary: Type 2 diabetes mellitus is an epidemic disease and represents a challenge for all health care systems. Although guidelines clearly define first-line treatment, there are several other promising treatments. Vildagliptin is one of them, resulting in a mean lifetime increase of 0.31 years compared to metformin alone and 1.19 more life years compared to other metformin combinations. Considering observational data, life years with dual vildagliptin-containing treatments were 0.37 more compared to other dual treatments. However, its high cost versus generic metformin and its unclear safety profile weakens its subsequent cost-effectiveness. Consequently, the incorporation of vildagliptin or its combination with metformin is currently not recommended for the Brazilian Health Care System. This may change as more data becomes available.