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1.
Eur J Med Chem ; 177: 153-170, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132531

RESUMO

The eukaryotic initiation factor 4E (eIF4E) is an emerging anticancer drug target for specific anticancer therapy as a promising approach to overcome drug resistance and promote chemotherapy antitumor efficacy. A series of bromophenol-thiazolylhydrazone hybrids were designed, synthesized and evaluated for their antitumor activities. Among of them, the most potent compound 3e (EGPI-1) could inhibit the eIF4E/eIF4G interaction. Further mechanism study demonstrated EGPI-1 played an antitumor role in multiple modes of action including regulating the activity of eIF4E by inhibiting the phosphorylation of eIF4E and 4EBP1, disrupting mitochondrial function through the mTOR/4EBP1 signaling pathway, and inducing autophagy, apoptosis and ROS generation. Moreover, EGPI-1 showed good safety and favorable pharmacokinetic properties in vivo. These observations demonstrate that EGPI-1 may serve as an excellent lead compound for the development of new anticancer drugs that target the eIF4E/eIF4G interface and as a chemical genetic probe to investigate the role of the eIF4E in biological processes and human diseases.


Assuntos
Antineoplásicos/farmacologia , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4G em Eucariotos/antagonistas & inibidores , Hidrazonas/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/metabolismo , Fator de Iniciação 4G em Eucariotos/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrazonas/síntese química , Hidrazonas/farmacocinética , Hidrazonas/toxicidade , Masculino , Camundongos , Simulação de Acoplamento Molecular , Fosforilação , Ligação Proteica , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/farmacocinética , Tiazóis/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Clin Appl Thromb Hemost ; 25: 1076029619847524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31088146

RESUMO

The currently available oral anti-Xa agents are claimed to produce their anticoagulant and antithrombotic effects solely by the inhibition of factor Xa. This study profiled various anti-Xa drugs in routinely used laboratory assays to demonstrate that their effects are not solely related to the anti-Xa activities. Apixaban, betrixaban, edoxaban, and rivaroxaban were obtained commercially. Native and citrated whole blood was used for the activated clotting time (ACT) and thromboelastography (TEG). Citrated plasma was used for monitoring the prothrombin time (PT), activated partial thromboplastin time (aPTT), Heptest, and prothrombinase-induced clotting time (PiCT) tests. An amidolytic method was used for the determination of anti-Xa effects. Thrombin-induced fibrinokinetics was monitored optically. Thrombin generation studies were carried out using the calibrated automated thrombogram. All of the anti-Xa agents produced concentration- and assay-dependent effects. In the ACT at 2.5 µg/mL and TEG at 1.0 µg/mL, edoxaban exhibited the strongest anticoagulation effect. In the PiCT, PT, and aPTT assay at 1 µg/mL, edoxaban showed stronger effects than other agents. The half maximal inhibitory concentration of these agents for the inhibition of factor Xa ranged from 340 to >1000 ng/mL. In the thrombin generation inhibition assay, apixaban showed the strongest activity. In the fibrinokinetics, different anti-Xa agents produced varying degrees of inhibition. These results demonstrate that the measured anti-Xa activity alone does not fully reflect the overall biologic spectrum of these agents.


Assuntos
Benzamidas , Inibidores do Fator Xa , Fator Xa/metabolismo , Tempo de Protrombina , Pirazóis , Piridinas , Piridonas , Rivaroxabana , Benzamidas/farmacocinética , Benzamidas/farmacologia , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/farmacologia , Humanos , Tempo de Tromboplastina Parcial , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Rivaroxabana/farmacocinética , Rivaroxabana/farmacologia , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tromboelastografia
3.
Eur J Pharm Sci ; 135: 83-90, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125680

RESUMO

The aim of this research was to develop an in silico modeling and simulation approach to predict the oral performance of a poorly soluble drug candidate, T2CP, formulated as an amorphous solid dispersion and an amorphous powder. The dissolution and precipitation profiles of T2CP of the two amorphous formulations were evaluated in biorelevant media using USP 2 paddle apparatus. Three equations, the Noyes-Whitney equation for dissolution and separate equations describing nucleation and crystal growth, were fitted simultaneously to the in vitro profiles to estimate the dissolution and precipitation parameters for each formulation. The in silico prediction model for the amorphous formulations was designed using STELLA Professional software and the simulated profiles were compared with the observed plasma profiles in dogs. The STELLA model was able to describe the complex characteristics of in vitro dissolution and precipitation of the amorphous formulations well. The predicted plasma concentration profiles using the estimated dissolution and precipitation parameters of the two amorphous formulations were close to the profiles observed in dogs. This research paves the way for further application of biorelevant in vitro methods in combination with in silico tools to mechanistically forecast the in vivo performance of enhanced formulations.


Assuntos
Piperidinas/farmacocinética , Pirrolidinas/farmacocinética , Tiazóis/farmacocinética , Administração Oral , Animais , Simulação por Computador , Cães , Composição de Medicamentos , Excipientes , Absorção Intestinal , Masculino , Modelos Biológicos , Tamanho da Partícula , Piperidinas/administração & dosagem , Porosidade , Pirrolidinas/administração & dosagem , Solubilidade , Comprimidos , Tiazóis/administração & dosagem
4.
Rev Assoc Med Bras (1992) ; 65(2): 141-148, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30892436

RESUMO

Mirabegron is a kind of ß3 adrenergic receptor agonist which is an effective drug for the treatment of overactive bladder. In this research, a UPLC-MS/MS method is developed and validated for the study of mirabegron pharmacokinetic in rats. A protein precipitation method is applied for sample preparation with acetonitrile. m/z 397.3→379.6, m/z 326.4→121.0 for mirabegron, tolterodine (IS), respectively in the positive ion mode was performed for quantitation. The method is reliable and reproducible in our study (intra-day precision≤11.06%, inter-day precision≤11.43%) with concentration curves linear from 5 to 2500 ng/mL(R2>0.999). Stability studies demonstrated that mirabegron was stable under a variety of storage conditions. This method was successfully applied for determining mirabegron in rats after oral and intravenous administration.


Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Tiazóis/farmacocinética , Acetanilidas/administração & dosagem , Acetanilidas/sangue , Administração Intravenosa , Administração Oral , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/sangue , Animais , Cromatografia Líquida de Alta Pressão , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Tiazóis/administração & dosagem , Tiazóis/sangue
5.
Expert Rev Cardiovasc Ther ; 17(4): 319-330, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30897988

RESUMO

INTRODUCTION: Edoxaban is the last direct oral anticoagulant marketed for the prevention of stroke among patients with nonvalvular atrial fibrillation (AF). Areas covered: ENGAGE AF-TIMI 48 was the pivotal clinical trial that led to the approval of edoxaban 60 mg once daily. After the publication of this study, a great number of substudies and post hoc analyses have been published, together with some observational studies. The aim of this review was to update the current evidence about the use of edoxaban in AF patients. Expert opinion: In the ENGAGE AF-TIMI 48 trial, edoxaban 60 mg was noninferior to warfarin for the prevention of stroke or systemic embolism, but significantly reduced the risk of bleeding, major adverse cardiac events and death from cardiovascular causes. The relative efficacy and safety of edoxaban 60 mg compared with warfarin were independent of different clinical conditions, such as prior stroke, age, risk of falls, renal function, hepatic disease, ischemic heart disease, heart failure, valvular heart disease, or cancer. Data about the effectiveness and safety of edoxaban in real-life patients are scarce, but consistent with those of the pivotal clinical trial. Edoxaban seems a cost-effective alternative to warfarin among AF patients with moderate to high thromboembolic risk.


Assuntos
Fibrilação Atrial/complicações , Inibidores do Fator Xa/uso terapêutico , Piridinas/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Tromboembolia/prevenção & controle , Anticoagulantes/uso terapêutico , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Inibidores do Fator Xa/farmacocinética , Hemorragia/induzido quimicamente , Humanos , Piridinas/farmacocinética , Acidente Vascular Cerebral/etiologia , Tiazóis/farmacocinética , Tromboembolia/etiologia , Varfarina/uso terapêutico
6.
Eur J Med Chem ; 167: 245-268, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772607

RESUMO

A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1'R,2'S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC50 = 0.003 nM) than daclatasvir (GT1b EC50 = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC50 > 50 µM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.


Assuntos
Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Tiazóis/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Amidas/química , Animais , Disponibilidade Biológica , Cães , Humanos , Ratos , Sialiltransferases/antagonistas & inibidores , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/uso terapêutico
7.
Nihon Yakurigaku Zasshi ; 153(2): 79-87, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30745518

RESUMO

Ravuconazole is a fourth generation azole exerting strong antifungal activity, with low drug-drug interaction and hepatic dysfunction risks. Fosravuconazole l-lysine ethanolate (fosravuconazole; NAILIN® Capsules 100 mg) was developed as a ravuconazole prodrug. Ravuconazole exerts strong antifungal activity against various pathogenic fungi including dermatophytes and Candida. Through prodrug formation, pharmacokinetic improvement was achieved, and bioavailability after oral administration reached 100%. The plasma ravuconazole concentration became 10-35 times higher than with current oral anti-onychomycosis drugs, and showed good skin and nail tissue transition plus tissue retention. This improvement obtained with fosravuconazole reflects its superior pharmacokinetic properties. We conducted a clinical trial with fosravuconazole orally administered once a day (100 mg ravuconazole) for 12 weeks in Japanese onychomycosis patients. The ravuconazole concentration in nail tissues exceeded the MIC90 against dermatophytes, even after treatment completion. Furthermore, the placebo-controlled, double-blind, comparative trial showed significantly superior effects (at 48 weeks after starting treatment, with a complete cure rate of 59.4%, a marked clinical improvement rate of 83.1%, and a mycological cure rate by direct microscopy of 82.0%). The major adverse reactions were laboratory abnormalities and gastrointestinal disorders with no severe symptoms, suggesting good tolerability. Fosravuconazole has fewer drug-drug interactions, is not affected by food, and is also expected to improve medication adherence since the administration period is only 12 weeks and there is no drug-free period as required with pulse therapy. Thus, fosravuconazole has many favorable pharmacological properties and can reasonably be expected to become a new oral treatment option for onychomycosis.


Assuntos
Antifúngicos/uso terapêutico , Lisina/uso terapêutico , Onicomicose/tratamento farmacológico , Triazóis/uso terapêutico , Administração Oral , Antifúngicos/farmacocinética , Cápsulas , Método Duplo-Cego , Humanos , Lisina/análogos & derivados , Lisina/farmacologia , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Tiazóis/farmacocinética , Tiazóis/uso terapêutico , Triazóis/farmacocinética
8.
AAPS PharmSciTech ; 20(1): 37, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604142

RESUMO

The purpose of this study was to research a novel combination of Plasdone-S630 and HPMCAS-HF as hot-melt carrier used in ziprasidone hydrochloride for enhanced oral bioavailability and dismissed food effect. Ziprasidone hydrochloride solid dispersion (ZH-SD) was prepared by hot-melt extrusion technique, and its optimized formulation was selected by the central composite design (CCD), which was characterized for powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), in vitro dissolution study, and stability study. Finally, the in vivo study in fasted/fed state was carried out in beagle dogs. Based on PXRD analysis, HME technique successfully dispersed ziprasidone with a low crystallinity hydrochloride form in the polymers. According to the analysis of FTIR, hydrogen bonds were formed between drug and polymers during the process of HME. Without any noticeable bulk, crystalline could be found from the micrograph of ZH-SD when analyzed the result of scanning electron microscope (SEM). Pharmacokinetics studies indicated that the bioavailability of ZH-SD formulation had no significant difference in fasted and fed state, and the Cmax and AUC of ZH-SD were two fold higher than Zeldox® in fasted state. This result indicated that ziprasidone has achieved a desired oral bioavailability in fasted state and no food effect.


Assuntos
Jejum , Metilcelulose/análogos & derivados , Piperazinas/síntese química , Povidona/síntese química , Tiazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cães , Combinação de Medicamentos , Jejum/metabolismo , Metilcelulose/administração & dosagem , Metilcelulose/síntese química , Metilcelulose/metabolismo , Excipientes Farmacêuticos/administração & dosagem , Excipientes Farmacêuticos/metabolismo , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Povidona/administração & dosagem , Povidona/metabolismo , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Difração de Raios X/métodos
9.
J Coll Physicians Surg Pak ; 29(1): 73-74, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30630575

RESUMO

Medical expulsive therapy (MET) is used especially in distal ureteral stones to reduce colics and decrease the number of endourological surgical interventions. A broad spectrum of agents can be used for the relaxation and the dilatation of the ureter, reducing the intraureteric pressure. Alfa-blockers, calcium channel blockers, phosphodiesterase (PDE) inhibitors, and spasmolytics have been shown as effective in clinical trials on urolithiasis. It is a fact that the urothelium itself, the interstitial cells and the ureteric smooth muscle, have B-beta-2 and beta-3 adrenoreceptors. Stimulation of these receptors results in relaxation of the ureter. A recent beta-3 agonist, mirabegron, is commonly used for overactive bladder nowadays. The mechanism of action is adrenergic agonism that affects with the storage phase of the bladder, without interfering the voiding phase, which is regulated by parasympathetic pathways, commonly muscarinic. Agonism of the beta-3 receptors in the ureter has been shown to decrease the intraluminal pressure. By this mechanism, mirabegron can be thought as an alternative MET agent. Acting through different pathways, and having low adverse effect profile, can be thought as the most striking advantages of mirabegron as a MET. In vitro and in vivo trials should be conducted to support this hypothesis.


Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Tiazóis/farmacocinética , Ureter/efeitos dos fármacos , Cálculos Ureterais/tratamento farmacológico , Humanos , Relaxamento Muscular/efeitos dos fármacos
10.
Eur J Med Chem ; 164: 352-365, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30605833

RESUMO

The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/química , PPAR delta/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Tiazóis/farmacologia , Animais , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Camundongos , Tiazóis/química , Tiazóis/farmacocinética
11.
PLoS One ; 14(1): e0211000, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30653612

RESUMO

In Alzheimer's Disease (AD) dual-tracer positron emission tomography (PET) studies with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and 11C-labelled Pittsburgh Compound B (PIB) are used to assess metabolism and cerebral amyloid-ß deposition, respectively. Regional cerebral metabolism and blood flow (rCBF) are closely coupled, both providing an index for neuronal function. The present study compared PIB-derived rCBF, estimated by the ratio of tracer influx in target regions relative to reference region (R1) and early-stage PIB uptake (ePIB), to FDG scans. Fifteen PIB positive (+) patients and fifteen PIB negative (-) subjects underwent both FDG and PIB PET scans to assess the use of R1 and ePIB as a surrogate for FDG. First, subjects were classified based on visual inspection of the PIB PET images. Then, discriminative performance (PIB+ versus PIB-) of rCBF methods were compared to normalized regional FDG uptake. Strong positive correlations were found between analyses, suggesting that PIB-derived rCBF provides information that is closely related to what can be seen on FDG scans. Yet group related differences between method's distributions were seen as well. Also, a better correlation with FDG was found for R1 than for ePIB. Further studies are needed to validate the use of R1 as an alternative for FDG studies in clinical applications.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Tomografia por Emissão de Pósitrons/métodos , Idoso , Compostos de Anilina/farmacocinética , Encéfalo/metabolismo , Radioisótopos de Carbono/farmacocinética , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Feminino , Radioisótopos de Flúor/farmacocinética , Fluordesoxiglucose F18/farmacocinética , Glucose/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Compostos Radiofarmacêuticos/farmacocinética , Tiazóis/farmacocinética
12.
Drugs Today (Barc) ; 54(11): 647-655, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30539164

RESUMO

Avatrombopag maleate (Doptelet; Dova Pharmaceuticals) is an oral, small-molecule second-generation thrombopoietin (TPO) receptor agonist under development for the treatment of thrombocytopenia. Recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease on the basis of the results of two phase III trials, it is currently under investigation for treatment of immune thrombocytopenia (two randomized trials demonstrating efficacy have already been completed), chemotherapy-induced thrombocytopenia and perioperative thrombocytopenia in patients undergoing major surgical procedures. This review will evaluate the preclinical pharmacology, pharmacokinetics, clinical studies, safety, indications and drug interactions of avatrombopag, with a focus on its use for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease.


Assuntos
Fármacos Hematológicos/administração & dosagem , Hepatopatias/cirurgia , Tiazóis/administração & dosagem , Tiofenos/administração & dosagem , Trombocitopenia/tratamento farmacológico , Animais , Doença Crônica , Interações de Medicamentos , Fármacos Hematológicos/efeitos adversos , Fármacos Hematológicos/farmacocinética , Humanos , Hepatopatias/sangue , Hepatopatias/diagnóstico , Período Perioperatório , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Tiofenos/efeitos adversos , Tiofenos/farmacocinética , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Resultado do Tratamento
13.
Int J Nanomedicine ; 13: 4711-4725, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30154656

RESUMO

Background: The objective of this study was to develop a more bio-available and safe nanosuspension of meloxicam (MX), which could dramatically improve inflammation targeting. Methods and results: MX-loaded bovine serum albumin (BSA) nanosuspensions were prepared using acid-base neutralization in aqueous solution and the prepared nanosuspensions were characterized. The results obtained showed that the prepared nanosuspensions had a narrow size distribution with a mean particle size of 78.67±0.22 nm, a polydispersity index of 0.133±0.01, and a zeta potential of -11.87±0.91 mV. The prepared MX nanosuspensions were spherically wrapped by BSA with a smooth surface as shown by transmission electron microscopy. Stability studies showed that the nanosuspensions were physically stable at 4°C with a shelf life of at least 6 months. In the in vitro dissolution test, the MX-loaded BSA nanosuspension (MX-BSA-NS) exhibited sustained release. In addition, an in vivo pharmacokinetic study in rats following intravenous injection showed that the half-life (t1/2), mean residence time (MRT), and area under the concentration-time curve (AUC0-∞) of MX-BSA-NS was increased by 169.83%, 150.13%, and 148.80%, respectively, in comparison with MX conventional solution (MX solution). Furthermore, results from inflammation targeting studies showed that the concentration of MX increased significantly in inflamed tissues but was reduced in normal tissues compared with the MX solution group after injection of MX-BSA-NS. Conclusion: The prepared MX-BSA-NS significantly increased the inflammation-targeting properties and bioavailability of MX, suggesting its potential as a promising formulation for the targeted drug delivery of MX in future clinical applications.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Sistemas de Liberação de Medicamentos , Inflamação/tratamento farmacológico , Nanopartículas/administração & dosagem , Soroalbumina Bovina/química , Tiazinas/farmacologia , Tiazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Feminino , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Meloxicam , Nanopartículas/química , Coelhos , Ratos , Ratos Sprague-Dawley , Suspensões , Tiazinas/química , Tiazinas/farmacocinética , Tiazóis/química , Tiazóis/farmacocinética , Distribuição Tecidual
14.
Eur J Med Chem ; 156: 831-846, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30053721

RESUMO

PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, ß, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 µM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Descoberta de Drogas , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/química , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos Sprague-Dawley , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/uso terapêutico
15.
Drugs ; 78(8): 833-844, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29869204

RESUMO

The first-in-class ß3-adrenoceptor agonist mirabegron is indicated in the EU (Betmiga™), Japan (Betanis™) and several other countries for the management of overactive bladder (OAB) syndrome. Evidence for its use in this setting includes several large phase 3 trials. Compared with placebo, oral mirabegron for 12 weeks reduced the frequency of micturition and generally also that of incontinence, with other benefits including reduced urgency, increased void volume and improved health related quality-of-life (HR-QOL). Mirabegron comparisons versus tolterodine are descriptive; however, in a 12-week powered comparison versus solifenacin in patients dissatisfied with antimuscarinic efficacy, mirabegron did not demonstrate noninferiority in reducing micturition frequency or significantly differ in terms of improving other urinary symptoms. Urinary and HR-QOL benefits of mirabegron were sustained over up to 52 weeks of treatment and the drug was generally well tolerated, with a numerically lower incidence of dry mouth than antimuscarinics. Real-world data support the trial findings and indicate possible persistence and adherence benefits for mirabegron over antimuscarinics. Mirabegron use is not generally restricted by patient age, sex or antimuscarinic treatment status, although data in men (from a phase 4 study and phase 3 trial subanalyses) are variable; additional studies in older and male OAB patients are awaited with interest. Although further longer-term efficacy and tolerability data would be beneficial, current clinical evidence indicates that mirabegron provides an alternative to antimuscarinics for the management of OAB in adults, including those for whom antimuscarinics have proven unsuitable.


Assuntos
Acetanilidas/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Agentes Urológicos/uso terapêutico , Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Feminino , Humanos , Masculino , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/uso terapêutico , Transdução de Sinais , Tiazóis/farmacocinética , Resultado do Tratamento , Incontinência Urinária/tratamento farmacológico , Agentes Urológicos/farmacocinética
16.
Praxis (Bern 1994) ; 107(13): 683-687, 2018 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-29921184

RESUMO

The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease Abstract. Increasing life expectancy in Western countries is associated with a high prevalence of multiple chronic diseases which is defined by the term "multimorbidity". Many of these patients suffer from chronic kidney disease (CKD) and thrombogenic comorbidities such as atrial fibrillation with the need for oral anticoagulation. For decades vitamin K antagonists have been exclusively prescribed for oral anticoagulation. However, due to altered pharmacokinetics and bioavailability of these drugs in CKD, a significant risk of bleeding exists. The introduction of direct oral anticoagulants as a new and promising alternative to vitamin K antagonists was -especially for CKD patients - highly anticipated. However, data from randomized studies are missing for older patients with advanced CKD. Consequently, a careful evaluation of the risk-benefit ratio is recommended for this sensitive patient population.


Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Arteriopatias Oclusivas/tratamento farmacológico , Fibrilação Atrial/tratamento farmacológico , Doença das Coronárias/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , Tromboembolia/tratamento farmacológico , Anticoagulantes/farmacocinética , Comorbidade , Contraindicações , Dabigatrana/efeitos adversos , Dabigatrana/farmacocinética , Dabigatrana/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Piridonas/efeitos adversos , Piridonas/farmacocinética , Piridonas/uso terapêutico , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Rivaroxabana/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Tiazóis/uso terapêutico , Vitamina K/antagonistas & inibidores
17.
Eur J Pharm Biopharm ; 129: 145-153, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29857135

RESUMO

The synergistic effect of nanosizing and lipid-based drug delivery systems (LBDDS) was explored to enhance formulation drug loading levels and improve drug solubilisation in the gastrointestinal environment. A novel formulation combining drug nanocrystals and silica-lipid hybrid (SLH) microparticles as a solid-state LBDDS was developed for the challenging poorly water-soluble drug, ziprasidone. A ziprasidone nanosuspension was fabricated via high-pressure homogenisation, achieving a mean particle size of 280 nm. In vitro dissolution studies revealed the nanosuspension to exhibit a significant 2.4-fold increase in the extent of drug dissolution, relative to pure drug. Novel ziprasidone nanocrystal-loaded SLH microparticles (ncSLH) were formulated by freeze-drying a precursor drug-loaded emulsion with drug nanocrystals and silica nanoparticles. Drug loading levels were increased at least 17-fold relative to conventional SLH microparticles, resulting in an increase in crystalline drug content and a change in surface atomic composition. The in vitro performance was evaluated by quantifying solubilisation levels during simulated intestinal lipolysis studies. Novel ncSLH significantly improved the in vitro fasted state solubilisation of ziprasidone (up to 4.7-fold), thus indicating the potential for such a formulation to overcome some of the various challenges faced by poorly water-soluble, brick-dust drug molecules.


Assuntos
Portadores de Fármacos/química , Liberação Controlada de Fármacos , Nanopartículas/química , Piperazinas/administração & dosagem , Tiazóis/administração & dosagem , Administração Oral , Disponibilidade Biológica , Química Farmacêutica , Liofilização , Gotículas Lipídicas/química , Lipídeos/química , Microscopia Eletrônica de Varredura , Nanopartículas/ultraestrutura , Piperazinas/química , Piperazinas/farmacocinética , Dióxido de Silício/química , Solubilidade , Tiazóis/química , Tiazóis/farmacocinética , Água/química
18.
Int J Pharm ; 546(1-2): 235-246, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-29758343

RESUMO

The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro-resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro-resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate-free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II).


Assuntos
Anti-Inflamatórios não Esteroides , Antiulcerosos , Omeprazol , Tiazinas , Tiazóis , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Antiulcerosos/administração & dosagem , Antiulcerosos/química , Antiulcerosos/farmacocinética , Cápsulas , Química Farmacêutica , Citratos/química , Estudos Cross-Over , Combinação de Medicamentos , Liberação Controlada de Fármacos , Excipientes/química , Feminino , Gelatina/química , Humanos , Concentração de Íons de Hidrogênio , Masculino , Meloxicam , Omeprazol/administração & dosagem , Omeprazol/química , Omeprazol/farmacocinética , Pós , Equivalência Terapêutica , Tiazinas/administração & dosagem , Tiazinas/química , Tiazinas/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/química , Tiazóis/farmacocinética
20.
Eur J Med Chem ; 151: 110-120, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29605807

RESUMO

A new series of phenylthiazoles with t-butyl lipophilic component was synthesized and their antibacterial activity against a panel of multidrug-resistant bacterial pathogens was evaluated. Five compounds demonstrated promising antibacterial activity against methicillin-resistant staphylococcal strains and several vancomycin-resistant staphylococcal and enterococcal species. Additionally, three derivatives 19, 23 and 26 exhibited rapid bactericidal activity, and remarkable ability to disrupt mature biofilm produced by MRSA USA300. More importantly, a resistant mutant to 19 couldn't be isolated after subjecting MRSA to sub-lethal doses for 14 days. Lastly, this new series of phenylthiazoles possesses an advantageous attribute over the first-generation compounds in their stability to hepatic metabolism, with a biological half-life of more than 9 h.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Animais , Antibacterianos/farmacocinética , Células CACO-2 , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/fisiologia , Testes de Sensibilidade Microbiana , Ratos Sprague-Dawley , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Tiazóis/farmacocinética
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