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1.
J Recept Signal Transduct Res ; 39(3): 283-293, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31538846

RESUMO

A new series of benzothiazol-2-ylcarbamodithioate functional compounds 5a-f has been designed, synthesized and characterized by spectral data. These compounds were screened for their in vitro antibacterial activity against strains of Staphylococcus aureus (NCIM 5021, NCIM 5022 and methicillin-resistant isolate 43300), Bacillus subtilis (NCIM 2545), Escherichia coli (NCIM 2567), Klebsiella pneumoniae (NCIM 2706) and Psudomonas aeruginosa (NCIM 2036). Compounds 5a and 5d exhibited significant activity against all the tested bacterial strains. Specifically, compounds 5a and 5d showed potent activity against K. pneumoniae (NCIM 2706), while compound 5a also displayed potent activity against S. aureus (NCIM 5021). Compound 5d showed minimum IC50 value of 13.37 µM against S. aureus MurD enzyme. Further, the binding interactions of compounds 5a-f in the catalytic pocket have been investigated using the extra-precision molecular docking and binding free energy calculation by MM-GBSA approach. A 30 ns molecular dynamics simulation of 5d/modeled S. aureus MurD enzyme was performed to determine the stability of the predicted binding conformation.


Assuntos
Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeo Sintases/antagonistas & inibidores , Staphylococcus aureus/enzimologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacocinética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Peptídeo Sintases/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Termodinâmica
2.
J Pharmacol Exp Ther ; 371(1): 162-170, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31371478

RESUMO

The effect of dotinurad [(3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ 6-1,3-benzothiazol-3-yl)methanone] was compared with that of commercially available uricosuric agents-namely, benzbromarone, lesinurad, and probenecid. Its effect on urate secretion transporters was evaluated using probe substrates for respective transporters. Dotinurad, benzbromarone, lesinurad, and probenecid inhibited urate transporter 1 (URAT1) with IC50 values of 0.0372, 0.190, 30.0, and 165 µM, respectively. Dotinurad weakly inhibited ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and OAT3, with IC50 values of 4.16, 4.08, and 1.32 µM, respectively, indicating higher selectivity for URAT1. The hypouricemic effects of dotinurad and benzbromarone were evaluated in Cebus monkeys. Dotinurad, at doses of 1-30 mg/kg, concomitantly decreased plasma urate levels and increased fractional excretion of urate (FEUA) in a dose-dependent manner. On the contrary, benzbromarone, at a dose of 30 mg/kg, showed a modest effect on plasma urate levels. The inhibitory effect of dotinurad on urate secretion transporters was evaluated in Sprague-Dawley rats, with sulfasalazine and adefovir as probe substrates of ABCG2 and OAT1, respectively. Drugs, including febuxostat as a reference ABCG2 inhibitor, were administered orally before sulfasalazine or adefovir administration. Dotinurad had no effect on urate secretion transporters in vivo, whereas benzbromarone, lesinurad, probenecid, and febuxostat increased the plasma concentrations of probe substrates. These results suggested dotinurad is characterized as a selective urate reabsorption inhibitor (SURI), which is defined as a potent URAT1 inhibitor with minimal effect on urate secretion transporters, including ABCG2 and OAT1/3, because of its high efficacy in decreasing plasma urate levels compared with that of other uricosuric agents. SIGNIFICANCE STATEMENT: Our study on the inhibitory effects on urate transport showed that dotinurad had higher selectivity for urate transporter 1 (URAT1) versus ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter (OAT) 1/3 compared to other uricosuric agents. In Cebus monkeys, dotinurad decreased plasma urate levels and increased fractional excretion of urate in a dose-dependent manner. To determine the inhibitory effect of dotinurad on urate secretion transporters, we studied the movement of substrates of ABCG2 and OAT1 in rats. Dotinurad had no effect on these transporters, whereas the other uricosuric agents increased the plasma concentrations of the substrates. These results suggested dotinurad as a potent and selective urate reabsorption inhibitor is characterized by increased efficacy with decreasing plasma urate levels.


Assuntos
Benzotiazóis/farmacologia , Uricosúricos/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Benzotiazóis/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Haplorrinos , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ácido Úrico/sangue , Ácido Úrico/urina , Uricosúricos/efeitos adversos
3.
Colloids Surf B Biointerfaces ; 183: 110434, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31437607

RESUMO

Shellac is a biomaterial obtained from secretion of lac insects. Nanoparticles based on shellac are prepared by nanoprecipitation and miniemulsion techniques. The corrosion inhibitor 2-mercaptobenzothiazole can be efficiently encapsulated in nanoparticles. Release kinetics of the inhibitor from the nanocarriers is controlled by pH of the surrounding environment as well as the introduction of other biopolymers such as lignin and zein. To overcome the low colloidal stability of shellac nanoparticles in saline conditions, shellac is conjugated with poly(ethylene glycol) moieties. After PEGylation, nanoparticles with higher critical aggregation concentration are obtained and provide release kinetics of 2-mercaptobenzothiazole similar to shellac nanoparticles.


Assuntos
Coloides/química , Nanopartículas/química , Polietilenoglicóis/química , Resinas Vegetais/química , Benzotiazóis/administração & dosagem , Benzotiazóis/química , Benzotiazóis/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Lignina/química , Zeína/química
4.
Cancer Chemother Pharmacol ; 84(4): 799-807, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31385001

RESUMO

PURPOSE: Quizartinib, a potent, selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, is currently in phase 3 development for patients with FLT3-internal tandem duplication-mutated acute myeloid leukemia (AML). Acid-reducing agents (ARAs; e.g., proton pump inhibitors) are frequently used during AML treatment. Since quizartinib demonstrates pH-dependent solubility, the effect of lansoprazole coadministration on pharmacokinetics (PK) of quizartinib tablet formulation was assessed. METHODS: An open-label, parallel-group study randomized 64 healthy adults to single-dose quizartinib 30 mg alone (reference) or lansoprazole (60 mg once daily, days 1-5) + single-dose quizartinib 30 mg (day 5) (test). Plasma concentrations of quizartinib and its active metabolite, AC886, were measured to 504 h postdose; the effect of lansoprazole on quizartinib PK was assessed by analysis of variance. RESULTS: Quizartinib geometric mean ratios (test/reference) and 90% confidence intervals for maximum observed plasma concentration (Cmax), area under the concentration-time curve to last measurable drug concentration (AUClast), and AUC to infinity were 86.11% (78.4%, 94.6%), 93.96% (79.6%, 110.9%), and 95.30% (80.2%, 113.3%), respectively. Comparisons showed a modest decrease in quizartinib absorption when co-administered with lansoprazole, with lower limits for Cmax and AUClast just below 80-125% limits. Treatment-emergent adverse events were mild or moderate; the most frequent in either treatment group were headache [quizartinib alone: (n = 3) 10%], upper respiratory tract infection [quizartinib alone: (n = 2) 6.7%; lansoprazole + quizartinib: (n = 3) 9.1%], and muscle tightness [quizartinib alone: (n = 2) 6.7%]. CONCLUSIONS: Concomitant lansoprazole had minimal effect on quizartinib PK as a formulated tablet, indicating that quizartinib can be administered with ARAs.


Assuntos
Benzotiazóis , Lansoprazol , Compostos de Fenilureia , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzotiazóis/administração & dosagem , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversos , Lansoprazol/farmacocinética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
5.
Int J Hematol ; 110(6): 654-664, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31359361

RESUMO

Expanded therapeutic options are warranted for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. The present phase 1, multicenter, open-label, dose-escalation and dose-expansion study was conducted to assess the safety, pharmacokinetics, and efficacy of multiple-dose monotherapy of the FLT3 inhibitor, quizartinib, in Japanese patients with R/R AML. Patients received oral quizartinib, once daily, under fasting conditions in 28-day cycles. Sixteen patients (median age, 68.0 years; male, 56.3%; FLT3-ITD positive, 43.8%) received quizartinib (9, 3, and 4 patients at 20, 30, and 60 mg/day, respectively; median treatment duration, 95.0 days; median relative dose intensity, 100.0%). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were electrocardiogram QT prolonged (43.8%, grade 1 or 2) followed by nausea and pyrexia (37.5% each). No quizartinib-related deaths were reported. A dose-dependent increase of quizartinib and its active metabolite AC886 levels was observed at the steady state. The composite complete remission rate was 37.5%. Quizartinib was well tolerated in Japanese R/R AML patients at doses up to 60 mg/day; quizartinib 60 mg/day was considered as the recommended dose for the Japanese patient population in a subsequent study.Trial registration ClinicalTrials.gov identifier NCT02675478.


Assuntos
Benzotiazóis/farmacocinética , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/farmacocinética , Idoso , Benzotiazóis/administração & dosagem , Benzotiazóis/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases , Terapia de Salvação/efeitos adversos , Terapia de Salvação/métodos , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
6.
Eur J Med Chem ; 177: 12-31, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129451

RESUMO

Synthesis of novel and potent hit molecules has an eternal demand. It is our continuous study to search novel bioactive hit molecules and as a part of this, a series of novel N'-isonicotinoyl-2-methyl-4-(pyridin-2-yl)-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-3-carbohydrazide analogs (5a-5n) were synthesized with good yields by the conventional method. The various novel compounds have been characterized and identified by many analytical technique such as IR, 1H NMR, 13C NMR, mass spectral analysis, and elemental analysis. All the synthetic analogs (5a-5n) are evaluated for their in vitro antibacterial and anti-mycobacterial activities against different bacterial strains. Molecular docking and Molecular dynamics studies were helped in revealing the mode of action of these compounds through their interactions with the active site of the Mycobacterium tuberculosis enoyl reductase (InhA) enzyme. The calculated ADMET descriptors for the synthesized compounds validated good pharmacokinetic properties, confirming that these compounds could be used as templates for the development of new Anti-mycobacterial agents.


Assuntos
Antituberculosos/farmacologia , Benzotiazóis/farmacologia , Isoniazida/análogos & derivados , Isoniazida/farmacologia , Pirimidinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Benzotiazóis/síntese química , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Coenzima A Ligases/química , Coenzima A Ligases/metabolismo , Isoniazida/metabolismo , Isoniazida/farmacocinética , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética
7.
Eur J Med Chem ; 175: 149-161, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078865

RESUMO

Six novel 2-arylimidazo[2,1-b]benzothiazole (IBT) derivatives were synthesized as potential tridentate radiotracers for AD imaging purposes. Two of these ligands (6a,b) were successfully labeled with 99mTc radionuclide at high radiochemical purity using fac-[99mTc(CO)3(H2O)3]+ synthon. [99mTc]7a and [99mTc]7b were evaluated as single photon emission computed tomography (SPECT) imaging agents for Aß plaque in AD. [99mTc]7a and [99mTc]7b exhibited suitable affinity toward Aß aggregates with IC50 values of 33.2 and 102.5 nM, respectively. The IC50 value of these radiotracers depends on the length of the spacer (alkyl chain). In biodistribution study, these complexes showed good initial brain uptakes (0.78 and 0.86% ID/g at 2 min post-injection) and fast blood clearance. Autoradiography results confirmed that these small 99mTc complexes (Mw about 600 Da) can bind to Aß plaques in the brain sections of the rat AD model. Histopathological staining with Congo red approved the presence of Aß plaques in these brain sections.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Benzotiazóis/metabolismo , Imidazóis/química , Compostos de Organotecnécio/metabolismo , Placa Amiloide/diagnóstico por imagem , Compostos Radiofarmacêuticos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Doença de Alzheimer/metabolismo , Animais , Benzotiazóis/química , Benzotiazóis/farmacocinética , Barreira Hematoencefálica , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Compostos de Organotecnécio/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição Tecidual
8.
Molecules ; 24(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30987056

RESUMO

Tozadenant is one of the selective adenosine A2a receptor antagonists with a potential to be a new Parkinson's disease (PD) therapeutic drug. In this study, a liquid chromatography-mass spectrometry based bioanalytical method was qualified and applied for the quantitative analysis of tozadenant in rat plasma. A good calibration curve was observed in the range from 1.01 to 2200 ng/mL for tozadenant using a quadratic regression. In vitro and preclinical in vivo pharmacokinetic (PK) properties of tozadenant were studied through the developed bioanalytical methods, and human PK profiles were predicted using physiologically based pharmacokinetic (PBPK) modeling based on these values. The PBPK model was initially optimized using in vitro and in vivo PK data obtained by intravenous administration at a dose of 1 mg/kg in rats. Other in vivo PK data in rats were used to validate the PBPK model. The human PK of tozadenant after oral administration at a dose of 240 mg was simulated by using an optimized and validated PBPK model. The predicted human PK parameters and profiles were similar to the observed clinical data. As a result, optimized PBPK model could reasonably predict the PK in human.


Assuntos
Benzotiazóis/sangue , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Antagonistas do Receptor A2 de Adenosina , Animais , Benzotiazóis/farmacocinética , Ratos , Verapamil/sangue , Verapamil/farmacocinética
9.
J Med Chem ; 62(5): 2638-2650, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30768272

RESUMO

The synthesis and evaluation of three novel 99mTc complexes (99mTc-1-3) and their corresponding Re complexes (Re-1-3), in which the phenyl ring of 2-phenylbenzothiazole or 2-phenylbenzimidazole is replaced by the cyclopentadienyl tricarbonyl [Cp99mTc(CO)3] core, are reported. Both 99mTc and Re complexes were prepared from the corresponding ferrocenyl derivatives, and the Re complexes were fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. The complexes exhibit effective in vitro binding to ß-amyloid (Aß) plaques and fibrils, inhibit Aß fibril formation, and significantly reduce Aß-induced cytotoxicity and reactive oxygen species production in neuronal cell cultures. The brain uptake of the 99mTc complexes ranges between 7.94 and 3.99% ID/g at 2 min p.i., being the highest recorded for potential 99mTc Aß plaque imaging probes in mice. Powered by their high brain uptake, the complexes represent strong theranostic candidates against Alzheimer's disease combining single-photon-emission computed tomography diagnostic (99mTc complexes) and antiamyloid therapeutic (Re complexes) potential.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Benzimidazóis/farmacocinética , Benzotiazóis/farmacocinética , Compostos de Organotecnécio/farmacocinética , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Peptídeos beta-Amiloides/metabolismo , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/química , Benzimidazóis/uso terapêutico , Benzotiazóis/administração & dosagem , Benzotiazóis/química , Benzotiazóis/uso terapêutico , Células Cultivadas , Cristalografia por Raios X , Humanos , Camundongos , Distribuição Tecidual
10.
J Alzheimers Dis ; 67(2): 503-513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30584141

RESUMO

The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-ß (Aß) plaques, a key mediator of neurodegenerative changes in Alzheimer's disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected with either thioflavin S, a fluorescent Aß-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aß plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aß plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Peptídeos beta-Amiloides/genética , Animais , Benzotiazóis/farmacocinética , Disponibilidade Biológica , Compostos Férricos/farmacocinética , Humanos , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nanopartículas , Permeabilidade , Placa Amiloide/patologia
11.
Mol Imaging Biol ; 21(1): 140-148, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29869063

RESUMO

PURPOSE: To identify the most vulnerable network among typical and three variants of Alzheimer's disease (AD) and to link amyloid-ß (Aß) deposition and downstream network dysfunction. PROCEDURES: In this study, 38 typical AD, 11 frontal variants, 8 logopenic variants, 6 posterior variants, and 20 normal controls were enrolled. 2-(4'-[11C] Methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) and 2-deoxy-2-[18]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) imaging were performed. Voxel-wise statistical analysis was used for [18F]FDG analysis, whereas two-sample t test was performed between each AD group and control group. Moreover, the goodness of fit (GOF) of t-maps with brain functional network templates was assessed, and the most vulnerable network in each phenotypic of AD was chosen as volume of interests (VOIs). [11C]PIB binding potential (BPND) of VOIs were generated by using PMOD software. In addition, statistical analysis of BPND among four types of AD in each specific network was calculated by SPSS software. RESULTS: The hypometabolism patterns indicated that in typical and frontal variants of AD, the most vulnerable network was the left executive control network (GOF score = 4.3, 5.0). For the logopenic variant, the highest GOF score (1.9) belonged to the auditory network. For the posterior variant, the higher visual network was the most vulnerable (GOF score = 6.0). The [11C]PIB BPND showed that there were no significant differences (p > 0.05) among AD groups within the specific networks. CONCLUSION: The phenotypic diversity of AD correlates with specific functional network failure; however, Aß plaques do not associate with specific network vulnerability.


Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Encefalopatias Metabólicas/metabolismo , Encéfalo/metabolismo , Rede Nervosa , Placa Amiloide/metabolismo , Idoso , Doença de Alzheimer/classificação , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Benzotiazóis/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalopatias Metabólicas/etiologia , Encefalopatias Metabólicas/patologia , Radioisótopos de Carbono/farmacocinética , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Placa Amiloide/complicações , Placa Amiloide/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Fatores de Tempo , Distribuição Tecidual
12.
IEEE Trans Biomed Eng ; 66(3): 843-847, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30047868

RESUMO

OBJECTIVE: In vivo bioluminescence imaging (BLI) is a promising tool for monitoring the growth and metastasis of tumors. However, quantitative BLI research based on intravenous (IV) injection is limited, which greatly restricts its further application. To address this problem, we designed a pharmacokinetic (PK) model which is suitable for applying on IV administration of small amounts of D-Luciferin. METHODS: After three weeks of postimplantation, mkn28-luc xenografted mice were subjected to 40-min dynamic BLI immediately following D-Luciferin intravenous injection on days 1, 3, 5, 7, and 9. Furthermore, the PK model was applied on dynamic BLI data to obtain the sum of kinetic rate constants (SKRC). RESULTS: Results showed that the SKRC values decreased rapidly with the growth of the tumor. There was a statistical difference between the SKRC values measured at different time points, while the time point of luminous intensity peak was unaffected by the growth of the tumor. CONCLUSION: In short, our results imply that dynamic BLI combined with our PK model can predict tumor growth earlier and with higher sensitivity compared to the conventional method, which is crucial for improving drug evaluation efficacy. In addition, the dynamic BLI may provide a valuable reference for the noninvasive acquiring arterial input function, which may also provide a new application prospect for hybrid PET-optical imaging.


Assuntos
Medições Luminescentes/métodos , Imagem Óptica/métodos , Administração Intravenosa , Animais , Benzotiazóis/administração & dosagem , Benzotiazóis/farmacocinética , Xenoenxertos/diagnóstico por imagem , Masculino , Camundongos , Camundongos Nus , Imagem Molecular , Neoplasias Experimentais/diagnóstico por imagem
13.
Neurology ; 92(2): e136-e147, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30530797

RESUMO

OBJECTIVE: To characterize the distribution of tau pathology in patients with amyotrophic lateral sclerosis/parkinsonism dementia complex on the Kii Peninsula (Kii ALS/PDC) by tau PET using [11C]PBB3 as ligand. METHODS: This is a cross-sectional study of 5 patients with ALS/PDC and one asymptomatic participant with a dense family history of ALS/PDC from the Kii Peninsula who took part in this study. All were men, and their age was 76 ± 8 (mean ± SD) years. Thirteen healthy men (69 ± 6 years) participated as healthy controls (HCs). Dynamic PET scans were performed following injection of [11C]PBB3, and parametric PET images were generated by voxel-by-voxel calculation of binding potential (BP* ND) using a multilinear reference tissue model. [11C] Pittsburgh compound B (PiB) PET, MRI, and cognitive tests were also performed. RESULTS: A voxel-based comparison of [11C]PBB3 BP* ND illustrated PET-detectable tau deposition in the cerebral cortex and white matter, and pontine basis including the corticospinal tract in Kii ALS/PDC patients compared with HCs (uncorrected p < 0.05). Group-wise volume of interest analysis of [11C]PBB3 BP* ND images showed increased BP* ND in the hippocampus and in frontal and parietal white matters of Kii ALS/PDC patients relative to HCs (p < 0.05, Holm-Sidak multiple comparisons test). BP* ND in frontal, temporal, and parietal gray matters correlated with Mini-Mental State Examination scores in Kii ALS/PDC patients (p < 0.05). All Kii ALS/PDC patients were negative for [11C]PiB (ß-amyloid) except one with marginal positivity. CONCLUSION: [11C]PBB3 PET visualized the characteristic topography of tau pathology in Kii ALS/PDC, corresponding to clinical phenotypes of this disease.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico por imagem , Esclerose Amiotrófica Lateral/metabolismo , Encéfalo/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Benzotiazóis/farmacocinética , Encéfalo/efeitos dos fármacos , Estudos Transversais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Japão/epidemiologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Trítio/farmacocinética
14.
Int J Pharm ; 556: 172-180, 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30553002

RESUMO

Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33-51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzotiazóis/farmacocinética , Encéfalo/metabolismo , Proteínas de Neoplasias/metabolismo , Compostos de Fenilureia/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Benzotiazóis/administração & dosagem , Disponibilidade Biológica , Cães , Feminino , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Compostos de Fenilureia/administração & dosagem , Distribuição Tecidual , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
15.
J Am Chem Soc ; 140(48): 16428-16432, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30427680

RESUMO

The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, current small molecule inhibitors suffer from limited efficacy in the clinic. Conversion of a FLT-3 inhibitor (quizartinib) into a proteolysis targeting chimera (PROTAC) results in a compound that induces degradation of FLT-3 ITD mutant at low nanomolar concentrations. Furthermore, the PROTAC is capable of inhibiting cell growth more potently than the warhead alone while inhibiting fewer off-target kinases. This enhanced antiproliferative activity occurs, despite a slight reduction in the PROTAC's kinase inhibitory activity, via an increased level of apoptosis induction suggesting nonkinase roles for the FLT-3 ITD protein. Additionally, the PROTAC is capable of inducing FLT-3 ITD degradation in vivo. These results suggest that degradation of FLT-3 ITD may provide a useful method for therapeutic intervention.


Assuntos
Antineoplásicos/uso terapêutico , Benzotiazóis/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzotiazóis/farmacocinética , Benzotiazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos Nus , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/metabolismo
16.
Bioconjug Chem ; 29(11): 3886-3895, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30354072

RESUMO

Molecular entities that localize in tumor tissue are clinically important for targeted delivery of diagnostic, imaging, and therapeutic reagents. Often these targeting entities are designed for specific receptors (e.g., EGFR or integrin receptors). However, there is a subset of cyanine-7 dyes that apparently localize in every type of solid tumor tissue (at least, no exceptions have been reported so far), and they persist there for several days. Consequently, these dyes can be used for near-IR optical imaging of tumors in animal studies, they can be conjugated with cytotoxic species to give experimental theranostics, and there is potential for expanding their use into the development of clinically useful derivatives. Data presented in the literature and in this work indicate that the half-lives of these compounds in serum at 37 °C is on the order of minutes to a few hours, so what accounts for the persistent fluorescence of these dyes in tumor tissue over periods of several days? Literature, solely based on tissue culture experiments featuring a particular receptor blocker, indicates that uptake of these dyes is mediated by the organic anion transporter proteins (OATPs). Data presented in this paper agrees with that conclusion for short-term uptake, but significantly expands understanding of the likely reasons for long-term uptake and persistent tumor localization in vivo.


Assuntos
Benzotiazóis/metabolismo , Carbocianinas/metabolismo , Corantes Fluorescentes/metabolismo , Neoplasias/metabolismo , Benzotiazóis/química , Benzotiazóis/farmacocinética , Carbocianinas/química , Carbocianinas/farmacocinética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Humanos , Modelos Moleculares , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Transportadores de Ânions Orgânicos/metabolismo , Albumina Sérica Humana/metabolismo
17.
Alzheimers Res Ther ; 10(1): 75, 2018 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-30075734

RESUMO

BACKGROUND: Amyloid pathology is the pathological hallmark in Alzheimer's disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline. METHODS: From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with [18F]flutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging. RESULTS: We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan. CONCLUSIONS: A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Transtornos Cognitivos/etiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/farmacocinética , Apolipoproteínas E/genética , Benzotiazóis/farmacocinética , Artérias Carótidas/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Imageamento Tridimensional , Cooperação Internacional , Imagem por Ressonância Magnética , Magnetoencefalografia , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Tomografia de Coerência Óptica
18.
BMC Cancer ; 18(1): 790, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081867

RESUMO

BACKGROUND: Quizartinib, an inhibitor of class III receptor tyrosine kinases (RTKs), is currently in phase 3 development for the treatment of acute myeloid leukemia (AML) bearing internal tandem duplications in the FLT3 gene. Aberrant RTK signaling is implicated in the pathogenesis of a variety of solid tumors, suggesting that inhibiting quizartinib-sensitive RTKs may be beneficial in precision cancer therapy. METHODS: This was a phase 1, open-label, modified Fibonacci dose-escalation study of orally administered quizartinib in patients with advanced solid tumors whose disease progressed despite standard therapy or for which there was no available standard treatment. Patients received quizartinib dihydrochloride (henceforth referred to as quizartinib) once daily throughout a 28-day treatment cycle. The primary endpoint was evaluation of the maximum tolerated dose (MTD) of quizartinib. Secondary endpoints included preliminary evidence of antitumor activity and determination of the pharmacokinetic and pharmacodynamic parameters of quizartinib. RESULTS: Thirteen patients were enrolled. Five patients received a starting dose of quizartinib 135 mg/day; dose-limiting toxicities (DLTs) of grade 3 pancytopenia, asymptomatic grade 3 QTc prolongation, and febrile neutropenia were observed in 1 patient each at this dose. A lower dose of quizartinib (90 mg/day [n = 8]) was administered without DLTs. The most common treatment-related treatment-emergent adverse events (AEs) were fatigue (n = 7, 54%), dysgeusia (n = 5, 38%), neutropenia (n = 3, 23%), and QTc prolongation (n = 3, 23%). Overall, all patients experienced at least 1 AE, and 4 experienced serious AEs (2 patients each in the 135-mg and 90-mg dose groups) including hematologic AEs, infections, and gastrointestinal disorders. Six patients (including 3 patients with gastrointestinal stromal tumors [GIST]) had a best response of stable disease. CONCLUSION: The MTD of quizartinib in patients with advanced solid tumors was 90 mg/day. Overall, the safety and tolerability of quizartinib were manageable, with no unexpected AEs. Quizartinib monotherapy had limited evidence of activity in this small group of patients with advanced solid tumors. TRIAL REGISTRATION: Clinical Trials Registration Number: NCT01049893 ; First Posted: January 15, 2010.


Assuntos
Antineoplásicos/administração & dosagem , Benzotiazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/enzimologia , Neoplasias/patologia , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Estados Unidos , Tirosina Quinase 3 Semelhante a fms/metabolismo
19.
J Environ Sci Health B ; 53(11): 761-769, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30024815

RESUMO

The degradation dynamics and terminal residues of dufulin enantiomers were investigated in two typical corn plants. A convenient and precise chiral method by high-performance liquid chromatography coupled with tandem triple quadrupole mass spectrometry (HPLC/MS/MS) using a Chiralpak IC column was developed and validated for measuring dufulin enantiomers in corn plants and corn. The two enantiomers of dufulin quickly dissipated in the corn plant, and no noticeable stereoselectivity was observed during degradation or in the final residues. After 30% rac-dufulin wettable powder with a 1- to 1.5-fold dose of the recommended value was sprayed two to three times on corn plants, the residue levels of S-(+)-dufulin and R-(-)-dufulin in corn from both sites were lower than or equal to 0.0520 mg kg-1 on days 7, 14 and 21 after the last application. The dietary risk assessment indicated that dufulin did not exhibit obvious dietary health risks in corn samples when good agricultural practices were implemented. The findings from this study may be used to better understand the chiral profiles of dufulin in the environment and the effect of dufulin residues in corn on health.


Assuntos
Benzotiazóis/química , Benzotiazóis/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Zea mays/efeitos dos fármacos , Biodegradação Ambiental , Humanos , Nível de Efeito Adverso não Observado , Medição de Risco , Estereoisomerismo , Zea mays/metabolismo
20.
J Control Release ; 286: 1-9, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30016731

RESUMO

CX-5461 is currently in Phase I/II clinical trials for advanced hematologic malignancies and triple negative or BRCA-deficient breast cancer. The compound is currently administered to patients intravenously (i.v.) at low pH (3.5) due to solubility challenges. Reliance of low pH to enhance solubility of CX-5461 can adversely impact pharmacokinetics, biodistribution and therapeutic potential. We have addressed this solubility issue through a formulation method that relies on the interactions between CX-5461 and copper. Copper binds CX-5461 through the nitrogens of the pyrazine ring. Here, we describe synthesizing this copper-complexed CX-5461 (Cu(CX-5461)) within liposomes. CX-5461 was added to copper-containing liposomes and incubated at 60 °C for 30 min. The pharmacokinetics of CX-5461 was assessed in mice following a single i.v. injection at 30 mg/kg. Efficacy studies were completed in multiple subcutaneous mouse xenografts as well as in a bone marrow engraftment model of acute myeloid leukemia (AML). The novel Cu(CX-5461) formulation was stable at pH 7.4 and exhibited increased plasma circulation longevity, increasing the total exposure to CX5461 by an order of magnitude. Cu(CX-5461) was more active than CX-5461 in AML models in vivo. In HCT116-B46 and Capan-1 solid tumour models that are BRCA-deficient, the Cu(CX-5461) formulation engendered activity that was comparable to that of the low pH CX-5461 formulation. We have generated the first Cu(CX-5461) formulation suitable for i.v. administration that is more efficacious than the existing low-pH formulation in pre-clinical models of AML. The Cu(CX-5461) formulation may serve as an alternative formulation for CX-5461 in BRCA-deficient cancers.


Assuntos
Antineoplásicos/administração & dosagem , Benzotiazóis/administração & dosagem , Cobre/administração & dosagem , Naftiridinas/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzotiazóis/química , Benzotiazóis/farmacocinética , Benzotiazóis/uso terapêutico , Linhagem Celular Tumoral , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/uso terapêutico , Cobre/química , Cobre/farmacocinética , Cobre/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Lipossomos/química , Camundongos , Naftiridinas/química , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , RNA Ribossômico/antagonistas & inibidores , RNA Ribossômico/metabolismo , Distribuição Tecidual
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