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1.
Biomed Chromatogr ; 33(7): e4525, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30822365

RESUMO

A rapid, sensitive and selective liquid chromatography-tandem mass spectrometry method for the detection of tandospirone (TDS) and its active metabolite 1-[2-pyrimidyl]-piperazine (1-PP) in Sprague-Dawley rat plasma is described. It was employed in a pharmacokinetic study. These analytes and the internal standards were extracted from plasma using protein precipitation with acetonitrile, then separated on a CAPCELL PAK ADME C18 column using a mobile phase of acetonitrile and 5 mm ammonium formate acidified with formic acid (0.1%, v/v) at a total flow rate of 0.4 mL/min. The detection was performed with a tandem mass spectrometer equipped with an electrospray ionization source. The method was validated to quantify the concentration ranges of 1.000-500.0 ng/mL for TDS and 10.00-500.0 ng/mL for 1-PP. Total time for each chromatograph was 3.0 min. The intra-day precision was between 1.42 and 6.69% and the accuracy ranged from 95.74 to 110.18% for all analytes. Inter-day precision and accuracy ranged from 2.47 to 6.02% and from 98.37 to 105.62%, respectively. The lower limits of quantification were 1.000 ng/mL for TDS and 10.00 ng/mL for 1-PP. This method provided a fast, sensitive and selective analytical tool for quantification of tandospirone and its metabolite 1-PP in plasma necessary for the pharmacokinetic investigation.


Assuntos
Buspirona/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Isoindóis/sangue , Piperazinas/sangue , Pirimidinas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Buspirona/sangue , Buspirona/química , Buspirona/farmacocinética , Estabilidade de Medicamentos , Feminino , Isoindóis/química , Isoindóis/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Piperazinas/química , Piperazinas/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
2.
Drugs ; 78(13): 1377-1382, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30120738

RESUMO

Tecovirimat (TPOXX®) is an orthopoxvirus-specific antiviral drug developed by SIGA Technologies in conjunction with the US Department of Health and Human Services' Biomedical Advances Research and Development Authority. It acts by inhibiting the activity of the orthopoxvirus VP37 envelope wrapping protein, thereby preventing the formation of egress-competent enveloped virions, which are essential for dissemination of the virus in the host. In July 2018, oral tecovirimat was approved in the USA for the treatment of human smallpox disease caused by variola virus in adults and paediatric patients weighing ≥ 13 kg. Tecovirimat was approved under the US FDA's Animal Rule, in which marketing approval is based on its efficacy in relevant animal models. An intravenous formulation of tecovirimat is undergoing phase I development for the treatment of smallpox infection. This article summarises the milestones in the development of tecovirimat leading to this first approval for the treatment of human smallpox disease in adults and paediatric patients weighing ≥ 13 kg.


Assuntos
Antivirais/uso terapêutico , Benzamidas/uso terapêutico , Isoindóis/uso terapêutico , Varíola/tratamento farmacológico , Administração Intravenosa , Animais , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Aprovação de Drogas , Humanos , Isoindóis/administração & dosagem , Isoindóis/efeitos adversos , Isoindóis/farmacocinética , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
3.
N Engl J Med ; 379(1): 44-53, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29972742

RESUMO

BACKGROUND: Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. Because clinical trials in a context of natural disease are not possible, an alternative developmental path to evaluate efficacy and safety was needed. METHODS: We investigated the efficacy of tecovirimat in nonhuman primate (monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox therapeutics by an expert advisory committee. We also conducted a placebo-controlled pharmacokinetic and safety trial involving 449 adult volunteers. RESULTS: The minimum dose of tecovirimat required in order to achieve more than 90% survival in the monkeypox model was 10 mg per kilogram of body weight for 14 days, and a dose of 40 mg per kilogram for 14 days was similarly efficacious in the rabbitpox model. Although the effective dose per kilogram was higher in rabbits, exposure was lower, with a mean steady-state maximum, minimum, and average (mean) concentration (Cmax, Cmin, and Cavg, respectively) of 374, 25, and 138 ng per milliliter, respectively, in rabbits and 1444, 169, and 598 ng per milliliter in nonhuman primates, as well as an area under the concentration-time curve over 24 hours (AUC0-24hr) of 3318 ng×hours per milliliter in rabbits and 14,352 ng×hours per milliliter in nonhuman primates. These findings suggested that the nonhuman primate was the more conservative model for the estimation of the required drug exposure in humans. A dose of 600 mg twice daily for 14 days was selected for testing in humans and provided exposures in excess of those in nonhuman primates (mean steady-state Cmax, Cmin, and Cavg of 2209, 690, and 1270 ng per milliliter and AUC0-24hr of 30,632 ng×hours per milliliter). No pattern of troubling adverse events was observed. CONCLUSIONS: On the basis of its efficacy in two animal models and pharmacokinetic and safety data in humans, tecovirimat is being advanced as a therapy for smallpox in accordance with the FDA Animal Rule. (Funded by the National Institutes of Health and the Biomedical Advanced Research and Development Authority; ClinicalTrials.gov number, NCT02474589 .).


Assuntos
Antivirais/administração & dosagem , Benzamidas/administração & dosagem , Isoindóis/administração & dosagem , Monkeypox/tratamento farmacológico , Infecções por Poxviridae/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Animais , Antivirais/efeitos adversos , Antivirais/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Isoindóis/efeitos adversos , Isoindóis/farmacocinética , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Monkeypox/mortalidade , Vírus da Varíola dos Macacos , Infecções por Poxviridae/mortalidade , Coelhos , Vírus Vaccinia , Adulto Jovem
4.
Molecules ; 23(6)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29914049

RESUMO

Indobufen is a new generation of anti-platelet aggregation drug, but studies were not sufficient on its anticoagulant effects. In the present study, the anticoagulant activity of indobufen was determined by monitoring the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) in rabbit plasma. We evaluated the anticoagulant mechanisms on the content of the platelet factor 3,4 (PF3,4), and the coagulation factor 1, 2, 5, 8, 10 (FI, II, V, VIII, X) in rabbits, as well as the in vivo bleeding time and clotting time in mice. The pharmacodynamic differences between indobufen and warfarin sodium, rivaroxaban, and dabigatran were further studied on thrombus formation and the content of FII and FX in rats. Animal experiments showed that intragastric-administrated indobufen can significantly reduce the APTT, PT, TT, PF3, FI, II, V, VIII, and X plasma contents. Its inhibitory effect on plasma FII was better than thrombin inhibitor dabigatran with effect on FX better than FXa inhibitor rivaroxaban. These results suggest that indobufen has some anticoagulant effects as strong as some conventional anticoagulants. The mechanism may be related to both exogenous and endogenous coagulation system.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Isoindóis/farmacologia , Fenilbutiratos/farmacologia , Fator Plaquetário 3/metabolismo , Fator Plaquetário 4/metabolismo , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Testes de Coagulação Sanguínea , Dabigatrana/farmacocinética , Feminino , Isoindóis/química , Isoindóis/farmacocinética , Masculino , Estrutura Molecular , Tempo de Tromboplastina Parcial , Fenilbutiratos/química , Fenilbutiratos/farmacocinética , Tempo de Protrombina , Coelhos , Ratos , Rivaroxabana/farmacocinética , Tempo de Trombina
5.
AAPS PharmSciTech ; 19(6): 2519-2532, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29948984

RESUMO

Diabetes mellitus is one of the leading causes of death due to the persistent hyperglycemia that leads to potential complications. Lack of patients' adherence to their prescribed medication regimens, due to the requirement of frequent dosing, leads to failure of 40-50% of patients to manage their disease. Thus, microsponges of the novel short half-life mitiglinide calcium (MTG) were formulated using Quasi-emulsion solvent diffusion method, employing Eudragit RS100, ethyl cellulose, and polyvinyl alcohol, then characterized in terms of production yield, entrapment efficiency, particle size, in vitro buoyancy, in vitro drug release, and in vivo pharmacokinetics in rabbits. Optimization was done using response surface methodology; the optimized formulation was investigated by FTIR, DSC, and SEM. Results revealed that the optimized MTG microsponge was successfully formulated with high production yield (61.61% ± 0.6), entrapment efficiency (77.7% ±1.37), and particle size of 192.76 µm and it remained buoyant over simulated gastric fluid for 24 h with high percentage of in vitro buoyancy (91.01% ± 2.5). Moreover, it sustained the in vitro drug release with cumulative % release of 83.74 ± 1.5 after 24 h. This microsponge was highly porous in nature with interconnected pores where MTG was entrapped with good compatibility as confirmed by SEM, DSC, and FTIR analysis; Pharmacokinetic studies showed improvement in Cmax and AUC0-∞ (1.92- and 20.68-fold, respectively) with marked prolongation in MRT and t1/2 (7.22- and 7.97-fold, respectively) than the marketed tablet. Thus, it is a promising approach to improve diabetic patients' compliance by eliminating the necessity of frequent dosing thus attaining better diabetes control.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Hipoglicemiantes/química , Isoindóis/química , Animais , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Isoindóis/administração & dosagem , Isoindóis/farmacocinética , Tamanho da Partícula , Poríferos , Coelhos
6.
Bioorg Med Chem Lett ; 28(10): 1892-1896, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29636218
7.
BMC Pharmacol Toxicol ; 18(1): 54, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28676080

RESUMO

BACKGROUND: Mitiglinide is a widely used agent for diabetic treatment. We established a pharmacokinetic-pharmacodynamic (PK-PD) model to illustrate the relationship between mitiglinide plasma concentration and its glucose lowering effects in healthy volunteers. METHODS: The volunteers participated in the test after the administration of a single dose of 10 mg mitiglinide. The drug concentration in Plasma and the values of glucose levels were determined by LC-MS/MS assay and hexokinase method. A PK-PD model was established with a series of equations to describe the relationship between plasma medicine and glucose, and the equations were solved numerically and fitted to the data with the Phoenix NLME software. RESULTS: The results of the two-compartment model analysis were based on the maximum likelihood criterion and visual inspection of the fittings. The terminal elimination half-life (t 1/2) was 1.69 ± 0.16 h and the CL/F was 7.80 ± 1.84 L/h. The plasma glucose levels began to decline by 0.2 h, and hit its bottom decreasing values of 2.6 mg/L at 0.5 h after administration. The calculated parameter and fitting curve indicated that the model established in our experiment fitted well. CONCLUSIONS: A PK/PD model illustrates that the relationship between mitiglinide concentration in plasma and glucose lowering effect in healthy volunteers was established. The results of our experiment suggested that the model can be used reasonably to predict the relationship between PK and PD in mitiglinide, which could be used in diabetes mellitus dosage control in clinical trials and other fields.


Assuntos
Hipoglicemiantes/farmacologia , Hipoglicemiantes/farmacocinética , Isoindóis/farmacologia , Isoindóis/farmacocinética , Modelos Biológicos , Administração Oral , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , Glicemia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Hipoglicemiantes/sangue , Isoindóis/sangue , Masculino , Adulto Jovem
8.
Clin Cancer Res ; 23(20): 6215-6226, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28679777

RESUMO

Purpose: HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins, is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities, or are unable to cross the blood-brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivoExperimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo were assessed in non-tumor-bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient-derived GSC xenograft mouse glioma models.Results: Onalespib-mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII, and AKT, disrupted their downstream signaling, and decreased the proliferation, migration, angiogenesis, and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts.Conclusions: Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo, which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas. Clin Cancer Res; 23(20); 6215-26. ©2017 AACR.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Dacarbazina/análogos & derivados , Glioma/metabolismo , Glioma/patologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoindóis/farmacologia , Animais , Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dacarbazina/farmacocinética , Dacarbazina/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Expressão Gênica , Glioma/tratamento farmacológico , Glioma/mortalidade , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Isoindóis/farmacocinética , Camundongos , Células-Tronco Neoplásicas/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
9.
Bioorg Med Chem Lett ; 27(15): 3317-3325, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28610984

RESUMO

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Citocinas/química , Citocinas/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nicotinamida Fosforribosiltransferase/química , Nicotinamida Fosforribosiltransferase/metabolismo , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/uso terapêutico
10.
Int J Immunopathol Pharmacol ; 30(3): 215-226, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28604143

RESUMO

Indoleamine 2,3-dioxygenase (IDO) is involved in tumor immune escape and resistance to chemotherapy, and is clinically correlated with tumor progression. IDO inhibitors show marginal efficacy as single agents; therefore, combinations of these inhibitors with other therapies hold promise for cancer therapy. The aim of this study was to investigate the synergistic antitumor effects of IDO inhibitor NLG919 in combination with different regimens of paclitaxel in a murine B16-F10 melanoma model. NLG919 increased the cytotoxic activity of paclitaxel toward B16-F10 cells in the presence of pretreatment with interferon (IFN)-γ in vitro. In B16-F10 tumor-bearing mice, NLG919 was uniformly distributed throughout tumors and decreased kynurenine levels and kynurenine/tryptophan ratios in tumors and plasma for 6-12 h. NLG919 suppressed tumor growth in a dose-dependent manner and exhibited maximum efficacy at 100 mg/kg. In combination with different regimens of paclitaxel, NLG919 displayed synergistic antitumor effects, and NLG919 did not increase the side effects of paclitaxel. Within the tumors, the percentage of CD3+, CD8+, and CD4+ T cells and secretion of IFN-γ and interleukin-2 were synergistically increased, whereas the percentage of CD4+CD25+ regulatory T cells was decreased. NLG919 can potentiate the antitumor efficacy of paclitaxel without increasing its side effects, suggesting that the combination of IDO inhibitor-based immunotherapy with chemotherapy could be a potential strategy for cancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Isoindóis/uso terapêutico , Melanoma Experimental/tratamento farmacológico , Paclitaxel/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Quimioterapia Combinada , Imidazóis/farmacocinética , Imidazóis/farmacologia , Interferon gama/imunologia , Interleucina-2/imunologia , Isoindóis/farmacocinética , Isoindóis/farmacologia , Cinurenina/sangue , Cinurenina/metabolismo , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Paclitaxel/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Triptofano/sangue , Triptofano/metabolismo , Carga Tumoral/efeitos dos fármacos
11.
Drug Metab Pharmacokinet ; 31(6): 395-404, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27745731

RESUMO

The effect of drugs in the central nervous system (CNS) is closely related to occupancy of their target receptor. In this study, we integrated plasma concentrations, in vitro/in vivo data for receptor or protein binding, and in silico data, using a physiologically based pharmacokinetic model, to examine the predictability of receptor occupancy in humans. The occupancy of the dopamine D2 receptor and the plasma concentrations of the antipsychotic drugs quetiapine and perospirone in humans were collected from the literature or produced experimentally. Association and dissociation rate constants and unbound fractions in the serum and brain were determined in vitro/in vivo using human D2 receptor-expressing membrane fractions, human serum and mouse brain. The permeability of drugs across the blood-brain barrier was estimated based on their physicochemical properties. The effect of a metabolite of perospirone, ID-15036, was also considered. The time profiles of D2 receptor occupancy following oral dose of quetiapine and perospirone predicted were similar to the observed values. This approach could assist in the design of clinical studies for drug development and the prediction of the impact of drug-drug interactions on CNS function in clinical settings.


Assuntos
Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Receptores de Dopamina D2/metabolismo , Adulto , Animais , Antipsicóticos/sangue , Simulação por Computador , Antagonistas dos Receptores de Dopamina D2/sangue , Antagonistas dos Receptores de Dopamina D2/metabolismo , Humanos , Isoindóis/sangue , Isoindóis/farmacocinética , Cinética , Masculino , Camundongos Endogâmicos ICR , Tomografia por Emissão de Pósitrons , Fumarato de Quetiapina/sangue , Fumarato de Quetiapina/farmacocinética , Racloprida/metabolismo , Tiazóis/sangue , Tiazóis/farmacocinética , Adulto Jovem
12.
J Med Chem ; 59(7): 3098-111, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-26987013

RESUMO

Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Isoindóis/química , Receptores CCR/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Técnicas de Química Sintética , Quimiotaxia/efeitos dos fármacos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Isoindóis/administração & dosagem , Isoindóis/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Receptores CCR/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética
13.
Eur J Nucl Med Mol Imaging ; 43(5): 974-982, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26627081

RESUMO

PURPOSE: Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition. METHODS: Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 × 50 mg/kg), and were imaged with PET using either (18)F-FDG or (124)I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining. RESULTS: AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with (124)I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with (124)I-AbD19384 as well as (18)F-FDG uptake, were not significantly altered by AT13387 treatment. CONCLUSION: We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues.


Assuntos
Benzamidas/farmacocinética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico por imagem , Receptores ErbB/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Receptores de Hialuronatos/metabolismo , Isoindóis/farmacocinética , Animais , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Carcinoma de Células Escamosas/radioterapia , Linhagem Celular , Feminino , Fluordesoxiglucose F18 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Radioisótopos do Iodo , Isoindóis/efeitos adversos , Isoindóis/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tomografia por Emissão de Pósitrons , Radioimunoterapia , Compostos Radiofarmacêuticos
14.
J Med Chem ; 58(18): 7164-72, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26258602

RESUMO

Inhibition of triacylglycerol (TAG) biosynthetic enzymes has been suggested as a promising strategy to treat insulin resistance, diabetes, dyslipidemia, and hepatic steatosis. Monoacylglycerol acyltransferase 3 (MGAT3) is an integral membrane enzyme that catalyzes the acylation of both monoacylglycerol (MAG) and diacylglycerol (DAG) to generate DAG and TAG, respectively. Herein, we report the discovery and characterization of the first selective small molecule inhibitors of MGAT3. Isoindoline-5-sulfonamide (6f, PF-06471553) selectively inhibits MGAT3 with high in vitro potency and cell efficacy. Because the gene encoding MGAT3 (MOGAT3) is found only in higher mammals and humans, but not in rodents, a transgenic mouse model expressing the complete human MOGAT3 was used to characterize the effects of 6f in vivo. In the presence of a combination of diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2) inhibitors, an oral administration of 6f exhibited inhibition of the incorporation of deuterium-labeled glycerol into TAG in this mouse model. The availability of a potent and selective chemical tool and a humanized mouse model described in this report should facilitate further dissection of the physiological function of MGAT3 and its role in lipid homeostasis.


Assuntos
Aciltransferases/antagonistas & inibidores , Isoindóis/química , Sulfonamidas/química , Aciltransferases/genética , Animais , Células Cultivadas , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Cães , Humanos , Isoindóis/farmacocinética , Isoindóis/farmacologia , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Triglicerídeos/biossíntese
15.
Drug Des Devel Ther ; 9: 3377-91, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26170623

RESUMO

To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.


Assuntos
Benzofuranos/farmacologia , Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/prevenção & controle , Isoindóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/farmacologia , Antipirina/análogos & derivados , Antipirina/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzofuranos/sangue , Benzofuranos/síntese química , Benzofuranos/farmacocinética , Disponibilidade Biológica , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Carragenina , Linhagem Celular , Modelos Animais de Doenças , Edaravone , Fibrinolíticos/farmacologia , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/psicologia , Isoindóis/sangue , Isoindóis/síntese química , Isoindóis/farmacocinética , Masculino , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Estresse Oxidativo/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/psicologia , Relação Estrutura-Atividade , Trombose/sangue , Trombose/induzido quimicamente , Trombose/prevenção & controle , Distribuição Tecidual
16.
J Labelled Comp Radiopharm ; 57(11): 632-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25251383

RESUMO

SCH 900567 is a specific inhibitor of tumor necrosis factor-alpha converting enzyme and is a potential candidate for the treatment of rheumatoid arthritis. [(3) H]SCH 900567 was synthesized to support the initial drug metabolism and pharmacokinetics studies. Stable isotope-labeled [(13) C3 , (15) N]SCH 900567 was requested by the bioanalytical group as an internal standard for Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development as well as by the drug metabolism and pharmacokinetics group for a potential microdose study. [(13) C3 , (15) N]SCH 900567 is synthesized via a linear sequence of seven steps from commercially available materials in 2.6% overall yield. [(14) C]SCH 900567 was needed for a quantitative whole body autoradiography studies and was prepared from unlabeled Active Pharmaceutical Ingredient (API) via hydrolysis of the hydantoin moiety followed by rebuilding the hydantoin ring using potassium [(14) C]cyanate to give the desired product in 42.8% overall yield. Activation of the hydantoin moiety of SCH 900567 to achieve hydrolysis followed by derivatization of the resulting amino acid to avoid decarboxylation during cyclization is also discussed.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Hidantoínas/síntese química , Isoindóis/síntese química , Compostos Radiofarmacêuticos/síntese química , Proteína ADAM17 , Radioisótopos de Carbono/química , Hidantoínas/farmacocinética , Isoindóis/farmacocinética , Radioisótopos de Nitrogênio/química , Trítio/química
17.
Drug Metabol Drug Interact ; 29(3): 191-202, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24825095

RESUMO

BACKGROUND: To evaluate potential drug-drug interactions with the atypical antipsychotic lurasidone. METHODS: Seven phase I studies were conducted to investigate the effects of repeated dosing of ketoconazole, diltiazem, rifampin, or lithium on the pharmacokinetics (PK) of single oral doses of lurasidone, or the effects of repeated dosing of lurasidone on the PK of digoxin, midazolam, or the oral contraceptive norgestimate/ethinyl estradiol. Two 6-week, phase III studies included evaluation of the potential for interaction between lurasidone and lithium or valproate. Maximum serum or plasma concentration (Cmax) and area under the concentration-time curve (AUC) were calculated. RESULTS: Concomitant ketoconazole administration resulted in a 6.8-fold increase in lurasidone Cmax and a 9.3-fold increase in lurasidone AUC; concomitant diltiazem administration resulted in 2.1- and 2.2-fold increases, respectively. Rifampin decreased lurasidone Cmax and AUC (one-seventh and one-fifth of lurasidone alone, respectively). Steady-state dosing with lurasidone increased Cmax and AUC0-24 (AUC from time 0 to 24 h postdose) of digoxin by 9% and 13%, respectively, and of midazolam by 21% and 44%, respectively. There were no significant interactions between lurasidone and lithium, valproate, ethinyl estradiol, or norelgestromin (the major active metabolite of norgestimate). CONCLUSIONS: Lurasidone PK is altered by strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, and coadministration is contraindicated; whereas moderate CYP3A4 inhibitors have less effect, and lurasidone dosage restrictions are recommended. No dose adjustment for lurasidone is needed when administered with lithium or valproate. Dose adjustment is not required for lithium, valproate, digoxin (a P-glycoprotein substrate), or midazolam or oral contraceptives (CYP3A4 substrates) when coadministered with lurasidone.


Assuntos
Antipsicóticos/farmacocinética , Isoindóis/farmacocinética , Tiazóis/farmacocinética , Antipsicóticos/efeitos adversos , Área Sob a Curva , Ensaios Clínicos Fase I como Assunto , Citocromo P-450 CYP3A/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Diltiazem/farmacologia , Interações de Medicamentos , Quimioterapia Combinada , Humanos , Isoindóis/efeitos adversos , Cetoconazol/farmacologia , Compostos de Lítio/farmacologia , Cloridrato de Lurasidona , Rifampina/farmacologia , Tiazóis/efeitos adversos
18.
Sci Rep ; 4: 3794, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24445843

RESUMO

Many diabetic patients complicated with wild to severe depression. It is unclear in diabetic medication whether depression perturbs the drug metabolic process of the hypoglycemic agents or not. The present study was designed to investigate the impact of chronic unpredicted mild stress (CUMS) -induced depression on mitiglinide (MGN) pharmacokinetics in rats. Adult female Sprague-Dawley rats in CUMS group were subjected to different types of stressors and the stress procedures lasted for 8 weeks. Control group without receiving stress had free access to food and water. Open-field test and 5-HT levels were assayed to evaluate the depression. After CUMS all rats were given 2.5 mg/kg of mitiglinide per os. The blood samples were collected at different time and mitiglinide plasma concentration was measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Non-compartmental statistical moment analysis was processed with DAS software. In CMUS-induced depression group, peak concentration (Cmax), peak time (Tmax), area under curve (AUC0 → ∞), mean residence time (MRT0 → ∞), and half-life (T1/2z) were reduced while total plasma clearance (CLz/F) was increased compared to control group. These preliminary results indicated that CUMS-induced depression alter the drug metabolic process of mitiglinide in rats. This finding will be significant in clinic.


Assuntos
Depressão/sangue , Complicações do Diabetes/sangue , Hipoglicemiantes/administração & dosagem , Isoindóis/farmacocinética , Animais , Cromatografia Líquida , Depressão/complicações , Depressão/tratamento farmacológico , Depressão/metabolismo , Complicações do Diabetes/tratamento farmacológico , Humanos , Hipoglicemiantes/sangue , Isoindóis/administração & dosagem , Isoindóis/sangue , Ratos , Estresse Psicológico/sangue , Estresse Psicológico/patologia , Espectrometria de Massas em Tandem
19.
J Med Chem ; 56(14): 5940-8, 2013 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-23808489

RESUMO

Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.


Assuntos
Isoindóis/síntese química , Antagonistas do Receptor de Neuroquinina-1/síntese química , Oxazóis/síntese química , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Interações de Medicamentos , Glucuronídeos/metabolismo , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Taxa de Depuração Metabólica , Antagonistas do Receptor de Neuroquinina-1/química , Antagonistas do Receptor de Neuroquinina-1/farmacocinética , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Oxazóis/química , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fragmentos de Peptídeos/farmacologia , Substância P/análogos & derivados , Substância P/farmacologia
20.
PLoS One ; 8(4): e61514, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23637845

RESUMO

Plasma pharmacokinetics of ST-246, smallpox therapeutic, was evaluated in mice, rabbits, monkeys and dogs following repeat oral administrations by gavage. The dog showed the lowest Tmax of 0.83 h and the monkey, the highest value of 3.25 h. A 2- to 4-fold greater dose-normalized Cmax was observed for the dog compared to the other species. The mouse showed the highest dose-normalized AUC, which was 2-fold greater than that for the rabbit and monkey both of which by approximation, recorded the lowest value. The Cl/F increased across species from 0.05 L/h for mouse to 42.52 L/h for dog. The mouse showed the lowest VD/F of 0.41 L and the monkey, the highest VD/F of 392.95 L. The calculated extraction ratios were 0.104, 0.363, 0.231 and 0.591 for mouse, rabbit, monkey and dog, respectively. The dog showed the lowest terminal half-life of 3.10 h and the monkey, the highest value of 9.94 h. The simple allometric human VD/F and MLP-corrected Cl/F were 2311.51 L and 51.35 L/h, respectively, with calculated human extraction ratio of 0.153 and terminal half-life of 31.20 h. Overall, a species-specific difference was observed for Cl/F with this parameter increasing across species from mouse to dog. The human MLP-corrected Cl/F, terminal half-life, extraction ratios were in close proximity to the observed estimates. In addition, the first-in-humans (FIH) dose of 485 mg, determined from the MLP-corrected allometry Cl/F, was well within the dose range of 400 mg and 600 mg administered in healthy adult human volunteers.


Assuntos
Antivirais/farmacocinética , Benzamidas/farmacocinética , Isoindóis/farmacocinética , Infecções por Poxviridae/tratamento farmacológico , Administração Oral , Adulto , Animais , Antivirais/administração & dosagem , Área Sob a Curva , Benzamidas/administração & dosagem , Benzamidas/sangue , Peso Corporal , Cães , Feminino , Meia-Vida , Humanos , Isoindóis/administração & dosagem , Isoindóis/sangue , Macaca fascicularis , Masculino , Camundongos , Orthopoxvirus , Coelhos
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