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1.
J Pharm Biomed Anal ; 177: 112858, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31518862

RESUMO

Eliglustat is an oral substrate reduction therapy drug and has been approved as a first-line treatment for adults with Gaucher disease type 1 (GD 1). In the present study, we aimed to develop and establish an accurate and simple ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the measurement of eliglustat concentration in rat plasma. The goal of chromatographic separation of eliglustat and the internal standard (bosutinib) was finished on an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 µm) column. Acetonitrile and 0.1% formic acid in water were employed as the mobile phase in a mode of gradient elution with the 0.40 mL/min flow rate. The detection was carried out on a XEVO TQ-S triple quadrupole tandem mass spectrometer coupled with electrospray ionization (ESI) interface in the positive-ion mode. Multiple reaction monitoring (MRM) was used to monitor the precursor-to-product ion transitions of m/z 405.4 → 84.1 for eliglustat and m/z 530.2 → 141.2 for bosutinib (IS), respectively. It was found that the linearity of the method in the range of 1-500 ng/mL was good for eliglustat. The values of intra- and inter-day accuracy and precision were all within the acceptance limits, and no matrix effect was found in this method. The current developed method was further performed to support in vivo pharmacokinetic study of eliglustat after oral treatment with 10 mg/kg eliglustat to rats.


Assuntos
Monitoramento de Medicamentos/métodos , Inibidores Enzimáticos/farmacocinética , Doença de Gaucher/tratamento farmacológico , Pirrolidinas/farmacocinética , Administração Oral , Compostos de Anilina/administração & dosagem , Compostos de Anilina/sangue , Animais , Cromatografia Líquida de Alta Pressão/métodos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Estudos de Viabilidade , Humanos , Limite de Detecção , Masculino , Nitrilos/administração & dosagem , Nitrilos/sangue , Pirrolidinas/administração & dosagem , Pirrolidinas/sangue , Quinolinas/administração & dosagem , Quinolinas/sangue , Ratos , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
2.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1130-1131: 121829, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31670104

RESUMO

S011-2111 is a semicarbazone and chalcone hybrid demonstrating antiproliferative tumor cell-selective effects along with unique antimetastatic potential by mitigating PP2A-ß-catenin signalling pathway. The present study envisaged to explore the in vitro and in vivo pharmacokinetics of S011-2111. A sensitive and selective liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated to determine S011-2111. It has high permeability across intestinal membrane as observed in in situ single-pass intestinal perfusion study. It has high plasma protein binding and poor aqueous solubility. It was rapidly partitioning into plasma of blood, where it was moderately stable. In mice liver microsomal stability study, S011-2111 was stable against cytochrome P450 enzymes but undergoes rapid glucuronidation with intrinsic clearance of 148.6 ±â€¯48.3 µL/min/mg. Following 100 mg/kg oral dosing of S011-2111, the compound was detectable in the plasma samples up to 24 h with a maximum plasma concentration of 45 ±â€¯16.5 ng/mL at 2.4 ±â€¯0.1 h and absolute bioavailability of 1.68%. Knowledge from this research will assist in further development of S011-2111 as an anti-cancer agent.


Assuntos
Cromatografia Líquida/métodos , Inibidores Enzimáticos , Proteína Fosfatase 2/antagonistas & inibidores , Espectrometria de Massas em Tandem/métodos , beta Catenina/antagonistas & inibidores , Animais , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Eritrócitos , Feminino , Absorção Intestinal , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray/métodos
3.
AAPS PharmSciTech ; 20(5): 218, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31187334

RESUMO

The aim of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for enhancement of the oral bioavailability of isoliquiritigenin (ISL) as well as evaluate its in vivo anti-hyperuricemic effect in rats. The ISL-loaded self-microemulsifying drug delivery system (ISL-SMEDDS) was comprised of ethyl oleate (EO, oil phase), Tween 80 (surfactant), and PEG 400 (co-surfactant). The ISL-SMEDDS exhibited an acceptable narrow size distribution (44.78 ± 0.35 nm), negative zeta potential (- 10.67 ± 0.86 mV), and high encapsulation efficiency (98.17 ± 0.24%). The in vitro release study indicated that the release rates of the formulation were obviously higher in different release media (HCl, pH 1.2; PBS, pH 6.8; double-distilled water, pH 7.0) compared with the ISL solution. The oral bioavailability of the ISL-SMEDDS was enhanced by 4.71 times in comparison with the free ISL solution. More importantly, ISL-SMEDDS significantly reduced uric acid level by inhibiting xanthine oxidase (XOD) activity in the model rats. Collectively, the prepared ISL-SMEDDS proved to be potential carriers for enhancing the solubility and oral bioavailability of ISL, as well as ameliorating its anti-hyperuricemic effect.


Assuntos
Chalconas/administração & dosagem , Chalconas/sangue , Sistemas de Liberação de Medicamentos/métodos , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Emulsões , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Masculino , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/administração & dosagem , Tensoativos/metabolismo
4.
Int J Clin Pharm ; 41(4): 1047-1055, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129889

RESUMO

Background The effects of mycophenolic acid exposure in the early period after transplantation on clinical outcomes have been reported; however, mycophenolic acid exposure in the early period after transplantation in Asian kidney transplant recipients who receive 1.5 g/d mycophenolate mofetil has never been investigated. Objective To determine mycophenolic acid exposure on day 3 post-transplantation in kidney transplant recipiens who receive 1.5 g/d mycophenolate mofetil. The effects of the reduced renal function on mycophenolic acid area under the concentration-time curve (AUC) and the achievement of the target AUC on the incidence of biopsy proven acute rejection during the first month post-transplantation were also evaluated. Setting A university hospital Method Blood samples and 24-h urine were collected on day 3 post-transplantation. Main outcome measures The mycophenolic acid AUC was calculated by linear trapezoidal rule and compared with the target of 45 mg*h/L. Results Of 42 Thai kidney transplant recipiens, the mean mycophenolic acid AUC of 45.1 mg*h/L (SD 14.7) was comparable to the AUC target (P = 0.962). Significant differences of the mycophenolic acid AUC were observed between patients with urine output of < 2400 mL and those with urine output ≥ 2400 mL (35.3 ± 6.6 and 47.4 ± 15.2, respectively; P = 0.002), and between patients with 24-h measured CrCl < 25 mL/min and those with CrCl ≥ 25 mL/min (38.0 (29.0, 42.2) and 49.2 ± 14.0, respectively; P = 0.017). Proportions of overall biopsy proven acute rejection among patients with mycophenolic acid AUC of < 45 and ≥ 45 mg*h/L were comparable (20.0% and 23.5%, respectively; P = 1.000). Conclusions After the starting dosage of 1.5 g/d mycophenolate mofetil, the mean mycophenolic acid AUC on day 3 post-kidney transplantation is comparable with the target of 45 mg*h/L. Severely reduced renal function significantly influences mycophenolic acid exposure.


Assuntos
Rejeição de Enxerto/epidemiologia , Transplante de Rim/estatística & dados numéricos , Ácido Micofenólico/farmacocinética , Transplantados/estatística & dados numéricos , Adolescente , Adulto , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Feminino , Rejeição de Enxerto/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/sangue , Tailândia/epidemiologia , Adulto Jovem
5.
PLoS One ; 14(2): e0212973, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30817774

RESUMO

BACKGROUND: Marinobufagenin (MBG) is an endogenous cardiotonic steroid (CTS) that inhibits the Na+/K+-ATPase. Human MBG is significantly increased in end-stage renal disease and immunization against MBG attenuates cardiovascular fibrosis in a rat model of uremic cardiomyopathy. Mineralocorticoid antagonists (MRA) block MBG binding sites and decrease proteinuria in chronic kidney disease (CKD) patients. We therefore aimed to investigate the association of MBG and albuminuria, as a marker of renal damage, as well as MBG and decline of glomerular filtration rate (GFR). METHODS: The Graz endocrine causes of hypertension (GECOH) study is a single center study of adults routinely referred for screening of endocrine hypertension. Plasma MBG was measured by an enzyme-linked immunoassay, and in a post-hoc analysis, follow-up creatinine levels were obtained. Patients with proteinuria >3.5g/day at baseline were excluded from further evaluation. RESULTS: We measured MBG concentrations in 40 hypertensive subjects and excluded one patient due to pre-existing proteinuria. Plasma MBG was significantly correlated with albuminuria (Spearman ρ = .357; p = .028) and proteinuria (ρ = .336; p = .039). In linear regression analysis, the association remained significant after adjustment for age, sex, and BMI (ß = .306; p = .036), and for mean systolic blood pressure (ß = .352; p = .034). In follow-up analyses (N = 30), MBG was significantly associated with decline in GFR after adjustment for time-to-follow-up (ß = -.374; p = .042). CONCLUSION: The findings suggest that MBG plasma concentrations were associated with albuminuria as well as decline in kidney function. Whether MBG predicts hard renal endpoints warrants further investigations.


Assuntos
Bufanolídeos/sangue , Taxa de Filtração Glomerular/fisiologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Adulto , Idoso , Albuminúria/sangue , Albuminúria/fisiopatologia , Animais , Biomarcadores/sangue , Cardiotônicos/sangue , Inibidores Enzimáticos/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Proteinúria/fisiopatologia , Ratos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia
6.
Clin Exp Med ; 19(2): 235-243, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30859346

RESUMO

Prognostic significance of serum microcystin in hepatocellular carcinoma has not been well investigated. The aim of the study was to reveal the relationship between serum microcystin-LR and prognosis in these patients. There were 650 early-stage hepatitis B-induced hepatocellular carcinoma patients, who were not affected by hepatitis C, cirrhosis, heavy drinking or excessive aflatoxin exposure. All of them underwent hepatectomy and were followed up for 5 years. Tumor relapse and overall death were recorded. Blood specimens were collected on admission and at the time of relapse. Serum levels of microcystin-LR and fluorescent oxidation products (FlOP_360, FlOP_320 and FlOP_400) were measured separately using enzyme-linked immunosorbent assay and fluorescence spectrometry. Multifactorial COX regression analysis suggested that serum microcystin-LR ≥ 0.97 ng/ml was associated with the increased risk of the tumor relapse (HR: 1.53, 95% CI: 1.35-1.77) and serum microcystin-LR ≥ 1.09 ng/ml was related to the higher risk of the overall death (HR: 1.58, 95% CI: 1.35-1.84) in the follow-up period. Furthermore, there was a linear relationship between serum level of microcystin-LR and serum levels of FlOP_360, FlOP_320 and FlOP_400 (P = 0.001, P = 0.023, P = 0.047). Serum levels of these fluorescent oxidation products were also higher in the patients with tumor relapse (P < 0.001, P < 0.001, P = 0.001) or overall death (P < 0.001, P = 0.001, P = 0.002) compared with the remaining patients. Serum microcystin-LR independently worsens the prognosis partly through promoting oxidative stress in patients with hepatocellular carcinoma.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Inibidores Enzimáticos/sangue , Microcistinas/sangue , Estresse Oxidativo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Inibidores Enzimáticos/metabolismo , Feminino , Seguimentos , Hepatite B Crônica/complicações , Humanos , Masculino , Microcistinas/metabolismo , Pessoa de Meia-Idade , Prognóstico , Recidiva , Soro/química , Análise de Sobrevida
7.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1110-1111: 116-123, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30802754

RESUMO

BLU-554 is a potent, highly selective oral FGFR4 inhibitor. A bioanalytical assay for quantification of BLU-554 in mouse plasma and six tissue homogenates (brain, kidney, liver, lung, small intestine, and spleen) was developed and validated using liquid chromatography with tandem mass spectrometric detection and with erlotinib as internal standard. After protein precipitation with acetonitrile in a 96-well format and separation on an XBridge® Peptide BEH C18 column by gradient elution using 0.2% (v/v) ammonium hydroxide (in water) and methanol, analytes were ionized by positive electrospray and monitored in the selected reaction monitoring mode by triple quadrupole mass spectrometry. The assay was validated in a 1-1000 ng/ml concentration range using calibration in mouse plasma. Precisions (intra-day and inter-day) were in the range 2.8-10.1% and accuracies were in between 88.5 and 96.6% for all levels in all matrices. The assay was successfully applied for a pilot pharmacokinetic and tissue distribution study in wild-type mice.


Assuntos
Cromatografia Líquida/métodos , Inibidores Enzimáticos/sangue , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Análise dos Mínimos Quadrados , Limite de Detecção , Masculino , Camundongos , Reprodutibilidade dos Testes
8.
Emergencias (Sant Vicenç dels Horts) ; 31(1): 39-42, feb. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-182435

RESUMO

Introducción: La intoxicación digitálica es un motivo frecuente de consulta en los servicios de urgencias hospitalarios (SUH). El objetivo de este estudio es conocer la mortalidad asociada a dicha intoxicación. Método: Estudio descriptivo y observacional de las intoxicaciones digitálicas atendidas en los SUH de 4 hospitales de Cataluña durante los años 2013-15. Se recogieron datos relativos a la intoxicación, la mortalidad inmediata y a los 30 días. Se analizó la existencia de posibles factores asociados a la mortalidad. Resultados: Se registraron 171 intoxicaciones digitálicas. Siete eran agudas (4,1%) y 164 (95,9%) crónicas. La mortalidad inmediata fue del 6,4% y a los 30 días fue del 13,4%. El análisis binario no identificó ningún factor relacionado con la mortalidad inmediata. En cuanto a la mortalidad a 30 días, los pacientes que fallecieron tenían con mayor frecuencia una intoxicación aguda (13% vs 2,7%; p= 0,05), había más intoxicaciones con intencionalidad suicida (8,7% vs 0,7%; p= 0,048), más afectación renal (21,7% vs 9,5%; p= 0,037), menos sintomatología neurológica (4,3% vs 17,8%; p= 0,005), mayor digoxinemia (4,7 mg/dl vs 3,7 mg/dl; p= 0,027) y menor puntuación en el índice de Barthel (IB) (49,1 (33,4) vs 70,3 (28,5); p= 0,006). El análisis de regresión logística identificó la digoxinemia como un factor independiente de mortalidad inmediata y la puntuación en el IB en la mortalidad a 30 días. Conclusiones: La digoxinemia se relaciona con la mortalidad inmediata y el IB se relaciona con la mortalidad a 30 días


Background and objective: Digoxin poisoning is a frequent reason for seeking emergency care. This study aimed to assess mortality related to digoxin poisoning. Methods: Descriptive observational study of digoxin poisonings attended in the emergency departments of 4 hospitals in Catalonia from 2013 through 2015. We gathered data relevant to the poisonings and recorded immediate and 30-day mortality. Factors possibly related to mortality were explored. Results: A total of 171 digoxin poisonings were attended. Seven (4.1%) were acute and 164 (95.9%) were chronic. The immediate and 30-day mortality rates were 6.4% and 13.4%, respectively. Bivariate analysis did not identify factors related to immediate mortality. However, the variables more often associated with 30-day mortality in this analysis were acute poisoning (after which 13% died vs 2.7% of those with chronic poisoning, P=.05), suicide attempts (8.7% of whom died vs 0.7%, P=.048), more compromised renal function (21.7% vs 9.5%, P=.037), fewer neurologic symptoms (4.3% vs 17.8% with more symptoms, P=.005), higher mean digoxin concentrations (4.7 mg/dL in those who died vs 3.7 mg/dL, P=.027), and a lower Barthel index (mean [SD] 49.1 [33.4] in those who died vs 70.3 [28.5]; P=.006). Logistic regression analysis identified serum digoxin concentration to be independently associated with immediate mortality. A lower Barthel index was associated with 30-day mortality. Conclusions: Immediate mortality is related to a high digoxin concentration in serum, and 30-day mortality to a low Barthel index


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Digoxina/envenenamento , Inibidores Enzimáticos/envenenamento , Envenenamento/mortalidade , Digoxina/sangue , Serviço Hospitalar de Emergência , Inibidores Enzimáticos/sangue , Envenenamento/sangue , Envenenamento/diagnóstico , Espanha/epidemiologia
9.
Emergencias ; 31(1): 39-42, 2019 02.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30656872

RESUMO

OBJECTIVES: Digoxin poisoning is a frequent reason for seeking emergency care. This study aimed to assess mortality related to digoxin poisoning. MATERIAL AND METHODS: Descriptive observational study of digoxin poisonings attended in the emergency departments of 4 hospitals in Catalonia from 2013 through 2015. We gathered data relevant to the poisonings and recorded immediate and 30-day mortality. Factors possibly related to mortality were explored. RESULTS: A total of 171 digoxin poisonings were attended. Seven (4.1%) were acute and 164 (95.9%) were chronic. The immediate and 30-day mortality rates were 6.4% and 13.4%, respectively. Bivariate analysis did not identify factors related to immediate mortality. However, the variables more often associated with 30-day mortality in this analysis were acute poisoning (after which 13% died vs 2.7% of those with chronic poisoning, P=.05), suicide attempts (8.7% of whom died vs 0.7%, P=.048), more compromised renal function (21.7% vs 9.5%, P=.037), fewer neurologic symptoms (4.3% vs 17.8% with more symptoms, P=.005), higher mean digoxin concentrations (4.7 mg/dL in those who died vs 3.7 mg/dL, P=.027), and a lower Barthel index (mean [SD] 49.1 [33.4] in those who died vs 70.3 [28.5]; P=.006). Logistic regression analysis identified serum digoxin concentration to be independently associated with immediate mortality. A lower Barthel index was associated with 30-day mortality. CONCLUSION: Immediate mortality is related to a high digoxin concentration in serum, and 30-day mortality to a low Barthel index.


Assuntos
Digoxina/envenenamento , Inibidores Enzimáticos/envenenamento , Envenenamento/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Digoxina/sangue , Serviço Hospitalar de Emergência , Inibidores Enzimáticos/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Envenenamento/sangue , Envenenamento/diagnóstico , Espanha/epidemiologia
10.
Bioorg Chem ; 82: 129-138, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30312868

RESUMO

Pyrimidine-fused compounds are of great interest for the discovery of potent bioactive agents. This study describes the synthesis of novel pyranopyrimidines 3a-f and pyranotriazolopyrimidines 4a-d derivatives via the cyclocondensation reaction of α-functionalized iminoether 2, which was obtained from 2-amino-3-cyanopyrane 1, with a series of primary aromatic amines and hydrazides, respectively. Structures of all synthesized compounds were established on the basis of spectroscopic methods including 1H NMR, 13C NMR and ES-HRMS. They were finally tested for their anticoagulant and anti-tyrosinase activities. Significant results have been obtained and the structure-activity relationship (SAR) was discussed with the help of molecular docking analysis.


Assuntos
Anticoagulantes/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Piranos/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Agaricus/enzimologia , Anticoagulantes/sangue , Anticoagulantes/síntese química , Anticoagulantes/química , Sítios de Ligação , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monofenol Mono-Oxigenase/química , Tempo de Tromboplastina Parcial , Piranos/sangue , Piranos/síntese química , Piranos/química , Pirimidinas/sangue , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Triazóis/sangue , Triazóis/síntese química , Triazóis/química
11.
Mod Rheumatol ; 29(6): 1002-1006, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30289014

RESUMO

Objectives: This study aimed to determine the association between the dosage and pharmacokinetics of mycophenolate mofetil (MMF) in juvenile patients with autoimmune diseases.Methods: Totally, 29 patients were administered oral MMF. The blood concentrations of mycophenolate acid (MPA) at seven points, the area under the time-concentration curve (MPA-AUC0-12h), the peak concentration (Cmax), and the time to peak concentration (Tmax) were measured. To obtain a dose-normalized MPA-AUC0-12h value, the actual measured MPA-AUC0-12h value was divided by the dose value of the morning administration corrected for body weight (BW) or body surface area (BSA). The patients were classified into three age groups (group 1, ≤10 years; group 2, >10-≤15 years; and group 3, >15 years), and pharmacokinetic parameters were compared among the groups.Results: In total, we obtained 37 measurements. The actual measured MPA-AUC0-12h values and the MPA-AUC0-12h values corrected for dose per BW and Tmax were lower in young patients. The MPA-AUC0-12h values corrected for dose per BSA and Cmax were comparable among all the groups.Conclusion: In patients with juvenile autoimmune diseases, determining MMF administration dosage according to BSA may facilitate MPA-AUC0-12h value prediction.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Inibidores Enzimáticos/sangue , Imunossupressores/sangue , Ácido Micofenólico/sangue , Adolescente , Criança , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Adulto Jovem
12.
J Pharm Biomed Anal ; 162: 205-214, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30265980

RESUMO

S012-1332 is the first DNA ligase I inhibitor that demonstrated in vivo anti-breast cancer activity. The present study aimed to assess the in vivo pharmacokinetics of S012-1332 in rats and interpret them with in vitro findings. A sensitive and selective liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated to determine S012-1332. Following oral administration, the absolute bioavailability was 7.04%. The absorption was prolonged which can be explained by low solubility in simulated gastric fluid and several folds higher solubility in simulated intestinal fluid. The effective permeability across the intestinal membrane in in situ single pass perfusion study for S012-1332 was 5.58 ± 1.83 * 10-5 cm/sec compared to 5.99 ± 0.65 * 10-5 cm/sec for carbamazepine, with no significant difference, indicating S012-1332 has high permeability. It was rapidly partitioning into plasma in blood, where it was stable. Plasma protein binding was moderate which may have attributed to the rapid distribution out of the vascular compartment. The pharmacokinetics of S012-1332 was characterized by extensive clearance as seen with rat liver and intestinal microsomes. In vitro results elucidate the in vivo pharmacokinetic data. These findings provide crucial information for further development of S012-1332 as anti-breast cancer agent.


Assuntos
Antineoplásicos/farmacocinética , DNA Ligase Dependente de ATP/antagonistas & inibidores , Inibidores Enzimáticos/farmacocinética , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Disponibilidade Biológica , Cromatografia Líquida , DNA Ligase Dependente de ATP/metabolismo , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Inativação Metabólica , Absorção Intestinal , Mucosa Intestinal/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Permeabilidade , Ligação Proteica , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Solubilidade , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
13.
Xenobiotica ; 49(11): 1338-1343, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30507339

RESUMO

1. S-EPA is a sulfur-substitution analog of epacadostat (EPA), an effective small molecule indoleamine 2,3-dioxgenase1 (IDO) inhibitor. By in vitro and in vivo experiments, pharmacokinetic differences of two closely related analogs, S-EPA and EPA was investigated in this study. 2. Liver microsomes clearance experiments showed S-EPA had comparable metabolic stability with EPA in rat and human liver microsomes. The whole blood distribution experiments showed the distribution ratio of S-EPA in blood cells to plasma in mice, rats, dogs and monkey was 1.2, 4.8, 2.2 and 40.6, respectively. While the distribution ratio of EPA ranged from 0.94 to 1.30 in mice, rats, dogs and was 3.1 in monkeys. 3. The pharmacokinetic study in rats showed the exposure (AUClast) of S-EPA in plasma and blood cells was 1.7-fold and 3.9-fold higher than that of EPA, respectively. Moreover, the exposure ratio of S-EPA in blood cells to plasma was 3.7, while the ratio of EPA was 1.6. 4. In CT26 tumor bearing mice, the IDO inhibition of S-EPA and EPA on plasma or tumor kynurenine was generally consistent. And the inhibition ratio could reach at more than 50% at 3 h after single dose, at least lasting up to 8 h.


Assuntos
Inibidores Enzimáticos/farmacocinética , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Oximas/farmacocinética , Sulfetos/farmacocinética , Sulfonamidas/farmacocinética , Animais , Linhagem Celular Tumoral , Cães , Estabilidade de Medicamentos , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Humanos , Cinurenina/sangue , Cinurenina/metabolismo , Macaca fascicularis , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Transplante de Neoplasias , Oximas/sangue , Oximas/química , Ratos Sprague-Dawley , Sulfetos/sangue , Sulfetos/química , Sulfonamidas/sangue , Sulfonamidas/química
14.
Chem Pharm Bull (Tokyo) ; 66(12): 1131-1152, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504630

RESUMO

A novel series of 2-acyl-3-carboxyl-tetrahydroisoquinoline derivatives were synthesized and biologically evaluated. Among them, (S)-2-{(E)-3-furan-2-ylacryloyl}-7-[(2E,4E)-5-(2,4,6-trifluorophenyl)penta-2,4-dienyloxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound 17u) was identified as a potent protein tyrosine phosphatase 1B (PTP1B) inhibitor without peroxisome proliferator-activated receptor (PPAR) γ activation: PTP1B inhibition IC50=0.19 µM and PPARγ ΕC50>10 µM. Compound 17u exhibited mixed-type inhibition for PTP1B, and this mode of inhibition was rationalized by computational ligand docking into the catalytic and allosteric sites of PTP1B. Compound 17u also showed high oral absorption at 10 mg/kg (per os (p.o.), Cmax=4.67 µM) in rats, significantly reduced non-fasting plasma glucose and triglyceride levels with no side effects at 30 mg/kg/d (p.o.) for 4 weeks, and attenuated elevations in plasma glucose levels in the oral glucose tolerance test performed 24 h after its final administration in db/db mice. In conclusion, the substituted 2-acyl-3-carboxyl-tetrahydroisoquinoline is a novel scaffold of mixed-type PTP1B inhibitors without PPARγ activation, and compound 17u has potential as an efficacious and safe anti-diabetic drug as well as a useful tool for investigations on the physiological and pathophysiological effects of mixed-type PTP1B inhibition.


Assuntos
Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos , Simulação de Acoplamento Molecular , Estrutura Molecular , PPAR gama/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/sangue , Tetra-Hidroisoquinolinas/química
15.
Acta Neuropathol Commun ; 6(1): 103, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30270813

RESUMO

Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients' daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairments in male mice, as demonstrated in the Y-maze test of spontaneous alternation, the novel object/place recognition test, and the puzzle box test. Normalization of cognitive impairment was associated with reversal of cisplatin-induced synaptosomal mitochondrial deficits and restoration of synaptic integrity. Mechanistically, cisplatin induced deacetylation of the microtubule protein α-tubulin and hyperphosphorylation of the microtubule-associated protein tau. These cisplatin-induced changes were reversed by HDAC6 inhibition. Our data suggest that inhibition of HDAC6 restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptosomal mitochondrial function and synaptic integrity and thereby to reversal of CICI. Remarkably, our results indicate that short-term daily treatment with the HDAC6 inhibitor was sufficient to achieve prolonged reversal of established behavioral, structural and functional deficits induced by cisplatin. Because the beneficial effects of HDAC6 inhibitors as add-ons to cancer treatment have been demonstrated in clinical trials, selective targeting of HDAC6 with brain-penetrating inhibitors appears a promising therapeutic approach for reversing chemotherapy-induced neurotoxicity while enhancing tumor control.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Disfunção Cognitiva , Inibidores Enzimáticos/uso terapêutico , Desacetilase 6 de Histona/metabolismo , Tauopatias/enzimologia , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/enzimologia , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/sangue , Proteínas de Fluorescência Verde/metabolismo , Desacetilase 6 de Histona/ultraestrutura , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Pirimidinas/sangue , Pirimidinas/uso terapêutico , Proteínas Recombinantes de Fusão/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Sinaptossomos/patologia , Sinaptossomos/ultraestrutura , Tauopatias/induzido quimicamente , Tauopatias/tratamento farmacológico , Fatores de Tempo , Tubulina (Proteína)/metabolismo , Proteínas tau/metabolismo
16.
Bioorg Med Chem Lett ; 28(23-24): 3721-3725, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348490

RESUMO

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , Animais , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Humanos , Lipase/sangue , Lipase/metabolismo , Camundongos , Modelos Moleculares , Pirimidinonas/sangue , Pirimidinonas/síntese química , Relação Estrutura-Atividade
17.
J Chromatogr A ; 1579: 121-128, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30361035

RESUMO

Developing an easy to use, cheap and fast analytical methodology is highly demanded for clinical practices, such as therapeutic drug monitoring (TDM). The present work deals with the development of an analytical methodology for the analysis of four basic anticancer drugs, namely tyrosine kinase inhibitors (TKIs), in human plasma by combining salting-out assisted liquid-liquid extraction (SALLE) with capillary electrophoresis (CE). This SALLE-CE methodology makes a full use of the advantages of both techniques by combining extraction, on-line concentration and separation in a simple way. First, plasma samples containing TKIs are mixed with acetonitrile (ACN) in appropriate volumes to precipitate proteins. After vortexing and centrifugation, sodium chloride (NaCl) is added to the plasma-ACN mixture to induce a two phases separation. TKIs are efficiently extracted (60-100% extraction efficiency) in the upper (mostly organic) phase which is directly analyzed by capillary electrophoresis (CE) coupled to UV detection. The high content of ACN in the upper phase allows the stacking of the analytes in the capillary (on-line stacking) during analysis. For the first time thanks to this electrophoretic process, the injected sample volume can be as large as 80% of the capillary volume (till the detector window). Good linearity was obtained for each TKI in the concentration range 60-2000 ng/ml with correlation coefficient (r²) between 0.997 and 0.999. LOD and LOQ in human plasma with such large injected volume were determined from 16 to 280 ng/ml and from 62 to 900 ng/ml respectively depending on the TKI. Recoveries for the four TKIs ranged from 60 to 100%. The repeatability of the SALLE-CE methodology for the analysis of TKIs in human plasma was evaluated with injected sample volume equal to 80% of the capillary volume till detector window. Relative standard deviations (RSDs) of less than 1.24 and 2.84% on migration times and corrected peak areas respectively were obtained at the LOQ. The sensitivity was enhanced by 61 to 265 folds confirming the applicability of the proposed methodology for the assay of TKIs in patients' plasma.


Assuntos
Análise Química do Sangue/métodos , Eletroforese Capilar , Inibidores Enzimáticos/sangue , Extração Líquido-Líquido , Proteínas Tirosina Quinases/antagonistas & inibidores , Cloreto de Sódio/química , Acetonitrilos/química , Centrifugação , Inibidores Enzimáticos/metabolismo , Humanos , Plasma/química
18.
Clin Drug Investig ; 38(11): 1053-1060, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30203386

RESUMO

BACKGROUND AND OBJECTIVE: Baloxavir marboxil is a prodrug that is metabolized to baloxavir acid, which suppresses viral replication by inhibiting cap-dependent endonuclease with a single oral administration. As the mode of action of baloxavir marboxil is different from that of neuraminidase inhibitors, such as oseltamivir, combination treatment with these drugs can be a treatment option, particularly for severe influenza infection. The aim of this study was to assess the drug-drug interaction between baloxavir marboxil and oseltamivir. METHODS: Eighteen healthy adult subjects received three treatments in a crossover fashion: single administration of baloxavir marboxil 40 mg alone, repeated twice-daily administration of oseltamivir at 75 mg for 5 days, or single administration of baloxavir marboxil at 40 mg in combination with repeated twice-daily administration of oseltamivir at 75 mg for 5 days. RESULTS: The ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve of baloxavir acid after co-administration compared to baloxavir marboxil alone were 1.03 (0.92-1.15) and 1.01 (0.96-1.06), respectively. The ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve of oseltamivir carboxylate, the active form of oseltamivir, after co-administration compared to oseltamivir alone were 0.96 (0.93-1.00) and 0.99 (0.96-1.01), respectively, at steady state on day 5. Treatment-emergent adverse events reported were mild and not considered to be related to the study drug. CONCLUSION: The lack of a clinically meaningful drug-drug interaction between baloxavir marboxil and oseltamivir has been established.


Assuntos
Oseltamivir/administração & dosagem , Oseltamivir/sangue , Pró-Fármacos/administração & dosagem , Pró-Fármacos/metabolismo , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/sangue , Estudos Cross-Over , Avaliação Pré-Clínica de Medicamentos/métodos , Interações de Medicamentos/fisiologia , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Antivir Ther ; 23(7): 555-566, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29927386

RESUMO

BACKGROUND: This double-blind, first-in-human Phase I study evaluated pharmacokinetics, safety and tolerability of AL-794 (prodrug of ALS-033719), a potent endonuclease inhibitor of influenza A and B in healthy volunteers. METHODS: Healthy adult volunteers were randomized to AL-794 (50-2,000 mg single ascending doses, fasting) or placebo (5 cohorts, n=6:2 AL-794: placebo/cohort) in part 1, and AL-794 (50-600 mg multiple ascending doses, twice-daily, fed or fasted) or placebo (3 cohorts, n=8:2 AL-794: placebo/cohort) for 7 days in part 2. In part 3, 8 healthy volunteers from part 1 received 450 mg AL-794 (n=6) or placebo (n=2) following a high-fat meal. All dosing was done with an oral suspension. Blood and urine samples for pharmacokinetics were collected at scheduled times and analysed for ALS-033719 and ALS-033927 (inactive glucuronide) plasma concentrations using LC-MS/MS. RESULTS: ALS-033719 plasma concentrations increased dose proportionately up to 150 mg but less than proportionately above 150 mg. Steady-state was generally achieved by the third dose. ALS-033719 exposure increased following administration with a standard meal (19%-33%) or high-fat meal (3-3.6-fold). ALS-033927 was the major metabolite observed. Renal elimination was negligible (0.2%). Seventeen AL-794-treated healthy volunteers reported ≥1 treatment-emergent adverse event (TEAE; part 1: n=6, 24%; part 2: n=11, 69%). The most common TEAEs were headache (part 1: n=3; part 2: n=5) and dizziness (part 1: n=2; part 2: n=6). CONCLUSIONS: AL-794 up to 200 mg twice daily achieved ALS-033719 exposures which are expected to be efficacious and were generally tolerated. Further studies are planned to characterize safety and antiviral activity.


Assuntos
Antivirais/farmacocinética , Inibidores Enzimáticos/farmacocinética , Serina Endopeptidases/farmacocinética , Administração Oral , Adulto , Antivirais/efeitos adversos , Antivirais/sangue , Área Sob a Curva , Tontura/diagnóstico , Tontura/etiologia , Método Duplo-Cego , Esquema de Medicação , Endonucleases/antagonistas & inibidores , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/sangue , Jejum , Cefaleia/diagnóstico , Cefaleia/etiologia , Voluntários Saudáveis , Humanos , Influenza Humana/prevenção & controle , Masculino , Segurança do Paciente , Serina Endopeptidases/efeitos adversos , Serina Endopeptidases/sangue , Proteínas Virais/antagonistas & inibidores
20.
Biomol Concepts ; 9(1): 53-63, 2018 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29779013

RESUMO

Treatment with analogues of the SERCA-inhibitor Thapsigargin is a promising new approach for a wide variety of cancer entities. However, our previous studies on various tumor cells suggested resistance of SEC62 over-expressing tumors to this treatment. Therefore, we proposed the novel concept that e.g. lung-, prostate-, and thyroid-cancer patients should be tested for SEC62 over-expression, and developed a novel therapeutic strategy for a combinatorial treatment of SEC62 over-expressing tumors. The latter was based on the observations that treatment of SEC62 over-expressing tumor cells with SEC62-targeting siRNAs showed less resistance to Thapsigargin as well as a reduction in migratory potential and that the siRNA effects can be mimicked by the Calmodulin antagonist Trifluoperazine. Therefore, the combinatorial treatment of SEC62 over-expressing tumors was proposed to involve Thapsigargin and Trifluoperazine. Here, we addressed the impact of Thapsigargin and Trifluoperazine in separate and combined treatments of heterotopic tumors, induced by inoculation of human hypopharyngeal squamous cell carcinoma (FaDu)-cells into the mouse flank. Seeding of the tumor cells and/or their growth rate were significantly reduced by all three treatments, suggesting Trifluoperazine is a small molecule to be considered for future therapeutic strategies for patients, suffering from Sec62-overproducing tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Hipofaríngeas/tratamento farmacológico , Proteínas de Membrana Transportadoras/metabolismo , Tapsigargina/uso terapêutico , Trifluoperazina/uso terapêutico , Animais , Calmodulina/antagonistas & inibidores , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células , Inibidores Enzimáticos/sangue , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias Hipofaríngeas/genética , Camundongos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço , Tapsigargina/sangue , Trifluoperazina/sangue
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