RESUMEN

Purpose: To explore the diagnostic efficacy and optimal diagnosis threshold of T-SPOT.TB for active tuberculosis in adults and to evaluate the influential factors for T-SPOT.TB results. Patients and Methods: A retrospective study of 1193 adult inpatients from April 2015 to March 2018 in Ruijin Hospital was conducted. All included patients underwent T-SPOT.TB assay, and were divided into two groups, active tuberculosis (ATB) and non-active tuberculosis (non-ATB) groups. Their demographic data, underlying diseases, personal history and laboratory findings were collected to calculate the diagnostic efficacy at different diagnosis thresholds and analyze the impact factors. Symptoms and imaging features of ATB patients were recorded and analyzed. Results: A total of 114 ATB patients and 1079 non-ATB patients were included in the study, and ATB patients had a higher level of T-SPOT.TB than the non-ATB group. Sensitivity and specificity of T-SPOT.TB for diagnosing ATB are 78.95% and 68.58% as the threshold at 6sfu. In the diagnosis accordance curves, ESAT-6, CFP-10, and max (ESAT-6 or CFP-10) reached the plateau at 40sfu, while sum (ESAT-6 and CFP-10) reached the plateau at 70sfu. Multivariate logistic regression analysis showed that obsolescent tuberculosis (p=0.001), smoking history(p=0.005), diabetes(p=0.035) and advanced age (≥65 years old) (p=0.031) were risk factors for false-positive result of T-SPOT.TB. In terms of imaging features, logistic regression analysis suggested that the thin-wall cavitary lesion was the only feature associated with the result of T-SPOT.TB. Conclusion: As for using T-SPOT.TB test to diagnose active tuberculosis, increased threshold could significantly elevate the diagnosis accordance. And we suggest that the threshold of T-SPOT.TB could be increased to 40sfu for diagnosing ATB. Attention should be paid when diagnose ATB in population with obsolescent tuberculosis, smoking history, diabetes and advanced age, for the risk of false-positive.

RESUMEN

OBJECTIVE: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). METHODS: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. RESULTS: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. CONCLUSIONS: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2.
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Asunto(s)

1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Éteres Fenílicos/efectos adversos , Pirimidinonas/efectos adversos , Adulto , Inhibidores del Citocromo P-450 CYP3A/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Masculino , Éteres Fenílicos/farmacocinética , Éteres Fenílicos/farmacología , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Simvastatina/farmacología , Método Simple Ciego

RESUMEN

INTRODUCTION: Small peptides are approved as treatments for type 2 diabetes mellitus and may have utility in metabolic diseases. These peptides often have short half-lives requiring delivery either as a sustained-release formulation or via a device. The opportunity to study their pharmacokinetics using simple solution formulations delivered by continuous subcutaneous infusion may facilitate the drug development process. METHODS: Here, we investigated the systemic exposure of an exemplar peptide (exenatide) when infused in healthy subjects using a Paradigm(®) Revel™ insulin infusion pump (Medtronic MiniMed). Four infusion regimens were tested: Constant 24-h infusion (16.5 µg/day), constant 7-day infusion (25.5 µg/day in Cohort 2), and two different 7-day escalation regimens (ranging from 7 to 58.5 µg/day in Cohort 1 and 25.5-58.5 µg/day in Cohort 3). RESULTS: While the overall exenatide pharmacokinetics were in line with those expected, the observed within-subject concentration variability was considerable. CONCLUSION: Our work identifies sources of potential pharmacokinetic variability relating to the method of delivery and the drug's formulation that will be valuable to investigators contemplating the delivery of peptides via insulin infusion pumps. FUNDING: GlaxoSmithKline. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01857895.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Sistemas de Infusión de Insulina , Péptidos/efectos adversos , Péptidos/farmacocinética , Ponzoñas/efectos adversos , Ponzoñas/farmacocinética , Relación Dosis-Respuesta a Droga , Exenatida , Femenino , Semivida , Humanos , Hipoglucemiantes/administración & dosificación , Infusiones Subcutáneas , Masculino , Péptidos/administración & dosificación , Ponzoñas/administración & dosificación

RESUMEN

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Metilaminas/química , Metilaminas/farmacología , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidores , Tiazepinas/química , Tiazepinas/farmacología , Animales , Ácidos y Sales Biliares/metabolismo , Perros , Estabilidad de Medicamentos , Células HEK293 , Humanos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/uso terapéutico , Masculino , Metilaminas/metabolismo , Metilaminas/uso terapéutico , Ratones , Ratas , Solubilidad , Tiazepinas/metabolismo , Tiazepinas/uso terapéutico

RESUMEN

Bile acids are recognized as metabolic modulators. The present study was aimed at evaluating the effects of a potent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acid concentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreased HbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 and three-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines and the liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucose lowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in the distal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetes mellitus.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Hipoglucemiantes/uso terapéutico , Absorción Intestinal/efectos de los fármacos , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidores , Tiazepinas/uso terapéutico , Animales , Ácidos y Sales Biliares/análisis , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Heces/química , Regulación de la Expresión Génica/efectos de los fármacos , Péptido 1 Similar al Glucagón/sangre , Hipoglucemiantes/administración & dosificación , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Isoxazoles/administración & dosificación , Isoxazoles/uso terapéutico , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Zucker , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Tiazepinas/administración & dosificación

RESUMEN

Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic beta-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.

Asunto(s)

Glucemia/metabolismo , Resina de Colestiramina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Péptido 1 Similar al Glucagón/biosíntesis , Hipoglucemiantes/uso terapéutico , Obesidad/tratamiento farmacológico , Animales , Glucemia/análisis , Resina de Colestiramina/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Expresión Génica , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/análisis , Hipoglucemiantes/farmacología , Insulina/sangre , Resistencia a la Insulina , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Receptores X del Hígado , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Receptores Nucleares Huérfanos/genética , Receptores Nucleares Huérfanos/fisiología , Péptido YY/metabolismo , Ratas , Ratas Zucker , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/fisiología

RESUMEN

Propranolol is a noncardioselective beta-adrenergic antagonist that has been recently reported to prolong the QTc interval on the surface electrocardiogram in humans when overdosed [Farhangi, V., Sansone, R.A. (2003). QTc prolongation due to propranolol overdose. Int. J. Psychiatry Med. 33, 201-202.]. To examine the underlying mechanisms for these clinical findings, we studied the effects of propranolol on the human cardiac potassium channels encoded by the ether-a-go-go-related gene (ERG) using the whole cell voltage-clamp technique. We found that propranolol blocked hERG currents in a concentration-dependent manner with an IC50 of 9.9+/-1.3 microM which is relevant to the predicted plasma level of propranolol in this case report. The present study demonstrated that propranolol can inhibit hERG channels. The interaction between propranolol and hERG channels could lead to delayed cardiac repolarization and might be a molecular mechanism for the previously reported QTc prolongation when propranolol is overdosed.

Asunto(s)

Canales de Potasio con Entrada de Voltaje/fisiología , Propranolol/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go , Humanos , Potenciales de la Membrana/efectos de los fármacos , Técnicas de Placa-Clamp , Canales de Potasio con Entrada de Voltaje/genética

RESUMEN

The conserved residues, Arg-349 and Asp-373, of the renal Na(+)/dicarboxylate cotransporter (NaDC-1) have been shown in our previous studies to affect substrate affinity and cation binding. In this study, amino acids surrounding Arg-349 and Asp-373 were individually mutated to cysteines and their sensitivity to methanethiosulfonate reagents (MTS) was tested. Only three of the 21 mutants were sensitive to MTS reagents: R349C, S372C, and D373C. The R349C mutant had reduced activity which was restored by chemical modification with MTSEA. The effect of MTSEA was only observed in the presence of sodium, indicating that Arg-349 is conformationally accessible. The succinate transport activity of the S372C mutant was stimulated by both MTSEA and MTSET. The D373C mutant was very sensitive to inhibition by MTSET (K(i) = 0.5 microM) in sodium buffer. The inhibition of D373C by MTSET was prevented by substrate, suggesting that the substrate-induced conformational change occludes the residue. We conclude that the accessibility of Arg-349 and Asp-373 is likely to change with the conformational states of the transport cycle.

Asunto(s)

Arginina , Ácido Aspártico , Transportadores de Ácidos Dicarboxílicos/química , Transportadores de Anión Orgánico Sodio-Dependiente/química , Simportadores/química , Sustitución de Aminoácidos , Animales , Sitios de Unión , Biotinilación , Membrana Celular/metabolismo , Cisteína , Transportadores de Ácidos Dicarboxílicos/metabolismo , Femenino , Cinética , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Oocitos/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Conformación Proteica , Estructura Secundaria de Proteína , Proteínas Recombinantes/química , Sodio/metabolismo , Especificidad por Sustrato , Simportadores/metabolismo