RESUMEN
Essentials DS-1040 inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa). Infusion of DS-1040 was safe and well tolerated in healthy young and elderly subjects. DS-1040 substantially decreased TAFIa activity but had no impact on bleeding time. DS-1040 may provide an option of safer thrombolytic therapy. SUMMARY: Background Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue-type plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low molecular weight compound that inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), and was developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases. Objectives This first-in-human, randomized, placebo-controlled, three-part, phase 1 study was conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of DS-1040 in healthy subjects. Subjects/Methods Young (18-45 years) or elderly (65-75 years) subjects (N = 103) were randomized to receive single ascending doses of DS-1040 ranging from 0.1 mg to 40 mg, or placebo, administered either as a 0.5-h intravenous infusion or as a 24-h continuous infusion. Results All doses of DS-1040 were tolerated, and no serious adverse events (AEs) or discontinuations resulting from AEs occurred during the study. Bleeding time remained within the normal range for all doses tested in all subjects. Plasma exposure of DS-1040 increased proportionally with increase in dose. Elderly subjects had higher exposures to DS-1040 and prolonged elimination times, probably because of decreased renal clearance. DS-1040 caused a substantial dose-dependent and time-dependent decrease in TAFIa activity and in 50% clot lysis time. The levels of D-dimer, indicative of endogenous fibrinolysis, increased in some individuals following DS-1040 treatment. No effects of DS-1040 on coagulation parameters or platelet aggregation were observed. Conclusions The novel fibrinolysis-enhancing agent DS-1040 has favorable pharmacokinetic/pharmacodynamic properties and a favorable safety profile, warranting further clinical development.
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Carboxipeptidasa B2/antagonistas & inhibidores , Fibrinólisis/efectos de los fármacos , Fibrinolíticos/administración & dosificación , Inhibidores de Proteasas/administración & dosificación , Adolescente , Adulto , Factores de Edad , Anciano , Pruebas de Coagulación Sanguínea , Carboxipeptidasa B2/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Fibrinolíticos/efectos adversos , Fibrinolíticos/farmacocinética , Voluntarios Sanos , Hemorragia/inducido químicamente , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/farmacocinética , Factores de Riesgo , Adulto JovenRESUMEN
WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6ß-hydroxycortisol (6ß-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6ß-OHF/F in healthy Chinese. METHODS: Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6ß-OHF concentrations were measured using UPLC. RESULTS AND DISCUSSION: There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6ß-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6ß-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 hâng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. WHAT IS NEW AND CONCLUSION: There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6ß-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6ß-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study.
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Biomarcadores/orina , Citocromo P-450 CYP3A/genética , Hidrocortisona/análogos & derivados , Hidrocortisona/orina , Midazolam/farmacocinética , Polimorfismo Genético/genética , Adulto , Pueblo Asiatico/genética , Biomarcadores/sangre , Estudios Cruzados , Genotipo , Humanos , Masculino , Midazolam/administración & dosificación , Midazolam/sangre , Tacrolimus/uso terapéutico , Adulto JovenRESUMEN
This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second-generation BCR-ABL tyrosine kinase inhibitor. After a once- or twice-daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration-time curve (AUC) and peak serum concentration (C(max)) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility-limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once-daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high-fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).
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Antineoplásicos/farmacocinética , Interacciones Alimento-Droga , Proteínas de Fusión bcr-abl/farmacocinética , Proteínas Tirosina Quinasas/farmacocinética , Pirimidinas/farmacocinética , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Área Bajo la Curva , Grasas de la Dieta , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Proteínas de Fusión bcr-abl/administración & dosificación , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Solubilidad , Adulto JovenRESUMEN
AIMS: To assess the effects of exercise intervention on nurses' health-related physical fitness. BACKGROUND: Regular exercise that includes gymnastics or aerobics has a positive effect on fitness. In Taiwan, there are not much data which assess the effects of exercise intervention on nurses' health-related physical fitness. Many studies have reported the high incidence of musculoskeletal disorders (MSDs) in nurses However, there has been limited research on intervention programs that are designed to improve the general physical fitness of nurses. DESIGN: A quasi-experimental study was conducted at a medical centre in central Taiwan. METHODS: Ninety nurses from five different units of a hospital volunteered to participate in this study and participated in an experimental group and a control group. The experimental group engaged in a three-month intervention program consisting of treadmill exercise. Indicators of the health-related physical fitness of both groups were established and assessed before and after the intervention. RESULTS: Before intervention, the control group had significantly better grasp strength, flexibility and durability of abdominal muscles than the experimental group (p < 0.05). After the intervention, logistic regression was used to adjust for marital status, work duration, regular exercise and workload and found that the experimental group performed significantly better (p < 0.05) on body mass index, grasp strength, flexibility, durability of abdominal and back muscles and cardiopulmonary function. CONCLUSIONS: This study demonstrates that the development and implementation of an intervention program can promote and improve the health-related physical fitness of nurses. RELEVANCE TO CLINICAL PRACTICE: It is suggested that nurses engage in an exercise program while in the workplace to lower the risk of MSDs and to promote working efficiency.
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Enfermeras y Enfermeros , Aptitud Física , Adulto , Humanos , Encuestas y Cuestionarios , TaiwánRESUMEN
The pharmacokinetics of acetaminophen have been well studied in different populations, especially in Caucasians. However, limited studies on acetaminophen pharmacokinetics have been conducted in the native Chinese and few such data have been reported in the English language literature. Previous published studies suggested that environmental and genetic factors may cause inter-individual difference in acetaminophen disposition, thus we investigated the pharmacokinetics of acetaminophen in Hong Kong Chinese subjects. A single 500 mg oral dose of acetaminophen was administered to 12 healthy male Chinese subjects under fasting conditions. Multiple blood samples were obtained after drug administration. Plasma acetaminophen concentrations were determined using HPLC, and its main pharmacokinetic parameters were generated. In comparison to other published data, acetaminophen half-life was considerably longer (15-62%), and oral clearance was lower (16-56%) in Hong Kong Chinese as compared to Australian Chinese, Caucasians (USA, UK, Australia), and subjects from Pakistan, Denmark, Spain and South Africa. Similarities however were found in the pharmacokinetic parameters between Hong Kong Chinese and Mainland Chinese subjects. The observed pharmacokinetic parameters of acetaminophen in Hong Kong Chinese subjects may be different from other ethnic populations. Further studies are needed to verify this hypothesis.
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Acetaminofén/farmacocinética , Analgésicos no Narcóticos/farmacocinética , Acetaminofén/sangre , Administración Oral , Adulto , Analgésicos no Narcóticos/sangre , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Semivida , Hong Kong , Humanos , Masculino , Tasa de Depuración Metabólica , Grupos RacialesRESUMEN
The protocol used for coupling of monoclonal antibodies with mixed anhydride of DTPA for subsequent radiolabeling with indium-111 affects the integrity of the immunoreactivity of the antibody preparations. To analyze the effect of minor methodological variations on coupling characteristics, a two-step addition of DTPA to antimyosin antibody with gentle mixing was compared to a single addition with vigorous stirring. The molar ratios of DTPA to antibody were also varied. The polymer formation was assessed by SDS-PAGE and immunoreactivity was assessed by solid phase radioimmunoassay using human heart myosin as the antigen. The immunoreactivity was significantly decreased in the two-step, gentle-mixing method where polymer formation was evident. The one-step, vigorous-stirring method of DTPA incorporation produced no polymerization and no loss of immunoreactivity.