RESUMEN
Pantethine and fursultiamine have been evaluated for their clinical usefulness in the treatment and prevention of uncomplicated postoperative adhesive intestinal obstruction. In recent years, the actions of drugs used to treat gastrointestinal diseases have been elucidated pharmacologically from the viewpoints of gastrointestinal peptide levels. We examined the effects of pantethine and fursultiamine on plasma levels of calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)-, motilin- and substance P (SP)-like immunoreactive substances (IS) in healthy subjects. An open-labeled study was conducted on five healthy volunteers. Each subject was administered a single oral dose of pantethine, fursultiamine and placebo at intervals of one month. Venous blood samples were collected before and at 20, 40, 60, 90, 120, 180 and 240 min after each administration. Plasma peptide levels were measured using a highly sensitive enzyme immunoassay. A single oral dose of pantethine resulted in significant increases of plasma CGRP- and VIP-IS levels compared to placebo. Furthermore, areas under the plasma concentration-time curves (AUC(0-240)) of CGRP- and VIP-IS were significantly higher after pantethine administration compared with placebo. On the other hand, fursultiamine had no effect on plasma levels and AUC(0-240) of CGRP-, VIP-, motilin- and SP-IS. This study demonstrated the different effects of pantethine and fursultiamine from the viewpoint of plasma gastrointestinal peptide changes. The pharmacological effects of pantethine may be closely related to the changes in plasma CGRP- and VIP-IS levels.
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Péptido Relacionado con Gen de Calcitonina/metabolismo , Fursultiamina/farmacología , Motilina/metabolismo , Panteteína/análogos & derivados , Sustancia P/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Complejo Vitamínico B/farmacología , Adulto , Péptido Relacionado con Gen de Calcitonina/sangre , Péptido Relacionado con Gen de Calcitonina/efectos de los fármacos , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/fisiología , Humanos , Masculino , Terapia Molecular Dirigida , Motilina/sangre , Motilina/efectos de los fármacos , Panteteína/farmacología , Sustancia P/sangre , Sustancia P/efectos de los fármacos , Péptido Intestinal Vasoactivo/sangre , Péptido Intestinal Vasoactivo/efectos de los fármacosRESUMEN
INTRODUCTION: Carriers of reduced-function CYP2C19 allele on antiplatelet therapy show diminished platelet inhibition and higher rate of clinical risk. The purpose of this study was to determine cut-off levels of VerifyNow P2Y12 system associated with effective inhibition of on-clopidogrel platelet aggregation to predict carriers of CYP2C19 reduced-function allele among patients undergoing percutaneous coronary intervention (PCI). MATERIALS AND METHODS: We enrolled 202 consecutive patients with stable coronary artery disease (CAD) undergoing PCI and treated with clopidogrel. All patients underwent CYP2C19 genotyping and measurement of residual platelet aggregation by VerifyNow system. RESULTS: Carriers of CYP2C19 reduced-function allele constituted 131 (65%) of 202 CAD patients. Platelet inhibition measured by P2Y12 reaction units (PRU) and %inhibition was diminished in carriers compared with noncarriers (PRU: 290.0±81.2 vs 217.6±82.4, p<0.001, %inhibition: 17.9±17.8 vs 35.5±22.8, p<0.001, respectively). Multiple logistic regression analysis identified PRU and %inhibition as significant predictors of carrier state [odds ratio (OR) 4.95; 95% confidence interval (95%CI): 2.49 to 9.85; p<0.001, OR 5.55; 95%CI: 2.80 to 10.99; p<0.001, respectively]. Receiver-operating characteristic analysis showed that PRU and %inhibition were significant predictors of carrier state [area under the curve (AUC) 0.736 (95%CI: 0.664 to 0.808; p<0.001), AUC 0.727 (95%CI: 0.651 to 0.803; p<0.001), respectively]. The cut-off levels of PRU and %inhibition were 256 and 26.5% for the identification of carriers. CONCLUSIONS: Our results suggested that the cut-off levels of PRU and %inhibition to discriminate carriers of CYP2C19 reduced-function allele from noncarriers are potentially useful clinically to provide optimal clopidogrel therapy in patients with stable CAD undergoing PCI.
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Angioplastia Coronaria con Balón/métodos , Hidrocarburo de Aril Hidroxilasas/genética , Enfermedad de la Arteria Coronaria/terapia , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Ticlopidina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Aspirina/uso terapéutico , Clopidogrel , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/enzimología , Enfermedad de la Arteria Coronaria/genética , Citocromo P-450 CYP2C19 , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Plaquetaria , Ticlopidina/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVES: The aim of this study was to establish the population protein binding parameters of valproic acid (VPA) in patients with epilepsy receiving VPA monotherapy and those receiving VPA combined with other antiepileptic drugs. METHODS: One hundred and thirty nine data sets from 63 Japanese patients with epilepsy were analysed. These patients were separated into two groups: VPA monotherapy and VPA combined with other binding-sensitive antiepileptic drugs, including phenytoin, clonazepam, clobazam, carbamazepine and phenobarbital (VPA polytherapy). The population protein-binding parameters of VPA were obtained by non-linear least-squares method in each group. KEY FINDINGS: The mean (95% confidence interval) dissociation constants were 38.9 µm (33.2-44.6 µm) and 36.9 µm (26.7-47.1 µm), and the numbers of binding sites were 1.36 (1.27-1.44) and 1.33 (1.19-1.47) in the monotherapy and polytherapy groups, respectively. No significant differences in the binding parameters of VPA to serum albumin were observed between the two groups. CONCLUSIONS: The steady-state serum albumin binding of VPA in Japanese patients with epilepsy is not affected by co-administration of other antiepileptic drugs. These findings suggest that serum VPA concentration is stable at the steady state with regard to interaction by protein binding, even when other antiepileptic drugs with moderate-to-high binding properties are co-administered.
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Anticonvulsivantes/metabolismo , Epilepsia/tratamiento farmacológico , Albúmina Sérica/metabolismo , Ácido Valproico/metabolismo , Adolescente , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Quimioterapia Combinada , Femenino , Humanos , Lactante , Cinética , Masculino , Persona de Mediana Edad , Unión Proteica , Estudios Retrospectivos , Albúmina Sérica Humana , Ácido Valproico/administración & dosificación , Ácido Valproico/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: CYP2C19*2 loss-of-function allele in Caucasians may be associated with wide interindividual variability in platelet response to clopidogrel, and the incidence of gene mutation varies with racial differences, especially between Asians and Caucasians. The aim was to examine the impact of CYP2C19 genotype on the residual platelet reactivity in Japanese patients with coronary heart disease (CHD) during antiplatelet therapy. METHODS AND RESULTS: We measured the CYP2C19 genotype and platelet aggregation in 201 patients with stable CHD. Moreover, we examined the relation of CYP2C19 polymorphism to cardiovascular events in 98 patients treated with stent implantation. The distribution of CYP2C19 genotype was 37%, 33%, 11%, 11%, 7%, and 1% in CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Residual platelet reactivity was lower in patients during dual antiplatelet therapy (DAT) than in those with aspirin (3975 ± 1569 aggregation units minute (AU min) vs 5850 ± 938 AU min, p<0.05). In the DAT group, the platelet reactivity decreased significantly in the wild-type homozygotes (CYP2C19*1/*1), subsequently in the *2, or *3 heterozygotes (*1/*2, *1/*3), and was not well inhibited in the *2, and/or *3 homozygotes (*2/*2, *2/*3, *3/*3; 3194 ± 1570 AU min, 4148 ± 1400 AU min, and 5088 ± 1080 AU min, respectively). However, when the duration of DAT was used to divide subjects into 2 groups, <7 days, and >7 days, patients carrying the variant allele showed significantly decreased platelet reactivities at >7 days compared with those at <7 days. Moreover, the incidence of cardiovascular events was higher in patients carrying at least one variant allele than in wild-type homozygotes. CONCLUSIONS: CYP2C19 polymorphism may be associated with high residual platelet reactivity and the occurrence of cardiovascular events.
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Hidrocarburo de Aril Hidroxilasas/genética , Enfermedad Coronaria/sangre , Enfermedad Coronaria/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Agregación Plaquetaria , Polimorfismo Genético , Ticlopidina/análogos & derivados , Anciano , Alelos , Pueblo Asiatico , Enfermedades Cardiovasculares/genética , Clopidogrel , Citocromo P-450 CYP2C19 , Procedimientos Endovasculares , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Stents , Ticlopidina/administración & dosificaciónRESUMEN
AIMS: To establish whether the SCN1A IVS5-91 G > A polymorphism of the SCN1A gene, which encodes the neuronal sodium channel alpha subunit, affects responsiveness to the antiepileptic drugs (AEDS) carbamazepine and/or phenytoin. METHODS: SCN1A IVS5-91 G > A polymorphism was genotyped in 228 Japanese epileptic patients treated with AEDs. The association between AED responsiveness and the polymorphism was estimated by logistic regression analysis, adjusting for clinical factors affecting the outcome of AED therapy. RESULTS: The frequency of the AA genotype was significantly higher in carbamazepine-resistant patients (odds ratio, 2.7; 95% confidence interval (CI), 1.1, 7.1) and was insignificantly higher in AED-resistant patients. CONCLUSIONS: This is the first report demonstrating an association between the SCN1A polymorphism and carbamazepine-resistant epilepsy.
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Anticonvulsivantes/administración & dosificación , Carbamazepina/administración & dosificación , Epilepsia/tratamiento farmacológico , Proteínas del Tejido Nervioso/genética , Fenitoína/administración & dosificación , Polimorfismo Genético/genética , Canales de Sodio/genética , Adulto , Relación Dosis-Respuesta a Droga , Epilepsia/genética , Femenino , Genotipo , Humanos , Masculino , Canal de Sodio Activado por Voltaje NAV1.1 , Resultado del TratamientoRESUMEN
Several studies have investigated the association between the ABCB1 polymorphism and drug-resistant epilepsy. However, the effect of ABCC2 polymorphisms on anti-epileptic drug (AED) responsiveness remains unknown. The ABCC2 polymorphisms have been genotyped in 279 Japanese epileptic patients treated with AEDs. The association between the AED responsiveness and the polymorphisms was estimated by a haplotype-based analysis. No genotype or haplotype was associated with drug-resistant epilepsy. On the other hand, the delGCGC haplotype at G-1774delG, C-24T, G1249A and C3972T was over represented among the epileptic patients with a complication of mental retardation in comparison with those without (32.4% vs 22.0%; P=0.009); and the G-1774delG allele was also associated with mental retardation (P=0.03). No association between the ABCC2 genotypes or haplotypes, and the responsiveness of AEDs was observed, although this finding was inconclusive because of the small sample size.