Asunto(s)
Benzazepinas/farmacología , Benzazepinas/uso terapéutico , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/uso terapéutico , Quinoxalinas/farmacología , Quinoxalinas/uso terapéutico , Tabaquismo/tratamiento farmacológico , Animales , Benzazepinas/metabolismo , Ensayos Clínicos Fase III como Asunto , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Humanos , Nicotina/farmacología , Agonistas Nicotínicos/metabolismo , Núcleo Accumbens/metabolismo , Quinoxalinas/metabolismo , Receptores Nicotínicos/metabolismo , Cese del Hábito de Fumar , VareniclinaRESUMEN
INTRODUCTION: : We examined the effects of methylphenidate hydrochloride (MPH) on the cardiovascular system using in vivo and in vitro study methods in accordance with the ICH-S7B guideline. METHODS: MPH was orally administered at doses of 3, 10 and 30 mg/kg to unrestrained conscious dogs implanted with a telemetry transmitter and attached with body surface electrodes, and electrocardiogram (ECG) leads. The QTcF interval was determined while heart rate (HR), and blood pressure (BP) were measured. Action potentials in isolated guinea-pig papillary muscle and the rapid component of the delayed rectifier potassium current (I(Kr)) in HEK-293 cells stably transfected with hERG were also investigated at concentrations of 0.1, 0.3 and 1 microg/mL (0.37, 1.1 and 3.7 micromol/L) of MPH. RESULTS: No ECG changes were observed except for a shortening of the QT interval due to a shortening of the RR interval at the maximum dose tested, 30 mg/kg. The only observed change was an elevation of BP in dogs at the dose of 30 mg/kg, which is approximately 10 times higher than the maximum therapeutic dose for use in children with attention deficit hyperactivity disorder (ADHD). Neither APD prolongation nor I(Kr) inhibition was observed by MPH in the in vitro studies up to the maximum concentration tested, 1 microg/mL (3.7 micromol/L), which is approximately 34 times higher than the clinically attainable unbound plasma MPH concentrations in children with ADHD. DISCUSSION: These results suggest that it is unlikely that MPH affects ventricular repolarization processes at the therapeutically recommended dose levels in patients with ADHD.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Metilfenidato/farmacología , Potenciales de Acción/efectos de los fármacos , Administración Oral , Animales , Presión Sanguínea/efectos de los fármacos , Línea Celular , Estimulantes del Sistema Nervioso Central/efectos adversos , Canales de Potasio de Tipo Rectificador Tardío/antagonistas & inhibidores , Perros , Relación Dosis-Respuesta a Droga , Electrocardiografía , Canales de Potasio Éter-A-Go-Go/genética , Canales de Potasio Éter-A-Go-Go/fisiología , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Técnicas In Vitro , Masculino , Metilfenidato/efectos adversos , Músculos Papilares/efectos de los fármacos , Músculos Papilares/fisiología , TelemetríaAsunto(s)
Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Espironolactona/análogos & derivados , Animales , Eplerenona , Humanos , Hipertensión/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Ratas , Receptores de Esteroides/efectos de los fármacos , Espironolactona/administración & dosificación , Espironolactona/farmacología , Espironolactona/uso terapéuticoAsunto(s)
Antineoplásicos/farmacología , Ácidos Borónicos/farmacología , Ácidos Borónicos/uso terapéutico , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Bortezomib , HumanosAsunto(s)
Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Anestesia General , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/farmacología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Anestésicos por Inhalación , Animales , Ensayos Clínicos Fase III como Asunto , Combinación de Medicamentos , Humanos , Infusiones Intravenosas , Éteres Metílicos , Propofol , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Remifentanilo , SevofluranoAsunto(s)
Antifúngicos , Candidiasis Bucal/tratamiento farmacológico , Itraconazol , Administración Oral , Animales , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Antifúngicos/farmacología , Candidiasis Bucal/microbiología , Modelos Animales de Enfermedad , Farmacorresistencia Fúngica , Hongos/efectos de los fármacos , Humanos , Absorción Intestinal , Itraconazol/administración & dosificación , Itraconazol/efectos adversos , Itraconazol/farmacocinética , Itraconazol/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , SolucionesRESUMEN
Aromatase is the rate-limiting enzyme playing a role at the final step of estrogen biosynthesis, which is attracting attention as the target enzyme of hormone therapy of postmenopausal breast cancer. Exemestane (Aromasin) is a novel steroidal irreversible aromatase inhibitor that was approved in Japan as a therapeutic drug for postmenopausal breast cancer. Exemestane selectively inhibits aromatase activity in vitro, in a time-dependent and irreversible manner, suggesting the mechanism of action that exemestane covalently binds to aromatase as a pseudo-substrate and inactivates the enzyme. In vivo studies show the inhibitory effect of exemestane on the ovarian aromatase activity and plasma estradiol level of PMSG-primed rats. In studies using DMBA-induced rat mammary tumor models, exemestane shows antitumor activity in both conventional (premenopausal) and ovariectomized, testosterone-treated postmenopausal models. Despite its steroidal structure, exemestane does not have hormonal or anti-hormonal activity, except for a slight androgenic activity. In the early and late phase II clinical trials conducted in Japan on postmenopausal breast cancer patients who received 25 mg/day of exemestane, the response rates were 31.4% and 24.2%, respectively. Blood estrogen levels were also markedly reduced. These results confirmed the clinical relevance of non-clinical study results, as well as the possibility of extrapolation to foreign trial data.