RESUMEN
INTRODUCTION: The measurement of cardiovascular endpoints in standard toxicology studies remains a challenge as the routinely used non-invasive methods require physical restraint, causing an increase of sympathetic neural activity, leading to excitement and potentially hypertension in the experimental animals. In this study, a miniature telemetry blood pressure transmitter was used to evaluate if the acute hyper- and hypotension could be detected in free moving cynomolgus monkeys as well as physically restrained animals using positive control drugs. Furthermore, as a comparator, routine high definition oscillometry (HDO) was performed in restrained animals. METHODS: Hemodynamic parameters were monitored continuously from conscious, freely moving animals following oral administration of vehicle (water) or 1 and 10mg/kg of etilefrine, and 1 and 4mg/kg of dihydralazine as positive control articles. A second dose session was performed to confirm the reproducibility of results and a third dose session combined with physical restraint procedures for blood collection and HDO measurements. RESULTS: There was a dose-dependent, statistically significant increase in the systolic blood pressure following oral doses of etilefrine at all 3 dose sessions. This effect was less apparent during session 3, probably due to the physical restraint applied for the blood sampling and HDO measurement. No differences in the blood pressure were measured using HDO. On all three dose sessions following oral doses of dihydralazine the expected statistically significant decrease in the diastolic pressure could be clearly measured even when the telemetric data recordings were combined with physical restraint. DISCUSSION: Due to the advantages of the minimally invasive telemetry technique compared to HDO and the possibility of prolonged measurement periods, it is an invaluable tool for blood pressure measurement in freely moving animals in toxicology studies.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial/veterinaria , Presión Sanguínea/efectos de los fármacos , Dihidralazina/toxicidad , Etilefrina/toxicidad , Macaca fascicularis/fisiología , Restricción Física/veterinaria , Administración Oral , Animales , Monitores de Presión Sanguínea/veterinaria , Dihidralazina/administración & dosificación , Relación Dosis-Respuesta a Droga , Etilefrina/administración & dosificación , Modelos AnimalesRESUMEN
A diverse set of techniques (curiosity, chimney test, changes in barbiturate-induced sleep time, spontaneous motor activity, swimming ability, body temperature) was used to study theophylline (T)-induced changes in CNS etilefrine (E). T antagonized the depressive effects produced by high doses of E. Nevertheless, the LD50 of E was not modified when both drugs were administered simultaneously.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Etilefrina/farmacología , Teofilina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Interacciones Farmacológicas , Etilefrina/toxicidad , Femenino , Masculino , Ratones , Ratas , Ratas WistarRESUMEN
Reaction of an antihypotensive drug, etilefrin [alpha-[(ethylamino)methyl]-m-hydroxybenzyl alcohol], with nitrite under mildly acidic conditions produced N-nitrosoetilefrin [alpha-[(N-nitrosoethylamino)methyl]-m-hydroxybenzyl alcohol] (a mixture of syn and anti forms) (Iab) and diazo-N-nitrosoetilefrin [1-(4-diazo-3-oxo-1,5-cyclohexadienyl-2-(N-nitrosoethylamino )ethanol] (a mixture of syn and anti forms) (IIab). Treatment of etilefrin with an equivalent amount of nitrite at pH 3 and 37 degrees C for 4 h gave Iab (yield, 30%) and IIab (yield, 5%). Treatment of etilefrin with 4 eq of nitrite under the same conditions gave Iab (23%) and IIab (53%). Compounds Iab and IIab were each composed of two isomers due to the configuration of the N-nitroso group. While compound Iab was not mutagenic, compound IIab showed mutagenicity to Salmonella typhimurium TA98 and TA100 strains without metabolic activation. Specific mutagenic activity of IIab was 300 his+ revertant colonies for both TA98 and TA100 strains with a dose of 0.1 mumol. Addition of a microsomal activation system little affected the activity. It is noteworthy that this orally administered drug can produce a direct-acting mutagen by reaction with nitrite, which is present in the digestive tract.
Asunto(s)
Etilefrina/análogos & derivados , Etilefrina/análisis , Mutágenos/síntesis química , Nitritos/análisis , Nitrosaminas/síntesis química , Fenilefrina/análogos & derivados , Cromatografía en Capa Delgada , Etilefrina/síntesis química , Etilefrina/toxicidad , Nitrosaminas/toxicidadRESUMEN
The radioprotective effect (RPE) of some arylalkylamines (AAAs) was studied in experiments on mice. Mesaton and its close analogues were injected subcutaneously 15 minutes prior to irradiation at a dose of 800 rad. The protective effect is exerted by AAAs in low doses (25--50 mumole/kg), the compounds show stable and high RPE (80--80% survival, dose reduction factor being 1.3--1.4) and low toxicity (LD50 = 4--8 mumole/kg). AAAs studied are not less effective than aminothiols. Their pharmacological spectrum--K = LD50/ED50 (200--500) is superior to that of known aminothiols and indolylalkylamines.