RESUMEN
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
Etilefrine pivalate is synthesized by esterification of etilefrine with pivalic acid anhydride. The pharmacodynamics were investigated in 8 subjects suffering from the orthostatic syndrome. Cardiocirculatory parameters were measured in the lying and standing position for 3 h after the oral ingestion of 30 mg of etilefrine pivalate. In the supine position only minor effects on the blood pressure were seen. In three subjects with true orthostatic syndrome the systolic blood pressure was increased from 10 to 60 min after medication. Up to 30 min positive inotropic effects were seen. During 70 degree tilt etilefrine pivalate could stabilize the blood pressure 20 min after medication, the pathological increase in heart rate was reduced. In non-orthostatic patients positive inotropic effects were seen in the lying position only. Blood pressure and heart rate were not influenced in the supine position.
Asunto(s)
Etilefrina/farmacología , Etilefrina/uso terapéutico , Hipotensión Ortostática/tratamiento farmacológico , Fenilefrina/análogos & derivados , Presión Sanguínea/efectos de los fármacos , Etilefrina/análogos & derivados , Hemodinámica/efectos de los fármacos , Humanos , Hipotensión Ortostática/fisiopatología , Contracción Miocárdica/efectos de los fármacos , Postura , Factores de TiempoRESUMEN
Etilefrine pivalate (K 30 052, Ep) and etilefrine (E) were compared in regard to their effects on the circulation of cats and dogs and in regard to their effects on isolated organs (papillary muscles, atria, vena cava caudalis) of guinea pigs and rabbits. The effects of Ep and E were qualitatively equal. Ep was less effective than E on isolated organs and after intravenous injection, it was however more effective after oral or intraduodenal application. This result is in line with the hypothesis that Ep is inactivated during the first-pass to a smaller extent than E and is split after absorption to E and pivalinic acid.
Asunto(s)
Etilefrina/farmacología , Hemodinámica/efectos de los fármacos , Fenilefrina/análogos & derivados , Animales , Gatos , Chinchilla , Perros , Etilefrina/análogos & derivados , Cobayas , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Músculos Papilares/efectos de los fármacos , Pletismografía , Conejos , Especificidad de la Especie , Factores de TiempoRESUMEN
An open and a placebo-controlled double-blind trial were carried out to measure the effect of a long-term treatment (2-6 months) with etilefrine pivalate (K 30 052, Ep) on blood pressure of 60 patients suffering from orthostatic dysregulation. Oral administration of the agent took place once daily, each dose containing 20 mg. While the acute response to a single dose was comparatively weak, long-term administration had a marked and long-lasting effect both on systolic blood pressure (+40.3 mmHg) and blood pressure amplitude (+37.5 mmHg) (p less than 0.01). Steady state values were reached only when duration of therapy was approaching 6 months. The increase in blood pressure amplitude points to an augmentation of stroke volume, whereas heart rate was virtually unaltered. Peripheral resistance appears not to be increased since diastolic pressure was unchanged. The elevation in blood pressure amplitude was fully reversible within 9 weeks of wash-out, thus hinting at functional rather than structural (sclerotic) changes in the cardiovascular system.
Asunto(s)
Antihipertensivos/uso terapéutico , Etilefrina/uso terapéutico , Hipertensión/tratamiento farmacológico , Fenilefrina/análogos & derivados , Anciano , Antihipertensivos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Ensayos Clínicos como Asunto , Método Doble Ciego , Etilefrina/efectos adversos , Etilefrina/análogos & derivados , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Postura , Distribución Aleatoria , Factores de TiempoRESUMEN
The influence of equimolar oral doses of etilefrine pivalate (K 30 052, Ep) and etilefrine on blood pressure of patients suffering from orthostatic dysregulation was compared. Both drugs augmented the systolic blood pressure in both, the upright and horizontal body posture. Diastolic blood pressure was not influenced. The resulting increase in blood pressure amplitude points to an augmentation of cardiac stroke volume. Ep in equimolar doses was nearly twice as active as etilefrine. This result is in line with the hypothesis that acylation of etilefrine with pivalinic acid inhibits the first-pass inactivation nearly completely.
Asunto(s)
Antihipertensivos/uso terapéutico , Etilefrina/uso terapéutico , Hipertensión/tratamiento farmacológico , Fenilefrina/análogos & derivados , Anciano , Antihipertensivos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Ensayos Clínicos como Asunto , Método Doble Ciego , Etilefrina/efectos adversos , Etilefrina/análogos & derivados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distribución Aleatoria , Factores de TiempoRESUMEN
In a double-blind trial of 3 months 24 hypotensive patients suffering from migraine were treated with etilefrine pivalate (K 30 052, Ep, 20 mg p.o.) or dihydroergotamine (DHE, 5 mg) or placebo. The number of attacks of migraine was significantly reduced after the 3-month treatment with Ep resp. DHE comparing with placebo. Duration of attacks, intensity and number of additional analgetic drugs were also clearly reduced after medication of Ep and DHE - in contrast to placebo medication. Effectiveness and tolerance of Ep were estimated well and occurring side-effects were only of short duration. Thus the antihypotonics Ep and DHE offer an effective therapeutic scheme for migraine in hypotensive patients. This is in accordance with the fact that hypotension plays an important role in the occurrence of migraine.
Asunto(s)
Etilefrina/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Fenilefrina/análogos & derivados , Adulto , Anciano , Ensayos Clínicos como Asunto , Dihidroergotamina/efectos adversos , Dihidroergotamina/uso terapéutico , Método Doble Ciego , Etilefrina/efectos adversos , Etilefrina/análogos & derivados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distribución Aleatoria , Factores de TiempoRESUMEN
A series of 3'-(O-acyl) derivatives of etilefrine (alpha-[(ethylamino)methyl]-3'-hydroxybenzyl alcohol) was synthesized. Correlations between structure and solubility, pKa value, lipophilicity, and esterase-catalyzed hydrolysis were demonstrated. Of special interest is the 3'-(O-pivaloyl) derivative, which shows, in addition to favorable solubility and improved lipophilicity, marked stability against enzymatic cleavage in blood along with a high rate of hydrolysis in the liver.
Asunto(s)
Etilefrina/análogos & derivados , Fenilefrina/análogos & derivados , Animales , Fenómenos Químicos , Química Física , Etilefrina/síntesis química , Etilefrina/metabolismo , Femenino , Humanos , Hidrólisis , Técnicas In Vitro , Cinética , Ratas , SolubilidadRESUMEN
The relative bioavailability of a prodrug of etilefrine, its stearic acid ester, was determined by means of plasma levels and renal excretion. The comparison of the plasma levels and renal excretion was carried out in a cross-over design in six subjects. 3H-etilefrine (20 mg) and 3H-2-etylamino-1-(3-stearoylphenyl)ethanol hydrochloride (44.42 mg) were administered orally in equimolecular amounts. The stearic acid ester of etilefrine does not appear in the blood; the ester is split even during absorption. The relative bioavailability of the stearic acid ester of etilefrine, which was determined from the comparison of the areas under the plasma level and the renal excretion, amounts to 51% related to etilefrine. The investigation of the renal excretory products after administration of etilefrine and its prodrug showed the same metabolic pattern. The sulfuric acid ester of etilefrine is the main metabolite. In addition to etilefrine, two basic metabolites are excreted. According to mass- and NMR-spectrometric findings, these two metabolites are two isomeric tetrahydroisoquinolines which formally developed by condensation of etilefrine with formaldehyde. These tetrahydroisoquinolines are excreted free and conjugated with sulfuric acid.