RESUMEN
Synthetic cathinones continue to proliferate in clandestine drug markets worldwide. N-ethylnorpentylone (also known as N-ethylpentylone or ephylone) is a popular emergent cathinone, yet little information is available about its toxicology and pharmacology. Here we characterize the analytical quantification, clinical presentation, and pharmacological mechanism of action for N-ethylnorpentylone. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to quantify N-ethylnorpentylone in blood obtained from human cases. Clinical features exhibited by the intoxicated individuals are described. The activity of N-ethylnorpentylone at plasma membrane transporters for dopamine (DAT), norepinephrine (NET) and 5-HT (SERT) was assessed using in vitro assays measuring uptake inhibition and evoked release of [3 H] neurotransmitters in rat brain synaptosomes. Our LC-MS/MS method assayed N-ethylnorpentylone concentrations with limits of detection and quantification of 1 and 5 ng/mL, respectively. Quantitation was linear from 5 to 500 ng/mL, and the method displayed specificity and reproducibility. Circulating concentrations of N-ethylnorpentylone ranged from 7 to 170 ng/mL in clinical cases, and the associated symptoms included palpitations, tachycardia, agitation, hallucinations, coma and death. N-Ethylnorpentylone was a potent inhibitor at DAT (IC50 = 37 nM), NET (IC50 = 105 nM) and SERT (IC50 = 383 nM) but displayed no transporter releasing activity. We present a validated method for quantifying N-ethylnorpentylone in human case work. The drug is a psychomotor stimulant capable of inducing serious cardiovascular and neurological side-effects which can be fatal. In vitro findings indicate that N-ethylnorpentylone exerts its effects by potent blockade of DAT and NET, thereby elevating extracellular levels of dopamine and norepinephrine in the brain and periphery.
Asunto(s)
Benzodioxoles/sangre , Benzodioxoles/farmacología , Butilaminas/sangre , Butilaminas/farmacología , Adolescente , Adulto , Animales , Benzodioxoles/toxicidad , Butilaminas/toxicidad , Estimulantes del Sistema Nervioso Central/sangre , Estimulantes del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/toxicidad , Cromatografía Liquida , Inhibidores de Captación de Dopamina/sangre , Inhibidores de Captación de Dopamina/farmacología , Femenino , Humanos , Límite de Detección , Masculino , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Ratas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sinaptosomas/metabolismo , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
Vasovagal or neurocardiogenic syncope is a common clinical situation and, as with other entities associated with orthostatic intolerance, the underlying condition is a dysfunction of the autonomic nervous system. This article reviews various aspects of vasovagal syncope, including its relationship with orthostatic intolerance and the role of the autonomic nervous system in it. A brief history of the problem is given, as well as a description of how the names and associated concepts have evolved. The response of the sympathetic system to orthostatic stress, the physiology of the baroreflex system and the neurohumoral changes that occur with standing are analyzed. Evidence is presented of the involvement of the autonomic nervous system, including studies of heart rate variability, microneurography, cardiac innervation, and molecular genetic studies. Finally, we describe different studies on the use of beta-blockers and norepinephrine transporter inhibitors (sibutramine, reboxetine) and the rationality of their use to prevent this type of syncope.
El síncope vasovagal o neurocardiogénico es una situación clínica común, y así como en otras entidades asociadas con la intolerancia ortostática, la condición de base es una disfunción del sistema nervioso autónomo. En este artículo se revisan diversos aspectos sobre el síncope vasovagal, incluyendo su relación con la intolerancia ortostática y el papel que juega el sistema nervioso autónomo. Se da una breve reseña histórica del problema, así como una descripción de la forma en que han evolucionado los términos y conceptos asociados al mismo. Se hace un análisis sobre la respuesta del sistema nervioso simpático al estrés ortostático, la fisiología del sistema barorreflejo y los cambios neurohumorales que ocurren. Se muestra evidencia sobre el papel del sistema nervioso autónomo, incluyendo estudios sobre variabilidad de la frecuencia cardiaca, microneurografía, inervación cardiaca y estudios genéticos moleculares. Finalmente, se describen diferentes estudios sobre el uso de betabloqueadores e inhibidores del transportador de noradrenalina (sibutramina, reboxetina) y la justificación de su uso en la prevención de este tipo de síncope.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Sistema Nervioso Simpático/fisiopatología , Síncope Vasovagal/fisiopatología , Barorreflejo , Ciclobutanos/farmacología , Ciclobutanos/uso terapéutico , Frecuencia Cardíaca/fisiología , Humanos , Biología Molecular , Morfolinas/farmacología , Morfolinas/uso terapéutico , Reboxetina , Síncope Vasovagal/tratamiento farmacológicoRESUMEN
Experimental data suggest that halothane anesthesia is associated with significant changes in dopamine (DA) concentration in some brain regions but the mechanism of this effect is not well known. Rat brain cortical slices were labeled with [(3)H]DA to further characterize the effects of halothane on the release of this neurotransmitter from the central nervous system. Halothane induced an increase on the release of [(3)H]DA that was dependent on incubation time and anesthetic concentration (0.012, 0.024, 0.048, 0.072 and 0.096 mM). This effect was independent of extracellular or intracellular calcium. In addition, [(3)H]DA release evoked by halothane was not affected by TTX (blocker of voltage-dependent Na(+) channels) or reserpine (a blocker of vesicular monoamine transporter). These data suggest that [(3)H]DA release induced by halothane is non-vesicular and would be mediated by the dopamine transporter (DAT) and norepinephrine transporter (NET). GBR 12909 and nomifensine, inhibitors of DAT, decreased the release of [(3)H]DA evoked by halothane. Nisoxetine, a blocker of NET, reduced the release of [(3)H]DA induced by halothane. In addition, GBR 12909, nisoxetine and, halothane decrease the uptake of [(3)H]DA into rat brain cortical slices. A decrease on halothane-induced release of [(3)H]DA was also observed when the brain cortical slices were incubated at low temperature and low extracellular sodium, which are known to interfere with the carrier-mediated release of the neurotransmitter. Ouabain, a Na(+)/K(+) ATPase pump inhibitor, which induces DA release through reverse transport, decreased [(3)H]DA release induced by halothane. It is suggested that halothane increases [(3)H]DA release in brain cortical slices that is mediated by DAT and NET present in the plasma membrane.