Monitorización de niveles plasmáticos de fenitoína / Phenytoin plasma levels monitoring

La fenitoína es un fármaco utilizado ampliamente en la práctica clínica para el tratamiento de la epilepsia mayor, de las crisis convulsivas parciales y convulsiones tónico-clónicas generalizadas y menos frecuentemente para otros trastonos como las arritmias cardiacas o las neuralgias del trigémino. Es uno de los fármacos que más frecuentemente se monitorizan por el laboratorio clínico debido a varios motivos: 1. posee un margen terapeútico estrecho con un índice terapeútico bajo; 2. la relación entre la dosis y el nivel plasmático puede resultar impredecible debido a la gran variación interindividual; 3. la cinética de metabolismo es saturable dentro del rango terapeútico, lo que significa que pequeñas variaciones de la dosis pueden producir grandes aumentos de niveles plasmáticos. Las indicaciones de su monitorización son las sospechas de falta de cumplimiento terapéutico o de intoxicación y la presentación de convulsiones. En este trabajo revisamos las propiedades farmacológicas de la fenitoína estudiando especialmente la farmacocinética, las reacciones adversas debidas a sobredosis y los métodos analíticos empleados en el laboratorio para su medida (AU)

Fenobarbital: farmacocinética, toxicología y monitorización por el Laboratorio / Phenobarbital: pharmacokinetics, toxicology and monitoring by clinical lanoboratory

El fenobarbital es un agente antiepiléptico muy utilizado en el tratamiento de las crisis tónico-clónicas parciales y generalizadas. Su estrecho rango terapéutico y su elevada capacidad depresora del sistema nervioso central junto con su capacidad de producir autoinducción enzimática hace que sea uno de los fármacos más frecuentemente monitorizados en el laboratorio clínico. En este trabajo revisamos la farmacología del fenobarbital, estudiando además la farmacocinética, las reacciones adversas debidas a la intoxicación, las indicaciones de su monitorización y los métodos empleados en el laboratorio para la medida de los niveles plasmáticos (AU)

Maternal exposure to the synthetic cannabinoid HU-210: effects on the endocrine and immune systems of the adult male offspring.

Natural and synthetic cannabinoid receptor agonists have been described to exert profound effects on both the neuroendocrine integration and the functional responses of the immune system. In the present study, Wistar rats were exposed to the highly potent cannabinoid agonist HU-210 (1, 5 and 25 microg/kg) during gestation and lactation and the ensuing effects on several endocrine and immune parameters of the adult male offspring were analyzed. Perinatal exposure to HU-210 partially affected the distribution of lymphocyte subpopulations in the spleen and peripheral blood. The major changes observed occur after maternal exposure to the 25 microg/kg dose of HU-210. There was a reduction in the T-helper subpopulation in the spleen and a dose-related decrease in the rate of T(helper)/T(cytotoxic) in peripheral blood lymphocytes. Concanavalin-A and lipopolysaccharide-induced proliferation were normal in all the groups tested. In the same animals, perinatal exposure to HU-210 did not affect basal levels of growth hormone, IGF-1, prolactin, or follicle-stimulating hormone. Basal values of luteinizing hormone were elevated in animals given the 1 microg/kg dose of HU-210. Corticosterone levels were reduced in the animals exposed to the higher dose of HU-210 during gestation and lactation. These animals exhibited a decreased responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis to the stimulation with a single injection of HU-210 (20 microg/kg, i.v.) at adult ages, which may reflect the onset of long-lasting tolerance to the HPA-activating properties of cannabinoids. The opposite pattern of response was found in the animals given the 1 microg/kg dose, in which a sensitization of the corticosterone response to acute HU-210 was observed. The present work reveals that maternal exposure to cannabinoids results in minor changes in the development of the immune system, but may induce long-lasting alterations in the functional status of the HPA axis.

Maternal exposure to low doses of delta9-tetrahydrocannabinol facilitates morphine-induced place conditioning in adult male offspring.

The possible existence of an increased susceptibility to the reinforcing properties of morphine was analyzed in male and female rats born from mothers exposed to delta9-tetrahydrocannabinol (THC, 1, 5, or 20 mg/kg) during gestation and lactation. Maternal exposure to low doses of THC (1 and 5 mg/kg), relevant for human consumption, resulted in an increased response to the reinforcing effects of a moderate dose of morphine (350 microg/kg), as measured in the place-preference conditioning paradigm (CPP) in the adult male offspring. These animals also displayed an enhanced exploratory behavior in the defensive withdrawal test. However, only females born from mothers exposed to THC 1 mg/kg exhibited a small increment in the place conditioning induced by morphine. The possible implication of the hypothalamo-pituitary-adrenal axis (HPA) was analyzed by monitoring plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in basal and moderate-stress conditions (after the end of the CPP test). Female offspring perinatally exposed to THC (1 or 5 mg/kg) displayed high basal levels of corticosterone and a blunted adrenal response to the HPA-activating effects of the CPP test. However, male offspring born from mothers exposed to THC (1 or 5 mg/kg) displayed the opposite pattern: normal to low basal levels of corticosterone, and a sharp adrenal response to the CPP challenge. The present study reveals that maternal exposure to low doses of THC results in an increased sensitivity to the reinforcing effects of morphine in the adult male offspring, and in sexually dimorphic behavioral and endocrine alterations in the adaptative responses to stressors such as novelty or place-preference testing. These results support the growing evidence of the importance of monitoring the long-term consequences of maternal consumption of cannabis derivatives.

Characterization of the acute endocrine actions of (-)-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl (HU-210), a potent synthetic cannabinoid in rats.

In the present study we have characterized the effects of the acute administration of the synthetic cannabinoid (-)-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl (HU-210, 4, 20 and 100 microg/kg), on the secretion of prolactin, growth hormone, luteinizing hormone, follicle-stimulating hormone, adrenocorticotropic hormone and corticosterone in adult male rats. HU-210 administration resulted in a dose-dependent inhibition of plasma growth hormone, follicle-stimulating hormone and luteinizing hormone 60 min after the acute intraperitoneal injection, starting at 20 microg/kg. Plasma adrenocorticotropic hormone and corticosterone levels revealed a dose-dependent activation of the pituitary-adrenal axis after acute exposure to HU-210. Plasma prolactin levels reflected a biphasic action of HU-210: the 4 microg/kg dose resulted in high prolactin levels and the 20 and 100 microg/kg doses induced a decrease in the levels of this hormone. The time course of the endocrine effects of HU-210 was examined using the 20 microg/kg dose and was found to parallel the onset of the immobility and hypothermic effects of this cannabinoid. HU-210 (20 microg/kg) was also found to block the hormonal surges of luteinizing hormone, follicle-stimulating hormone and prolactin occurring during the afternoon of the proestrus phase in adult female rats. This dose induced activation of tubero-infundibular dopaminergic neurons, as reflected by the decrease in hypothalamic contents of dopamine in both males and females in the afternoon of the proestrus phase. The actions of HU-210 during early postnatal development revealed a delayed maturation of the endocrine response to HU-210, with respect to the behavioral effects. The findings of the present study reveal that HU-210 induces a set of endocrine alterations closely related to those described for natural cannabinoids such as delta9-tetrahydrocannabinol but at doses 50-200 times lower than those required for delta9-tetrahydrocannabinol.

Role of the endogenous cannabinoid system in the regulation of motor activity.

One of the prominent pharmacological features of drugs acting at the brain cannabinoid receptor (CB1) is the induction of alterations in motor behavior. Catalepsy, immobility, ataxia, or the impairment of complex behavioral acts are observed after acute administration of either natural and synthetic cannabinoid receptor agonists or the endogenous CB1 ligand anandamide. The dense presence of CB1 receptors in the cerebellum and in the basal ganglia, especially at the outflow nuclei (substantia nigra and the internal segment of the globus pallidus), supports the existence of an endogenous cannabinoid system regulating motor activity. In the basal ganglia, the functionality of the anandamide-CB1 system is poorly understood. Dual effects are often observed after the administration of CB1 ligands in animal models of pharmacological manipulation of basal ganglia transmitter systems, indicating that the activity of the anandamide-CB1 system depends on the ongoing activation of the different elements of the basal ganglia. This finding is in agreement with the proposed activity-dependent release of anandamide from a plasmalemma precursor. Additionally, a potential state-dependent bidirectional coupling of the CB1 receptor to the adenylate cyclase transduction system has also been described. From this perspective, the endogenous cannabinoid system can be proposed as a local regulator of neurotransmission processes within the basal ganglia. This system may serve as a counterregulatory homeostatic mechanism preserving the functional role of basal ganglia circuits in coding the serial order of events that constitute movement.

The dopamine receptor agonist 7-OH-DPAT modulates the acquisition and expression of morphine-induced place preference.

The present study investigated the effects of systemic administration of the putative dopamine D3 receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on the acquisition and expression of morphine-induced place preference in male Wistar rats. Using a a 3-day schedule of conditioning it was found that 7-OH-DPAT in a broad dose range (0.01, 0.25 and 5.0 mg/kg) did not produce significant place preference. However, the administration of either 0.25 or 5.0 mg/kg of 7-OH-DPAT 15 min prior to the exposure to morphine (1 mg/kg) prevented the acquisition of a morphine place preference, whereas the 0.01 mg/kg dose of the dopamine receptor agonist was uneffective. In addition, when 7-OH-DPAT was acutely administered 15 min prior to the testing session of an already established morphine place preference, the 0.01 mg/kg dose prevented the expression of this conditioned response. This effect was not observed with either 0.25 and 5.0 mg/kg doses of this dopamine D3 receptor agonist. It was suggested that the different dose related effects of 7-OH-DPAT on the acquisition and expression of morphine place preference might be related to the intrinsic ability of this agonist for interacting with pre- and postsynaptic dopamine D3 receptors located in limbic projecting areas of the mesencephalic dopamine system, although involvement of dopamine D2 receptors cannot be excluded. The pattern of effects seen with 7-OH-DPAT suggests that it may be useful for treating opiate dependence and craving.

Long-term behavioral effects of perinatal exposure to delta 9-tetrahydrocannabinol in rats: possible role of pituitary-adrenal axis.

This work evaluated motor behaviors in adult male and female rats exposed to delta 9-tetrahydrocannabinol (THC, 5 mg/kg) during gestation and lactation. The possibility that perinatal THC exposure induces sensitization to other drugs of abuse has also been addressed by evaluating morphine place preference conditioning (MPP) in the adult offspring. Maternal exposure to THC resulted in long-term effects on motor behaviors such as rearing, grooming and sniffing, in the adult offsprings of both sexes. Additionally, female offspring exposed to THC showed greater locomotor activity than controls, when measured using an actimeter. THC-exposed males exhibited an increased exploratory behavior in a plus-maze paradigm. When the adult animals were tested for MPP, THC-exposed offspring of both sexes exhibited an enhanced sensitivity to the rewarding effects of a moderate dose of morphine (350 micrograms/kg), an effect which was more marked in the males. These results showed that perinatal exposure to this psychoactive cannabinoid affected motor behaviors in the adult, suggesting a psychomotor activation very similar to that observed after gestational exposure to other drugs of abuse. A possible role of a THC-induced hypothalamus-pituitary-adrenal (HPA) axis activation was also evaluated in the present study. THC-exposed females exhibited higher levels of both corticotropin releasing factor (CRF-41) in the medial basal hypothalamus (MBH) and plasma corticosterone, whereas THC-exposed males showed the lower levels of both endocrine parameters. Since glucocorticoids are important modulators of both brain development, and adult brain function, these results indicate a possible role of HPA axis disturbances in the mediation of the behavioral effects described after perinatal THC exposure.

Repeated stimulation of D1 dopamine receptors enhances (-)-11-hydroxy-delta 8-tetrahydrocannabinol-dimethyl-heptyl-induced catalepsy in male rats.

Dopaminergic and cannabinoid receptors are localized in the outflow nuclei of the basal ganglia. We have investigated the possible interrelation of these receptors in the regulation of motor activity in male rats. To this end we have first studied the behavioural effects of the highly potent cannabinoid receptor agonist (-)11-hydroxy-delta 8-tetrahydrocannabinol-dimethylheptyl (HU-210, 20 micrograms mg) after chronic stimulation of dopamine D1 and D2 receptors. The catalepsy induced by the synthetic cannabinoid, measured as the descent latency in the bar test, was enhanced in male rats chronically treated with the dopamine D1 receptor agonist SKF38393 (8 mg kg-1, twice a day during 21 days). However, animals exposed to the dopamine D2 agonist quinpirole (1 mg kg-1 daily during 21 days) displayed the same degree of catalepsy as those exposed to HU-210 alone. Although a possible involvement of D2 receptors cannot be excluded, this finding suggests a predominant role for dopamine D1 receptors in the regulation of the cataleptic response to cannabinoids. The possible cross-talk between dopamine D1 and cannabinoid receptors is further supported by the decreased responsiveness to the acute behavioural effects of SKF38393 (8 mg kg-1) observed in animals chronically exposed to HU-210 (20 micrograms kg-1 daily during 14 days).