5 research outputs found

    Estudios farmacocinéticos y biofarmacéuticos del acamprosato en la rata.

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    RESUMEN El acamprosato o bis-acetilhomoaurinato c√°lcico es un f√°rmaco que se emplea en la terapia de mantenimiento de la abstinencia en pacientes dependientes del alcohol. Sin embargo, uno de los problemas m√°s importantes en su manejo cl√≠nico deriva de su reducida biodisponibilidad oral en magnitud (BD), que se sit√ļa en torno a un 11% en humanos. Por ello, mediante el empleo de diversos y sencillos dise√Īos experimentales se ha abordado el estudio de dos de los procesos menos conocidos de su farmacocin√©tica, la absorci√≥n y la eliminaci√≥n. El estudio de la linealidad farmacocin√©tica del acamprosato se ha realizado tras la administraci√≥n intravenosa r√°pida de 2.8, 11 √≥ 22 mg del f√°rmaco, as√≠ como tras su perfusi√≥n endovenosa a 2.6, 132.5 √≥ 530.0 ¬Ķg/min. La comparaci√≥n de los principales par√°metros farmacocin√©ticos obtenidos, no revel√≥ ninguna diferencia estad√≠sticamente significativa entre ellos. Por tanto, a tenor de los resultados obtenidos parece ser que el acamprosato presenta una disposici√≥n lineal en el √°mbito de concentraciones estudiadas, tanto en condiciones de estado estacionario como tras su administraci√≥n intravenosa r√°pida. En lo relativo a su eliminaci√≥n, nuestros resultados indican claramente que el acamprosato se elimina inalterado por v√≠a renal casi en exclusividad ( = 95.0 ¬Ī 13.9%). Los elevados valores de aclaramiento total estimados tras la administraci√≥n intravenosa r√°pida de diferentes dosis de acamprosato, as√≠ como los de aclaramiento total y renal calculados en estado estacionario, sugieren que la filtraci√≥n glomerular no es el √ļnico mecanismo de excreci√≥n renal implicado en su eliminaci√≥n. Con el objetivo de confirmar la existencia de un proceso de secreci√≥n tubular activa paralelo a la filtraci√≥n glomerular, que podr√≠a ser responsable de los elevados valores de aclaramiento del f√°rmaco, se administr√≥ conjuntamente el acamprosato con probenecid, conocido inhibidor de la secreci√≥n tubular activa. Los niveles plasm√°ticos promedio del f√°rmaco en los animales tratados con probenecid (10 √≥ 20 mg) fueron claramente superiores a los obtenidos en el grupo control, obteni√©ndose un incremento significativo (p<0.001) en sus valores de . Es decir, a la luz de todas nuestras experiencias el acamprosato se elimina inalterado a trav√©s de la orina de los animales tratados utilizando dos mecanismos: la filtraci√≥n glomerular y la secreci√≥n tubular activa. La BD del acamprosato en la rata, se determin√≥ tras la administraron de 2.8 √≥ 22 mg de acamprosato por v√≠a oral, obteni√©ndose un valor de disponibilidad biol√≥gica que se situ√≥ en torno al 20%. Paralelamente, la comparaci√≥n estad√≠stica de los valores de semivida de eliminaci√≥n del acamprosato obtenidos tras su administraci√≥n intravenosa r√°pida y oral mostr√≥ la existencia de diferencias estad√≠sticamente significatvas (p<0.001) entre ellos. Estos resultados demuestran la existencia de un comportamiento Flip-Flop en la farmacocin√©tica del acamprosato tras su administraci√≥n por v√≠a oral. La perfusi√≥n in situ de una soluci√≥n de 560 ¬Ķg/ml de acamprosato en los diferentes tramos en los que se dividi√≥ el intestino delgado de la rata (proximal, medio √≥ distal) demostr√≥ que los valores de ka del f√°rmaco no var√≠an a lo largo del intestino delgado de la rata, siendo su baja permeabilidad intestinal (ka= 0.36 ¬Ī 0.12 h-1) la principal causa de su reducida BD. Finalmente, se trat√≥ de incrementar su BD mediante el empleo de distintos promotores de la absorci√≥n intestinal. A trav√©s de diversas metodolog√≠as, in vitro, in situ e in vivo, se ha podido establecer que la absorci√≥n intestinal del acamprosato se produce mayoritariamente por difusi√≥n pasiva a trav√©s de la ruta paracelular en el intestino delgado de la rata. Los estudios in situ e in vitro indicaron que el caprato s√≥dico (13 √≥ 16 mM) es capaz de incrementar la permeabilidad intestinal del acamprosato. Sin embargo, los resultados de los estudios realizados in vivo no mostraron incrementos significativos en los valores de biodisponibilidad en magnitud del f√°rmaco en presencia, incluso, de elevadas concentraciones (50 mM) de este promotor. __________________________________________________________________________________________________Acamprosate is a drug used in relapse prevention of alcoholism. The purpose of the present study was to investigate the mechanisms involved in the absorption and elimination of this drug in the rat. In order to study the linearity of acamprosate disposition, rats received 2.8, 11 or 22 mg of the drug as an intravenous bolus. Moreover, acamprosate was perfused by the intravenous route at three different constant infusion rates (2.65, 132.5 and 530.0 ¬Ķg/min). The statistical analysis of the pharmacokinetic parameters did not reveal any significant difference, indicating that acamprosate disposition was linear within the range of the doses assayed. Relating to its elimination, the obtained results indicated that the administered dose was excreted unchanged and exclusively by renal route( = 95.0 ¬Ī 13.9%). Moreover, values were clearly higher than the glomerular filtration rate, suggesting the existence of a highly efficient tubular secretion mechanism in the renal excretion of the drug. To confirm this hypothesis, two groups of rats were intravenously treated with probenecid (10 or 20 mg) prior to acamprosate administration. Probenecid provoked a statistically significant (p<0.001) dose-dependent increase in mean plasma levels of acamprosate, demonstrating the existence of a tubular secretion process on the renal excretion of acamprosate in the rat. The acamprosate bioavailability in rats, estimated after the oral administration of 2.8 or 22 mg of the drug, was around 20 %. The statistical analysis reveal the existence of differences among the values estimated after oral and intravenous administration.This fact suggests the existence of a flip-flop phenomenon involved in acamprosate pharmacokinetics after oral administration. We perfused an isotonic solution of acamprosate (560 ¬Ķg/ml) in the proximal, middle or distal segment of the small intestine of the animals. The topographic study of acamprosate absorption in the rat revealed non-significant differences among values tested. So, there is not a preferent zone in the acamprosate intestinal absorption in the rat and, probably, this low value is responsible for the low bioavailability of the drug after oral administration. Finally, we made an attempt to improve acamprosate bioavailability through the modulation of its intestinal absorption with several enhancers using in situ, in vitro and in vivo models. Only sodium caprate (C10) was able to increase the of acamprosate and the apparent permeability ( ) obtained in Caco-2 cells (around 2-fold). However, the drug bioavailability in rats (around 20%) did not improve in presence of any of the C10 concentration tested. It is concluded that acamprosate absorption occurs likely via paracellular pathway and can be enhanced by sodium caprate in situ and in vitro but not in viv

    The Effects of N-Acetylcysteine on the Rat Mesocorticolimbic Pathway: Role of mGluR5 Receptors and Interaction with Ethanol

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    N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol use disorder (AUD), although its mechanism of action is already being debated. In this paper, we set out to assess both the potential involvement of the glutamate metabotropic receptors (mGluR) in the possible dual effect of NAC administered at two different doses and NAC's effect on ethanol-induced activation. To this aim, 30 or 120 mg/kg of NAC was intraperitoneally administered to rats with the presence or absence of the negative allosteric modulator of mGluR5 (MTEP 0.1 mg/kg). Thereafter, the cFOS IR-cell expression was analyzed. Secondly, we explored the effect of 120 mg/kg of NAC on the neurochemical and behavioral activation induced by intra-VTA ethanol administration (150 nmol). Our results showed that the high NAC dose stimulated cFOS expression in the NAcc, and that this effect was suppressed in the presence of MTEP, thus suggesting the implication of mGluR5. Additionally, high doses could attenuate the ethanol-induced increase in cFOS-expression in the NAcc, probably due to a phenomenon based on the long-term depression of the MSNs. Additional experiments are required to corroborate our hypothesis

    Different brain oxidative and neuroinflammation status in rats during prolonged abstinence depending on their ethanol relapse-like drinking behavior: Effects of ethanol reintroduction

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    Rationale: Accumulating evidence suggests that chronic alcohol consumption is associated with excessive oxidative damage and neuroinflammatory processes and these events have been associated to early alcohol withdrawal. In the present research we wonder if brain oxidative stress and neuroinflammation remains altered during prolonged withdrawal situations and whether these alterations can be correlated with relapse behavior in alcohol consumption. The effects of alcohol reintroduction were also evaluated. Methods: We have used a model based on the alcohol deprivation effect (ADE) within a cohort of wild-type male Wistar rats. Two subpopulations were identified according to the alcohol relapse-like drinking behavior displayed (ADE and NO-ADE subpopulations). Oxidized and reduced glutathione content was determined within the hippocampus and the amygdala using a mass spectrometry method. The levels of mRNA of seven different inflammatory mediators in the prefrontal cortex of rats were quantified. All the analyses were performed in two different conditions: after 21-day alcohol deprivation (prolonged abstinence) and after 24 h of ethanol reintroduction in both subpopulations. Results: ADE and NO-ADE rats showed different endophenotypes. ADE rats always displayed a significant lower alcohol intake rate and ethanol preference than NO-ADE rats. The results also demonstrated the existence of altered brain redox and neuroinflammation status after prolonged abstinence exclusively in ADE rats. Moreover, when ethanol was reintroduced in the ADE subpopulation, altered oxidative stress and neuroinflammatory markers were restored. Conclusions: Present findings provide new mechanisms underlying the neurobiology of relapse behavior and suggest the development of new pharmacological approaches to treat alcohol-induced relapse

    Efficacy of N-acetylcysteine in the prevention of alcohol relapse-like drinking: Study in long-term ethanol-experienced male rats

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    Alcohol use disorders are chronic and highly relapsing disorders, thus alcoholic patients have a high rate of recidivism for drug use even after long periods of abstinence. The literature points to the potential usefulness of N-acetylcysteine (NAC) in the management of several substance use disorders probably due to its capacity to restore brain homeostasis of the glutamate system disrupted in addiction. However, there is little evidence in the case of alcohol. The aim of this study was to explore the potential anti-relapse efficacy of NAC using the alcohol deprivation effect (ADE) model in long-term experienced rats. Two experiments were performed in male Wistar rats to: (a) test the efficacy of NAC to prevent relapse and (b) discriminate the best administration schedule (intermittent vs. continuous) for NAC. In the first experiment, animals were implanted with mini-osmotic pumps delivering 0 or 1 mg/hr NAC during 14 days. In a second experiment, rats received 0, 60, or 100 mg/kg once daily by subcutaneous injection. The efficacy to prevent ADE was evaluated in both experiments. NAC subcutaneously administered, either by continuous infusion or by intermittent injections regimen, is able to block the ADE. The best results were obtained after using 60 mg/kg NAC dose. Our findings support the hypothesis that NAC may represent a valuable therapy in the management of alcohol relapse.GVA2016-09

    Glutamate and opioid antagonists modulate dopamine levels evoked by innately attractive male chemosignals in the nucleus accumbens of female rats

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    Sexual chemosignals detected by vomeronasal and olfactory systems mediate intersexual attraction in rodents, and act as a natural reinforcer to them. The mesolimbic pathway processes natural rewards, and the nucleus accumbens receives olfactory information via glutamatergic projections from the amygdala. Thus, the aim of this study was to investigate the involvement of the mesolimbic pathway in the attraction towards sexual chemosignals. Our data show that female rats with no previous experience with males or their chemosignals display an innate preference for male-soiled bedding. Focal administration of the opioid antagonist ő≤-funaltrexamine into the posterior ventral tegmental area does not affect preference for male chemosignals. Nevertheless, exposure to male-soiled bedding elicits an increase in dopamine efflux in the nucleus accumbens shell and core, measured by microdialysis. Infusion of the opioid antagonist naltrexone in the accumbens core does not significantly affect dopamine efflux during exposure to male chemosignals, although it enhances dopamine levels 40 minutes after withdrawal of the stimuli. By contrast, infusion of the glutamate antagonist kynurenic acid in the accumbens shell inhibits the release of dopamine and reduces the time that females spend investigating male-soiled bedding. These data are in agreement with previous reports in male rats showing that exposure to opposite-sex odors elicits dopamine release in the accumbens, and with data in female mice showing that the behavioral preference for male chemosignals is not affected by opioidergic antagonists. We hypothesize that glutamatergic projections from the amygdala into the accumbens might be important to modulate the neurochemical and behavioral responses elicited by sexual chemosignals in rats
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