CB1 cannabinoid receptor modulates MDMA acute responses and reinforcement

Background: 3, 4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug widely abused by young people. The endocannabinoid system is involved in the addictive processes induced by different drugs of abuse. However, the role of this system in the pharmacological effects of MDMA has not been yet clarified.Methods: Locomotion, body temperature and anxiogenic-like responses were evaluated after acute MDMA administration in CB1 knockout mice. Additionally, MDMA rewarding properties were investigated in the place conditioning and the intravenous self-administration paradigms. Extracellular levels of DA in the nucleus accumbens were also analyzed after a single administration of MDMA by in vivo microdialysis. Results: Acute MDMA administration increased locomotor activity, body temperature and anxiogenic-like responses in wild type mice, but these responses were lower or abolished in knockout animals. MDMA produced similar conditioned place preference and increased dopamine extracellular levels in the nucleus accumbens in both genotypes. Nevertheless, CB1 knockout mice failed to self-administer MDMA at any of the doses used. Conclusions: These results indicate that CB1 cannabinoid receptors play an important role in the acute prototypical effects of MDMA, and are essential in the acquisition of an operant behavior to self-administer this drug.

Factores que influyen en los comportamientos sexuales de prevención frente al virus de inmunideficiencia humana (VIH) en los adictos a las drogas por vía parenteral (ADVP)

Los datos existentes sobre el progresivo incremento de la infección con el virus de inmunodeficiencia humana (VIH) entre los adictos a las drogas por via parenteral (ADVP) y sus parejas e hijos, plantean la necesidad urgente de elaborar programas preventivos con el mayor grado de eficacia posible. En el presente trabajo nos proponemos tres objetivos: 1) Poner de manifiesto algunas insuficiencias observadas en los modelos deprevención que se aplican al caso del SIDA. 2) Conferir un énfasis especial a la influencia sobre los comportamientos preventivos frente al SIDA, de ciertos factores que, en general, no se tienen 10 bastante en cuenta en los modelos actuales como son: la magnitud del reforzamiento contingente a un determinado comportamiento y la demora con la que éste se recibe. 3) Exponer los resultados de una investigación realizada con drogadictos por via parenteral (Planes, 1991), cuyos objetivos eran conocer las relacionesexistentes entre la magnitud y la demora del reforzamiento contingente a los comportamientos sexuales preventivos y la frecuencia de dichos comportamientos

In vitro susceptibility to pentavalent antimony in Leishmania infantum strains is not modified during in vitro or in vivo passages but is modified after host treatment with meglumine antimoniate

Background: Leishmaniasis is a common parasitic disease in Southern Europe, caused by Leishmania infantum. The failures of current treatment with pentavalent antimonials are partially attributable to the emergence of antimony-resistant Leishmania strains. This study analyses the in vitro susceptibility to pentavalent antimony of intracellular amastigotes from a range of L. infantum strains, derived from the same infected animal, during in vitro and in vivo passages and after host treatment with meglumine antimoniate. Results: SbV-IC50 values for strains from two distinct isolates from the same host and one stock after two years of culture in NNN medium and posterior passage to hamster were similar (5.0 ± 0.2; 4.9 ± 0.2 and 4.4 ± 0.1 mgSbV/L, respectively). In contrast, a significant difference (P < 0.01, t test) was observed between the mean SbV-IC50 values in the stocks obtained before and after treatment of hosts with meglumine antimoniate (4.7 ± 0.4 mgSbV/L vs. 7.7 ± 1.5 mgSbV/L). Drug-resistance after drug pressure in experimentally infected dogs increased over repeated drug administration (6.4 ± 0.5 mgSbV/L after first treatment vs. 8.6 ± 1.4 mgSbV/L after the second) (P < 0.01, t test). Conclusions: These results confirm previous observations on strains from Leishmania/HIV co-infected patients and indicate the effect of the increasing use of antimony derivatives for treatment of canine leishmaniasis in endemic areas on the emergence of Leishmania antimony-resistant strains.

Degree of hermeticity of a multicompartment compliance aid: Implications for the quality of professional pharmaceutical services

A multicompartment compliance aid (MCA) is a blister-type repackaging system that aims to facilitate drug administration and thereby increase patient adherence. One of the characteristics of the MCA that should be taken into account is the moisture permeability, since this atmospheric condition is one of the most important factors that can modify the stability of medicines. In the current paper we report the moisture permeability tests performed on a MCA according to the US Pharmacopeia. This information on the suitability of the device will help pharmacists implement a high-quality professional service.

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokineticsa and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male SpragueDawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α=10.23 h−1, β=1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59±3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85±0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokineticpharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude,and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokineticsa and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α=10.23 h−1, β=1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59±3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85±0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude,and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.