Rh(II)-Catalyzed Alkynylcyclopropanation of Alkenes by Decarbenation of Alkynylcycloheptatrienes.

Alkynylcyclopropanes have found promising applications in both organic synthesis and medicinal chemistry but remain rather underexplored due to the challenges associated with their preparation. We describe a convenient two-step methodology for the alkynylcyclopropanation of alkenes, based on the rhodium(II)-catalyzed decarbenation of 7-alkynyl cycloheptatrienes. The catalytic system employed circumvents a fundamental problem associated with these substrates, which usually evolve via 6-endo-dig cyclization or ring-contraction pathways under metal catalysis. This unique performance unlocks a rapid access to a diverse library of alkynylcyclopropanes (including derivatives of complex drug-like molecules), versatile intermediates that previously required much lengthier synthetic approaches. Combining experiments and DFT calculations, the complete mechanistic picture for the divergent reactivity of alkynylcycloheptatrienes under metal catalysis has been unveiled, rationalizing the unique selectivity displayed by rhodium(II) complexes.

Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones.

The emergence of new synthetic cathinones continues to be a matter of public health concern. In fact, they are quickly replaced by new structurally related alternatives. The main goal of the present study was to characterize the pharmacological profile, the psychostimulant and rewarding properties of novel cathinones (pentedrone, N-ethyl-pentedrone, α-PVP, N,N-diethyl-pentedrone and α-PpVP) which only differs in their amino terminal substitution. Rat synaptosomes were used for [3H]dopamine uptake experiments. HEK293 transfected cells (hDAT, hSERT, hOCT; human dopamine, serotonin and organic cation transporter) were also used for [3H]monoamine uptake and transporter binding assays. Molecular docking was used to investigate the effect of the amino substitutions on the biological activity. Hyperlocomotion and conditioned place preference paradigm were used in order to study the psychostimulant and rewarding effects in mice. All compounds tested are potent inhibitors of DAT with very low affinity for SERT, hOCT-2 and -3, and their potency for inhibiting DAT increased when the amino-substituent expanded from a methyl to either an ethyl-, a pyrrolidine- or a piperidine-ring. Regarding the in vivo results, all the compounds induced an increase in locomotor activity and possess rewarding properties. Results also showed a significant correlation between predicted binding affinities by molecular docking and affinity constants (Ki) for hDAT as well as the cLogP of their amino-substituent with their hDAT/hSERT ratios. Our study demonstrates the role of the amino-substituent in the pharmacological profile of novel synthetic cathinones as well as their potency inhibiting DA uptake and ability to induce psychostimulant and rewarding effects in mice.

7,8-Dihydroxyflavone blocks the development of behavioral sensitization to MDPV, but not to cocaine: Differential role of the BDNF-TrkB pathway.

3,4-Methylenedioxypyrovalerone (MDPV) acts as a dopamine transporter blocker and exerts powerful psychostimulant effects. In this study we aimed to investigate the bidirectional cross-sensitization between MDPV and cocaine, as well as to evaluate the role of the BDNF-TrkB signaling pathway in the development of locomotor sensitization to both drugs. Mice were treated with MDPV (1.5 mg/kg) or cocaine (10 or 15 mg/kg) once daily for 5 days. After withdrawal (10 days), animals were challenged with cocaine (8 mg/kg) or MDPV (1 mg/kg). For biochemical determinations, MDPV (1.5 mg/kg) or cocaine (15 mg/kg) were administered acutely or repeatedly, and BDNF, D3R and G9a transcription levels as well as pro- and mature BDNF protein levels were determined. Our results demonstrate that repeated administration of MDPV or cocaine sensitizes to cocaine and MDPV locomotor effects. After an acute or a repeated exposure to MDPV, cortical mRNA BDNF levels were increased, while a decrease in mBDNF protein levels in the nucleus accumbens 2 h after repeated exposure was evidenced. Interestingly, such decline was involved in the development of locomotor sensitization, thus the pretreatment with 7,8-dihydroxyflavone (10 mg/kg), a TrkB agonist, blocked the development of sensitization to MDPV but not to cocaine, for which no changes in the BDNF-TrkB signaling pathway were observed at early withdrawal. In conclusion, a bidirectional cross-sensitization between MDPV and cocaine was evidenced. Our findings suggest that decreased BDNF-TrkB signaling has an important role in the behavioral sensitization to MDPV, pointing TrkB modulation as a target to prevent MDPV sensitization.

Neuroadaptive changes and behavioral effects after a sensitization regime of MDPV.

3,4-methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with cocaine-like properties. In a previous work, we exposed adolescent mice to MDPV, finding sensitization to cocaine effects, and a higher vulnerability to cocaine abuse in adulthood. Here we sought to determine if such MDPV schedule induces additional behavioral-neuronal changes that could explain such results. After MDPV treatment (1.5 mg kg-1, twice daily, 7 days), mice were behaviorally tested. Also, we investigated protein changes in various brain regions. MDPV induced aggressiveness and anxiety, but also contributed to a faster habituation to the open field. This feature co-occurred with an induction of ΔFosB in the orbitofrontal cortex that was higher than its expression in the ventral striatum. Early after treatment, D2R:D1R ratio pointed to a preponderance of D1R but, upon withdrawal, the ratio recovered. Increased expression of Arc, CDK5 and TH, and decrease in DAT protein levels persisted longer after withdrawal, pointing to a neuroplastic lasting effect similar to that involved in cocaine addiction. The implication of the hyperdopaminergic condition in the MDPV-induced aggressiveness cannot be ruled out. We also found an initial oxidative effect of MDPV, without glial activation. Moreover, although initially the dopaminergic signal induced by MDPV resulted in increased ΔFosB, we did not observe any change in NFκB or GluA2 expression. Finally, the changes observed after MDPV treatment could not be explained according to the autoregulatory loop between ΔFosB and the epigenetic repressor G9a described for cocaine. This provides new knowledge about the neuroadaptive changes involved in the vulnerability to psychostimulant addiction.

Exposure of adolescent mice to 3,4-methylenedioxypyrovalerone increases the psychostimulant, rewarding and reinforcing effects of cocaine in adulthood.

BACKGROUND AND PURPOSE: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with powerful psychostimulant effects. It selectively inhibits the dopamine transporter (DAT) and is 10-50-fold more potent as a DAT blocker than cocaine, suggesting a high abuse liability. The main objective of the present study was to assess the consequences of an early (adolescence) MDPV exposure on the psychostimulant, rewarding and reinforcing effects induced by cocaine in adult mice. EXPERIMENTAL APPROACH: Twenty-one days after MDPV pretreatment (1.5 mg·kg-1 , s.c., twice daily for 7 days), adult mice were tested with cocaine, using locomotor activity, conditioned place preference and self-administration (SA) paradigms. In parallel, dopamine D2 receptor density and the expression of c-Fos and ΔFosB in the striatum were determined. KEY RESULTS: MDPV treatment enhanced the psychostimulant and conditioning effects of cocaine. Acquisition of cocaine SA was unchanged in mice pretreated with MDPV, whereas the breaking point achieved under a progressive ratio programme and reinstatement after extinction were higher in this group of mice. MDPV decreased D2 receptor density but increased ΔFosB expression three-fold. As expected, acute cocaine increased c-Fos expression, but MDPV pretreatment negatively influenced its expression. ΔFosB accumulation declined during MDPV withdrawal, although it remained elevated in adult mice when tested for cocaine effects. CONCLUSION AND IMPLICATIONS: MDPV exposure during adolescence induced long-lasting adaptive changes related to enhanced responsiveness to cocaine in the adult mice that seems to lead to a higher vulnerability to cocaine abuse. This particular behaviour correlated with increased expression of ΔFosB.

The combination of MDPV and ethanol results in decreased cathinone and increased alcohol levels. Study of such pharmacological interaction.

Methylenedioxypyrovalerone (MDPV) is a new psychostimulant cathinone acting as a selective dopamine transporter blocker. Due to the concomitant consumption of ethanol (EtOH) and new psychoactive substances, it is of interest to explore a possible pharmacological interaction between MDPV and EtOH. In locomotor activity assays, EtOH (1g/kg i.p.) elicited a reduction in the stimulant effect induced by low doses of MDPV (0.1-0.3mg/kg, s.c.) in rats, jointly with a decrease in blood and brain MDPV concentrations. Experiments in rat liver microsomes showed different effects depending on the [MDPV]/[EtOH] relationship, evidencing, at certain concentrations, the enhancing effect of EtOH on MDPV metabolism. These suggest that EtOH interacts with MDPV at microsomal level, increasing its metabolic rate. The interaction between both substances was also supported by results in plasma EtOH concentration, which were significantly increased by MDPV, in such a manner that EtOH elimination rate was significantly reduced. The possible toxicological impact of this phenomenon deserves further investigation. In contrast, the rewarding properties of MDPV were unaltered by EtOH. Microdialysis experiments verified that, in the NAcc, both substances could also act synergistically, in such a manner that extracellular dopamine concentrations are maintained. Finally, if the psychostimulant effect induced by MDPV decreased with EtOH, it could favor the boosting and re-dosing in search of the desired effects. However, as the rewarding effect of each dose of the substance would not decrease, the addictive liability could increase considerably. Moreover, we must warn about the increase in EtOH concentrations when consumed concomitantly with MDPV.

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 pharmacokinetics 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), ß = 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.

Respuesta a los autores: La resolución de enfermería en las consultas urgentes de atención primaria / No disponible

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Evaluación de la eficacia de enfermería en la resoluciónde las consultas urgentes en atención primaria / Efficacy of nurse practitioner management of primary care emergency visits

Objetivo: Evaluar la eficacia de enfermería en la resolución de las consultas urgentes en atención primaria (AP) mediante la aplicación de los protocolos incorporados a la historia clínica informatizada (e-CAP).Método: Estudio descriptivo, transversal y retrospectivo. Se incluyeron de forma consecutiva todos los pacientes que solicitaron una consulta urgente para el mismo día en una área básica de salud (ABS) semiurbana de la provincia de Girona, entre el 15 de marzo al 15 de abril de 2010. Se valoró la aplicación por parte de enfermería de los protocolos de actuación consensuados para la atención de los motivos de consulta urgentes protocolizados en el e-CAP. Se analizaron las variables sociodemográficas (edad, sexo, país de origen), asistenciales (motivo de consulta) y de enfermería (antigüedad, lugar de trabajo). La eficacia de enfermería se valoró mediante el análisis de las re-consultas en menos de 48 horas y por las derivaciones a otro profesional. Resultados: Se analizaron 296 consultas. La edad media fue de 34,4 ± 25,5 años,53,3% fueron mujeres y 25,3% inmigrantes. El principal motivo de consulta fueron las heridas (12,5%). El 77,4% no reconsultó en las primeras 48 horas (80,5% motivos de consulta protocolizados vs 73,2% no protocolizados, p = 0,14). Los motivos protocolizados (57,1% de las consultas) tuvieron un menor porcentaje de derivación a otro profesional (33,1% protocolizados vs 64,6% no protocolizados p < 0,001). La reconsulta en los motivos protocolizados fue menor en inmigrantes (12,1% vs 29,4% p = 0,04) y en los pacientes más jóvenes (31,6 ± 24 años vs 41,1 ± 25,4 años p = 0,04).Conclusión: Enfermería tiene una alta capacidad de resolución de las consultas urgentes en AP. La eficacia de enfermería aumenta cuando atiende las consultas urgentes con un motivo de consulta protocolizado en el e-CAP (AU)

Objective: To assess the efficacy of nurse practitioner management of emergency visits by means of consensus protocols integrated into the computerized medical record system of a primary health care center. Methods: Descriptive, cross-sectional, retrospective study. All patients seeking appointments for same-day care within a semiurban health care district in the province of Girona, Spain, were included consecutively between March 15 and April15, 2010. We evaluated the nurses’ application of the appropriate computerized practice protocols in the system. Sociodemographic variables (age, sex, country of origin), care variables (reason for the visit), and nurse variables(seniority, place of work) were analyzed. The nurses’ efficacy was evaluated on the basis of revisits within 48 hours or the need for referral to another care provider. Results: A total of 296 visits were included. The mean (SD) patient age was 34.4 (25.5) years; 53.3% were women and25.3% were immigrants. Open wounds (12.5%) were the main reason for seeking care. No revisits within 48 hours were needed in 77.4% of the cases (80.5% of those treated by protocol did not revisit vs 73.2% of those whose care was not protocol-guided, P=.14). Conditions treated by protocol (57.1% of the visits) generated fewer referrals to another professional (33.1% of protocol-guided visits were referred vs 64.6% of non protocol-guided visits, P<.001). Immigrants made fewer revisits for problems treated by protocol (12.1% revisited vs 29.4% when no protocol was used, P=.04).Younger patients revisited less often (mean age of 31.5 [24] years for patients not revisiting vs 41.1 [25] years for revisitors, P=.04).Conclusions: The ability of the nursing staff to manage primary care emergency visits is high. Nurse practitioner efficacy increases when a computerized protocol is available to assist in managing a case (AU)

Psychometric evaluation of the Beck Depression Inventory-II with primary care medical patients.

This study evaluated the psychometric characteristics of the Beck Depression Inventory-II (BDI-II; A. T. Beck, R. A. Steer, & G. K. Brown, 1996) in a primary care medical setting. A principal-components analysis with Promax rotation indicated the presence of 2 correlated factors, Somatic-Affective and Cognitive, which explained 53.5% of the variance. A hierarchical, second-order analysis indicated that all items tap into a second-order construct of depression. Evidence for convergent validity was provided by predicted relationships with subscales from the Short-Form General Health Survey (SF-20; A. L. Stewart, R. D. Hayes, & J. E. Ware, 1988). A receiver operating characteristic analysis demonstrated criterion-related validity: BDI-II scores predicted a diagnosis of major depressive disorder (MDD), as determined by the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ). This study demonstrated that the BDI-II yields reliable, internally consistent, and valid scores in a primary care medical setting, suggesting that use of the BDI-II in this setting may improve detection and treatment of depression in these medical patients.

Pain and emotion: effects of affective picture modulation.

OBJECTIVE AND METHODS: Two experiments examined the impact of viewing unpleasant, pleasant, and neutral photographic slides on cold-pain perception in healthy men and women. In each experiment, participants viewed one of three slide shows (experiment 1 = fear, disgust, or neutral; experiment 2 = erotic, nurturant, or neutral) immediately before a cold-pressor task. Skin conductance and heart rate were recorded during the slide shows, whereas visual analog scale ratings of pain intensity and unpleasantness thresholds and pain tolerance were recorded during the cold-pressor task. RESULTS: Viewing fear and disgust slides decreased pain intensity and unpleasantness thresholds, but only the fear slides decreased pain tolerance. In contrast, viewing erotic, but not nurturant, slides increased pain intensity and unpleasantness threshold ratings on the visual analog scale in men, whereas neither nurturant nor erotic slides altered pain tolerance. CONCLUSIONS: These results are consistent with a motivational priming model that predicts that unpleasant affective states should enhance pain and that pleasant affective states should attenuate it.

Second-order confirmatory factor analysis of the WAIS-III. Wechsler Adult Intelligence Scale.

According to Vernon's structure-of-intellect paradigm, abilities can be conceptualized as a hierarchy, with a factor of general intelligence at the top of the hierarchy, and successively more specific abilities toward the bottom. This paradigm has proven useful for interpreting a number of Wechsler intelligence scales. However, most of the research with this paradigm has used exploratory factor analysis, and the validity of the paradigm for the newest Wechsler Adult Intelligence Scale (WAIS-III) has yet to be evaluated. The present study examined the WAIS-III using second-order confirmatory factor analysis, which is a more appropriate analytic tool when specific hypotheses are tested. Using the standardization sample for the WAIS-III (N = 2,450), support was found for the hierarchical factor structure with a second-order factor of general intelligence and four first-order factors of Verbal Comprehension, Perceptual Organization, Working Memory, and Processing Speed.

Reliability and validity of scores from the Singer-Loomis Type Deployment Inventory.

This paper focuses on the Singer-Loomis Type Deployment Inventory (SL-TDI), which is an alternative to the Myers-Briggs Type Indicator (MBTI). The SL-TDI utilizes a continuous, non-forced choice format and therefore is a more accurate representation of Jung's personality theory of psychological types. The purpose of the study reported here is to evaluate the reliability and validity of scores from the SL-TDI. Specifically, the goals were to (a) provide estimates of the internal consistency of SL-TDI scores; (b) evaluate the divergent validity of SL-TDI scores by examination of their relationships with the scores on a social desirability responding measure; and (c) examine the test-retest stability of scores from the SL-TDI. Strong support was found for both the reliability and validity of SL-TDI scores.