R(+)-pulegone impairs Ca²+ homeostasis and causes negative inotropism in mammalian myocardium

The present study aimed to investigate the inotropic effects of R(+)-pulegone, a monoterpene found in plant species belonging to the genus Mentha, on the mammalian heart. In electrically stimulated guinea pig atria, R(+)-pulegone reduced the contractile force (~83%) and decreased the contraction time measured at 50% of the maximum force amplitude (CT(50)) from 45.8 ± 6.2 ms to 36.9 ± 6.2 ms, suggesting that R(+)-pulegone may have an effect on Ca(2+) homeostasis. Nifedipine (40 μM), taken as a positive control, showed a very similar profile. To explore the hypothesis that R(+)-pulegone is somehow affecting Ca(2+) handling, we determined concentration-response curves for both CaCl(2) and BAY K8644. R(+)-pulegone shifted these curves rightward. Using isolated mouse ventricular cardiomyocytes, we measured whole-cell L-type Ca(2+) current and observed an I(Ca,L) peak reduction of 13.7 ± 2.5% and 40.2 ± 2.9% after a 3-min perfusion with 0.11 and 1.1mM of R(+)-pulegone, respectively. In addition, the intracellular Ca(2+) transient was decreased (72.9%) by 3.2mM R(+)-pulegone, with no significant changes in [Ca(2+)](i) transient decay kinetics. Moreover, R(+)-pulegone at 1.1mM prolonged the action potential duration at 10, 50, and 90% of repolarisation. The lengthening of the action potential duration may be attributed to the substantial blockade of the outward K(+) currents caused by 1.1mM of R(+)-pulegone (90.5% at 60 mV). These findings suggest that R(+)-pulegone exerts its negative inotropic effect on mammalian heart mainly by decreasing the L-type Ca(2+) current and the global intracellular Ca(2+) transient.     

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Liver tumor cells show several molecular alterations which favor pro-survival signaling. Among those, we have proposed the NADPH oxidase NOX1 as a prosurvival signal for liver tumor cells. On the one side, we have described that FaO rat hepatoma cells show NOX1-dependent partial resistance to apoptosis induced by Transforming Growth Factor beta (TGF-β). On the other side, we have shown that FaO cells, as well as different human hepatocellular carcinoma (HCC) cell lines, are able to proliferate in the absence of serum through the activation of a NOX1-dependent signaling pathway. The aim of this work was to analyze the effects of NADPH oxidase pharmacological inhibition in liver tumor cells using the inhibitor VAS2870. This compound inhibits dose-dependently autocrine increase of cell number in FaO rat hepatoma cells, and almost completely blocked ROS production and thymidine incorporation when used at 25 μM. Such inhibitory effect on autocrine growth is coincident with lower mRNA levels of EGFR (Epidermal Growth Factor Receptor) and its ligand TGF-α (Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover, NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-β. In summary, NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of liver cancer.     

Effects of mTOR and calcineurin inhibitors combined therapy in Epstein–Barr virus positive and negative Burkitt lymphoma cells

Post-transplant lymphoproliferative disorder is a severe complication in solid organ transplant recipients, which is highly associated with Epstein–Barr virus infection in pediatric patients and occasionally presents as Burkitt- or Burkitt-like lymphoma. The mammalian target of rapamycin (mTOR) pathway has been described as a possible antitumor target whose inhibition may influence lymphoma development and proliferation after pediatric transplantation. We treated Epstein–Barr virus positive (Raji and Daudi) and negative (Ramos) human Burkitt lymphoma derived cells with mTOR inhibitor everolimus alone and in combination with clinically relevant immunosuppressive calcineurin inhibitors (tacrolimus or cyclosporin A). Cell proliferation, toxicity, and mitochondrial metabolic activity were analyzed. The effect on mTOR Complex 1 downstream targets p70 S6 kinase, eukaryotic initiation factor 4G, and S6 ribosomal protein activation was also investigated. We observed that treatment with everolimus alone significantly decreased Burkitt lymphoma cell proliferation and mitochondrial metabolic activity. Everolimus in combination with cyclosporin A had a stronger suppressive effect in Epstein–Barr virus negative but not in Epstein–Barr virus positive cells. In contrast, tacrolimus completely abolished the everolimus-mediated suppressive effects. Moreover, we showed a significant decrease in activation of mTOR Complex 1 downstream targets after treatment with everolimus that was attenuated when combined with tacrolimus, but not with cyclosporin A. For the first time we showed the competitive effect between everolimus and tacrolimus when used as combination therapy on Burkitt lymphoma derived cells. Thus, according to our in vitro data, the combination of calcineurin inhibitor cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus.     

Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”)

3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) was first synthesised 80 years ago, but has recently received prominence as an illegally synthesised recreational drug of abuse. There is a widely held belief among misusers that it is safe. In the last 2–3 years there have been a number of reports of the drug producing severe acute toxicity and death and there are concerns that it may cause long term toxic damage to 5-hydroxytryptamine (5-HT) nerve terminals. There is a considerable literature on the acute pharmacological effects of MDMA in experimental animals, and this is reviewed. The drug produces both hyperthermia and the serotonin syndrome, a series of behavioural changes which result from increased 5-HT function. Acute clinical toxicity problems following MDMA ingestion also include hyperthermia and the appearance of the serotonin syndrome. The hyperthermia appears to precipitate other severe clinical problems and the outcome can be fatal. In agreement with others, we suggest that the recent increase in the number of reports of MDMA toxicity probably results from the widespread use of the drug at all night dance parties or raves. The phenomenon of amphetamine aggregation toxicity in mice was reported 40 years ago. If applicable to MDMA-induced toxicity in humans, all the conditions necessary to induce or enhance toxicity are present at raves: crowded conditions (aggregation), high ambient temperature, loud noise and dehydrated subjects. Administration of MDMA to rodents and non-human primates results in a long term neurotoxic decrease in 5-HT content in several brain regions and there is clear biochemical and histological evidence that this reflects neurodegeneration of 5-HT terminals. Unequivocal data demonstrating that similar changes occur in human brain do not exist, but limited and indirect clinical evidence gives grounds for concern. There are also data suggesting that long term psychiatric changes can occur, although there are problems of interpretation and these are reviewed. Suggestions for the rational treatment of the acute toxicity are made on the basis of both pharmacological studies in animals and current clinical practice. Cases presenting clinically are usually emergencies and unlikely to allow carefully controlled studies. Proposals include decreasing body temperature (possibly with ice), the use of dantrolene and anticonvulsant and sedative medication, particularly benzodiazepines. The use of neuroleptics requires care because of the theoretical risk of producing the neuroleptic malignant syndrome and the possibility of precipitating seizures. In rats, chlormethiazole antagonises the hyperthermia produced by MDMA and has been shown clinically to block MDMA-induced convulsive activity.     

Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase–saporin impairs attentional function and enhances the effects of guanfacine in the rat

Rationale Previous data indicate that depletion of cortical noradrenaline (NA) impairs performance of an attentional five-choice serial reaction time task (5CSRT) under certain conditions. This study employed a novel immunotoxin, anti-dopamine-beta hydroylase (DβH)–saporin, to make relatively selective lesions of the noradrenergic projections to the prefrontal cortex (PFC) in rats trained to perform the 5CSRT.Objectives The aim of this work is to examine (1) the effect of cortical noradrenaline depletion on sustained attentional performance in the 5CSRT under a variety of test conditions and (2) the effects of guanfacine, a selective α-2 adrenoceptor agonist on attentional performance in sham and NA-depleted rats.Materials and methods Animals received either intramedial prefrontal anti-DβH–saporin or vehicle and were tested on the baseline task with a variety of additional manipulations including (1) decreasing target duration, (2) increasing rate and (3) temporal unpredictability of target presentation and (4) systemic guanfacine.Results Anti-DβH-saporin infused into the PFC produced a substantial loss of DβH-positive fibers in that region and in other adjacent cortical areas. There was no significant depletion of DA or 5-HT. NA-depleted animals were not impaired on the baseline task, but were slower to respond correctly under high event rate conditions, and their discriminative accuracy was reduced when stimulus predictability decreased. Guanfacine significantly reduced discriminative accuracy in NA-depleted animals only.Conclusion Selective cortical NA depletion produced deficits on the 5CSRT test of sustained attention, especially when the attentional load was increased and in response to systemic guanfacine. These results are consistent with a role of coeruleo-cortical NA in the regulation of effortful attentional processes.     

Elevated impulsivity and impaired decision-making cognition in heavy users of MDMA (“Ecstasy”)

Objectives Structure of executive function was examined and we contrasted performance of substance dependent individuals (polysubstance users) and control participants on neuropsychological measures assessing the different executive components obtained. Additionally, we contrasted performance of polysubstance users with preference for cocaine vs heroin and controls to explore possible differential effects of the main substance abused on executive impairment. Methods Two groups of participants were recruited: abstinent polysubstance users and controls. Polysubstance users were further subdivided based on their drug of choice (cocaine vs heroin). We administered to all participants a comprehensive protocol of executive measures, including tests of fluency, working memory, reasoning, inhibitory control, flexibility, and decision making. Results Consistent with previous models, the principal component analysis showed that executive functions are organized into four separate components, three of them previously described: updating, inhibition, and shifting; and a fourth component of decision making. Abstinent polysubstance users had clinically significant impairments on measures assessing these four executive components (with effect sizes ranging from 0.5 to 2.2). Cocaine polysubstance users had more severe impairments than heroin users and controls on measures of inhibition (Stroop) and shifting (go/no go and category test). Greater severity of drug use predicted poorer performance on updating measures. Conclusion Executive functions can be fractionated into four relatively independent components. Chronic drug use is associated with widespread impairment of these four executive components, with cocaine use inducing more severe deficits on inhibition and shifting. These findings show both common and differential effects of two widely used drugs on different executive components.     

Impact of variation in the BDNF gene on social stress sensitivity and the buffering impact of positive emotions: Replication and extension of a gene–environment interaction

A previous study reported that social stress sensitivity is moderated by the brain-derived-neurotrophic-factor^Val66Met (BDNF rs6265) genotype. Additionally, positive emotions partially neutralize this moderating effect. The current study aimed to: (i) replicate in a new independent sample of subjects with residual depressive symptoms the moderating effect of BDNF^Val66Met genotype on social stress sensitivity, (ii) replicate the neutralizing impact of positive emotions, (iii) extend these analyses to other variations in the BDNF gene in the new independent sample and the original sample of non-depressed individuals.Previous findings were replicated in an experience sampling method (ESM) study. Negative Affect (NA) responses to social stress were stronger in “Val/Met” carriers of BDNF^Val66Met compared to “Val/Val” carriers. Positive emotions neutralized the moderating effect of BDNF^Val66Met genotype on social stress sensitivity in a dose–response fashion. Finally, two of four additional BDNF SNPs (rs11030101, rs2049046) showed similar moderating effects on social stress-sensitivity across both samples. The neutralizing effect of positive emotions on the moderating effects of these two additional SNPs was found in one sample.In conclusion, ESM has important advantages in gene–environment (GxE) research and may attribute to more consistent findings in future GxE research. This study shows how the impact of BDNF genetic variation on depressive symptoms may be explained by its impact on subtle daily life responses to social stress. Further, it shows that the generation of positive affect (PA) can buffer social stress sensitivity and partially undo the genetic susceptibility.     

Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected

Rationale Research concerning spatial memory in 3,4-methylenedioxymethamphetamine (MDMA) users has presented conflicting results showing either the presence or absence of spatial memory deficits. Two factors may have confounded results in abstinent users: memory task characteristics and polydrug use.Objectives The present study aims to assess whether a single dose of MDMA affects spatial memory performance during intoxication and withdrawal phase and whether spatial memory performance after MDMA is task dependent.Materials and methods Eighteen recreational MDMA users participated in a double-blind, placebo-controlled, three-way crossover design. They were treated with placebo, MDMA 75 mg, and methylphenidate 20 mg. Memory tests were conducted between 1.5 and 2 h (intoxication phase) and between 25.5 and 26 h (withdrawal phase) post-dosing. Two spatial memory tasks of varying complexity were used that required either storage of stimulus location alone (spatial memory task) or memory for location as well as processing of content or contextual information (change blindness task).Results After a single dose of MDMA, the subjects made larger localization errors and responded faster compared to placebo in the simple spatial memory task during intoxication phase. Inaccuracy was not due to increased response speed, as determined by regression analysis. Performance in the change blindness task was not affected by MDMA. Methylphenidate did not affect performance on any of the tasks.Conclusion It is concluded that a single dose of MDMA impairs spatial memory for location but leaves processing of contextual information intact.     

“Partying” Hard: Party Style,Motives for and Effects of MDMA Use at Rave Parties

This study examines motives for and consequences of MDMA use at different types of dance parties in the Netherlands (2001 and 2002). Participants were 490 visitors of three different types of rave parties, “club/mellow,” “trance/mainstream,” and “hardcore” (34% female, mean age 22.3 years, 76.5% MDMA users). Partygoers are motivated primarily by the energetic and euphoric effects they expect from MDMA. Quantity of MDMA use is associated with hardcore and trance/mainstream party style, with the motives of euphoria, sexiness, self-insight, and sociability/flirtatiousness (negative), and with gender, educational level (negative), and MDMA use by friends. Women report more (acute) negative effects—depression, confusion, loss of control, suspiciousness, edginess, nausea, dizziness—than men; and in particular, women who are motivated to cope with their problems by using MDMA are at risk. Men's polydrug use and notably their motivation to conform to friends by using MDMA are associated with negative effects.     

Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity

Aims Not every tablet sold as ecstasy contains MDMA (3,4-methylenedioxymethamphetamine). The historical origins and evolution of this mismatch will be reviewed, in order to estimate the proportions of ecstasy tablets containing MDMA at different periods over the past 30 years.Methods Surveys into the pharmacological constituents of ecstasy tablets, dosage levels, and empirical reports of their perceived purity, provide the main data for this review.Results During the 1980s and early 1990s there were few problems with the purity of ecstasy tablets, and the biochemical evidence shows that they nearly always contained MDMA. During the mid-1990s, the majority of ecstasy tablets continued to contain MDMA, while many others comprised MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxyethylamphetamine), or amphetamine drug mixtures. However, a small proportion (4–20% according to survey, time and place), comprised non-amphetamine drugs such as caffeine, ephedrine, ketamine, paracetamol, or placebo. During the late 1990s, the proportion of ecstasy tablets containing MDMA increased to around 80–90%. The latest reports suggest that non-MDMA tablets are now very infrequent, with purity levels between 90% and 100%. Dosage levels of tablets are also highly variable, with low dose tablet often encountered during the mid-1990s, and high dose tablets now seen more frequently. The theoretical and practical implications of these findings will be debated.Conclusions The ecstasy purity problem was predominantly a phenomenon of the mid to late 1990s, when many tablets contained substances other than MDMA. Before and since then, the proportion of ecstasy tablets containing MDMA has been very high.     

MDMA “ecstasy” alters hyperactive and perseverative behaviors in dopamine transporter knockout mice

Rationale Mice lacking the gene for the dopamine transporter (DAT) show a unique behavioral phenotype characterized by locomotor hyperactivity and repetitive circling in a novel environment. The hyperactivity of DAT (–/–) mice can be attenuated by psychostimulants and by serotonin uptake inhibitors, suggesting an important role for serotonin in the attenuation of locomotor hyperactivity in these mice.Objectives These studies characterized the effects of 3,4-methylenedioxy-N-methylamphetamine (MDMA), a serotonin releaser, on the amount and patterns of locomotor activity in DAT (+/+) and (–/–) mice. We compared the locomotor patterns produced by MDMA to those observed in DAT (–/–) mice, and examined whether MDMA altered the hyperactivity and perseverative locomotor patterns in DAT (–/–) mice.Methods The effects of MDMA (10, 30 mg/kg) on locomotor activity in DAT (+/+) mice were measured for 90 min in a video tracker system to determine the optimal dose for subsequent studies in DAT (+/+) and (–/–) mice. The effects of 20 mg/kg MDMA on patterns of locomotor activity in DAT (+/+) and (–/–) mice were measured for 90 min.Results In DAT (+/+) mice, MDMA increased locomotor activity and induced repetitive straight movement patterns. In DAT (–/–) mice, however, MDMA (20 mg/kg) attenuated the characteristic locomotor hyperactivity seen in these mice. In contrast, MDMA potentiated the thigmotaxis and decreased entropy observed in the DAT (–/–) mice.Conclusions The effects of MDMA observed here demonstrate that the different aspects of the abnormal locomotor behavior exhibited by DAT (–/–) mice can be independently manipulated by pharmacological treatments.     

Prototype perception and smoking: Are negative or positive social images more important in adolescence?

It is suggested that a more profound understanding of cigarette smoking among adolescents should include the social images they have of smokers. The main goal of the present study was to investigate the role of smoker prototypes in adolescents' smoking status and to compare the role of negative and positive smoker images. Data were collected from high school students in two counties of the Southern Plain Region of Hungary (N=548; ages between 14 and 21 years). The self-administered questionnaires contained items on sociodemographics, smoking occurrence, and smoker prototypes. Factor analysis revealed three smoker prototypes: a negative prototype (e.g., dull, childish), a positive social appearance prototype (e.g., cool, popular), and a positive individual competence prototype (such as smart, independent) all with satisfactory reliability. Odds ratios suggest that the role of the negative prototypes for nonsmokers is greater than the role of positive prototypes for smokers. For boys, positive individual competence prototype also seems to be important. Health promotion programs should focus on fostering negative social images in prevention.     

Be positive about negatives–recommendations for the publication of negative (or null) results

Both positive and negative (null or neutral) results are essential for the progress of science and its self-correcting nature. However, there is general reluctance to publish negative results, and this may be due a range of factors (e.g., the widely held perception that negative results are more difficult to publish, the preference to publish positive findings that are more likely to generate citations and funding for additional research). It is particularly challenging to disclose negative results that are not consistent with previously published positive data, especially if the initial publication appeared in a high impact journal. Ideally, there should be both incentives and support to reduce the costs associated with investing efforts into preparing publications with negative results. We describe here a set of criteria that can help scientists, reviewers and editors to publish technically sound, scientifically high-impact negative (or null) results originating from rigorously designed and executed studies. Proposed criteria emphasize the importance of collaborative efforts and communication among scientists (also including the authors of original publications with positive results).     

Are there social benefits? Exploring the role of positive consequences in the relationship between social anxiety symptoms and negative drinking consequences

Research has shown that college students with social anxiety experience more alcohol-related negative consequences, regardless of the amount of alcohol they consume. To better understand this relationship, it is important to examine social anxiety as a multidimensional construct, as well as explore the positive outcomes these students experience from drinking. The current study sought to examine the impact of positive drinking consequences on the relationship between behavioral (i.e. interaction and performance-type) and cognitive (i.e. fear of negative evaluation) social anxiety symptoms and alcohol-related negative consequences. Participants were 544 traditional age college students who reported consuming alcohol in the past month and completed measures of social anxiety symptoms, positive drinking consequences, and alcohol-related negative consequences. Positive drinking consequences moderated the relationship between social anxiety and alcohol-related negative consequences, such that students with more fear of negative evaluation and that experienced more positive drinking consequences reported more negative drinking consequences. Future directions and implications are discussed.     

α1-adrenoceptor subtype involved in the positive and negative inotropic responses to phenylephrine in rat papillary muscle

• 1.1. In rat papillary muscle, stimulation of α₁-adrenoceptors results in a biphasic inotropic response: a transient negative inotropic phase and a subsequent sustained positive inotropic phase. This study was designed to determine whether the positive and negative inotropic effects in this tissue are mediated by different α₁-adrenoceptor subtypes.
• 2.2. After treatment with the tumor-promoting compound, phorbol 12,13-dibutyrate, phenylephrine (in the presence of propranolol) produced only a positive inotropic effect. The selective α_1A-adrenoceptor antagonist, WB4101, significantly inhibited the positive inotropic effect. In contrast, inactivation of α_1B-adrenoceptors with chloroethylclonidine (CEC) did not alter the positive effect.
• 3.3. In the presence of the Ca²⁺ channel antagonist, nifedipine, phenylephrine induced only a sustained negative inotropic effect. The negative inotropic effect was significantly attenuated by WB4101, but was not affected by CEC.
• 4.4. We conclude that both the positive and negative inotropic responses of rat papillary muscle to phenylephrine are mediated exclusively by the WB4101-sensitive but CEC-resistant α₁-adrenoceptor subtype. The α₁-adrenoceptor subtype with such a property may correspond to the α_1A-subtype.

     

The negative GABAA modulator methyl β-carboline-3-carboxylate attenuates the behavioral effects of the positive GABAA modulators triazolam and pregnanolone in rhesus monkeys

RATIONALE: Many of the effects of benzodiazepines (BZs), barbiturates, and neuroactive steroids are mediated by the gamma-aminobutyric acid (GABA)(A) receptor complex. OBJECTIVES: This study tested the hypothesis that negative GABA(A) modulators attenuate the behavioral effects of different positive GABA(A) modulators that vary in their site of action on the receptor complex. METHODS: Rhesus monkeys responding under a multiple fixed ratio (FR:FR) schedule of food presentation and stimulus-shock termination received GABA(A) modulators under cumulative dosing procedures. RESULTS: The BZ site negative GABA(A) modulator methyl beta-carboline-3-carboxylate (beta-CCM), and not the BZ site neutral modulator flumazenil, decreased FR responding under the multiple schedule. FR responding was also decreased by positive modulators, including the BZ triazolam, the neuroactive steroid pregnanolone, and the barbiturate pentobarbital in that order of potency. beta-CCM, and not flumazenil, antagonized pregnanolone, suggesting that pregnanolone increased GABA-mediated chloride flux at a non-BZ site. beta-CCM antagonized triazolam with the slope of the Schild plot for beta-CCM and triazolam (food component) conforming to unity and yielding a pA2 value of 6.44. The effects of pentobarbital were not altered by beta-CCM, suggesting that barbiturates might act at a population of GABA(A) receptors different from those where neuroactive steroids and BZs act, or that barbiturate site positive GABA(A) modulators are not amenable to modulation by negative modulators. CONCLUSIONS: These results confirm a competitive interaction between beta-CCM and triazolam, and further demonstrate that the effects of neuroactive steroids on FR responding are attenuated by a BZ site negative GABA(A) modulator. Negative GABA(A) modulators might prove especially useful for characterizing important differences among positive GABA(A) modulators that act through different sites on the receptor complex.     

Maitake β-glucan enhances therapeutic effect and reduces myelosupression and nephrotoxicity of cisplatin in mice

Cisplatin is broadly used clinically as an anticancer drug. Despite its significant anticancer activity, cisplatin-induced nephrotoxicity and myelosuppression limit its use. MD-Fraction is glucan purified from maitake (Grifola frondosa), which has β-1, 6-main chain with β-1, 3-branches, has been reported to exhibit antitumor and antimetastatic activities by enhancing the immune system. In this study, we demonstrate that MD-Fraction in combination with cisplatin significantly enhanced antitumor and antimetastatic activity compared to cisplatin alone. MD-Fraction reduced decreases in body weight, spleen weight and the number of immunocompetent cells such as macrophages, DCs and NK cells in cisplatin-treated mice. MD-Fraction also induced IL-12p70 production by splenocytes, resulting in increased NK cell activity in cisplatin-treated mice. MD-Fraction significantly increased the mRNA expression of GM-CSF, G-CSF, M-CSF, IFN-γ, IL-12 p40 in splenocytes and reduced the decrease in the number of CFU-GM colonies in cisplatin-treated bone marrow. These facts suggest that MD-Fraction can reduce cisplatin-induced myelosuppression. Moreover, treatment with MD-Fraction significantly reduced cisplatin-induced nephrotoxicity accompanied by increases in serum creatinine level, necrosis and apoptosis of renal tubular cells. These results suggest that MD-Fraction in combination with cisplatin cannot only enhance antitumor and antimentastatic acitivity, but also reduce cisplatin-induced myelotoxicity and nephrotoxicity.     

Self-Reported Ecstasy/MDMA/“Molly” Use in a Sample of Nightclub and Dance Festival Attendees in New York City

Background: Ecstasy (MDMA) use has regained popularity in the United States, particularly in the form of “Molly,” which is often marketed as pure MDMA. Surveys have generally not included “Molly” in the definition of ecstasy, so rates of use may be underestimated. As popularity of ecstasy increases, research is needed to examine use among those at highest risk for use—nightlife attendees. Methods: We surveyed 679 young adults (age 18–25) entering nightclubs and festivals holding electronic dance music (EDM) parties in New York City in 2015. A variation of time-space sampling was utilized. We examined prevalence and correlates of self-reported lifetime ecstasy use. Results: Self-reported lifetime ecstasy use was common (42.8%, 95% CI: 32.8, 52.7). Use was most common among older participants, frequent party attendees, and those reporting higher levels of exposure to users. Those surveyed outside of festivals were less likely to report use compared to those surveyed outside of nightclubs (AOR = 0.37, p = .015). Over a third of ecstasy users (36.8%)reported use in pill, powder, and crystal form. Ecstasy users were also more likely to report use of other drugs, including novel psychoactive substances (e.g., 2C series drugs, synthetic cathinones [“bath salts”]). Half (50.4%) reported suspecting (21.9%) or finding out (28.5%) that their ecstasy had ever contained a drug other than MDMA. Conclusion: A large percentage of nightlife attendees in NYC report lifetime ecstasy use. Findings should inform prevention and harm reduction programming. Further research is needed as ecstasy continues to change (e.g., in form, purity, and name).     

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

Rationale 3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”) use has been associated with acute toxicities and persistent depletion of the neurotransmitter serotonin (5-HT).Objectives This study investigates whether sex differences in the acute and long-term effects of MDMA exist.Methods Male and female rats received saline or 15 mg/kg MDMA, ip, bid for 4 days. Temperature was monitored on days 1 and 4. Locomotor activity was measured in a second cohort of animals on days 1 and 4 and after recovery on day 14. The effects of MDMA on performance in a plus maze task and brain levels of serotonin (5-HT) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in a third cohort of animals 2 weeks after the last MDMA treatment.Results Locomotor activity and temperature increased after MDMA administration on day 1. The drug-induced increases in temperature but not locomotion attenuated with repeated MDMA administration. Male and female MDMA-treated rats spent less time in the open arms of the elevated plus maze and had less 5-HT and 5-HIAA in all brain regions 2 weeks after the end of treatment. Temperature effects of MDMA and persistent effects on plus maze and brain serotonin content were similar in males and females. In contrast, females exhibited markedly greater locomotor stimulation after acute MDMA and also showed sensitization to an acute challenge 2 weeks later.Conclusions MDMA elicits substantially greater locomotor activation in female rats than in males, but persistent effects on anxiety and serotonin content were similar in males and females. Funding: DA 09079. Christina N. Williams was supported by an RJR-Leon Golberg postdoctoral fellowship and ES07031.     

Penetration and release studies of positively and negatively charged nanoemulsions--is there a benefit of the positive charge?

The surface of all tissues, including the stratum corneum, carries a negative charge. Following that fact it is assumed that a positively charged topical formulation could lead to an enhanced penetration because of an increased interaction with the negative charge of the membrane. The intention of this study is to prove an enhanced penetration of a positively charged nanoemulsion compared to a negatively charged nanoemulsion, both containing prednicarbate. The release and penetration of these nanoemulsions, produced with the high pressure homogenization method, were investigated. Regarding these results reveals that the release of the negatively charged formulation is higher compared to the positively charged nanoemulsion, while the penetration of the positively charged nanoemulsion is enhanced compared to the negatively charged formulation. The results of the investigated positively charged nanoemulsion containing prednicarbate show that its topical use could be advantageous for the therapy of atopic dermatitis, especially regarding phytosphingosine, which was responsible for the positive charge.