Identification of (2-Aminopropyl)indole Positional Isomers in Forensic Samples.

Identification of (2-aminopropyl)indole positional isomers in forensic samples.

Drug Test Anal. 2013 Jul 8;
Scott KR, Power JD, McDermott SD, O’Brien JE, Talbot BN, Barry MG, Kavanagh PV

In 2012, 5-(2-aminopropyl)indole (5-API, 5-IT) was reported by Norwegian authorities to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS). The 3- isomer, 3-(2-aminopropyl)indole (3-API, AMT, alpha-methyltryptamine), has been available on the recreational drugs market for a somewhat longer time, having first been reported to the EMCDDA by Finnish authorities in 2001. Both isomers are available from online vendors of ‘legal highs’. Recently, three forensic drug cases (two tablets and one powder) were presented for routine analysis and the active constituent was tentatively identified as an API isomer. The six positional isomers (2-, 3-, 4-, 5-, 6- and 7-(2-aminopropyl)indoles) were synthesized and analyses by a combination gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS) showed that these could be readily discriminated thus facilitating the identification of 3-API in the tablets and 5-API in the powder. With exception of 5- and 6-APIs, which co-eluted, it was found possible to separate the isomers by GC without derivatization. LC separation also proved to be a feasible method for the discrimination of the isomers. Although the 2- and 7- isomers were not fully resolved by LC, it was found possible to distinguish them using their product ion spectra as the 2- isomer produced the m/z 132 fragment ion formed by loss of vinylamine, whereas the 7- isomer formed m/z 158 through loss of methylamine. In the synthesis 2-API, a novel tricyclic by-product was formed in an annulation reaction where the reaction solvent, tetrahydrofuran, was incorporated into the molecule. Copyright © 2013 John Wiley & Sons, Ltd. HubMed – addiction


The adverse health effects of chronic cannabis use.

Drug Test Anal. 2013 Jul 8;
Hall W, Degenhardt L

This paper summarizes the most probable of the adverse health effects of regular cannabis use sustained over years, as indicated by epidemiological studies that have established an association between cannabis use and adverse outcomes; ruled out reverse causation; and controlled for plausible alternative explanations. We have also focused on adverse outcomes for which there is good evidence of biological plausibility. The focus is on those adverse health effects of greatest potential public health significance – those that are most likely to occur and to affect a substantial proportion of regular cannabis users. These most probable adverse effects of regular use include a dependence syndrome, impaired respiratory function, cardiovascular disease, adverse effects on adolescent psychosocial development and mental health, and residual cognitive impairment. Copyright © 2013 John Wiley & Sons, Ltd. HubMed – addiction


Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.

Blood. 2013 Jul 8;
Cramer-Morales K, Nieborowska-Skorska M, Scheibner K, Padget M, Irvine DA, Sliwinski T, Haas K, Lee J, Geng H, Roy D, Slupianek A, Rassool FV, Wasik MA, Childers W, Copland M, Müschen M, Civin CI, Skorski T

Homologous recombination repair (HRR) protects cells from lethal effect of spontaneous and therapy-induced DNA double-stand breaks. HRR usually depends on BRCA1/2-RAD51 and RAD52-RAD51 serves as back-up. To target HRR in tumor cells a phenomenon called “synthetic lethality” was applied, which relies on addiction of cancer cells to one DNA repair pathway whereas normal cells operate two or more mechanisms. Using mutagenesis and peptide aptamer approach we pinpointed phenylalanine 79 in RAD52 DNA binding domain I (RAD52-F79) as valid target to induce synthetic lethality in BRCA1 and/or BRCA2 -deficient leukemias and carcinomas without affecting normal cells and tissues. Targeting RAD52-F79 disrupts RAD52 – DNA interaction resulting in accumulation of toxic DNA double stand breaks in malignant cells, but not in normal counterparts. In addition, abrogation of RAD52 – DNA interaction enhanced anti-leukemia effect of the already approved drugs. BRCA-deficient status predisposing to RAD52-dependent synthetic lethality could be predicted by genetic abnormalities such as oncogenes BCR-ABL1 and PML-RAR, and mutations in BRCA1 and/or BRCA2 genes, and also by gene expression profiles identifying leukemias displaying low levels of BRCA1 and/or BRCA2. We believe that this work may initiate personalized therapeutic approach in numerous patients with tumors displaying encoded and functional BRCA-deficiency. HubMed – addiction


Ghrelin and Nicotine Stimulate Equally the Dopamine Release in the Rat Amygdala.

Neurochem Res. 2013 Jul 9;
Palotai M, Bagosi Z, Jászberényi M, Csabafi K, Dochnal R, Manczinger M, Telegdy G, Szabó G

The orexigenic peptide ghrelin plays a prominent role in the regulation of energy balance and in the mediation of reward processes and reinforcement for addictive drugs, such as nicotine. Nicotine is the principal psychoactive component in tobacco, which is responsible for addiction and relapse of smokers. Ghrelin and nicotine activates the mesolimbicocortical dopaminergic pathways via growth hormone secretagogue receptors (GHS-R1A) and nicotinic acetylcholine receptors (nAchR), respectively, resulting in the release of dopamine in the nucleus accumbens, the amygdala and the prefrontal cortex. In the present study an in vitro superfusion of rat amygdalar slices was performed in order to investigate the direct action of ghrelin and nicotine on the amygdalar dopamine release. Ghrelin increased significantly the dopamine release from the rat amygdala following electrical stimulation. This effect was inhibited by both the selective GHS-R1A antagonist GHRP-6 and the selective nAchR antagonist mecamylamine. Under the same conditions, nicotine also increased significantly the dopamine release from the rat amygdala. This effect was antagonized by mecamylamine, but not by GHRP-6. Co-administration of ghrelin and nicotine induced a similar increase of amygdalar dopamine release. This stimulatory effect was partially reversed by both GHRP-6 and mecamylamine. The present results demonstrate that both ghrelin and nicotine stimulates directly the dopamine release in the amygdala, an important dopaminergic target area of the mesolimbicocortical pathway. HubMed – addiction