Pharmacological profile of novel psychoactive benzofurans

Background and Purpose

Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro.

Experimental Approach

We assessed the effects of the benzofurans 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB and 5-MAPDB and benzodifuran 2C-B-FLY on the human noradrenaline (NA), dopamine and 5-HT uptake transporters using HEK 293 cells that express the respective transporters. We also investigated the release of NA, dopamine and 5-HT from monoamine-preloaded cells, monoamine receptor-binding affinity and 5-HT_2A and 5-HT_2B receptor activation.

Key Results

All of the benzofurans inhibited NA and 5-HT uptake more than dopamine uptake, similar to methylenedioxymethamphetamine (MDMA) and unlike methamphetamine. All of the benzofurans also released monoamines and interacted with trace amine-associated receptor 1 (TA₁ receptor), similar to classic amphetamines. Most benzofurans were partial 5-HT_2A receptor agonists similar to MDMA, but also 5-HT_2B receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY very potently interacted with 5-HT₂ receptors and also bound to TA₁ receptors.

Conclusions and Implications

Despite very similar structures, differences were found in the pharmacological profiles of different benzofurans and compared with their amphetamine analogues. Benzofurans acted as indirect monoamine agonists that interact with transporters similarly to MDMA. The benzofurans also interacted with 5-HT receptors. This pharmacological profile probably results in MDMA-like entactogenic psychoactive properties. However, benzofurans induce 5-HT_2B receptor activation associated with heart valve fibrosis. The pharmacology of 2C-B-FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction.     

Mechanisms of right atrial tachycardia occurring late after surgical closure of atrial septal defects

Postatriotomy atrial tachycardia ablation. INTRODUCTION: In patients without structural heart disease, the most frequently occurring AT is the common atrial flutter. In patients with repaired congenital heart disease other mechanisms of AT may occur, due to the presence of an atriotomy that can provide a substrate for reentry. The aim of the present study was to identify the mechanisms of atrial tachycardia (AT) occurring late after atrial septum defect (ASD) repair, with the help of a three-dimensional electroanatomical mapping system. METHODS AND RESULTS: Twenty-two consecutive patients presenting with AT underwent complete electroanatomic mapping (CARTO, Biosense Webster, Diamond Bar, CA) of spontaneously occurring and inducible right ATs. Complete maps of 26 ATs were obtained. Three tachycardia mechanisms were identified: single-loop macroreentrant atrial tachycardia (MAT) (n=7), double-loop MAT (n=18), and focal AT (n=1). In all MATs, protected isthmuses were identified as the electrophysiological substrate of the arrhythmia, most frequently the cavotricuspid isthmus (CTI) (n=24), and a gap between the inferior vena cava and a line of double potentials (n=11). A mean number of 13.5+/-2.1 radiofrequency applications were delivered to transect these critical parts of the circuit. During a follow-up of 25+/-16 months the RF ablation was acutely successful in all patients. Thirteen patients (59%) had an early recurrence of MAT and needed an additional ablation procedure. One of those patients needed two additional ablation procedures. CONCLUSIONS: Three-dimensional electroanatomic mapping is useful to identify postsurgical AT mechanisms; the CTI isthmus is involved in 92% MAT, and if the right atrial free wall (RAFW) abnormal tissue related to surgical scar is present this substrate contributes to the MAT circuit.     

Genetic parameters and allele frequencies of five new European Standard Set STR loci (D10S1248, D22S1045, D2S441, D1S1656, D12S391) in the population of Romania

Aim

To establish allele frequencies and genetic parameters for 5 new European Standard Set short tandem repeat (STR) loci in the population of Romania and to compare them with those in other populations.

Methods

DNA was isolated using QIAamp 96 DNA Swab BioRobot Kit and Chelex 100 methods. Polymerase chain reaction amplification was done using Investigator ESSplexPlus Kit (D1S1656, D2S441, D2S1338, D3S1358, D8S1179, D10S1248, D12S391, D16S539, D18S51, D19S433, D21S11, D22S1045, FGA, TH01, and vWA). For DNA typing, Applied Biosystems 3500/3500xL Genetic Analyzer was used. Statistical analysis was done using Powerstats, GDA, and Arlequin software.

Results

Power of discrimination and polymorphism information content was highest for two new ESS loci, D1S1656 and D12S391. Comparison of allele frequencies for 5 new ESS loci in Romanian population with previously published population data showed significant differences for all compared populations, with the exception of Hungary. Geographically more distant populations, such as Spain, Sweden, United Kingdom, Germany, and Portugal differed more than closer populations.

Conclusion

New ESS STR loci are very useful for the analysis of forensic samples (persons or traces) due to their characteristics (shortness and high polymorphism). In comparisons with other common STR markers, they have a higher power of discrimination and also higher polymorphism information content, and could be used in any national DNA database.The establishment of standard sets (or common sets) of short tandem repeat (STR) markers which had first been a necessity for the forensic scientific community, as a result of globalization became a necessity for the worldwide law enforcement agencies. STR markers standard sets facilitate communication and judicial transmission of the forensic DNA typing results between different forensic groups or countries (1).Although several STR sets have been proposed (2), three of them are most frequently used: Interpol Standard Set of Loci – ISS (FGA, TH01, VWA, D3S1358, D8S1179, D18S51, D21S11), US Core Loci – CODIS (CSF1PO, FGA, TH01, TPOX, VWA, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11), and European Standard Set of Loci – ESS (D3S1358, VWA, D8S1179, D21S11, D18S51, TH01, FGA, D1S1656, D2S441, D10S1248, D12S391, D22S1045).The five new European Standard Set STR loci studied in Romanian population are an upgrade of an earlier version of ESS consisiting of 7 STRs (3), adopted by the European Council in 2001. The DNA Working Group of the European Network of Forensic Science Institutes (ENFSI) reviewed the usefulness of the ESS in light of the increased exchange of DNA analysis results in 2009 and recommended the expansion with 5 new ones (4).Romania adopted the new 5 ESS loci and started to use them at the national level at the beginning of 2012 as part of the Investigator ESSplex Plus Kit, which replaced the AmpFlSTR Identifiler PCR Amplification Kit used before for Romanian National DNA Database supplying. As a consequence, and due to the lack of any study involving D10S1248, D22S1045, D2S441, D1S1656, and D12S391 loci in the Romanian population, allele distribution and genetic parameters of these loci have to be determined. The aim of this study was to establish allele frequencies and genetic parameters for 5 new ESS loci in population of Romania and to compare them with those in other populations .     

Simulated dive in rats lead to acute changes in cerebral blood flow on MRI, but no cerebral injuries to grey or white matter

In this study, the effect of a simulated dive on rat brain was investigated using several magnetic resonance imaging (MRI)-methods and immunohistochemistry. Rats were randomly assigned to a dive- or a control group. The dive group was exposed to a simulated air dive to 600 kPa for 45 min. Pulmonary artery was monitored for vascular gas bubbles by ultrasound. MRI was performed 1 h after decompression and at one and 2 weeks after the dive with a different combination of MRI sequences at each time point. Two weeks after decompression, rats were sacrificed and brains were prepared for histology. Dived rats had a different time-curve for the dynamic contrast-enhanced MRI signal than controls with higher relative signal intensity, a tendency towards longer time to peak and a larger area under the curve for the whole brain on the acute MRI scan. On MRI, 1 and 2 weeks after dive, T₂-maps showed no signal abnormalities or morphological changes. However, region of interest based measurements of T₂ showed higher T₂ in the brain stem among decompressed animals than controls after one and 2 weeks. Microscopical examination including immunohistochemistry did not reveal apparent structural or cellular injuries in any part of the rat brains. These observations indicate that severe decompression does not seem to cause any structural or cellular injury to the brain tissue of the rat, but may cause circulatory changes in the brain perfusion in the acute phase.     

Maximal strength training improves work economy, rate of force development and maximal strength more than conventional strength training

This study compared maximal strength training (MST) with equal training volume (kg × sets × repetitions) of conventional strength training (CON) primarily with regard to work economy, and second one repetition maximum (1RM) and rate of force development (RFD) of single leg knee extension. In an intra-individual design, one leg was randomized to knee-extension MST (4 or 5RM) and the other leg to CON (3 × 10RM) three times per week for 8 weeks. MST was performed with maximal concentric mobilization of force while CON was performed with moderate velocity. Eight untrained or moderately trained men (26 ± 1 years) completed the study. The improvement in gross work economy was ?0.10 ± 0.08 L min^?1 larger after MST (P = 0.011, between groups). From pre- to post-test the MST and CON improved net work economy with 31 % (P < 0.001) and 18 % (P = 0.01), respectively. Compared with CON, the improvement in 1RM and dynamic RFD was 13.7 ± 8.4 kg (P = 0.002) and 587 ± 679 N s^?1 (P = 0.044) larger after MST, whereas isometric RFD was of borderline significance 3,028 ± 3,674 N s^?1 (P = 0.053). From pre- to post-test, MST improved 1RM and isometric RFD with 50 % (P < 0.001) and 155 % (P < 0.001), respectively whereas CON improved 1RM and isometric RFD with 35 % (P < 0.001) and 83 % (P = 0.028), respectively. Anthropometric measures of quadriceps femoris muscle mass and peak oxygen uptake did not change. In conclusion, 8 weeks of MST was more effective than CON for improving work economy, 1RM and RFD in untrained and moderately trained men. The advantageous effect of MST to improve work economy could be due to larger improvements in 1RM and RFD.