Pharmacology of novel psychoactive substances

This PhD work consists of an in vitro and in vivo part. In the in vivo part, we investigated the role of dopamine in the acute clinical effects of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) in healthy human subjects. The role of dopamine in the addictive effects of drug of abuse is well established, but whether it contributes to the acute psychotropic effects of MDMA is unclear. In this pharmacological interaction study, we used the dopamine and weak norepinephrine transporter inhibitor bupropion (Stahl et al. 2004) as a pharmacological tool to block the MDMA-induced dopamine release and to study the role of dopamine in the effects of MDMA. We hypothesized that bupropion would decrease the subjective effects of MDMA to the extent that they depend on MDMA-induced release of dopamine. We included 16 healthy human subjects in this double-blind, placebo-controlled, crossover study. Bupropion pretreatment slightly increased MDMA plasma concentration and prolonged but not reduced the subjective effects contrary to our hypothesis. Additionally, bupropion reduced the MDMA-induced elevations in plasma norepinephrine concentrations and the heart rate response to MDMA. These findings support a role for norepinephrine in the MDMA-induced cardiostimulant effects but no role for MDMA-induced transporter-mediated dopamine release in the elevated mood effects after MDMA administration. Possibly, most of the acute psychotropic effects of MDMA are mediated via transporter-mediated release of serotonin and norepinephrine as previously shown (Hysek et al. 2011, Hysek et al. 2012). In the second and main part of this work we characterized the pharmacological profiles of novel psychoactive substances (NPS). Specifically, we studied whether and how potently NPS interacted with the human transporters for norepinephrine, dopamine, and serotonin, stably expressed in human embryonic kidney (HEK293) cells. Additionally, we assessed binding affinity to the serotonin 5-HT1A, 5-HT2A, 5-HT2C-receptors and the activation potency and activation efficacy at 5-HT2A and 5-HT2B receptors. Furthermore, binding to alpha1A/2A-adrenergic, dopamine D1-3, histamine H1 receptors, as well as trace amine-associated receptor 1 (TAAR1) was also assessed. The NPS studied in this project included para-4-halogenated amphetamine derivatives, which were shown to be relatively more serotonergic than their non-4-halogenated counterparts and pyrovaleronering-substituted cathinones, which were highly potent dopamine transporter inhibitors with a high risk for abuse. Para-halogenated drugs (4-fluoroephedrine, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcathinone, and 4-bromomethcathinone) also released monoamines, similar to MDMA, whereas pyrovalerones were found to be pure uptake inhibitors. Most benzofurans were similar to MDMA but slightly more serotoninergic than MDMA and additionally activated the serotonin 5-HT2B receptor. The last big group of NPS studied in this project, were novel hallucinogens, which predominantly interacted with the 5-HT2A receptor. This serotonin receptor subtype mediates the hallucinogenic and hallucinogenic-like visual effects of classic serotonergic hallucinogens (Vollenweider et al. 1998, Nichols 2004, Halberstadt et al. 2013, Halberstadt et al. 2014, Halberstadt 2015). Compounds tested in this project included the benzodifuran 8-Bromo-2,3,6,7-benzo-dihydro-difuran-ethylamine (2C-B-FLY), 2C-drugs with their highly potent N-(2-methoxy)benzyl (NBOMe)-derivatives, and lysergic acid diethylamide (LSD). Interestingly, NBOMe derivatives displayed higher affinities at the 5-HT2A receptor than LSD, together with a high selectivity for 5-HT2A over the 5-HT1A receptor, contrary to LSD. NBOMes were partial 5-HT2A receptor agonists, similar to LSD. These novel drugs likely carry a high hallucinogenic potential when used recreationally by humans and the high binding to α1A-receptor (Ki < 1µM) may result in additional vasocontrictive and cardiovascular stimulant effects. Taken together, this PhD contributed to the understanding of the role of dopamine in the effects of MDMA, an important recreational substances. Additionally, we characterized the in vitro pharmacology of many novel designer drugs, which will be helpful in the prediction of the clinical toxicological effects of these newly used recreational drugs

Triage as a core sorting strategy in extreme core arrival scenarios

Surveys have indicated that the remanufacturing industry is concerned about the necessity of agile and prioritized core sorting due to its potential benefits to optimal core inventory and condition assessment, both at equipment and component levels. As such, core sorting holds a pivotal role in remanufacturing operations, however, extreme core arrivals, its stochastic nature and resulting sorting issues, warrant targeted modelling and analysis. This paper is devoted to triage as an agile sorting strategy in extreme arrival scenarios that can be utilized as a complementary core sorting strategy. A statistical model of extreme core arrivals is developed based on Extreme Value (EV) theory and related Generalized Extreme Value (GEV) and Fréchet (Fisher-Tippett type-II) distributions. The model is applied to extreme arrivals of valves in an industrial valve repair shop. Using a large sample size, distribution parameters are estimated and the stochastic behaviour of the extreme valve arrivals is evaluated and verified. An analogy between medical triage and remanufacturing triage is discussed, the results and applicability of extreme value analysis in remanufactured valve arrivals is presented, and a generic framework for prioritization of triage strategies is introduced

Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones

The pharmacology of novel psychoactive substances is mostly unknown. We evaluated the transporter and receptor interaction profiles of a series of para-(4)-substituted amphetamines and pyrovalerone cathinones. We tested the potency of these compounds to inhibit the norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporters (NET, DAT, and SERT, respectively) using human embryonic kidney 293 cells that express the respective human transporters. We also tested the substance-induced efflux of NE, DA, and 5-HT from monoamine-loaded cells, binding affinities to monoamine receptors, and 5-HT2B receptor activation. Para-(4)-substituted amphetamines, including 4-methylmethcathinone (mephedrone), 4-ethylmethcathinone, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcatinone (flephedrone), and 4-bromomethcathinone, were relatively more serotonergic (lower DAT:SERT ratio) compared with their analogs amphetamine, methamphetamine, and methcathinone. The 4-methyl, 4-ethyl, and 4-bromo groups resulted in enhanced serotonergic properties compared with the 4-fluoro group. The para-substituted amphetamines released NE and DA. 4-Fluoramphetamine, 4-flouromethamphetamine, 4-methylmethcathinone, and 4-ethylmethcathinone also released 5-HT similarly to 3,4-methylenedioxymethamphetamine. The pyrovalerone cathinones 3,4-methylenedioxypyrovalerone, pyrovalerone, α-pyrrolidinovalerophenone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, and 3,4-methylenedioxy-α-pyrrolidinobutiophenone potently inhibited the NET and DAT but not the SERT. Naphyrone was the only pyrovalerone that also inhibited the SERT. The pyrovalerone cathinones did not release monoamines. Most of the para-substituted amphetamines exhibited affinity for the 5-HT2A receptor but no relevant activation of the 5-HT2B receptor. All the cathinones exhibited reduced trace amine-associated receptor 1 binding compared with the non-β-keto-amphetamines. In conclusion, para-substituted amphetamines exhibited enhanced direct and indirect serotonergic agonist properties and are likely associated with more MDMA-like effects. The pharmacological profile of the pyrovalerone cathinones predicts pronounced stimulant effects and high abuse liability

Glacial reduction of AMOC strength and long term transition in weathering inputs into the Southern Ocean since the Mid Miocene: Evidence from radiogenic Nd and Hf isotopes

Combined seawater radiogenic hafnium (Hf) and neodymium (Nd) isotope compositions were extracted from bulk sediment leachates and foraminifera of Site 1088, ODP Leg 177, 2082 m water depth on the Agulhas Ridge. The new data provide a continuous reconstruction of long and short-term changes in ocean circulation and continental weathering inputs since the Mid-Miocene. Due to its intermediate water depth the sediments of this core sensitively recorded changes in admixture of North Atlantic Deep Water (NADW) to the Antarctic Circumpolar Current (ACC) as a function of the strength of the Atlantic Meridional Overturning Circulation (AMOC). Nd isotope compositions (εNd) range from -7 to -11 with glacial values generally 1 to 3 units more radiogenic than during the interglacials of the Quaternary. The data reveal episodes of significantly increased AMOC strength during late Miocene and Pliocene warm periods whereas peak radiogenic εNd values mark a strongly diminished AMOC during the major intensification of Northern Hemisphere Glaciation near 2.8 Ma and in the Pleistocene after 1.5 Ma. In contrast, the Hf isotope compositions (εHf) show an essentially continuous evolution from highly radiogenic values of up to +11 during the Miocene to less radiogenic present day values (+2 to +4) during the late Quaternary. The data document a long-term transition in dominant weathering inputs, where inputs from the South America are replaced by those from Southern Africa. Moreover, radiogenic peaks provide evidence for the supply of radiogenic Hf originating from Patagonian rocks to the Atlantic sector of the Southern Ocean via dust inputs

Pharmacological profile of novel psychoactive benzofurans

Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro.; 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-HT2A and 5-HT2B receptor activation.; 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-HT2A receptor agonists similar to MDMA, but also 5-HT2B receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY very potently interacted with 5-HT2 receptors and also bound to TA1 receptors.; 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-HT2B receptor activation associated with heart valve fibrosis. The pharmacology of 2C-B-FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction

Extinção de espécies no passado e na atualidade: uma abordagem interdisciplinar

Anais do II Seminário Seminário Estadual PIBID do Paraná: tecendo saberes / organizado por Dulcyene Maria Ribeiro e Catarina Costa Fernandes — Foz do Iguaçu: Unioeste; Unila, 2014A extinção dos dinossauros há cerca de 65 milhões de anos é motivo de estudos até os dias de hoje, desta forma é importante analisar as hipóteses que levaram esses animais a extinção. Com o intuíto de despertar nos estudantes do ensino básico a crítica fundamentada e a comparação com fatos atuais que ainda levam a extinção de diversas outras espécies de seres vivos foi abordada a partir de uma aula dialogada e com o uso de mídias, numa ação inicial dentro de um projeto maior, do Programa Institucional de Bolsas de Iniciação à Docência (PIBID). Para fixação do conteúdo os alunos realizaram trabalhos artísticos, montagem em 3D e fósseis em argila que despertou assim também o lado lúdico dos mesmos. Os resultados foram satisfatórios pois o interesse e a motivação dos alunos foi despertad