Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ(9)-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R).JWH-018, five potential monohydroxylated metabolites (M1-M5), and one carboxy metabolite (M6) were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [(3)H]CP-55,940, and then for CB1R intrinsic efficacy using an [(35)S]GTPγS binding assay. JWH-018 and M1-M5 bound CB1Rs with high affinity, exhibiting K(i) values that were lower than or equivalent to Δ(9)-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9)-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ(9)-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ(9)-THC, may contribute to the greater prevalence of adverse effects observed with JWH-018-containing products relative to cannabis

La nouvelle Bundeswehr et la démocratie allemande

Karst Heinz. La nouvelle Bundeswehr et la démocratie allemande. In: Politique étrangère, n°1 - 1959 - 24ᵉannée. pp. 53-66

Entstehung, Gestalt und Auswirkungen interethnischer Freundschaften im Jugendalter

In diesem Beitrag steht die Frage im Mittelpunkt, unter welchen Bedingungen interethnische Freundschaften im Jugendalter entstehen, welche Gestalt diese Freundschaften aufweisen und welche Auswirkungen sie mit sich bringen. Theoretisch wird argumentiert, dass interethnische Freundschaften vor allem in öffentlichen Sozialräumen entstehen und gepflegt werden, dass sich die Qualität zwischen interethnischen und intraethnischen Freundschaften nicht unterscheidet, und dass sich durch dauerhafte interethnische Freundschaften die kulturelle Offenheit Jugendlicher erhöht. Empirisch werden diese Annahmen durch eine Längsschnittstudie bei Hauptschuljugendlichen (N=237) deutscher Herkunft geprüft. Die Befunde ergeben, dass die theoretischen Annahmen im Kern zutreffend sind, jedoch auch einigen Beschränkungen unterliegen, die in der abschließenden Diskussion kritisch aufgegriffen werden. (DIPF/Orig.

Is small fiber neuropathy induced by gadolinium-based contrast agents?

OBJECTIVES: In recent years, complaints of patients about burning pain in arms and legs after the injection of gadolinium-based contrast agents (GBCAs) have been reported. In the current study, we investigated changes of small fibers in the epidermis as a potential cause of the patient complaints in a mouse model. METHODS: Six groups of 8 mice were intravenously injected with either a macrocyclic GBCA (gadoteridol, gadoterate meglumine, gadobutrol), a linear GBCA (gadodiamide or gadobenate dimeglumine) (1 mmol/kg body weight), or saline (NaCl 0.9%). Four weeks after injection, animals were euthanized, and footpads were assessed using immunofluorescence staining. Intraepidermal nerve fiber density (IENFD) was calculated, and the median number of terminal axonal swellings (TASs) per IENFD was determined. RESULTS: Nonparametric Wilcoxon signed-rank test revealed significantly lower IENFDs for all GBCAs compared with the control group (P < 0.0001) with the linear GBCAs showing significantly lower IENFDs than the macrocyclic GBCAs (P < 0.0001). The linear GBCAs presented significantly more TAS per IENFD than the control group (P < 0.0001), whereas no significant increase of TAS per IENFD compared with the control group was found for macrocyclic GBCAs (P < 0.237). INTERPRETATION: It is unclear whether or at what dosage the decrease of IENFDs and the increase of TAS per IENFD found in the current animal model will appear in humans and if it translates into clinical symptoms. However, given the highly significant findings of the current study, more research in this field is required

Nano-sized zeolites as modulators of thiacloprid toxicity on Chironomus riparius

This study investigated whether zeolites of different size (Y30 (nano-sized) and H-Beta(OH)-III (forming large aggregates/agglomerates composed of 50 nm small primary particles)) exerted acute toxicity on larvae of the non-biting midge, Chironomus riparius, and whether such zeolites are able to modulate the toxicity of a common insecticide, thiacloprid, by means of adsorption of a dissolved toxicant. We conducted acute toxicity tests with fourth instar larvae of C. riparius. In these tests, larvae were exposed to zeolites or thiacloprid solely, or to mixtures of both compounds. The mixtures comprised 1.0 µg/L thiacloprid in addition to low (5.2 mg/L), medium (18.2 mg/L), and high (391.7 mg/L) zeolite concentrations, resulting in different adsorption rates of thiacloprid. As biological endpoints, changes in mortality rates and in behavior were monitored every 24 h over a total investigation period of 96 h. Furthermore, we conducted chemical analyses of thiacloprid in the medium and the larvae and located the zeolite particles within the larvae by LA-ICP-MS imaging techniques. Our results demonstrate that both types of zeolites did not exert acute toxicity when applied as single-substances, but led to reduced acute toxicity of thiacloprid when applied together with thiacloprid. These results are in line with the sorption properties of zeolites indicating reduced bioavailability of thiacloprid, although our data indicate that thiacloprid can desorb from zeolites to some extent. While freely dissolved (i.e., non-sorbed) fraction of thiacloprid was a good parameter to roughly estimate toxic effects, it did not correlate with measured internal thiacloprid concentrations. Moreover, it was shown that both zeolite types were ingested by the larvae, but no indication for cellular uptake of them was found

Correction: Nano-sized Al2O3 reduces acute toxic effects of thiacloprid on the non-biting midge Chironomus riparius.

[This corrects the article DOI: 10.1371/journal.pone.0176356.]

Mortality rates (means ± SD) of larvae per test vessel.

<p>Larvae were exposed to either thiacloprid solely, a mixture of thiacloprid and 300 mg/L nano-Al₂O₃, or a mixture of 1000 mg/L nano-Al₂O_3, after 96 h of exposure (n = 12). Four comparisons (Likelihood ratio test and Fishers exact test, if necessary) were conducted (one for each thiacloprid concentration) and significant differences between the data displayed at the respective two ends of the horizontal lines are given (* p ≤ α when adjusted according to Holm-Bonferroni’s method [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176356#pone.0176356.ref023" target="_blank">23</a>], Fishers exact test). Nominal values are shown in this graph, whereas measured concentrations can be obtained from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176356#pone.0176356.t001" target="_blank">Table 1</a>.</p