Development of Comparative Toxicity Potentials of TiO₂ Nanoparticles for Use in Life Cycle Assessment

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In vitro toxicokinetics and analytical toxicology of three novel NBOMe derivatives - Phase I and II metabolism, plasma protein binding, and detectability in standard urine screening approaches studied by means of hyphenated mass spectrometry

Purpose Toxicokinetic studies are essential in clinical and forensic toxicology to understand drug-drug interactions, influence of individual polymorphisms, and elimination routes, as well as to evaluate targets for toxicological screening procedures. An N-(2-methoxybenzyl)-substituted phenethylamines (NBOMe analogues) intake has been associated with severe adverse reactions including deaths. 1-(1-Benzofuran-5-yl)-N-[(2-methoxyphenyl)methyl]propan-2-amine (5-APB-NBOMe), 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)-N-[(5-chloro-2-ethoxyphenyl)methyl]ethan-1-amine (2C-B-FLY-NB2EtO5Cl), and 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)-N-[(2-methoxyphenyl)methyl]ethan-1-amine (2C-BFLY-NBOMe) are three emerging NBOMe analogues, which have encountered on the drugs of abuse market. So far, their toxicokinetic data are completely unexplored. Methods The study included mass spectrometry-based identification of phase I and II metabolites following exposure to the terminally differentiated human hepatocellular carcinoma cells (HepaRG). The determination of enzymes involved in the major phase I/II metabolic steps and determination of plasma protein binding (PPB) was done. Finally, the evaluation of the toxicological detectability by different hyphenated mass spectrometry techniques in standard urine screening approaches (SUSAs) was investigated. Results The compounds were extensively metabolized in HepaRG cells mainly via O-dealkylation, hydroxylation, glucuronidation, and combinations thereof. CYP1A2, 2D6, 2C8, 2C19, and 3A4, were involved in the initial reactions of all investigated compounds. Glucuronidation of the phase I metabolites – when observed - was mainly catalyzed by UGT1A9. The PPB of all compounds was determined to be > 85%. Only the high-resolution mass spectrometry-based SUSA allowed detection of all compounds in rat urine but only via metabolites. Conclusions The toxicokinetic data provided by this study will help forensic and clinical toxicologists to reliably identify these substances in case of abuse and/or intoxication and will allow them a thorough risk assessment

P.016 Reduction in migraine-associated burden over 24 weeks of treatment with eptinezumab in patients with chronic migraine

Background: To examine changes in the occurrence, severity, and symptoms of headache episodes in patients with chronic migraine (CM) following eptinezumab treatment. Methods: PROMISE-2 (NCT02974153) was a double-blind, placebo-controlled, parallel-group trial that randomized adults with CM to eptinezumab 100 mg, 300 mg, or placebo IV every 12 weeks for up to 24 weeks (2 infusions). Headache episodes (migraine and non-migraine) and their characteristics were reported in daily electronic diaries during the 28-day baseline period and throughout the 24-week treatment period. Results: A total of 1072 patients were included. Patients reported a mean of 20.4–20.6 monthly headache days during baseline across treatment groups. Mean monthly headache days decreased by 8.9 (100 mg) and 9.7 (300 mg) with eptinezumab versus 7.3 with placebo over weeks 1-24. Mean monthly headache episodes also decreased by 8.4 (100 mg) and 9.0 (300 mg) compared to 7.1 with placebo over weeks 1-24. Among headaches occurring post-treatment, decreases in severe pain, nausea, phonophobia, photophobia, and physical activity limitations were numerically greater than placebo. Conclusions: In patients with CM, eptinezumab numerically decreased the frequency and severity of monthly headache days and episodes more than placebo. Patients treated with eptinezumab reported a decrease in burdensome symptoms of headache episodes.</jats:p

Hypothalamic Deep Brain Stimulation Influences Autonomic and Limbic Circuitry Involved in the Regulation of Aggression and Cardiocerebrovascular Control in the Göttingen Minipig

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Deep brain stimulation (DBS) in the ventral tuberal hypothalamus (VTH) is currently under investigation for the treatment of severe obesity. Stimulation impact on a number of closely related hypothalamic neural systems could potentially influence normal hypothalamic function and thereby generate adverse side effects. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; To assess the feasibility and safety of VTH DBS in a non-primate large animal model. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; In the VTH of 6 Göttingen minipigs, quadropolar leads were implanted bilaterally (n = 2) or unilaterally (n = 4), using optimized MRI sequences allowing identification of major diencephalic landmarks. Heart rate, weight, behavior and nighttime locomotor activity were recorded throughout the study period. Two of the unilaterally implanted minipigs were examined with [&lt;sup&gt;15&lt;/sup&gt;O]H&lt;sub&gt;2&lt;/sub&gt;O positron emission tomography (PET) scans performed in DBS-off and DBS-on mode. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; VTH DBS elicited an amplitude-dependent increase in heart rate and transient aggressive behavior. PET demonstrated that VTH DBS caused a global increase in cerebral blood flow velocities and decreased mean transit time. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; VTH DBS results in behavioral and physiological changes, which may derive from activation of closely related limbic and autonomic networks. Caution and further studies of longer length should be requested before this procedure is used more widely in humans.</jats:p