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Pharmacological Treatment of Obesity
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Amie A. Ogunsakin, Ayotunde O. Dokun
This is a fixed-dose combination of naltrexone and bupropion. It was FDA approved in September of 2014 for management of obesity. Naltrexone is an opioid antagonist, and bupropion is an aminoketone antidepressant that inhibits dopamine and norepinephrine re-uptake inhibitors, which stimulates pro-opiomelanocortin (POMC) neurons. The exact mechanism of the naltrexone/bupropion combination leading to weight loss is not fully understood [35]. The combination is theorized to work synergistically in the hypothalamus and the mesolimbic dopamine circuit to promote satiety, reduce food intake, and enhance energy expenditure. POMC cells located in the arcuate nucleus of the hypothalamus produce melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin, an endogenous opioid [36,37]. The alpha-MSH activates the melanocortin-4 receptor (MC4R), leading to decreased food intake, increased energy expenditure, and weight loss [38,39]. Beta-endorphin reduces activity of POMC cells by binding to the inhibitory mu-opioid receptor (MOP-R) [40]. Bupropion, a weak dopamine and norepinephrine reuptake inhibitor, enhances POMC cell production and release of alpha-MSH and beta-endorphin [41]. Naltrexone, an opioid antagonist, blocks the MOP-R; therefore, it disrupts beta-endorphin inhibitory feedback on POMC cells [41] (Figure 7.1).
Chronic pain and depression
Published in Peter R Wilson, Paul J Watson, Jennifer A Haythornthwaite, Troels S Jensen, Clinical Pain Management, 2008
Bupropion is a monocyclic compound with an aminoketone side chain. Whereas the structure is similar to sympathominetics, bupropion has no stimulant abuse potential. Bupropion effects dopaminergic and noradrenergic activity with negligible effects on serotonergic activity. The half-life of the parent compound is 21 hours, but the half-life of two active metabolites is in excess of 40 hours.
Drug-Induced Abnormalities of Liver Heme Biosynthesis
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
The pathway of heme biosynthesis is given in Figure 1. The first intermediate is 5-aminolevulinate (ALA), an aminoketone which results from the condensation of glycine with succinyl-CoA, carried out by the enzyme ALA-synthetase within the matrix compartment of the mitochondrion. Two molecules of ALA are then condensed with each other in the cytosol to the monopyrrole precursor, porphobilinogen (PBG). Four molecules of PBG then join together to form the symmnetrical, linear tetrapyrrole, hydroxymethylbilane. This intermediate undergoes cyclization under the influence of uroporphyrinogen III synthetase to the asymmetrical uroporphyrinogen (uro’gen) III, which is then decarboxylated stepwise by a cytoplasmic decarboxylase to produce coproporphyrinogen III. It should be noted that the real intermediates in the pathway are not uroporphyrin and coproporphyrin but their colorless reduced porphyrinogens (hexahydroporphyrins), in which the pyrrole rings are joined together by methylene bridges. The corresponding porphyrins, oxidative by-products of the pathway, cannot themselves be metabolized. This has led to the proposal (Heikel et al., 1958) that in certain porphyrias where uroporphyrin accumulates, the mechanism responsible may be accelerated oxidation of uroporphyrinogen, causing an “oxidative escape” of the intermediate from the metabolic pathway, a concept that will be discussed at some length later. Once coproporphyrinogen III is formed, it is taken up into the mitochondrion, where the remaining steps of heme biosynthesis take place. Coproporphyrinogen is first oxidized to protoporphyrinogen by coproporphyrinogen oxidase (this metabolic step involves oxidative decarboxylation of two propionic acid side chains to vinyl groups). Protoporphyrinogen is then oxidized to protoporphyrin by another oxidase and, finally, the last enzyme of heme biosynthesis, ferrochelatase, inserts ferrous iron into protoporphyrin to produce heme.
Benefits of Yoga on IL-6: Findings from a Randomized Controlled Trial of Yoga for Depression
Published in Behavioral Medicine, 2021
Nicole R. Nugent, Leslie Brick, Michael F. Armey, Audrey R. Tyrka, Kathryn K. Ridout, Lisa A. Uebelacker
Analyses were restricted to a set of 87 (NYoga = 48; NHLW = 39) individuals who had at least one inflammatory measure across each of the three time points (baseline, 3 week follow-up, 10 week follow-up). Across both treatment groups, participants in the study were primarily female (84%), White/Caucasian (88%), and had a mean age of 45.20 (SD = 12.72). All participants were taking antidepressant medications; slightly more than half of participants (52%) were taking an SSRI, 23% were taking an SNRI, 17% were taking an Aminoketone (e.g., bupropion), and the remaining 8% were taking either an anticonvulsant, tricyclic antidepressant, or tetracyclic antidepressant. See Table 1 for a breakdown of demographics and medications across each treatment group. Table 2 presents a summary of inflammatory protein means across time for each treatment group. A small number of blood samples were collected outside of the 2–6 pm scheduled window (e.g., 16.27% of blood draws at baseline, 10.94% of blood draws at week 3, and 22.58% of blood draws at week 10 were taken outside of the 2–6 pm time window). Consequently, we repeated all analyses in a subsample of individuals whose blood draws at all three assessments were taken within the 2– 6 pm time window.
Pharmaceutical strategies for smoking cessation during pregnancy
Published in Expert Opinion on Pharmacotherapy, 2018
Bupropion, originally approved as an antidepressant of the aminoketone class, selectively inhibits the presynaptic reuptake of dopamine and norepinephrine [41]. These effects are thought to reduce cravings and nicotine withdrawal. Bupropion also antagonizes nicotinic receptors which attenuate the effect of nicotine [42]. Serotonin receptors are affected by bupropion, although there is no evidence linking them to smoking cessation [43]. First trimester-exposure is especially of concern due to embryo development timing and concerns from an initial voluntary registry from the drug manufacturer [40,44]. These safety concerns have been assessed in multiple observational trials. Cole used data from a US health plan to evaluate the risk of congenital or cardiovascular malformations with 1213 first-trimester bupropion exposed infants compared to 4743 infants exposed to other antidepressants, and to 1049 infants not exposed to bupropion in the first trimester [45]. No increased risk with bupropion use was found. For all congenital malformations, the prevalence with bupropion was 23.1 per 1000 infants compared to 23.2 per 1000 for other antidepressant exposure, aOR: 0.95(CI: 0.62–1.45), and to 21.9 per 1000 outside of first-trimester bupropion exposure, aOR: 2.9(CI: 1.5–5.5). The risk of cardiovascular malformations was 10.7 per 1000 infants in the first-trimester bupropion group, 10.8 per 1000 in infants exposed to other antidepressants, aOR: 0.97(CI: 0.52–1.8), and 9.5 per 1000 infants exposed to bupropion outside of the first-trimester, aOR: 1.07(CI: 0.48–2.40).
Identification of three new phase II metabolites of a designer drug methylone formed in rats by N-demethylation followed by conjugation with dicarboxylic acids
Published in Xenobiotica, 2018
Monika Židková, Igor Linhart, Marie Balíková, Michal Himl, Veronika Dvořáčková, Eva Lhotková, Tomáš Páleníček
In two GC/MS studies (Kamata et al., 2006; Meyer et al., 2010), four urinary metabolites were identified in both rats and humans, namely 4-OH-3-MeO-MC, 3-OH-4-MeO-MC and 3-OH-MDMC. In a more recent GC/MS study, a small amount of two stereoisomers of MDDHMC was found in human urine along with MDC (Uralets et al., 2014). Unchanged methylone always strongly predominated over its metabolites in the urine. Phenolic metabolites, 4-OH-3-MeO-MC, 3-OH-4-MeO-MC, 4-OH-3-MeO-C and 3-OH-4-MeO-C were excreted mainly in conjugated forms as glucuronides and/or sulphates as demonstrated by increase of their concentration after hydrolytic treatment (Ellefsen et al., 2015; Kamata et al., 2006). More surprisingly, concentration of both MDMC and MDC also increased after acidic hydrolysis of the urine. Therefore, it appeared that part of MDMC and MDC is excreted in urine in a conjugated form (Kamata et al., 2006). Conjugation of MDMC and MDC, with either glucuronic acid or sulphate appears to be very unlikely when considering their aminoketone structure. Therefore, we hypothesised, that at least the primary amine, MDC, may form amidic conjugates with dicarboxylic acids, in analogy with recently identified phase II metabolites of mephedrone, i.e. N-succinylnormephedrone (Pozo et al., 2015), N-glutaryl- and N-adipoylnormephedrone (Linhart et al., 2016). To test this hypothesis, we synthesised reference standards of N-succinyl-, N-glutaryl- and N-adipoyl-MDC and analysed the urine of rats dosed subcutaneously with MDMC for these potential new metabolites.