Purpose/Background N-methyl-d-aspartate (NMDA) receptor (NMDAR) antagonists are potential agents for the treatment of several central nervous system disorders including major depressive disorder. Racemic methadone, l-methadone, and d-methadone all bind the NMDAR with an affinity similar to that of established NMDAR antagonists, whereas only l-methadone and racemic methadone bind to opioid receptors with high affinity. Therefore, d-methadone is expected to have no clinically significant opioid effects at therapeutic doses mediated by its NMDAR antagonism. Methods We conducted 2 phase 1, double-blind, randomized, placebo-controlled, single- and multiple-ascending-dose studies to investigate the safety and tolerability of oral d-methadone and to characterize its pharmacokinetic profile in healthy opioid-naive volunteers. Results d-Methadone exhibits linear pharmacokinetics with dose proportionality for most single-dose and multiple-dose parameters. Single doses up to 150 mg and daily doses up to 75 mg for 10 days were well tolerated with mostly mild treatment-emergent adverse events and no severe or serious adverse events. Dose-related somnolence and nausea occurred and were mostly present at the higher dose level. There was no evidence of respiratory depression, dissociative and psychotomimetic effects, or withdrawal signs and symptoms upon abrupt discontinuation. An overall dose-response effect was observed, with higher doses resulting in larger QTcF (QT interval corrected using Fridericia formula) changes from baseline, but none of the changes were considered clinically significant by the investigators. Mild, dose-dependent pupillary constriction of brief duration occurred particularly at the 60-mg dose or above in the single-ascending-dose study and at the dose of 75 mg in the multiple-ascending-dose study. No detectable conversion of d-methadone to l-methadone occurred in vivo. Conclusions These results support the safety and continued clinical development of d-methadone as an NMDAR antagonist for the treatment of depression and other central nervous system disorders.

We have determined the role of cholesteryl ester transfer protein (CETP) in selective uptake of high density lipoprotein (HDL)-derived cholesteryl esters (CE) by human adipose tissue, using organ culture or collagenase-digested adipocytes. Incubation of the fresh tissue fragments with HDL containing [ H]CE or125 I-apoprotein (apo) A-I resulted in significant uptake of HDL-CE-derived label. Addition of recombinant CETP (rCETP) increased CE uptake in a dose-response fashion. In contrast, little association of 125 I-apoA-I with adipose tissue was noted, and addition of rCETP did not alter apoA-I uptake or degradation. Incubation of adipose tissue with TP2, an anti-CETP monoclonal antibody, which inhibits neutral lipid transfer, markedly reduced selective uptake of HDL-CE. Studies using human adipocytes isolated by collagenase digestion also demonstrated selective uptake of HDL-CE and enhancement of this process by rCETP. To confirm that the association of HDL-CE-derived radioactivity with adipose tissue was not due to neutral lipid exchange between adipocytes and HDL, we measured changes in HDL composition following incubation of HDL and rCETP with isolated adipocytes. A decrease in HDL-CE concentration in the medium was observed, an effect which was markedly attenuated when incubations were carried out in the presence of monoclonal antibody TP2. Furthermore, the decrease in HDL-CE was accompanied by an increase in HDL free cholesterol, likely representing efflux of adipocyte cholesterol to HDL. There were no significant changes in phospholipid, apoA-I, or apoA-II in the medium following incubation with adipocytes. These data demonstrate a novel and important role for CETP in selective uptake of HDL-cholesteryl esters by human adipocytes and suggest that this pathway may be of quantitative physiological significance in HDL remodeling and adipocyte cholesterol accumulation.Uptake of HDL 1 -derived CE by adipocytes has been well documented and, in the obese state, plasma HDL-CE may be reduced as a consequence (1-3). The uptake of CE by adipose tissue is disproportionately greater than the uptake of HDL apolipoprotein (1, 4, 5). Thus, CE are transferred from HDL to adipocytes by a nonendocytotic process, known as selective cholesterol uptake (6 -9). The selective uptake of CE by adipose cells resembles in many ways the processes described in vivo for rat liver, ovary, and adrenal (6) and in vitro for adrenal cells (7, 10) and rat luteal cells (11). While many similarities in selective cholesteryl ester uptake have been noted in several tissues, the physiological consequences vary with cellular processing. It is likely that HDL can deliver cholesterol in the esterified form to adipocytes, where it is hydrolyzed to free cholesterol, which can then be stored in the oil droplet, equilibrate with the membrane, or efflux from the cell over time (12, 13). The role of CETP in reverse cholesterol transport has been well characterized (14). CETP is highly expressed in mammalian adipose tissue (15). There is also evidence of CET...

Objectives To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. Methods Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking (“at this moment”) visual analog scale. Results In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration. Conclusions In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant. Clinical Trial Registration ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.

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