The primary objective of this study was to compare the effects of oral linezolid with moclobemide and placebo on the pressor response to oral tyramine. Secondary objectives were to determine possible mechanisms of the effect based on changes in the pharmacokinetics of tyramine and to evaluate alternative methods for quantifying the pressor effect. Subjects received linezolid (625 mg bid orally), moclobemide (150 mg tid orally), or placebo for up to 7 days. Using the oral tyramine dose producing a >30 mmHg increase in systolic blood pressure (SBP) (PD>30), a positive pressor response was defined as a PD>30 index (pretreatment/treatment ratio of PD>30) of > or = 2. There were 8/10, 11/11, and 1/10 responders with linezolid, moclobemide, and placebo, respectively. Responses returned to baseline within 2 days of drug discontinuation. The ratio of mean greatest SBP and heart rate at the time of greatest SBP (GSBP/HR) increased linearly with tyramine dose both pretreatment and during treatment with linezolid and moclobemide. During treatment, responses to tyramine when subjects took linezolid or moclobemide were significantly different from placebo. Both drugs significantly decreased tyramine oral clearance compared with placebo. Urinary excretion of catecholamines and metabolites was consistent with MAOI activity of the drugs, but results were variable. The MAOI activity of linezolid is similar to that of moclobemide, a drug used clinically without food restrictions. Restrictions to normal dietary intake of tyramine-containing foods are not warranted when taking linezolid.

Background and ObjectiveThe inhibition of fatty acid amide hydrolase 1 (FAAH) has been proposed as a novel mechanism for treating pain syndromes by increasing the levels of endogenous cannabinoids (ECs). This study describes the safety, tolerability, pharmacokinetics and pharmacodynamics of V158866, a reversible FAAH inhibitor, after first administration to man.Methods51 healthy male subjects were recruited into this double-blind, randomised, placebo-controlled, adaptive dose, phase I single (Part A) and repeated ascending dose (Part B) study. The primary outcome was the safety and tolerability of V158866. Secondary outcomes were (1) pharmacokinetics of V158866 and (2) pharmacodynamics of V158866, as assessed by changes in plasma EC concentrations.ResultsSingle oral doses of 5–300 mg and repeated oral doses of 50–500 mg were evaluated. V158866 was well tolerated, with no apparent treatment-related effects on laboratory variables. V158866 was rapidly absorbed with a mean terminal elimination half-life of 9.6–18.3 h (Day 7; Part B). V158866 reached steady state within 2–3 days of administration, with an accumulation ratio, based on AUC0–24h, of approximately 2 on Day 7. V158866 showed a linear relationship between dose and AUC across the entire dose range. V158866 caused reversible, dose-related increases in plasma ECs. At hemi-equilibrium, there was a sigmoidal maximum effect relationship between plasma V158866 concentrations and changes in plasma ECs.ConclusionsV158866 is well tolerated, with linear pharmacokinetics suitable for once-daily administration, and reversible effects on plasma ECs. Maximum increases in plasma ECs occur with V158866 doses of 300–500 mg/day.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-016-0127-y) contains supplementary material, which is available to authorized users.

CORT125134 is an orally active, high‐affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first‐in‐human study was conducted to evaluate the dose‐related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty‐one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high‐fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half‐life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone.

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Context The ideal therapy for endometriosis (EM) and uterine fibroids (UF) would suppress estrogenic drive to the endometrium and myometrium, whilst minimizing vasomotor symptoms and bone loss associated with current treatments. An integrated neurokinin-kisspeptin system involving Substance P and neurokinin B acting at the neurokinin (NK) receptors 1 and 3, respectively, modulates reproductive hormone secretion and represents a therapeutic target. Objective To assess the effects of the novel NK1,3 antagonist elinzanetant on reproductive hormone levels in healthy women. Design Randomized, single-blinded, placebo-controlled study. Participants/Intervention Thirty-three women attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3/4, 9/10, 15/16 and 21/22 to measure serum reproductive hormones. In cycle 2, women were randomized to receive once daily oral elinzanetant 40, 80, 120 mg or placebo (N=8 or 9 per group). Results Elinzanetant dose-dependently lowered serum luteinizing hormone, estradiol (120 mg median change across cycle: -141.4 pmol/L, P=0.038) and luteal phase progesterone (120 mg change from baseline on day 21/22: -19.400 nmol/L, P=0.046). Elinzanetant 120 mg prolonged the cycle length by median of 7.0 days (P=0.023). Elinzanetant reduced the proportion of women with a luteal phase serum progesterone concentration >30 nmol/L (a concentration consistent with ovulation) in a dose-related manner in cycle 2 (P=0.002). Treatment did not produce vasomotor symptoms. Conclusions NK1,3 receptor antagonism with elinzanetant dose-dependently suppressed the reproductive axis in healthy women, with the 120 mg dose lowering estradiol to potentially ideal levels for UF and EM. As such, elinzanetant may represent a novel therapy to manipulate reproductive hormone levels in women with hormone driven disorders.