Characterization of the Safety and Pharmacokinetic Profile of D-Methadone, a Novel N-Methyl-D-Aspartate Receptor Antagonist in Healthy, Opioid-Naive Subjects: Results of Two Phase 1 Studies.

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.

Evaluation of the safety, pharmacodynamic, and pharmacokinetic effects following oral coadministration of immediate-release morphine with ethanol in healthy male participants.

OBJECTIVE: This paper aimed to evaluate the effects of coadministered immediate-release morphine and ethanol on safety, pharmacokinetic, and pharmacodynamic measures. METHODS: In the first stage of a randomized, double-blind, placebo-controlled, crossover study, 16 healthy men with a history of moderate drinking received morphine 50 mg+ethanol 0.7 g/kg, morphine 50 mg+ethanol placebo, and morphine placebo+ethanol 0.7 g/kg. In the second stage, participants received either a lower (30 mg) or higher (80 mg) morphine dose (alone and in combination with ethanol) depending on their tolerability to treatments in stage 1. Safety, pharmacodynamic (including visual analog scales, pupillometry, capnography, and psychomotor and cognitive measures), and pharmacokinetic assessments were conducted. RESULTS: With the exception of one severe adverse event (AE), all others were mild or moderate in intensity. Morphine resulted in dose-related increases in AEs. When morphine was administered with ethanol, similar AEs were observed (dizziness, headache, somnolence, nausea, and vomiting), but these were sometimes more frequent compared with those observed with either drug alone. No consistent additive or interaction effects were observed on pharmacodynamic measures. Ethanol had no apparent effects on the pharmacokinetics of morphine or its metabolites. CONCLUSIONS: Coadministration of single doses of morphine and ethanol tested in this study did not affect the safety, pharmacodynamics, or pharmacokinetics of morphine or ethanol administered alone. Copyright © 2014 John Wiley & Sons, Ltd.

Effect of maximum OTC doses of naproxen sodium or acetaminophen on low-dose aspirin inhibition of serum thromboxane B2.

OBJECTIVES: This study evaluated the platelet inhibitory effects of low-dose enteric-coated aspirin (EC-ASA) when used concomitantly with maximum over-the-counter (OTC) doses of naproxen sodium (NAPSO) or acetaminophen to determine whether NAPSO and acetaminophen interfere with the anti-platelet effect of aspirin. RESEARCH DESIGN AND METHODS: Phase I, randomized, open-label, multi-dose, three-period, parallel group, pharmacodynamic trial conducted in healthy male and female volunteers (n = 47 randomized subjects and n = 37 evaluable subjects), mean age 40.2 years. All subjects received 5 days of EC-ASA 81 mg once daily followed by 5 days of EC-ASA 81 mg once daily alone or co-administered with either NAPSO 220 mg three times daily or acetaminophen 1 g four times daily. PRIMARY OUTCOME MEASURE: Inhibition of serum thromboxane B(2) (TXB(2)), as a marker of platelet cyclooxygenase-1 (COX-1) inhibition, measured on Day 11. RESULTS: Mean inhibition of TXB(2) on Day 11 was >99% for subjects taking EC-ASA alone as well as for those who received EC-ASA co-administered with NAPSO or acetaminophen. For subjects taking EC-ASA monotherapy, mean serum TXB(2) inhibition was 99.7% (range 99.0-100%), for those taking EC-ASA with acetaminophen it was 99.6% (range 98.3-99.9%), and for those taking EC-ASA with NAPSO, mean serum TXB(2) inhibition was 99.7% (range 99.2-100%). STUDY LIMITATION: Small sample size and open-label trial design. CONCLUSIONS: The anti-platelet effect of EC-ASA 81 mg once daily was maintained following its co-administration with maximum OTC doses of NAPSO or acetaminophen.

Platelet inhibitory effects of OTC doses of naproxen sodium compared with prescription dose naproxen sodium and low-dose aspirin.

OBJECTIVES: Prescription dose naproxen has been reported to have an antiplatelet effect similar to low-dose aspirin (ASA). This study evaluated the platelet inhibitory effects of over-the-counter (OTC) doses of naproxen sodium (NAPSO) compared to that of a prescription dose of NAPSO and to low-dose enteric-coated aspirin (EC-ASA). RESEARCH DESIGN AND METHODS: This was a phase I, open-label, randomized, placebo-controlled, two-way crossover, multi-dose, pharmacodynamic trial conducted in healthy male and female volunteers (n = 48, mean age = 41.7 years). All subjects received 7 days of either prescription dose NAPSO (550 mg twice daily), OTC doses of NAPSO (220 mg two or three times daily), or placebo twice daily (period 1). After a minimum 6-day washout period, all subjects then received 7 days of EC-ASA 81 mg once daily (period 2). All study medications were taken by mouth. PRIMARY OUTCOME MEASURE: Inhibition of serum thromboxane B(2) (TXB(2)), as a marker of platelet cyclooxygenase-1 (COX-1) inhibition, measured 24 h after the day 7 morning dose. This was measured after both period 1 and period 2. RESULTS: After 7 days of treatment in period 1, mean inhibition of TXB(2) was 47% for placebo and > or =98% for all doses of NAPSO. After 7 days of EC-ASA 81 mg, mean inhibition of TXB(2) was > or = 97% (period 2). STUDY LIMITATIONS: Out-patient study setting. CONCLUSIONS: These data suggest that OTC doses of NAPSO (220 mg two or three times daily) have an antiplatelet effect similar to EC-ASA 81 mg and to prescription dose NAPSO (550 mg twice daily).

Systemic responses to hemodilution after transfusion with stored blood and with a hemoglobin-based oxygen carrier.

We assessed the systemic effects of exchanges with blood or hemoglobin (Hb) raffimer under conditions of critical oxygen delivery (Do(2)crit). We compared Do(2)crit in animals receiving Hb-based oxygen carrier (HBOC; Hemolink), fresh blood (collected <24 h), or stored blood (10 days) before hemodilution. Rats were randomized to control, blood, or HBOC isovolemic exchange. Oxygen consumption was measured by using expired gas (o(2)a) and blood (o(2)b) samples, whereas whole-body oxygen delivery (Do(2)) was calculated from cardiac output and arterial oxygen content. After exchange, rats were subjected to stepwise isovolemic hemodilution. Blood pressure, gases, acid-base status, glucose, Hb oxygen saturation, heart rate, and total peripheral resistance were also measured. We found that 1) HBOC-treated rats showed an increased mean arterial blood pressure and total peripheral resistance throughout the hemodilution, 2) Do(2)crit calculated with o(2)a or o(2)b gave identical results, 3) Do(2)crit was not different between animals receiving blood and those receiving HBOC, 4) the terminal Hb concentration (1.8 +/- 0.1 g/dL) and Do(2) (5 +/- 1 mL . min(-1) . kg(-1)) were similar for all animals, and 5) most oxygen transport and biochemical variables changed similarly during hemodilution. The data suggest that tolerance to Do(2)crit is not altered by 50% replacement of native Hb by stored blood or Hb raffimer.