TRV734 is an orally bioavailable G-protein-biased ligand at the μ-opioid receptor. In nonclinical studies it was potently analgesic while causing less gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A 2-part, first-in-human study was conducted with ascending doses of TRV734 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. TRV734 was well tolerated over the dose range 2 to 250 mg when administered orally. Plasma TRV734 maximum concentration and area under the plasma concentration-time curve generally increased with dose, while time to maximum concentration was similar across doses (0.5-1.3 h). The half-life increased with dose from 10 mg through 150 mg (0.75-2.28 h) but was similar from 150 mg through 250 mg. Pupil constriction, confirming central nervous system μ-opioid receptor engagement, correlated with higher plasma TRV734 concentrations; the greatest reductions in pupil diameter occurring between 0 and 4 hours after dosing (-2.9 mm/h, with reduction peaking at 1 hour, and returning to baseline by 8 hours). Following administration of TRV734 125 mg under fasted or fed conditions, there was no significant difference in bioavailability when given as a solution or drug in capsule to fasted subjects. When drug in capsule was given to subjects following a high-fat meal, absorption was slowed, resulting in decreased peak concentrations, but area under the plasma concentration-time curve was not affected.

TRV734, an oral G-protein biased ligand at the μ-opioid receptor has demonstrated differentiated pharmacology in preclinical studies compared to unbiased ligands. First-time-in-human data suggested that TRV734 was safe and well tolerated and caused effective pain relief after single doses of 150 to 250 mg. In this study, safety and tolerability of multiple ascending doses of TRV734, and single doses of TRV734 125 mg following various administration paradigms, in healthy subjects were evaluated. In both parts of the study, TRV734 was generally well tolerated with no serious adverse events.Pharmacokinetics of TRV734 were similar when TRV734 125 mg was administered following a high-fat or standard meal. Compared to either of the fed conditions, maximum concentration and area under the plasma concentration-time curve did not change, and time to maximum concentration was 1.5 hours later when TRV734 125 mg was administered as 3 split portions over 120 minutes under fasted conditions. Split doses of TRV734 delayed time to peak decrease in pupil diameter. Following multiple-dose administration of TRV734 60 to 175 mg every 6 hours, there was a trend of slightly less-than-dose proportional increase of maximum concentration, and area under the plasma concentration-time curve and accumulation was modest. Time to maximum concentration was ≈1 to 2 hours and elimination half-life ≈1.9 to 2.5 hours. The analgesic effect of TRV734 on the cold pain test was generally dose proportional and similar to that of oxycodone 10 mg immediate release, after both the first and last doses. There was a dose-related decrease in pupil diameter following administration of TRV734 up to TRV734 125 mg every 6 hours. A favorable trend in bowel function index for TRV734 warrants continued study.

More than half of students in the USA perform below a proficient level in math. Although evidence suggests that intervention in elementary school is critical to supporting struggling learners, and there are several research‐supported instructional practices to support students with math difficulties, the existing research is limited with regard to the impact of motivational strategies designed to improve students’ math skills. This study examined the effectiveness of specific motivational strategies used in the small‐group Accelerating Mathematics Performance through Practice Strategies (AMPPS‐SG) intervention program. A multiple baseline design was used with three instructional groups of second grade students to compare the relative effectiveness of three different conditions on students’ math computation skills. Condition 1 included all of the AMPPS‐SG instructional components. Condition 2 included all instructional procedures as well as goal‐setting, performance feedback, and reinforcement for performance. Condition 3 included all components used in Condition 2, as well as a group‐based reward contingency. Results showed that students’ performance during Condition 3 was significantly better than performance during Conditions 1 and 2.

<b><i>Introduction:</i></b> Hydrocarbons with sufficient water solubility allosterically modulate anesthetic-sensitive ion channels. Mint extracts L-carvone and methyl salicylate water solubility exceeds modulation cutoff values for γ-amino butyric acid type A (GABA_A) receptors, N-methyl-D-aspartate (NMDA) receptors, and type-2 voltage-gated sodium (Na_v1.2) channels. We hypothesized that mint extracts modulate these channels at concentrations that anesthetize rats. <b><i>Methods:</i></b> Channels were expressed separately in frog oocytes and studied using 2-electrode voltage clamp techniques at drug concentrations up to 10 mM. Normalized current effects were fit to Hill equations. Mint compounds were formulated in a lipid emulsion and administered IV to rats. When unresponsive to the tail clamp, rats were exsanguinated, and plasma drug concentrations were measured. <b><i>Results:</i></b> Both mint compounds caused concentration-dependent inhibition of all channels except for methyl salicylate which inhibited GABA_A receptors at low concentrations and potentiated at high concentrations. Plasma drug concentrations in anesthetized rats were 7.9 mM for L-carvone and 2.7 mM for methyl salicylate. This corresponded to ≥53% NMDA receptor inhibition and ≥78% Na_v1.2 channel inhibition by both compounds and 30% potentiation of GABA_A receptors by methyl salicylate. <b><i>Conclusion:</i></b> L-Carvone and methyl salicylate allosterically modulate cell receptor targets important to molecular actions of conventional anesthetics at concentrations that also induce general anesthesia in rats.