RESUMEN

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

RESUMEN

This study describes the seasonal distribution of larvae, nymph, and adult life stages for 3 species of ixodid ticks collected by tick drag and sweep methods from various habitats in the Republic of Korea (ROK). Grasses less than 0.5 m in height, including herbaceous and crawling vegetation, and deciduous, conifer, and mixed forests with abundant leaf/needle litter were surveyed at United States (US) and ROK operated military training sites and privately owned lands near the demilitarized zone from April-October, 2004 and 2005. Haemaphysalis longicornis Neumann adults and nymphs were more frequently collected from April-August, while those of Haemaphysalis flava Neumann and Ixodes nipponensis Kitaoka and Saito were collected more frequently from April-July and again during October. H. longicornis was the most frequently collected tick in grass habitats (98.9%), while H. flava was more frequently collected in deciduous (60.2%) and conifer (57.4%) forest habitats. While more H. flava (54.1%) were collected in mixed forest habitats than H. longicornis (35.2%), the differences were not significant. I. nipponensis was more frequently collected from conifer (mean 8.8) compared to deciduous (3.2) and mixed (2.4) forests.

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RESUMEN

As part of the 65th Medical Brigade tick-borne disease surveillance program to determine the abundance, geographical and seasonal distributions, and tick-borne pathogens present in the Republic of Korea, dragging and sweeping methods were compared to determine their efficiency for collecting ticks in grass and deciduous, conifer, and mixed forest habitats at military training sites and privately owned lands in northern Gyeonggi Province near the demilitarized zone from April-October, 2004-2005. Three species of Ixodid ticks, Haemaphysalis longicornis, Haemaphysalis flava, and Ixodes nipponensis, were collected. Overall, H. longicornis adults and nymphs were most frequently collected from grass and deciduous forest habitats, accounting for 98.2 and 66.2%, respectively, of all ticks collected. H. flava adults and nymphs were most frequently collected from conifer and mixed forests, accounting for 81.6, and 77.8%, respectively, of all ticks collected. I. nipponensis adults and nymphs accounted for 9.3% of all ticks collected from mixed forests, were less commonly collected from deciduous (4.1%) and conifer (4.1%) forests, and infrequently collected from grass habitats (0.9%). Overall, there were no significant differences between dragging and sweeping methods for the three species when the areas sampled were similar (sweeping = 2 x the area over the same transect). Adults and nymphs of H. longicornis were most commonly collected from April-August, while those of H. flava and I. nipponensis were most commonly collected during April-July and again during October. Larvae of all three species were most frequently observed from July-September.

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