Benzthiazide

To determine age-and sex-related changes in periocular morphology in Caucasians using a standardized protocol.

Healthy Caucasian volunteers aged 18–35 and 60–90 years old were recruited from the Department of Ophthalmology, Faculty of Medicine and University Hospital, Cologne, between October 2018 and May 2020. Volunteers with facial asymmetry, facial deformities, history of facial trauma, facial surgery, botox injection, eyelid ptosis, strabismus, or nystagmus, were excluded. Standardized three-dimensional facial photos of 68 young volunteers and 73 old volunteers were taken in this clinical practice. Position changes of endocanthion, pupil center, and exocanthion were analyzed in different age and gender groups, including palpebral fissure width (PFW): distance between endocanthions (En-En), pupil centers (Pu–Pu), exocanthions (Ex-Ex), endocanthion and nasion (En-Na), pupil center and nasion (Pu-Na), exocanthion and nasion (Ex-Na), endocanthion and pupil center (Pu-En), exocanthion and pupil center (Pu-Ex), and palpebral fissure inclination (PFI); angle of endocanthions to nasion (En-Na-En), pupils to nasion (Pu-Na-Pu), exocanthions to nasion (Ex-Na-Ex); endocanthion inclination (EnI), and exocanthion inclination (ExI).

PFW, En-En, Ex-Na, Pu-Ex, PFI, ExI, and Ex-Na-Ex were significantly different between the young and old groups (p ≤ 0.004). There were sex-related differences in PFW, Ex-Ex, En-Na, Pu-Na, Ex-Na, Pu-En, PFI, and EnI between both groups (p ≤ 0.041).

The position change of the pupil is minimal relative to age; it is preferred to establish the reference plane to describe periocular changes. The endocanthion tends to move temporally and inferiorly, while the exocanthion tends to shift nasally and inferiorly with age.

Commonly used pain therapeutics, such as opioid medications, exert dangerous side effects and lack effectiveness in treating some types of pain. Ketamine is also used to treat pain, but side effects limit its widespread use. (2R,6R)-hydroxynorketamine (HNK) is a ketamine metabolite that potentially shares some beneficial behavioral effects of its parent drug without causing significant side effects. This study compared the profile and potential mechanisms mediating the antinociception activity of ketamine and (2R,6R)-HNK in C57BL/6J mice. Additionally, this study compared the reversal of mechanical allodynia by (2R,6R)-HNK with gabapentin in a model of neuropathic pain. Unlike the near-immediate and short-lived antinociception caused by ketamine, (2R,6R)-HNK produced late-developing antinociception 24 hours following administration. Pharmacological blockade of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) prevented the initiation and expressionof (2R,6R)-HNK antinociception, suggesting the involvement of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-dependent glutamatergic mechanisms in the pain reduction-like responses. Blockade of opioid receptors with naltrexone partially prevented the antinociceptive effect of ketamine but was ineffective against (2R,6R)-HNK. Furthermore, (2R,6R)-HNK did not produce dystaxia, even when tested at doses five times greater than those needed to produce antinociception, indicating a superior safety profile for (2R,6R)-HNK over ketamine. Additionally, (2R,6R)-HNK reversed mechanical allodynia in a spared nerve injury model of neuropathic pain with similar short-term efficacy to gabapentin (within 4 hours) while outperforming gabapentin 24 hours after administration. These findings support the further study of (2R,6R)-HNK as a potentially valuable agent for treating different types of pain and establish certain advantages of (2R,6R)-HNK treatment over ketamine and gabapentin in corresponding assays for pain. SIGNIFICANCE STATEMENT: The ketamine metabolite (2R,6R)-HNK produced antinociception in male and female mice 24 hours after administration via activation of AMPA receptors. The effects of (2R,6R)-HNK differed in time course and mechanism and presented a better safety profile than ketamine. (2R,6R)-HNK also reversed allodynia in SNI-operated animals within 4 hours of treatment onset, with a duration of effect lasting longer than gabapentin. Taken together, (2R,6R)-HNK demonstrates the potential for development as a non-opioid analgesic drug.