The Ocular Penetration and Intraocular Pressure Lowering Effect of Topical Acetaminophen in the New Zealand White Rabbit.

Purpose: Emerging data suggest that acetaminophen lowers intraocular pressure (IOP) and has the potential to be repurposed as pharmacotherapy to treat open-angle glaucoma. However, pharmacokinetic data are lacking. This study aims to describe the pharmacokinetics of topical acetaminophen and its metabolite [N-arachidonoylaminophenol (AM404)] when administered individually and in combination, and to determine its effect on IOP in the ocular normotensive adult New Zealand White Rabbit (NZWR). Methods: A randomized control trial was conducted using topical 1% acetaminophen and 1% AM404. The study was divided into two sub-studies using both paired-eye and two-eye designs. Results: The mean [95% confidence interval of the mean (95% CI)] concentration of acetaminophen detected in the aqueous humor (AH) was 4.09 ppm (3.18-5.00) at 2 h and 0.92 ppm (0.60-1.24) at 4 h after an immediate dose of topical acetaminophen. The integral IOP, defined as the integral of IOP change from baseline over time, was -5.1 mmHg⋅h (95% CI: -10 to 0.41) for control,-7.5 mmHg⋅h (95% CI: -14 to -1.1) for half-hourly acetaminophen, and -4.4 mmHg⋅h (95% CI: -14 to 5.5) for hourly acetaminophen over a 4-h period. When comparing topical acetaminophen with AM404 dosed half-hourly over a 4-h period, the integral IOP was -2.3 mmHg⋅h (95% CI: -5.9 to 1.3) for control,-2.0 mmHg⋅h (95% CI: -5.6 to 1.7) for AM404, -1.7 mmHg⋅h (95% CI: -4.5 to 1.2) for acetaminophen, and -3.2 mmHg⋅h (95% CI: -5.4 to -0.96) for acetaminophen/AM404 combined. Conclusions: Acetaminophen, but not its metabolite AM404, penetrated the multilayered cornea via passive diffusion in a dose-dependent fashion. There was a nonsignificant tendency to cause a lowering of IOP over the 4-h dosing period with higher AH concentrations of acetaminophen. Topical AM404 did not show a significant IOP-lowering effect.

The neurologic phenotype of South African patients with HIV-associated neurocognitive impairment.

BACKGROUND: The neurologic manifestations of HIV include a spectrum of HIV-associated neurocognitive disorders, as well as a cluster of neurologic symptoms and signs. The neurologic manifestations have been modified but not eradicated by antiretroviral therapy (ART). We describe the neurologic phenotype in South African patients with predominant HIV-1 subtype C infection on ART and its association with neurocognitive impairment and efavirenz and 8-hydroxy-efavirenz concentrations. METHODS: We conducted a cross-sectional analysis of the neurologic examination findings of HIV+ patients with neurocognitive impairment and used multiple linear regression to explore associations with neurocognitive impairment, efavirenz, and 8-hydroxy-efavirenz pharmacokinetics (plasma and CSF). RESULTS: We included 80 participants established on ART (median 40 months) of which 72 (90%) were female. The median age was 35 (interquartile range [IQR], 32-42) and the median Global Deficit Score was 0.94 (IQR 0.63-1.36). We found associations between neurocognitive impairment and neurologic signs: gait (slow walking speed [p = 0.03; R2 = 0.06], gait ataxia [p < 0.01; R2 = 0.21], and abnormal gait appearance [p < 0.01; R2 = 0.18]); coordination (upper limb bradykinesia [p < 0.01; R2 = 0.10] and lower limb bradykinesia [p = 0.01; R2 = 0.10]); reflexes (jaw jerk [p = 0.04; R2 = 0.05] and palmomental response [p = 0.03; R2 = 0.06]); ocular signs (impaired smooth pursuit [p = 0.01; R2 = 0.09] and impaired saccades [p < 0.01; R2 = 0.15]); and motor signs (spasticity [p ≤ 0.01; R2 = 0.15] and muscle weakness [p = 0.01; R2 = 0.08]). No significant associations were found between plasma and CSF efavirenz or 8-hydroxy efavirenz concentrations and any neurologic sign. CONCLUSION: We found that individual neurologic signs were associated with neurocognitive impairment in South African HIV+ patients with predominant HIV-1 subtype C infection on ART and could be used in clinical practice to assess severity. REGISTRATION NUMBER: PACTR201310000635418.