Browsing by Author "Anderson, Sean Glen"

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    Pharmacology and intraocular pressure relationship of topical and systemic paracetamol in the adult New Zealand White Rabbit Eye
    (Stellenbosch : Stellenbosch University, 2022-02) Anderson, Sean Glen; Decloedt, Eric; Meyer, David; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology.
    ENGLISH ABSTRACT: Background The main modifiable risk factor in open-angle glaucoma is the increased intraocular pressure (IOP). The primary goal of therapy is to lower IOP in order to slow, or even halt disease progression. Paracetamol has the potential to be repurposed as pharmacotherapy to treat open-angle glaucoma. Endocannabinoid stimulation is now thought to be one of the proposed mechanism of actions of paracetamol and a proposed mechanism by which it lowers IOP. Paracetamol is metabolised to N-arachidonoylaminophenol (AM404) in the brain and spinal cord tissue. In vivo studies found that AM404 significantly increases and prolongs the pharmacological effect of exogenous anandamide, which in turn decreases IOP. Small randomised controlled trials of oral and intravenous (IV) paracetamol demonstrated intraocular lowering properties in humans. This project aims to describe the pharmacokinetics of topical and IV paracetamol and to determine its effect on IOP in the adult New Zealand White Rabbit. Study design and methodology A randomised control trial was conducted using IV and topical 1% paracetamol as well as topical 1% AM404. The study was divided into three separate protocols: Protocol 1: To study the corneal penetration properties of topical 1% paracetamol. Protocol 2: To study the ocular pharmacokinetics and IOP pharmacodynamics after an immediate dose of IV 1% paracetamol. Protocol 3: To study the ocular pharmacokinetics and IOP pharmacodynamics of topical 1% paracetamol, 1% AM404 and 1% paracetamol/AM404 combined. Each protocol utilised paired eye and two-eye design experiments. IOP measurements were done at different time intervals using the Icare Pro© tonometer depending on the experiment. Samples for concentration measurements were taken from the serum, aqueous humour (AH) and the vitreous, while the analysis was done using ultra-performance liquid chromatography, coupled to tandem high-definition mass spectrometry (UPLC-MS/MS). Results Protocol 1 Pharmacokinetics: The mean (95% CI) concentration of paracetamol detected in the AH was 4.09 ppm (3.18 to 5.00) at 2 hours and 0.92 ppm (0.60 to 1.24) at 4 hours after an immediate dose of topical 1% paracetamol. Protocol 2 Pharmacokinetics The mean (95% CI) highest paracetamol concentration detected was 14.99 ppm (11.73 – 18.25); 5.99 ppm (5.42 to 6.56) and 4.64 ppm (3.24 to 6.04) at 30 minutes post-dosing in the serum, AH and vitreous respectively. The serum concentration was 31.04 ppm when extrapolating back to 0 minutes. Based on the area under the curve (AUCt0-inf), the vitreous showed the greatest paracetamol exposure (2587.78 min⋅μg/mL) followed by the serum (1323.21 min⋅μg/mL) and the AH (796.25 min⋅μg/mL). The half-life (t1/2) and clearance of the vitreous, AH and serum was 368.20 min, 41.32 mL/min; 74.10 min, 126.37 mL/min and 29.10 min, 76.05 mL/min, respectively. Pharmacodynamics The mean (95% CI) change in IOP from baseline for the left and right eye was +0.30 mmHg (-0.69 to 1.28) at 30 minutes, -0.39 mmHg (-1.26 to 0.48) at 60 minutes, +0.98 mmHg (-1.29 to 3.24) at 90 minutes and -0.78 mmHg (-2.40 to 0.84) at 120 minutes post-dosing. Protocol 3 Pharmacokinetics Half-hourly topical 1% paracetamol had a median (IQR) cumulative AH concentration of 13.0 ppm (13.60) after a 4 hour dosing interval, while hourly topical 1% paracetamol had an AH concentration of 3.60 ppm (4.85). Cumulative mean (95% CI) AH concentrations of paracetamol after half-hourly topical drug application at 4 hours were 0.66 ppm (0.45 to 0.87) for paracetamol/AM404 combined, 0.08 ppm (0.04 to 0.12) for AM404 only and 0.79 ppm (0.52 to 2.17) for paracetamol only. AM404 was detected in the AH of one rabbit receiving paracetamol only eye drops where the recorded level was 0.008 ppm. Pharmacodynamics The integral IOP, defined as the integral of IOP change from baseline over time and calculated as an AUC was -5.1 mmHg⋅hr (95% CI, -10 to 0.41) for the control, -7.5 mmHg⋅hr (95% CI, - 14 to -1.1) for half-hourly topical 1% paracetamol and -4.4 mmHg⋅hr (95% CI, -14 to 5.5) for hourly topical 1% paracetamol over a 4-hour period. When comparing topical paracetamol with topical AM404, the integral IOP was -2.3 mmHg⋅hr (95% CI, -5.9 to 1.3) for the control, -2.0 mmHg⋅hr (95% CI, -5.6 to 1.7) for half-hourly topical 1% AM404, -1.7 mmHg⋅hr (95% CI, -4.5 to 1.2) for half-hourly topical 1% paracetamol and - 3.2 mmHg⋅hr (95% CI, -5.4 to -0.96) for half-hourly topical 1% paracetamol/AM404 combined. Conclusion Paracetamol, but not its metabolite AM404, penetrated the multi-layered cornea via passive diffusion in a dose-dependent fashion. AM404 was measured in the AH, which indicates potential breakdown of paracetamol into AM404 within the ocular tissues. We found a diurnal pattern with IOP lowest in the morning and highest in the afternoon. Additionally, IOP showed marked fluctuations over short periods. Using the integral IOP, it was found that there was a tendency to cause a lowering of IOP over time at higher concentrations of paracetamol in the AH, although this was not found to be significant. Topical AM404 did not show any significant IOP lowering effect.