Clinical Pharmacology

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This division was known as Pharmacology until 27 June 2013.

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Browsing Clinical Pharmacology by browse.metadata.advisor "Meyer, David"

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    Intravitreal Bevacizumab as anti-vascular endothelial growth factor in the management of complications of diabetic retinopathy
    (Stellenbosch : Stellenbosch University, 2018-12) Arevalo, J. Fernando; Meyer, David; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.
    ENGLISH ABSTRACT: Bevacizumab is a complete full-length humanized antibody that binds to all subtypes of vascular endothelial growth factor (VEGF) and is used successfully in tumor therapy as a systemic drug. Recent studies have demonstrated the usefulness of an intravitreal injection of bevacizumab (IVB) in the reduction of macular edema secondary to central retinal vein occlusion, and choroidal neovascularization secondary to age-related macular degeneration (AMD). The drug is extremely cost-effective compared to similar anti-VEGF drugs on the market, hence the need to examine its effect in diabetic eye disease (the ever-growing global health epidemic challenge) for application in middle to low income countries. The purpose of the current research is to determine if intravitreal bevacizumab (IVB) as anti-VEGF is helpful in the management of complications of diabetic retinopathy. We conducted several multicenter retrospective studies of eyes with complications from diabetic retinopathy treated with off-label IVB. Ten previously published studies (one prospective), and one unpublished prospective study are included here on the management of diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). We progressively reported over the years our experienced as we followed patients with DME treated with IVB at 6 months, 12 months, and 24 months of follow up. In addition, 5 year follow up data was added later on. We found that primary IVB at doses of 1.25 to 2.5 mg seem to provide stability or improvement in best correct visual acuity (BCVA), optical coherence tomography (OCT), and fluorescein angiography (FA) in diffuse DME at 24 months. The results show no evident difference between IVB at doses of 1.25 or 2.5 mg. However, the early visual gains due to IVB were not maintained 5 years after treatment. Later, we provide evidence to support the use of primary IVB with or without grid laser photocoagulation (GLP) as treatment of diffuse DME. Primary IVB without GLP seems to be superior to GLP alone to provide stability or improvement in best-corrected visual acuity in patients with diffuse diabetic macular edema at 24 months. We showed first that IVB resulted in marked regression of retinal neovascularization (RN) in patients with PDR and previous pan retinal photocoagulation (PRP), and rapid resolution of vitreous hemorrhage in three naive eyes. Six-months results of intravitreal bevacizumab at doses of 1.25 or 2.5 mg in patients with PDR did not reveal any safety concerns. Later, we published that IVB resulted in marked regression of RN in patients with PDR and previous pan-retinal photocoagulation at 2 years. Intravitreal bevacizumab in naive eyes resulted in control or regression of 42.1% of eyes without adjunctive laser or vitrectomy during 24 months of follow-up. Meaning that a large number of patients (almost 58%) needed PRP or vitrectomy. Another one of our studies demonstrated the usefulness of using preoperative IVB during small-gauge vitreoretinal surgery in eyes with tractional retinal detachment (TRD) in PDR. This was a prospective non-comparative study and patients had significant anatomic and functional success. In addition, we reported for the first time ever that TRD may occur or progress shortly following administration of IVB in patients with severe PDR (5.2% and 3.2% in two studies). Based on our data, we now believe that extreme care must be taken in using a dose of 2.5 mg or more of bevacizumab in patients with PDR. In addition, to have more than 15 years with a diagnosis of diabetes can increase the risk of TRD. Physicians must be prepared to perform the vitrectomy preferably before 13 days after the application of IVB and to perform a vitrectomy immediately on those patients in whom a TRD occurs. We recommend less than 5 days after injection as more than 80% of the retinal detachments developed after that period of time. Finally, in our prospective randomized clinical trial, pre-operative intravitreal bevacizumab therapy as adjuvant to PPV may be helpful and beneficial for patients with TRD secondary to severe PDR. Pre-operative IVB seems to reduce intraoperative bleeding, improving surgical visual field visualization, and reducing intraoperative and postoperative complications including iatrogenic retinal breaks and postoperative hemorrhage. In summary, IVB as anti-VEGF agent is helpful in the management of complications of diabetic retinopathy to prevent blindness with a more accessible drug worldwide.
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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.