There are several efforts to mitigate presbyopia symptoms using drugs targeting the iris sphincter and the dilator in presbyopic individuals. In 1990 Rosenfeld documented the use of phenylephrine and thymoxamine (an alpha antagonist) achieving 1.5 D accommodative amplitude lasting only two hours. 22 Benozzi reported a combination of Pilocarpine 1–2% combined with Diclofenac to treat presbyopic individuals for a 5 years period. At such dose 20% of patients experienced eye burning, and ocular discomfort right after drop instillation. 1% discontinued treatment due to intolerance to medication, 4% preferred glasses. 23
Brimonidine has a direct effect in pupil size after instillation. It has a miotic effect under photopic and scotopic conditions. 24 It has been used by refractive surgeons in the commercial presentations 0.2% and 0.15% to successfully palliate adverse effect of laser procedures such as glare and halos, obtaining the effect 30 minutes after instillation and lasting up to six hours. 25–26
The use of Brimonidine in a lower dose (0.1%) has shown a similar effect on pupil size than the regular concentrations. 27 Base line photopic pupil diameter was 3.73 mm +/- 0.46 range (3 to 4). One hour after PBO instillation in the non-dominant eye, pupil diameter was 2.63 mm +/-0.63 range (2 to 4) (p ≤ 0.039). In the Pilocarpine or Brimonidine group pupilar diameter was 3.13 mm +/-0.63 range (2 to 4) (p ≤ 0.059). Baseline scotopic pupil diameter was 4.63 mm +/-0.63 range (3.5 to 5). One hour after PBO instillation the pupil diameter was 2.68 mm +/- 0.60 range (2 to 4) (p ≤ 0.042). In the Pilocarpine or Brimonidine group, pupilar diameter was 2.9 mm +/- 0.66 range (2 to 4) (p ≤ 0.061) (Table 3). We researched the effect of low dose of Pilocarpine, Brimonidine and Oxymetazoline (PBO) mitigating the effects of presbyopia in eleven healthy individuals in order to avoid undesirable effects as pain, burning, discomfort and blurry distance vision. One hour after instillation of the compound in the non-dominant eye, Jaeger notation improved from 5.82 to 2.09 (p ≤ 0.0001) compared to low dose Pilocarpine 4.2 (p ≤ 0.102) and non-dominant low dose Brimonidine 3.5 (p ≤ 0.25) alone (Table 1). The combination showed a significant improvement in the Jaeger notation one hour after instillation compared to Pilocarpine and Brimonidine alone.
Renna published in 2016 a compound including Pilocarpine 0.247%, Phenylephrine 0.78%, Polyethylene glycol 0.09%, Nepafenac 0.023%, Pheniramine 0.034% and Naphazoline 0.003% instilled binocularly in 14 presbyopic subjects. 28 The results showed 2 to 3 lines of UNVA improvement. No patient had lost of UDVA in each eye and binocularly. Our study showed 2 to 6 lines of UNVA improvement. Average 3.73 lines compared to 1.6 with low dose Pilocarpine and 2.33 with low dose Brimonidine. Accordingly, no patients lost UDVA (Table 2). In 2018 Vargas, from the same study group published a series of 117 presbyopic patients using the same formulation achieving significant improving of UNVA in 92.3% of patients 2 hours post eye drop instillation. 14 patients reported headache, 1 patient was intolerant to the preparation. 29 Giovanna Benozzi reports in 2020 a retrospective series from 1 up to 8 years follow up of 910 patients, with high adherence to treatment and discontinuing the use of presbyopia spectacles. The most frequent side effect was dim vision 246 individuals (26%), headache 119 (12.9%), ocular surface burning 86 (9.3%). 30 Although is a small population, no patient reported headache in our series. Pain in the PBO non dominant eye was in AVS 0. Pain in the Pilocarpine or Brimonidine dominant eye in an AVS was reported by 2 patients grade 2 and 3 respectively. Hyperemia in the PBO non dominant eye was 1 in 1 eye of 11 (9%). Hyperemia in the Pilocarpine Brimonidine dominant eye was present in 4 patients: 3 with grade 1 hyperemia and 1 with grade 2 hyperemia (36%).
The combination of low dose Pilocarpine, a muscarinic parasympathomimetic, acting on receptors at the iris sphincter and the ciliary muscle, with Brimonidine and Oxymetazoline at low doses has an additive effect one hour after instillation. Brimonidine acts at the alpha 2 receptor of the iris dilator muscle, inhibiting its function and inducing indirect miosis. Combining those agents to induce miosis gave us the rationale to lower the concentration to achieve a similar result and avoiding the side effects such as pain and discomfort. We believe that lowering the Pilocarpine dose avoids ciliary muscle spasm related pain and induced myopia, affecting distance vision. None of our patients reported blurry vision at distance. No patient loss lines of UDVA. Oxymetazoline and alpha 1 and partial alpha 2 imidazolic agonist has a mydriatic effect. We believe it opposes the action of the Pilocarpine and Brimonidine, hence avoiding spasm of the iris sphincter, and allowing pupil movement. 31
This novel combination of Pilocarpine, Brimonidine and Oxymetazoline in low doses has an synergistic effect improving near vision in presbyopic patients, achieving at least up to 3.73 lines of near vision gain on the Jaeger notation. This compound has a potential use to mitigate the symptoms of presbyopia in healthy individuals. Further studies are being designed to document the long term effect of this compound in patients with presbyopia.