Improved Presbyopic Vision With Miotics.

OBJECTIVE: To evaluate the efficacy of using a parasympathomimetic drug (carbachol) with an alpha agonist (brimonidine) to create optically beneficial miosis to reduce the effect of presbyopia. METHODS: In this prospective, double-masked, randomized, placebo-controlled clinical trial, 48 naturally emmetropic and presbyopic subjects aged between 43 and 56 years with an uncorrected distance visual acuity of at least 20/20 in both eyes without additional ocular pathology were eligible for inclusion. Subjects were divided into 2 groups. The treatment group (n=30 eyes) received single dose of 2.25% carbachol plus 0.2% brimonidine eye drops. The control group (n=18 eyes) received placebo drops. Drops were given to all subjects in a masked fashion, in their nondominant eye. The minimum posttreatment follow-up was 3 months. The subjects' pupil size and both near and distance visual acuities were evaluated before and after treatment at 1, 2, 4, 8, and 10 hr, by a masked examiner at the same room illumination. RESULTS: Statistically significant improvement in near visual acuity was achieved in all subjects who received carbachol plus brimonidine drops (P<0.0001). In this masked study, all subjects liked and would use this therapy if it was available. None would use the placebo. There was no evidence of tolerance or tachyphylaxis during the study period. CONCLUSIONS: Improving the depth of focus by making the pupil smaller caused statistically significant improvement in near visual acuity in emmetropic presbyopic subjects. Carbachol plus brimonidine seem to be an acceptable and safe alternative to corrective lenses and surgical procedures.

Effects of intravitreal insulin and insulin signaling cascade inhibitors on emmetropization in the chick.

PURPOSE: Intravitreal insulin has been shown to be a powerful stimulator of myopia in chickens, in particular if the retinal image is degraded or defocused. In most tissues, the insulin receptor activates two main signaling pathways: a) the mitogen-activated protein kinase (MAPK) cascade (e.g., mitogen-activated protein kinasem kinase [MEK] and extracellular regulated kinase [ERK]) and b) the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. In the current study, insulin was injected, and these pathways were separately inhibited to determine which is activated when the retinal image is defocused by spectacle lenses. METHODS: Chicks were treated with either +7 D, -7 D, or no lenses. They were intravitreally injected with insulin, the MEK inhibitor U0126, the PI3K inhibitor Ly294002, or a combination of insulin and one of the inhibitors. Refractions and ocular dimension were measured at the beginning and after four days of treatment. The retinal proteins of the chicks were measured with western blots after 2 h and four days of treatment. Incubation occurred with anti-Akt1, anti-Erk1/2, anti-phospho-Akt(Thr308), and anti-phospho-Erk1/2((Thr202/Tyr204)) antibodies, and the ratio between the relative intensity of the phospho-form and the total-form was calculated. RESULTS: Chicks wearing positive lenses and injected with saline and with PI3K inhibitor compensated for the imposed defocus and became hyperopic. Insulin injections and insulin plus PI3K inhibitor injections prevented lens-induced hyperopia, whereas the MEK inhibitor alone and insulin plus MEK inhibitor had no effect. Obviously, the MEK inhibitor suppressed the effect of insulin on eye growth in the plus lens-treated animals. Chicks treated with negative lenses and injected with insulin, or with insulin plus MEK inhibitor, overcompensated for the imposed defocus. This effect of insulin was not detected in eyes injected with PI3K inhibitor plus insulin, suggesting that the PI3K inhibitor suppressed the effects of insulin in minus lens-treated animals. Insulin increased the ratio of phospho-Akt/total-Akt in animals with normal visual exposure but even more so in chicks wearing plus or minus lenses. The increase was blocked by simultaneous PI3K inhibitor injections in control eyes but not in lens-treated eyes. Insulin also increased the ratio of phospho-ERK/total-ERK in animals with normal visual exposure and in animals wearing positive lenses, compared to U0126- and Ly294002-injected eyes. In contrast, no significant activation of the MEK/ERK pathway was observed in the negative lens-treated animals. CONCLUSIONS: Intravitreal insulin promoted axial eye growth and stimulated both signaling pathways. The PI3K/Akt pathway was activated in control and plus and minus lens-treated eyes, but the MEK/ERK pathway was activated only with positive lenses or no lenses. With negative lenses, insulin did not stimulate the MEK/ERK signaling cascade. Independent of the pathway stimulated after insulin binding, the effect on insulin was always the same: an increase in eye growth.

The Adenosine Receptor Antagonist, 7-Methylxanthine, Alters Emmetropizing Responses in Infant Macaques.

Purpose: Previous studies suggest that the adenosine receptor antagonist, 7-methylxanthine (7-MX), retards myopia progression. Our aim was to determine whether 7-MX alters the compensating refractive changes produced by defocus in rhesus monkeys. Methods: Starting at age 3 weeks, monkeys were reared with -3 diopter (D; n = 10; 7-MX -3D/pl) or +3D (n = 6; 7-MX +3D/pl) spectacles over their treated eyes and zero-powered lenses over their fellow eyes. In addition, they were given 100 mg/kg of 7-MX orally twice daily throughout the lens-rearing period (age 147 ± 4 days). Comparison data were obtained from lens-reared controls (-3D/pl, n = 17; +3D/pl, n = 9) and normal monkeys (n = 37) maintained on a standard diet. Refractive status, corneal power, and axial dimensions were assessed biweekly. Results: The -3D/pl and +3D/pl lens-reared controls developed compensating myopic (-2.10 ± 1.07 D) and hyperopic anisometropias (+1.86 ± 0.54 D), respectively. While the 7-MX +3D/pl monkeys developed hyperopic anisometropias (+1.79 ± 1.11 D) that were similar to those observed in +3D/pl controls, the 7-MX -3D/pl animals did not consistently exhibit compensating myopia in their treated eyes and were on average isometropic (+0.35 ± 1.96 D). The median refractive errors for both eyes of the 7-MX -3D/pl (+5.47 D and +4.38 D) and 7-MX +3D/pl (+5.28 and +3.84 D) monkeys were significantly more hyperopic than that for normal monkeys (+2.47 D). These 7-MX-induced hyperopic ametropias were associated with shorter vitreous chambers and thicker choroids. Conclusions: In primates, 7-MX reduced the axial myopia produced by hyperopic defocus, augmented hyperopic shifts in response to myopic defocus, and induced hyperopia in control eyes. The results suggest that 7-MX has therapeutic potential in efforts to slow myopia progression.

Opposing effects of atropine and timolol on the color and luminance emmetropization mechanisms in chicks.

This study analyzed the luminance and color emmetropization response in chicks treated with the nonselective parasympathetic antagonist atropine and the sympathetic ß-receptor blocker timolol. Chicks were binocularly exposed (8h/day) for 4days to one of three illumination conditions: 2Hz sinusoidal luminance flicker, 2Hz sinusoidal blue/yellow color flicker, or steady light (mean 680lux). Atropine experiments involved monocular daily injections of either 20µl of atropine (18nmol) or 20µl of phosphate-buffered saline. Timolol experiments involved monocular daily applications of 2 drops of 0.5% timolol or 2 drops of distilled H2O. Changes in the experimental eye were compared with those in the fellow eye after correction for the effects of saline/water treatments. Atropine caused a reduction in axial length with both luminance flicker (-0.078±0.021mm) and color flicker (-0.054±0.017mm), and a reduction in vitreous chamber depth with luminance flicker (-0.095±0.023mm), evoking a hyperopic shift in refraction (3.40±1.77D). Timolol produced an increase in axial length with luminance flicker (0.045±0.030mm) and a myopic shift in refraction (-4.07±0.92D), while color flicker caused a significant decrease in axial length (-0.046±0.017mm) that was associated with choroidal thinning (-0.046±0.015mm). The opposing effects on growth and refraction seen with atropine and timolol suggest a balancing mechanism between the parasympathetic and ß-receptor mediated sympathetic system through stimulation of the retina with luminance and color contrast.

Revisiting the impact of phenylephrine hydrochloride on static and dynamic accommodation.

PURPOSE: Phenylephrine hydrochloride (PHCl), a commonly used mydriatic agent, causes a small but significant deterioration of accommodation. The relative roles of pharmacology and optics in this deterioration, however, remain unascertained. The study determined the combined impact of PHCl concentration (pharmacology) and pupil size (optics) on the static and dynamic characteristics of accommodation. MATERIALS AND METHODS: A total of 16 emmetropic Indian adults viewed a high-contrast visual target that switched between 67 and 33 cm viewing distance (1.5D stimulus) with their right eye (left eye occluded using infrared transmitting filter) through natural pupils and through 8, 6, 4, and 1 mm diameter artificial pupils. This protocol was repeated once without PHCl and once each with 2.5%, 5%, and 10% PHCl. Consensual accommodation of the left eye was recorded using infrared photorefraction (60 Hz). RESULTS: Relative to no PHCl, the horizontal pupil diameter of left eye was significantly larger (P < 0.001) and the response magnitude and peak velocity of accommodation and disaccommodation were modestly but significantly smaller (P < 0.02 for all) for all concentrations of PHCl tested. There was no significant difference in these parameters across the three drug concentrations (P > 0.4 for all). The response magnitude and peak velocity also decreased significantly with pupil diameter, at similar rates for the no PHCl and the three PHCl conditions (P < 0.001 for all). CONCLUSION: The reduction in accommodative performance with all drug concentrations and with pupil diameter suggests independent roles of pharmacology and optics in determining accommodative performance with PHCl. The reduction in accommodative performance is, however, modest and may be clinically irrelevant in Indian eyes.