Topical lipoic acid choline ester eye drop for improvement of near visual acuity in subjects with presbyopia: a safety and preliminary efficacy trial.

OBJECTIVES: This study evaluated the safety of topical lipoic acid choline ester (UNR844, 1.5%) ophthalmic solution and its efficacy in improving distance-corrected near visual acuity (DCNVA) in subjects with presbyopia. SUBJECTS AND METHODS: This was a prospective, randomized, double-masked, and multicentre clinical trial. Subjects with a diagnosis of presbyopia (n = 75) were randomized 2:1 to UNR844 or placebo. On days 1-7, all subjects were dosed unilaterally (twice a day, b.i.d.) in their non-dominant eye to ensure safety and tolerability prior to days 8-91 when dosing was changed to bilateral (b.i.d.). Clinical assessments, including DCNVA and adverse events (AEs), were recorded at each study visit. Patients who completed the study were recruited into a non-interventional follow-up study that monitored them until 7 months after their final UNR844 exposure. The primary endpoints were safety and the mean change in DCNVA from baseline in the study eye. RESULTS: UNR844 administration (n = 50) produced no safety concerns and was well-tolerated, with no clinically-relevant changes in best-corrected distance visual acuity, pupil size, intraocular pressure, or discontinuations due to adverse events. DCNVA improved in the study eye in the UNR844 group compared to placebo during the 91 days of treatment [UNR844 vs. placebo, mean change in LogMAR (SD); -0.159 (0.120) vs. -0.079 (0.116)]. Bilateral DCNVA improved, with 53.1% UNR844 vs. 21.7% placebo subjects gaining ≥10 letters. Improvements in DCNVA were sustained at 5 and 7 months after UNR844 dosing ceased. CONCLUSIONS: These results support further development of UNR844 ophthalmic solution for the treatment of presbyopia.

A 3-month safety and efficacy study of travoprost 0.004% ophthalmic solution compared with timolol in pediatric patients with glaucoma or ocular hypertension.

PURPOSE: To evaluate efficacy and safety of travoprost in pediatric patients with ocular hypertension or glaucoma and demonstrate its noninferiority to timolol. METHODS: Patients aged 2 months to <18 years with glaucoma or ocular hypertension were randomized to receive travoprost (0.004%) or timolol eye drops (0.25% for patients aged 2 months to <3 years and 0.5% for patients ≥3 years old) for 3 months in this double-masked, parallel-group study. Intraocular pressure (IOP) was measured and patients were evaluated at 2 weeks, 6 weeks, and 3 months after treatment. Change in IOP from baseline to 3 months was the primary endpoint, and the test of noninferiority was based on a margin of +3.0 mm Hg using the 95% 2-sided confidence interval of the mean change. RESULTS: Of 157 patients included (mean age, 9.6 years), 77 received travoprost and 75 timolol. All patients experienced a significant reduction in IOP in the study eye at 3 months: the mean IOP change from baseline was -5.4 mm Hg for travoprost; -5.3 mm Hg, for timolol. The mean difference between travoprost and timolol at month 3 was -0.1 mm Hg (95% CI, -1.5 to 1.4 mm Hg). The most common treatment-related adverse events for the travoprost group were ocular hyperemia and eyelash growth. No serious adverse events were reported. CONCLUSIONS: This study found travoprost to be noninferior to timolol in lowering IOP in patients with pediatric glaucoma or ocular hypertension. Travoprost was well-tolerated, and no treatment-related systemic adverse events were reported.

Vascular reactivity of optic nerve head and retinal blood vessels in glaucoma--a review.

Glaucoma is characterized by loss of retinal nerve fibers, structural changes to the optic nerve, and an associated change in visual function. The major risk factor for glaucoma is an increase in intraocular pressure (IOP). However, it has been demonstrated that a subset of glaucoma patients exhibit optic neuropathy despite a normal range of IOP. It has been proposed that primary open angle glaucoma could be associated with structural abnormalities and/or functional dysregulation of the vasculature supplying the optic nerve and surrounding retinal tissue. Under normal conditions, blood flow is autoregulated, i.e., maintained at a relatively constant level, in the retina and ONH, irrespective of variation in ocular perfusion pressure. A number of factors released by the vascular endothelium, including endothelin-1 and nitric oxide, are suggested to play an important role in the regulation of local perfusion in the retina and ONH. Most work to-date has investigated homeostatic hemodynamic parameters in glaucoma, rather than the measurement of the hemodynamic response to a provocation. Future work should comprehensively assess blood flow in all the ocular vascular beds and blood vessels supplying the eye in response to standardized stimuli in order to better understand the pathophysiology of glaucomatous optic neuropathy.

Retinal arteriolar vascular reactivity in untreated and progressive primary open-angle glaucoma.

Purpose. To determine (1) the magnitude of retinal arteriolar vascular reactivity to normoxic hypercapnia in patients with untreated primary open-angle glaucoma (uPOAG) or progressive (p)POAG and in control subjects and (2) the effect of treatment with 2% dorzolamide on retinal vascular reactivity in uPOAG. Methods. The sample comprised 11 patients with uPOAG (after undergoing treatment, they became treated (t)POAG), 17 patients with pPOAG (i.e., manifesting optic disc hemorrhage), and 17 age-similar control subjects. The partial pressure of end-tidal CO(2) (PetCO(2)) was stabilized at 38 mm Hg at baseline. After baseline (10 minutes), normoxic hypercapnia was then induced (15 minutes) with an automated gas flow controller. Retinal arteriolar and optic nerve head (ONH) blood hemodynamics were assessed. The procedures were repeated after treatment with 2% dorzolamide for 2 weeks in tPOAG. Results. Baseline arteriolar hemodynamics were not different across the groups. In control subjects, diameter, velocity, and flow increased (P < 0.001) in response to normoxic hypercapnia. There was no change in all three hemodynamic parameters to normoxic hypercapnia in uPOAG, whereas only blood flow increased (P = 0.030) in pPOAG. Vascular reactivity was decreased in uPOAG and pPOAG patients compared with that in control subjects. After treatment with topical 2% dorzolamide for 2 weeks, the tPOAG group showed an increase in diameter, velocity, and flow (P

The relationship between retinal vascular reactivity and arteriolar diameter in response to metabolic provocation.

PURPOSE: To compare the magnitude of vascular reactivity in response to metabolic provocation in retinal arterioles of varying diameter in healthy young subjects. METHODS: Ten healthy young subjects (26.2 +/- 3.5 years [mean +/- SD]) attended for three sessions. Session 1 was used to select two discrete hemodynamic measurement sites along the superior temporal arteriole. Retinal arteriolar blood flow was assessed at relatively narrow and wide sites. At sessions 2 and 3, CO(2) and O(2) were sequentially administered (and alternated across sessions) using manual gas flow control via a modified sequential rebreathing circuit to achieve target hypercapnia and hyperoxia. Blood flow was assessed for each gas phase. Total vascular reactivity capacity (TVRC) was taken as the difference in flow between hypercapnia and hyperoxia. RESULTS: The baseline diameter for the narrow and wide measurement sites was 92.4 microm (+/-13.6) and 116.7 microm (+/-12.7), respectively (ReANOVA; P < 0.0001). Hyperoxia induced a decrease in blood flow, whereas hypercapnia increased flow (P < 0.0001). TVRC was greater for the wide than for the narrow measurement sites (Delta flow narrow = 3.0 microL/min versus Delta flow wide = 6.6 microL/min; P < 0.0001). In terms of percentage change in flow relative to baseline, TVRC was the same between the wide and narrow sites (Delta narrow = 67% versus Delta wide = 61%; P > 0.05). CONCLUSIONS: In response to metabolic provocation, absolute TVRC was greater for retinal arteriolar measurement sites with wider baseline vessel diameters. However, percentage change in retinal blood flow was the same irrespective of initial arteriolar diameter.

Retinal arteriolar and capillary vascular reactivity in response to isoxic hypercapnia.

The aim of the study was to compare the magnitude of vascular reactivity of the retinal arterioles in terms of percentage change to that of the retinal capillaries using a novel, standardized methodology to provoke isoxic hypercapnia. Ten healthy subjects (mean age 25 years, range 21-31) were recruited. Subjects attended a single visit comprising two study sessions separated by 30 min. Subjects were fitted with a sequential re-breathing circuit connected to a computer-controlled gas blender. Each session consisted of breathing at rest for 10 min (baseline), increase of P(ET)CO(2) (maximum partial pressure of CO(2) during expiration) by 15% above baseline whilst maintaining isoxia for 20 min, and returning to baseline conditions for 10 min. Retinal hemodynamic measurements were performed using the Canon Laser Blood Flowmeter and the Heidelberg Retina Flowmeter in random order across sessions. Retinal arteriolar diameter, blood velocity and flow increased by 3.3%, 16.9% and 24.9% (p<0.001), respectively, during isoxic hypercapnia. There was also an increase of capillary blood flow of 34.8%, 21.6%, 24.9% (p< or =0.006) at the optic nerve head neuroretinal rim, nasal macula and fovea, respectively. The coefficient of repeatability (COR) was 5% of the average P(ET)CO(2) both at baseline and during isoxic hypercapnia and was 10% and 7% of the average P(ET)O(2) (minimum partial pressure of oxygen at end exhalation), respectively. The overall magnitude of retinal capillary vascular reactivity was equivalent to the arteriolar vascular reactivity with respect to percentage change of flow. The magnitude of isoxic hypercapnia was repeatable.

Impact of simulated light scatter on the quantitative, noninvasive assessment of retinal arteriolar hemodynamics.

We determine the impact of artificial light scatter on quantitative, noninvasive assessment of retinal arteriolar hemodynamics. One eye from each of 10 healthy young subjects between the ages of 18 and 30 (23.6+/-3.4) is randomly selected. To simulate light scatter, cells comprising a plastic collar and two plano lenses are filled with solutions of differing concentration of polystyrene microspheres (Polysciences Inc., USA). We prepare 0.002, 0.004, 0.006, and 0.008% microsphere concentrations as well as distilled water only. The Canon laser blood flowmeter (CLBF) is used to noninvasively assess retinal arteriolar blood flow. After a preliminary screening to confirm subject eligibility, seven arteriolar blood flow measurements are taken by randomly placing the cells between the instrument objective lens and the subjects' cornea. To achieve a baseline, subjects are first imaged with no cell in place. Both low- and high-intensity CLBF laser settings are assessed. Our light scatter model results in an artifactual increase of retinal arteriolar diameter (p<0.0001) and thereby increased retinal blood flow (p<0.0001). The 0.006 and 0.008% microsphere concentrations produce significantly higher diameter and flow values than baseline. Centerline blood velocity, however, is not affected by light scatter. Retinal arteriolar diameter values are significantly less with the high-intensity laser than with the low-intensity laser (p=0.0007). Densitometry assessment of vessel diameter is increasingly impacted as the magnitude of artificial light scatter increases; this effect can be partially negated by increasing laser intensity. A cataract is an inevitable consequence of aging and, therefore, care must be exercised in the interpretation of studies of retinal vessel diameter that use similar densitometry techniques.

Novel methodology to comprehensively assess retinal arteriolar vascular reactivity to hypercapnia.

PURPOSE: (1) Describe a new methodology that permits the comprehensive assessment of retinal arteriolar vascular reactivity in response to a sustained and stable hypercapnic stimulus. (2) Determine the magnitude of the vascular reactivity response of the retinal arterioles to hypercapnic provocation in healthy, young subjects. METHODOLOGY: Eleven healthy subjects of mean age 27 years (SD 3.43) participated in the study and one eye was randomly selected. A mask attached to a sequential rebreathing circuit, and connected to a gas delivery system, was fitted to the face. To establish baseline values, subjects breathed bottled air for 15 min and at least 6 blood flow measurements of the supero-temporal arteriole were acquired using the Canon Laser Blood Flowmeter (CLBF). Air flow was then decreased until a stable increase in fractional end-tidal CO(2) concentration (F(ET)CO(2)) of 10-15% was achieved. CLBF measurements were acquired every minute (minimum of 6 measurements) during the 20-minute period of elevated F(ET)CO(2). F(et)CO(2) was then reduced to baseline levels, and 6 further CLBF measurements were acquired. Respiratory rate, blood pressure, pulse rate and oxygen saturation were monitored continuously. RESULTS: Retinal arteriolar diameter, blood velocity and blood flow increased during hypercapnia relative to baseline (p=0.0045, p<0.0001 and p<0.0001, respectively). Group mean F(ET)CO(2) showed an increase of 12.0% (SD 3.6) relative to baseline (p<0.0001). CONCLUSIONS: This study describes a new methodology that permits the comprehensive assessment of retinal arteriolar vascular reactivity in response to a sustained and stable hypercapnic stimulus. Retinal arteriolar diameter, blood velocity and blood flow increased significantly in response to a hypercapnic provocation in young, healthy subjects.

The impact of artificial light scatter on scanning laser tomography.

PURPOSE: The impact of cataract (which frequently occurs alongside glaucoma) on scanning laser tomography (SLT) is poorly understood. The aim of this pilot study was to determine the impact of artificial light scatter on SLT estimates of optic nerve head (ONH) topography. METHODS: The sample comprised 10 healthy, young subjects of mean age 23.5 years. One eye of each subject was randomly selected. Cells filled with increasing concentrations of 0.50-microm diameter polystyrene microspheres were prepared. The cells were mounted in front of the objective lens of the Heidelberg Retina Tomograph (HRT) II and were tilted at an angle of 20 degrees to eradicate any surface reflections. Three sets of ONH scans were initially acquired without any light scatter cell in place and then three further sets were acquired for each of four different concentrations of microspheres in a randomized order. The impact of artificial light scatter on cup-to-disc area ratio, cup volume, rim volume, cup shape measure, height variation contour, and mean retinal nerve fiber layer (RNFL) thickness was evaluated. RESULTS: Repeated-measures analysis of variance showed that there was no significant change in cup-to-disc area ratio, cup volume, rim volume, height variation contour, cup shape measure, or mean RNFL thickness as a function of increasing light scatter cell concentration. CONCLUSION: Artificial light scatter had no statistically significant impact on the stereometric parameters of the HRT II. From a clinical perspective, useful SLT data can be acquired with confidence from patients with diagnosed/suspected glaucoma and concomitant cataract.

The impact of hypercapnia on retinal capillary blood flow assessed by scanning laser Doppler flowmetry.

AIM: To determine the effect of hypercapnia on retinal capillary blood flow using scanning laser Doppler flowmetry (SLDF). METHODS: One randomly selected eye of each of 10 normal healthy subjects (mean age 25 years, SD 2.3) was studied. Subjects breathed unrestricted air for 15 min before (baseline) and after raising fractional (percent) end-tidal concentration of CO2 (FETCO2) for 15 min by adding low flows of CO2 to air entering a sequential gas delivery circuit attached to a nasal mask. Five good quality baseline SLDF images were acquired both of the optic nerve head (ONH) and of the macula. Subsequently, a minimum of 7 sequential images were acquired during hypercapnia. Five further images were acquired of the ONH, or of the macula, after returning to unlimited air breathing. The respiratory parameters of subjects were continually monitored. RESULTS: The group mean increase in end-tidal CO2 was 14.13% (SD 4.10) relative to baseline. The nasal macula (P = 0.028) and foveal (P = 0.042) areas showed a significant increase in retinal capillary blood flow in response to hypercapnia while no significant change was noted in the ONH or temporal macula areas. Change in blood flow significantly correlated with change of FETCO2 and/or end-tidal PO2 for 3 of the 4 locations. CONCLUSIONS: Hypercapnia provoked a significant increase in retinal capillary blood flow in 2 of 4 retinal locations. Hypercapnia also induced a change in respiratory parameters that significantly correlated with change in retinal capillary blood flow in 3 of the 4 locations.

Comparison of different hyperoxic paradigms to induce vasoconstriction: implications for the investigation of retinal vascular reactivity.

PURPOSE: To compare the impact of three different techniques used to induce hyperoxia on end-tidal CO2 (PETCO2). The relationship between change in PETCO2 and retinal hemodynamics was also assessed to determine the clinical research relevance of this parameter. METHODS: The sample comprised 10 normal subjects (mean age, 25 years; range, 21-49 years). Each subject attended for three sessions. At each session, subjects initially breathed air followed by O2 only; O2 plus CO2, using a nonrebreathing circuit (with CO2 flow continually adjusted to negate drift of PETCO2); or air followed by O2, using a sequential rebreathing circuit. In addition, using a separate sample of eight normal subjects (mean age, 26.5 years; range, 24-36 years), a methodology that initially raised PETCO2 and then returned to homeostatic levels was used to determine the impact, if any, of perturbation of PETCO2 on retinal hemodynamics. RESULTS: The difference in group mean PETCO2 between baseline and elevated O2 breathing was significantly different (t-test, P = 0.0038) for O2-only administration with a nonrebreathing system. The sequential rebreathing technique resulted in a significantly lower difference (i.e., before and during hyperoxia) of individual PETCO2 (t-test, P = 0.0317). The PETCO2 perturbation resulted in a significant (P < 0.005) change of retinal arteriolar diameter, blood velocity, and blood flow. CONCLUSIONS: The sequential rebreathing technique resulted in a reduced variability of PETCO2. A relatively modest change in PETCO2 resulted in a significant change in retinal hemodynamics. Rigorous control of PETCO2 is necesssary to attain standardized, reproducible hyperoxic stimuli for the assessment of retinal vascular reactivity.