Hanna J. Garzozi

Treatment of Dry Eye Syndrome with Orally Administered CF101: Data from a Phase 2 Clinical Trial

OBJECTIVE To explore the safety and efficacy of CF101, an A(3) adenosine receptor agonist, in patients with moderate to severe dry eye syndrome. DESIGN Phase 2, multicenter, randomized, double-masked, placebo-controlled, parallel-group study. PARTICIPANTS Sixty-eight patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group. INTERVENTION Patients were treated orally with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2-week posttreatment observation. MAIN OUTCOME MEASURES An improvement of more than 25% over baseline at week 12 in one of the following parameters: (1) tear break-up time (BUT); (2) superficial punctate keratitis assessed by fluorescein staining results; and (3) Schirmer tear test 1 results. Clinical laboratory safety tests, ophthalmic examinations, intraocular pressure (IOP) measurements, electrocardiographic evaluations, vital sign measurements, and monitoring of adverse events. RESULTS A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101-treated group and the placebo group. Treatment with CF101 resulted in a statistically significant improvement in the mean change from baseline at week 12 of the corneal staining, BUT, and tear meniscus (TM) height in the CF101-treated group. CF101 was well tolerated and exhibited an excellent safety profile with no serious adverse events. A statistically significant decrease from baseline was observed in the IOP of the CF101-treated group in comparison with the placebo group. CONCLUSIONS CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate to severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study of the drug as a potential treatment for the signs and symptoms of dry eye syndrome. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

An update on retinal circulation assessment technologies

From the most basic standpoint, the eye offers a unique opportunity to study hemodynamics. The fundus of the eye is the only location in the human body where blood flow can be directly visualized. Multiple factors influence the control and regulation of the various facets of ocular blood flow, such as metabolic demands, nutrients, metabolic by-products, perfusion pressures, and dissolved gases. In addition, many therapies are already being designed, based on their effects on ocular blood flow. This review summarizes the major technologies currently being used to evaluate the inner retinal circulation and compares much of the recent data from these methods in health and in diabetic retinopathy, the most common vascular retinal disease. Theses techniques include the following: Fluorescein angiography (FA) with confocal scanning laser ophthalmoscopy (SLO), Heidelberg retina flowmetry (HRF, scanning laser Doppler flowmeter), laser Doppler velocimetry (LDV), and Canon laser blood flowmetry (CLBF). Two other techniques, color Doppler optical coherence tomography (CDOCT) and leukocyte staining are discussed briefly.

Collagen cross-linking: Strengthening the unstable cornea.

Corneal ectasia, a weakening of corneal integrity, occurs both due to acquired and congenital conditions such as keratoconus. It is a progressing condition that affects both visual acuity, and corneal stability. Various methods exist for correcting this impairment, however none address the inherit pathology, an increase laxity of the corneal stroma. Collagen cross-linking, a new, minimally invasive method, aims to strengthen the stroma by inducing cross links between neighboring collagen fibers. This method results in an increase in corneal tensile strength, with no medium term adverse effects on its normal architecture. Clinically, treated patients display improvement in both visual acuity and keratometric readings. This method may provide clinicians with easily accessible tools to stop the progression, and even correct visual deterioration due to corneal ectasia. Here we review the current information regarding this new method, as well as discuss its potential benefits and downfalls.

Effects of long-term hypotensive therapy with nonselective beta-blockers on ocular hemodynamics in primary open-angle glaucoma.

PURPOSE Vascular factors have been implicated in the progression of glaucoma, but the impact of long-term beta blocker therapy on ocular circulation remains largely undefined. The purpose of this study was to prospectively evaluate the level of retrobulbar blood flow in patients with primary open-angle glaucoma (POAG) before and during long-term treatment with a nonselective topical beta blocker, and to compare these measures with those in untreated control subjects. METHODS Twelve control subjects and 12 patients with POAG were tested for intraocular pressure (IOP), heart rate, blood pressure, contrast sensitivity, visual field sensitivity, and retrobulbar flow velocity as measured by color Doppler imaging (CDI). Patients were evaluated after 4 weeks of drug washout and again after 3 and 6 months of treatment with a nonselective beta blocking agent. Control subjects were tested once. RESULTS At baseline, patients with POAG had significantly higher IOP than normal controls; CDI measures of the central retinal artery (CRA) and short posterior ciliary artery (SPCA) in the patients were significantly different from those in control subjects. In the patients, treatment resulted in a significant reduction in IOP and in CRA and SPCA resistance index. CONCLUSION Untreated patients with POAG have altered circulation in the CRA and SPCA compared with subjects of similar age and gender. These measures recover significantly during topical beta blocker therapy. The relationship of the pretreatment deficit and posttreatment recovery of CDI blood flow measures to the progression and therapeutic impediment of glaucomatous optic nerve deterioration remains to be determined.

Relationship of Cerebral Blood Flow and Central Visual Function in Primary Open-angle Glaucoma

PurposeTo investigate the relations between middle cerebral artery (MCA) blood flow velocities and central visual function measured by foveal cone electroretinograms (ERG) and visual field. MethodsFifteen primary open-angle glaucoma patients were recruited. The eye with the more severe visual field defect (full threshold 24-2) and/or optic disc damage was chosen. Measurements included brachial arterial pressure, heart rate, visual acuity (logMAR), contrast sensitivity (CSV-1000), central visual field (Humphrey SITA 10-2), foveal cone ERG, and transcranial Doppler. Pearson correlation coefficients were estimated to assess the strength of the linear relationship between the MCA flow velocity and the other measured parameters. ResultsVisual field was successfully completed in 12 eyes. We were unable to obtain ERG responses and MCA velocity readings for 1 patient. A significant correlation was observed between MCA mean flow velocity and focal cone ERG amplitude [r=0.69, n=13, confidence interval (CI) 0.22, 0.90, P=0.009], but correlation between mean foveal cone ERG implicit time and middle cerebral was not statistically significant (r=0.011, n=13, CI 0.47, 0.63). A significant correlation was also observed between MCA mean flow velocity and mean sensitivity (r=0.76, n=12, CI 0.32, 0.93, P=0.005), and mean defect (r=0.73, n=12, CI 0.28, 0.92, P=0.007) of the central visual field, logMAR visual acuity (r=0.57, n=14, CI 0.05, 0.84, P=0.036), and contrast sensitivity (r=0.61, n=13, CI 0.09, 0.87, P=0.027). ConclusionsOur findings suggest that in certain primary open-angle glaucoma patients diminished central visual function may be one manifestation of widespread cerebrovascular insufficiency.

Interobserver repeatability of Heidelberg retinal flowmetry using pixel-by-pixel analysis

PurposeTo determine the interobserver reproducibility of Heidelberg retinal flowmeter (HRF) blood flow measurements using independently selected study areas for pixel-by-pixel analysis. Patients and MethodsBlood flow measurements were performed on 257 scans from 15 patients, 14 of whom had glaucoma or ocular hypertension. HRF was used to record capillary perfusion in a 2560×640 μm area of the supratemporal peripapillary region and pixel-by-pixel analysis was performed from an area adjacent to the optic disc with a minimum of 1600 pixels. Each observer independently selected the area for analysis. The percentage of pixels with <1 arbitrary unit of flow (no flow) and 10, 25, 50, 75, and 90th percentiles of flow values was calculated. Interobserver variability was assessed by estimating the intraclass correlation coefficient (ICC) and its 95% confidence interval. Bland-Altman plots of the difference between the 2 physicians versus the average of the 2 physicians for each outcome were created. ResultsICC was 0.79 (range: 0.74 to 0.83) for mean flow values. For 0, 10, 25, 50, 75, and 90th percentiles of flow, the ICC was 0.67 (0.60 to 0.73), 0.74 (0.68 to 0.79), 0.82 (0.78 to 0.86), 0.85 (0.82 to 0.88), 0.85 (0.81 to 0.88), and 0.77 (0.72 to 0.82), respectively. Zero flow pixels had a nonsignificant mean difference between observers (P=0.542), whereas the remainder of the flow values demonstrated significant mean differences. ConclusionsThis study demonstrates that independent observers can review high-quality HRF scans and may produce different absolute values while retaining strong consistency of agreement when independently selecting areas for analysis using the pixel-by-pixel method.

The Effects of Droperidol in Perforating Keratoplasty

Purpose: To evaluate the intraoperative and postoperative effects of droperidol administered with general anesthesia during perforating keratoplasty. Methods: A prospective, randomized, double-masked clinical trial. Twenty-seven patients undergoing penetrating keratoplasty under general anesthesia were included. Patients were assigned randomly to two groups. Fifteen subjects received droperidol during induction of general anesthesia. Twelve control patients received general anesthesia without droperidol. Results: Droperidol significantly reduced fellow eye intraocular pressure (p < 0.0001). Intraoperative anterior chamber depth was significantly deeper with droperidol (p = 0.0002). Iris bulging was observed in 25% of the control group and 0% with droperidol. There was significantly less postoperative nausea in the droperidol group (p = 0.038). There was less postoperative vomiting in the droperidol group, although the difference was not significant (p = 0.07). Postoperative wound gaping was observed in 2 patients; both of them did not receive droperidol. Conclusions: Droperidol effectively reduces intraoperative and postoperative complications in keratoplasty surgery.