Volume 4, Number 21

Monday, May 24, 2004

In this issue: (click heading to view article)
		R-cadherin Antagonists for Treating Neovascular Diseases with Abnormal Angiogenesis
		Blood-retinal Barrier Permeability in Patients With Essential Hypertension
		Chlamydia psittaci and Ocular Adnexal Lymphomas May Be Associated
		Intraocular and Plasma Levels of Cellular Fibronectin in Uveitis and Diabetes Patients
		Tear Function and Ocular Surface Findings in Premature and Term Babies
		Briefly

R-cadherin Antagonists for Treating Neovascular Diseases with Abnormal Angiogenesis Adult bone marrow contains a population of hematopoietic stem cells (HSCs) that can give rise to cells capable of targeting sites of neovascularization in the peripheral or retinal vasculature. However, relatively little is known about the mechanism of targeting of these cells to sites of neovascularization. Investigators at the Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, analyzed subpopulations of HSCs for the expression of a variety of cell surface adhesion molecules and found that R-cadherin, a calcium-dependent cell-cell adhesion molecule important for normal retinal endothelial cell guidance, was preferentially expressed by functionally targeting HSCs. Preincubation of HSCs with function-blocking anti-R-cadherin antibodies or novel R-cadherin-specific peptide antagonists effectively prevented targeting of bone marrow-derived cells to the developing retinal vasculature in vivo. Whereas control-injected HSCs targeted to all three normal developing retinal vascular layers, blocking R-cadherin-mediated adhesion resulted in mistargeting of the HSCs to the normally avascular outer retina. According to the authors of the study, the results suggest that vascular targeting of bone marrow-derived HSCs is dependent on mechanisms similar to those used by endogenous retinal vascular endothelial cells. Thus, R-cadherin antagonists may be useful in the treatment of neovascular diseases in which circulating HSCs contribute to abnormal angiogenesis.

SOURCE: Dorrell MI, Otani A, Aguilar E, et al. Adult bone marrow-derived stem cells use R-cadherin to target sites of neovascularization in the developing retina. Blood 2004;103(9):3420-7.

Blood-retinal Barrier Permeability in Patients With Essential Hypertension The permeability of the blood-retinal barrier in patients with essential hypertension (EH) is significantly higher than that in normotensive patients, and this may explain a damaging effect of EH on the BRB, according to researchers at Poland's Jagiellonian University Medical College in Cracow. Investigators conducted a fluorophotometric evaluation of BRB integrity in patients with EH who did not have signs of BRB damage. Of the 55 subjects in the study, 36 had EH and 19 were normotensive, healthy volunteers; 22 were men and 33 were women. The protocol included ophthalmic examination, fluorescein angiography, fluorophotometry, laboratory tests (total cholesterol, LDL and HDL cholesterol, triglycerides, fibrinogen, serum creatinine concentration, fasting glucose concentration, oral glucose test), urinary cotinine concentration measurement and cotinine-creatinine ratio (CCR) calculation. The permeability of the blood-retinal barrier in patients with EH was significantly higher than in the control group (2.24 +/- 0.68 vs. 1.64 +/- 0.64 nm/s). In hypertensive patients with CCR greater than 50 ng/mg, the permeability of the blood-retinal barrier was significantly higher than that of healthy volunteers not exposed to smoke (2.32 vs. 1.68 nm/s).

SOURCE: Pogrzebielski A, Lubaszewski W, Starzycka M, Kawecka-Jaszcz K. Fluorophotometric evaluation of blood-retinal barrier permeability in patients with essential hypertension. Ophthalmologica 2004;218(3):180-4.

Chlamydia psittaci and Ocular Adnexal Lymphomas May Be Associated Ocular adnexal lymphomas may be antigen-driven disorders; however, the source of the putative antigen or antigens is still unknown. Investigators at Italy's San Raffaele H Scientific Institute (Milan) and the Centro di Riferimento Oncologico, IRCCS National Cancer Institute (Aviano) assessed whether Chlamydiae infection is associated with the development of ocular adnexal lymphomas. Results showed that patients with ocular adnexal lymphoma had a high prevalence of Chlamydia psittaci infection in tumor tissue and PBMCs. They also determined that persistent C. psittaci infection may contribute to the development of these lymphomas, as was also supported by the clinical responses observed in their study with C. psittaci–eradicating antibiotic therapy. Researchers used polymerase chain reaction to detect the presence of C. psittaci, C. trachomatis and C. pneumoniae DNA in 40 ocular adnexal lymphoma samples, 20 non-neoplastic orbital biopsies, 26 reactive lymphadenopathy samples, and peripheral blood mononuclear cells (PBMCs) from 21 lymphoma patients and 38 healthy individuals. They treated seven patients with Chlamydia-positive PBMCs with doxycycline, and they assessed objective response in four patients with measurable lymphoma lesions. They used the Fisher exact test to analyze differences in Chlamydiae DNA detection between the case patients and the control subjects. All statistical tests were two-sided. Eighty percent (32 of 40) of the ocular adnexal lymphoma samples carried C. psittaci DNA, whereas all lymphoma samples were negative for C. trachomatis and C. pneumoniae. In contrast, none of the 20 non-neoplastic orbital biopsies (0 percent versus 80 percent) and only three of 26 (12 percent) reactive lymphadenopathy samples (12 percent versus 80 percent) carried the C. psittaci DNA. Nine of 21 (43 percent) patients with Chlamydia-positive lymphomas carried C. psittaci DNA in their PBMCs, whereas none (0 percent) of the healthy PBMC donors carried C. psittaci DNA in their PBMCs (43 percent versus 0 percent). One month after doxycycline treatment, chlamydial DNA was no longer detectable in the PBMCs of all seven treated patients, and objective response was observed in two of the four evaluable patients.

SOURCE: Ferreri AJM, Guidoboni M, Ponzoni M, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 2004;96(8):586-94.

Intraocular and Plasma Levels of Cellular Fibronectin in Uveitis and Diabetes Patients Investigators in the Netherlands recently conducted a study to determine intraocular and plasma levels of cellular fibronectin (cFN) in patients with uveitis or diabetes mellitus (DM); to assess the association with disease activity, macular edema and vascular leakage on fluorescein angiography; and to determine whether cFN is locally produced in the eye. Researchers determined intraocular and plasma levels of cFN by ELISA in 39 patients with uveitis (23 active, 16 non-active), in 11 patients with DM (eight with and three without diabetic retinopathy) and in 17 control patients. They studied the influence of diabetic retinopathy, inflammatory activity, vascular leakage and macular edema on intraocular and plasma cFN levels and determined local production of cFN by calculating absolute and relative intraocular-to-plasma ratios. They then compared aqueous and vitreous levels of cFN. Results showed no differences in plasma cFN levels between patients with uveitis, DM or controls. Intraocular cFN levels were significantly raised in patients with uveitis and DM, specifically in those with active disease. Further, intraocular cFN levels were significantly elevated in patients with macular edema or vascular leakage, irrespective of whether it was associated with uveitis or DM. Intraocular cFN levels were consistently higher in the vitreous than the aqueous. Intraocular production of cFN was documented by elevated absolute and relative intraocular to plasma ratios in nine out of 11 patients tested. The authors concluded that elevated intraocular cFN levels were found in uveitis and DM patients, especially in those with active processes, intraocular vascular damage and macular edema. The results suggest that locally produced cFN levels reflect intraocular vascular damage.

SOURCE: Probst K, Fijnheer R, Schellekens P, Rothova A. Intraocular and plasma levels of cellular fibronectin in patients with uveitis and diabetes mellitus. Br J Ophthalmol 2004;88(5):667-72.

Tear Function and Ocular Surface Findings in Premature and Term Babies This prospective case-control study by Turkey's Uludag University School of Medicine described the ocular surface and tear function findings for 48 eyes of 24 premature babies seen at the school between March and September 2002, and 50 eyes of 25 healthy-term babies. All subjects underwent routine ophthalmic examinations; corneal sensitivity measurements; Schirmer test with anesthesia, with and without nasal stimulation; primary Jones test; fluorescein staining of the ocular surface and conjunctival impression cytology. Premature and term babies were compared for corneal sensitivity, lacrimal drainage system patency, tear function and ocular surface staining parameters, goblet cell density and squamous metaplasia grade. Researchers also investigated the relation of these parameters to the status of the ocular surface. Mean corneal sensitivity scores were 45+/- 5.0mm and 55 +/- 4.5mm in the premature and term babies, respectively. Premature babies had a mean corneal fluorescein staining score of 1.5 +/- 0.25 points, compared with 0.22 +/- 0.28 points in the term babies. The mean Schirmer test scores without and with stimulation were 1.5+ /- 2.5mm and 4.15 +/- 2.5mm in the premature babies, respectively, compared with 15 +/- 3.5mm and 18.75 +/- 4.5mm in the term babies. The intragroup and intergroup Schirmer test scores were statistically significant. The primary Jones test was positive in 20.8 percent of eyes in the premature babies and positive in 84 percent of eyes in the term babies. The premature babies with positive primary Jones test results all had corneal epithelial defects or severe superficial punctuate keratopathy. Mean conjunctival impression cytology squamous metaplasia scores were 1.86 +/- 1.2 in the premature babies and 0.86 +/- 0.47 in the term babies. Mean goblet cell densities were 393 +/- 484 cells/mm2 and 739+/-503 cells/mm2 in the premature and term babies, respectively. The authors of the study concluded that decreased corneal sensitivity, reduced tearing and lacrimal drainage patency are important determinants of ocular surface disease in premature infants. They add that premature newborns with low Schirmer test scores and a patent lacrimal system may experience corneal and conjunctival epithelial problems, and that they should be carefully checked for the presence of dry eye complications.

SOURCE: Dogru M, Karakaya H, Baykara M, et al. Tear function and ocular surface findings in premature and term babies. Ophthalmol 2004;111(5):901-5.

 

BRIEFLY INTERIM RESULTS OF TRIAL ANNOUNCED FOR CA4P FOR WET AMD. Oxigene, Inc., has released interim results from its Phase I/II clinical trial of Combretastatin A4 Prodrug (CA4P) in patients with wet age-related macular degeneration. In the dose escalation study, seven patients received treatment with CA4P, including one on the first-dose level who experienced objective biological response to the investigational drug as measured by optical coherence tomography. The area of choroidal neovascularization in the patient's study eye decreased by approximately 100 microns. In addition, a 35-year-old patient with myopic macular degeneration experienced a significant improvement in visual acuity after he received CA4P treatment under a special exemption from the FDA. The patient had had visual acuity of 20/50 in the study eye, with active leakage in both eyes that had persisted after other treatment approaches. After treatment with systemically administered CA4P, his vision was restored to 20/20 with significantly reduced leakage in each eye. The authors report that CA4P has been well tolerated up to doses of 36 mg/m2; side effects were increased blood pressure and pulse and an increase in QTc interval below clinical significance. No serious or dose-limiting adverse events were reported. Dosing is underway in the second of three patient cohorts established to evaluate CA4P at 27, 36 and 45 mg/m2. Fifteen patients are expected to be enrolled in the trial. AMO SIGNS LICENSING AGREEMENT FOR ACCOMMODATING IOL. Advanced Medical Optics, Inc. (AMO) has signed a one-year research and evaluation licensing agreement with Quest Vision Technologies, Inc. to develop accommodating intraocular lens (IOL) designs for presbyopes. The agreement will allow AMO access to new accommodating IOL technologies to expand its refractive IOL offerings, which currently includes the Array multifocal IOL and Verisyse phakic IOL. AMO also expects to acquire the Tecnis multifocal IOL as part of its planned acquisition of Pfizer's surgical ophthalmology business, slated to close this summer. The Array and Tecnis IOLs are approved for correction of presbyopia in Europe. Under terms of the agreement, AMO will own a minority interest in Quest Vision, with an option to purchase the company after one year. It will also have access to several issued and pending patents for design approaches encompassing axial movement and shape-changing technology. No other terms were disclosed. FALCON, B&L RECEIVE FDA APPROVAL OF GENERIC ANTI-INFECTIVE MEDICATION. The FDA has approved the generic ofloxacin ophthalmic solution 0.3%, manufactured by Falcon Pharmaceuticals, Ltd. (an affiliate of Alcon, Inc.) and Bausch & Lomb. Ofloxacin is therapeutically equivalent to Ocuflox (Allergan) and is indicated for treating infections caused by susceptible strains of bacteria in conjunctivitis and corneal ulcer conditions. The generic medication will be available immediately from both companies in two sizes, 5mL and 10mL. It has a 24-month shelf life from time of manufacture.

 

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