Volume 5, Number 2
Monday, January 17, 2005



In this issue: (click heading to view article)
Editorial: An Opportunity Not to be Missed
Effects of Amniotic Membrane on RPE Cell Differentiation
Trabecular Bypass Stents Decrease IOP in Cultured Human Anterior Segments
Stimulation of Neovascularization by Pigment Epithelium-derived Growth Factor
Intravitreal Triamcinolone-induced Elevated IOP and Posterior Subcapsular Cataract
Briefly











Editorial: An Opportunity Not to be Missed

I recently read, in one of our local papers, an article about a plastic surgeon in Southwest Florida who was being sanctioned by the state of Florida for performing procedures in a facility that was not accredited by any state agency or institution. In addition, he did not have in place any transfer agreements with local hospitals should an unexpected crisis arise necessitating a hospitalization. The matter came to the attention of state regulators when several of his colleagues blew the whistle on him. The surgeon in question essentially offered no explanation other than to claim that the entire event arose out of jealously on the part of his colleagues.

I applaud those professionals who were forthright and stood up for proper patient care. I am concerned that there may be many missed opportunities for us to monitor our own colleagues--for a variety of reasons. When that happens, no one wins, including the physician who may be causing harm. I believe that if we monitor ourselves, then lawyers and government agencies may find less to poke at in our profession. We may be on the horizon of real malpractice reform with the current administration. Let us not give the opposition an opportunity to run the ship aground--we may not have such an opportunity again in our professional lifetimes.

Stephen E. Pascucci, MD
Medical Editor
[email protected]

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Effects of Amniotic Membrane on RPE Cell Differentiation

Retinal pigment epithelial (RPE) cells cultured on amniotic membrane (AM) may be a useful matrix substrate for retaining the differentiated and epithelial phenotype of RPE for subretinal transplanation, according to a study by the Tokyo Medical and Dental School.

Researchers cultured human RPE cells on the basement membrane side of dispase-treated AM. After one week of cellular confluence, they terminated the cultures, collected conditioned medium and extracted total RNA. Next, researchers evaluated the expression pattern of several genes considered to participate in the function of differentiated RPE. Ultrastructural changes were evaluated by transmission electron microscopy.

Morphologically, RPE cells cultured on AM exhibited ultrastructural epithelial features, such as microvilli of the apical membrane and intercellular junctions. Gene expression of RPE65, CRALBP, bestrophin and tyrosinase-related protein-2 was upregulated in RPE cells cultured on AM, compared to cells cultured on plastic. In addition, protein production of vascular endothelial growth factor, thrombospondin-1, and pigment epithelium derived factor was markedly increased in cells cultivated on AM. Gene expression of cathepsin D, brain-derived neurotrophic factor and basic fibroblast growth factor, however, did not differ between RPE cells cultured on plastic and those cultured on AM.

SOURCE: Ohno-Matsui K, Ichinose S, Nakahama S, et al. The effects of amniotic membrane on retinal pigment epithelial cell differentiation. Mol Vis 2005;11:1-10.
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Trabecular Bypass Stents Decrease IOP in Cultured Human Anterior Segments

Bypassing the trabecular meshwork using a stent lowers intraocular pressure (IOP) in cultured human anterior segments, according to a study by the Mayo Clinic in Rochester, MN.

Investigators placed anterior segments from 21 human eyes obtained at autopsy in perfusion culture, and they inserted trabecular bypass stents through the trabecular meshwork, with the lumen of the tube opening into Schlemm"s canal. Eyes received from one to four stents, placed equidistantly. In eyes receiving one or two stents, additional stents were later added, up to four per eye.

IOP was lowered after placement of a single stent, from 21.4 +/- 3.8 mmHg to 12.4 +/- 4.2 mmHg. This corresponded to an 84 percent increase in facility of outflow. Eyes receiving more than one stent had final IOP of 11.9 +/- 3.7 mmHg. Nine eyes had sequential addition of stents, and seven of these had a further decrease of IOP (13.6 +/- 4.1 mmHg to 10.0 +/- 4.3 mmHg). Excision of the entire meshwork between stents dropped IOP to 6.3 +/- 3.2 mmHg, indicating some residual meshwork or canal resistance remained even after placement of three stents. The authors believe that this technique holds promise as a new clinical surgery for treating glaucoma.

SOURCE: Bahler CK, Smedley GT, Zhou J, Johnson DH. Trabecular bypass stents decrease intraocular pressure in cultured human anterior segments. Am J Ophthalmol 2004;138(6):988-94.
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Stimulation of Neovascularization by Pigment Epithelium-derived Growth Factor

Ophthalmic researchers at Washington University School of Medicine, St. Louis, examined the effect of pigment epithelium-derived growth factor (PEDF) on laser-induced choroidal neovascularization (CNV). The results of this animal study showed that PEDF demonstrates opposing effects on CNV and endothelial cell function: whereas low doses are inhibitory, high doses can augment the development of the neovasculature.

Investigators anesthetized adult C57Bl/6 mice and placed four laser spots in each quadrant of the fundus with a krypton red laser (614 nm, 50 micrometers, 0.05 second, 200 mW). The animals were treated with various doses of PEDF administered with mini-osmotic pumps implanted subcutaneously. Seven days after laser treatment, mice were perfused with 3% fluorescein isothiocyanate (FITC) high-molecular-weight dextran, the eyes enucleated and neovascularization analyzed by confocal microscopy. Data were recorded as the volume of the neovascular complex. The effect of PEDF on endothelial cell migration, vascular tube formation in synthetic basement membrane and VEGF production was also determined.

Results showed that mice receiving a lower dose of PEDF (90 microg/mL) had significantly decreased areas of CNV. A high dose of PEDF (360 microg/mL) significantly increased CNV, whereas an intermediate dose (180 microg/mL) of PEDF had no effect. PEDF inhibited endothelial cell migration and vascular tube formation at lower doses (0.5 to 5 microg/mL). High doses of PEDF (25 to 50 microg/mL) stimulated endothelial cell migration, enhanced vascular tube formation in vitro and stimulated VEGF production from endothelial cells. Neutralizing anti-VEGF antibody completely reversed the stimulatory effects of high doses of PEDF on CNV in vivo.

The authors believe that these results suggest that the effects of PEDF on neovascularization are more complex than originally believed, and that caution should be exercised when considering PEDF therapies.

SOURCE: Apte RS, Barreiro RA, Duh E, et al. Stimulation of neovascularization by the anti-angiogenic factor PEDF. Invest Ophthalmol Vis Sci 2004;45(12):4491-7.
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Intravitreal Triamcinolone-induced Elevated IOP and Posterior Subcapsular Cataract

Investigators at the Save Sight and Eye Health Institute, University of Sydney, NSW, Australia, recently studied the connection between elevated intraocular pressure (IOP) and accelerated cataract formation in patients treated with intravitreal triamcinolone, and found a strong association. This suggests that the mechanism responsible for the development of steroid-induced posterior subcapsular cataract (PSC) and raised IOP may be similar.

The study included patients with phakic eyes who participated in the Intravitreal Triamcinolone Study, a randomized clinical trial of intravitreal triamcinolone for age-related macular degeneration (AMD). The treatment group included 57 eyes; the control group included 54 eyes. One eye per patient was studied. Intervention was 4 mg of intravitreal triamcinolone (treatment group) or 1 ml subconjunctival saline (controls). Main outcome measures included IOP rise of at least 5 mmHg (IOP responders) and progression of posterior subcapsular cataract by two or more grades using photographic standards from the Age Related Eye Disease Study.

Progression of PSC by two or more grades in the treatment group was significantly higher among 16 IOP responders (51 percent after two years) than among 37 nonresponders (three percent). No significant progression of PSC occurred in the placebo group or the opposite eye of the treatment group. Progression of cortical cataracts was also significantly higher among responders than nonresponders (15 percent vs. three percent). The progression of nuclear cataracts (13 percent vs. three percent) was not significantly different between IOP responders and nonresponders. The authors concluded that although steroid-related cataracts are unlikely to develop in eyes that do not experience elevated IOP after intravitreal triamcinolone, those eyes that do experience elevated IOP also have a very high risk of rapidly experiencing posterior subcapsular lens opacification.

SOURCE: Gillies MC, Kuzniarz M, Craig J, et al. Intravitreal triamcinolone-induced elevated intraocular pressure is associated with the development of posterior subcapsular cataract. Ophthalmol 2005;112(1):139-43.
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BRIEFLY
  • BAUSCH & LOMB LICENSES PLASMIN FROM BAYER FOR OPHTHALMIC USE. Bayer HealthCare LLC, Biological Products Division, has granted Bausch & Lomb an exclusive worldwide license to Bayer’s Plasmin technology for ophthalmic use. Plasmin, which is derived from processed human plasma, is believed to have potential for use in developing novel therapies for ocular conditions. Bayer is pursuing development of Plasmin in non-ocular indications for use as a thrombolytic agent to dissolve blood clots in veins and arteries. Under the terms of the agreement, Bausch & Lomb will be responsible for development of Plasmin for use in ophthalmology, and will make milestone payments to Bayer based on the development and registration progress. Bausch & Lomb will also pay ongoing royalties based on product sales. The companies did not release other details of the agreement.
  • ISTA PHARMACEUTICALS LAUNCHES VITRASE IN THE UNITED STATES. ISTA Pharmaceuticals, Inc., has announced the U.S. market launch of Vitrase (hyaluronidase injection) ovine in a 200 USP Units/mL vial in sterile solution and Vitrase (hyaluronidase for injection) lyophilized ovine in a 6200 USP Units multi-purpose vial. Both are for use as a spreading agent to facilitate the absorption and dispersion of other injected drugs, for hypodermoclysis and as an adjunct in subcuteanous urography. Vitrase is a proprietary formulation of highly purified, preservative-free ovine hyaluronidase, which has been studied extensively in several ophthalmic conditions. Vitrase represents ISTA"s second new product launch within the past six months; Istalol, a once-a-day formulation of timolol for the treatment of glaucoma, was introduced in July 2004. First shipments of Vitrase to physicians, hospitals, ambulatory surgery centers and wholesalers will begin within the next few weeks. For more information, call 877-484-8727.
  • NEW DEVICE FOR MEASURING IOP AND CORNEAL THICKNESS CLEARED BY FDA. RetinaPharma, a privately held portfolio company of the Hopkins Capital Group, LLC, has received 510(k) FDA clearance to market its TonoPach, a patented device that enables more accurate intraocular pressure (IOP) determination in patients. TonoPach permits simultaneous determination of IOP and corneal thickness at the same location on the cornea, allowing the eyecare practitioner can adjust IOP measurements to take into account the effects of corneal thickness. A large, randomized, five-year National Eye Institute (NEI) study published in mid-2002 showed that patients" corneal thickness was the single most important biometric parameter in risk assessment for patients with glaucoma or ocular hypertension. The study showed a highly significant correlation of corneal thickness that, combined with IOP measurement, predicts the likelihood of damage to the visual field. The TonoPach is the first instrument that concurrently measures both biometrics. For more information, go to www.hopkinscap.com.
  • PHASE III TRIAL FOR DRY AMD EXCEEDS PATIENT RECRUITMENT GOAL. OccuLogix, Inc., has enrolled 185 patients for participation in a Phase III clinical trial using its RHEO System to treat the dry form of age-related macular degeneration (AMD), thus exceeding its goal of 180 patients. The RHEO System is being evaluated to determine whether it improves microvascular circulation in the eye by filtering high molecular weight proteins and other macromolecules from the patient"s plasma through a treatment process known as Rheopheresis. MIRA-1, or Multicenter Investigation of Rheopheresis for AMD, is a randomized, placebo-controlled trial designed to evaluate the safety and efficiency of RHEO Therapy in patients with intermediate- to late-stage dry AMD. If successful, MIRA-1 is expected to support OccuLogix"s application with the FDA to obtain approval to market the RHEO System in the United States. Patients in the trial receive either eight RHEO Therapy or eight placebo procedures respectively over 10 weeks. The study"s primary endpoint is the mean change in best spectacle-corrected visual acuity applying the Early Treatment Diabetic Retinopathy Scale (ETDRS). Secondary and tertiary endpoints include legal driving, vision improvement, vision loss, drusen reduction and progression to legal blindness.

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