OCULAR SAFETY OF TOPICAL NALTREXONE

Background: Over the past 18 years, Dr. Sassani has worked with Dr. Zagon's research team delineating the role of the opioid growth regulatory system in corneal epithelial homeostasis and wound healing. We have demonstrated that the native opioid peptide, [Met5]-enkephalin, termed opioid growth factor (OGF) is a tonically active, receptor-mediated inhibitor of corneal epithelial cell division. Conversely, blockade of the opioid growth factor receptor (OGFr) by the opioid antagonist Naltrexone (NX) upregulates corneal epithelial cell division. We have demonstrated further that NTX accelerates the rate of corneal epithelial wound healing in healthy rodents and rabbits and reverses the delay in corneal epithelial wound healing characteristic of diabetic keratopathy. No drug-related side effects have been found in animals treated with NTX.Objective/Hypothesis: Our research suggests that NTX will be useful to expedite corneal epithelial wound healing in normal individuals who suffer ocular trauma or in individuals with delayed corneal wound healing, such as diabetics. Moreover, our animal experiments indicate that such treatment will be safe as well as effective.Specific Aims: Phase I clinical trials, demonstrating the safety of topically applied NTX in normal volunteers are required by the Food and Drug Administration (FDA) before its clinical evaluation relative to expediting human corneal epithelial wound healing can be undertaken. The study we propose has been delineated by the FDA as fulfilling its requirements for the Phase I clinical trial. Therefore, its specific aim is to demonstrate in human volunteers the safety of the most concentrations of topical NTX most likely to be used in the clinical setting.Study Design: Utilizing concentrations of 10-6 M, 5 x 10-6 M, 10-5 M, and 5 x 10-5 M NTX dissolved in Vigamox brand of moxifloxacin hydrochloride ophthalmic solution (Alcon), volunteers will receive four drops of the test solution or Ocuflox without NTX over a 24-hour period. They will be examined utilizing clinical observation and standard clinical tests of ocular health within the first 24 hours of drug administration and one week later for evidence of adverse side effects from the medication.Impact: Corneal epithelial wounds, whether secondary to combat trauma or to systemic diseases, such as diabetes mellitus, expose the cornea to significant complications such as infection, ulceration scarring, or even perforation. Expediting corneal epithelial wound healing through the use of topical NTX will reduce the likelihood of such complications in a safe and effective manner using the characteristics of the naturally occurring opioid growth regulatory system.