Efficacy and safety of a novel naltrexone treatment for dry eye in type 1 diabetes

Abstract

BackgroundDry eye disease (DED) is a prevalent complication of diabetes and presents as reduced tear production and/or increased corneal surface sensitivity often with secondary ocular surface changes. This study examined the safety and efficacy of a proprietary new eye drop formulation for topical treatment of DED.MethodsType 1 diabetes (T1D) was established in male Sprague-Dawley rats to study the efficacy and safety of the investigational compound that contained 20 μg/ml of naltrexone (NTX). Tear production was measured by the Schirmer’s 1 test, and ocular surface sensitivity was measured using an aesthesiometer. Diabetic rats received twice daily applications of a single drop (~ 0.02 ml) of the proprietary formulation (NTX-001) or vehicle onto one eye. For comparison, some diabetic rats received eye drops containing NTX in sterile Vigamox®. Safety was monitored by assessment of ocular histopathology in naïve male rats and naïve male rabbits receiving twice daily treatment of two drops for 30 days.ResultsDry eye in T1D rats was reversed within hours of a single treatment of NTX-001, and over a period of 10 days NTX-001 restored corneal sensitivity and reversed dry eye relative to values measured in diabetic rats receiving vehicle. In comparison to NTX dissolved in Vigamox®, the proprietary NTX-001 was more effective at reversing dry eye. Safety studies in naïve rats and rabbits revealed no visible ocular pathology after 30 days of treatment.ConclusionsAn investigational new eye drop containing 20 μg/ml NTX effectively reversed tear film deficits and restored corneal surface sensitivity in diabetic animals without causing toxic side effects.

Dysregulation of the OGF–OGFr pathway correlates with elevated serum OGF and ocular surface complications in the diabetic rat

“…Type 1 diabetes rat model T1D was induced in six-week old male Sprague-Dawley rats (Charles River) by injection of 50 mg/kg STZ (Sigma-Aldrich) dissolved in buffer at pH 4.5 for two consecutive days. 13,17 Rats were fasted for 18 h prior to each injection; this method produced hyperglycemia (blood glucose levels > 250 mg/dL) within 72 h and resulted in minimal lethality. A cohort of hyperglycemic rats was implanted with insulin implants (LinShin, Canada) within 24 h of detecting hyperglycemia, and identified as the T1D-INS group.…”

“…[6][7][8][9][10] Using several models of type 1 and type 2 diabetes, we have documented that blockade of the OGF-OGFr pathway by the potent opioid receptor antagonist naltrexone (NTX) reverses many of the epithelial-associated complications of T1D including delayed corneal wound healing, dry eye, decreased corneal sensitivity, and the repair rate of full-thickness cutaneous wounds. [11][12][13][14][15][16][17] Application of NTX topically or systemically was effective at reversing many of the ocular surface complications observed in the animal models. These data were supportive of human research; however, it was not known exactly when and to what extent the OGF-OGFr regulatory pathway became dysregulated in diabetes.…”

An eye on the dog as the scientist's best friend for translational research in ophthalmology: Focus on the ocular surface

“…Whorl-like 65 Whorl-like 65 Corneal sensitivity (g/mm 2 ) 0. 0.42-0.47 69,70 Stiffness/elastic modulus (kPa) i…”

“…From highest to lowest, the sensitivity of the cornea to mechanical stimulus is as follows: humans (0.2-1.0 g/mm 2 ), rats (0.42-0.47 g/mm 2 ), mice (0.59 g/mm 2 ), dogs (2.16-2.9 g/mm 2 ), and rabbits (6.21-10 g/mm 2 ). 2,[66][67][68][69][70] The murine model is the most extensively studied of all laboratory species…”

The expression of miRNA-146a-5p and its mechanism of treating dry eye syndrome

“…Dry eye syndrome is usually accompanied by in ammation [22]. Under the action of the body's immune system, a certain number of lymphocytes in ltrate the ocular surface tissue and lacrimal gland, releasing a large number of in ammatory factors, causing the appearance of in ammation in the body, further affecting the tear secretion system of the human body, leading to pathological changes in the amount and composition of tear secretion [23]. In order to escape the attack from the lacrimal immune system, these lymphocytes secrete in ammatory factors, which also have the effect of affecting the secretion of normal glands; in addition, in ammatory factors can also exert effects on sympathetic and parasympathetic nerves, so that the sensory nerve function corresponding to the ocular surface decline, eventually destroying the integrity of the tear lm [24].…”