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Aims: Non-healing wounds are a major complication for the 27 million individuals in the United States with diagnosed diabetes. This study investigated the efficacy of a novel formulation to treat diabetic foot ulcers by targeting an underlying pathophysiology of diabetes. Main methods: The proprietary GMP formulations utilized increasing dosages of naltrexone (NTX) to block the inhibitory peptide Opioid Growth Factor (OGF) from binding to the OGF receptor (OGFr). Efficacy of topical application was studied using male Sprague-Dawley rats with uncontrolled (T1D) or insulin-controlled (T1D-INS) diabetes. Wound closure time, tensile strength of healed skin, and angiogenesis were endpoints. Serum drug dispersion was assessed. Key findings: Residual wound areas were significantly reduced within 2 days of surgery in T1D rats receiving either 0.5% or 1% NTX. By day 10, NTX-treated wounds were 5-fold smaller than those measured on T1D rats receiving vehicle. Tensile strength measurements and morphology studies revealed that NTX treatment of cutaneous wounds on T1D or T1D-INS rats accelerated epithelialization, accelerated angiogenesis, and increased the integrity of healed skin. Topical application of NTX resulted in no visible toxicity, and the NTX was not detected in serum. Significance: Proprietary GMP formulations up to 1% NTX were found to be effective and safe for topical treatment of full-thickness cutaneous wounds in diabetic rats. The mechanism of action involves blockade of the OGF-OGFr axis, a pathway known to become dysregulated with diabetes. These data warrant proof-of-concept human clinical trials for treatment of diabetic foot ulcers.

Abstract Background Dry 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. Methods Type 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. Results Dry 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. Conclusions An 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.

The Opioid Growth Regulatory System consists of opioid growth factor (OGF), [Met5]-enkephalin, and its unique receptor (OGFr). OGF inhibits cell division when bound to OGFr. Conversely, blockade of the interaction of OGF and OGFr, using the potent, long-acting opioid receptor antagonist, naltrexone (NTX), results in increased DNA synthesis and cell division. The authors have demonstrated both in vitro and in vivo that the addition of exogenous OGF or an increase in available OGFr decreases corneal epithelial cell division and wound healing. Conversely, blockade of the OGF-OGFr interaction by NTX or a decrease in the production of the OGFr increases corneal epithelial cell division and facilitates corneal epithelial wound healing. The authors also have demonstrated that depressed corneal and cutaneous wound healing, dry eye, and abnormal corneal sensitivity in type 1 and type 2 diabetes in animals can be reversed by OGF-OGFr blockade by NTX. Thus, the function of the Opioid Growth Regulatory System appears to be disordered in diabetic animals, and its function can be restored with NTX treatment. These studies suggest a fundamental role for the Opioid Growth Regulatory System in the pathobiology of diabetic complications and a need for studies to elucidate this role further.