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R. Li, K. Meerovitch, T. Lama, P. Jain, H. U. Saragovi, G. Cumberlidge; An NGF Mimetic, MIM-D3, Demonstrates Therapeutic Efficacy in a Rat Model of Scopoloamine-Induced Dry Eye. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3661.
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The purpose of the study was to evaluate the efficacy of MIM-D3, an NGF peptidomimetic, agonist of TrkA and potential mucin secretagogue, following multiple topical instillations in a rat model of scopolamine-induced dry eye.
The dry eye model was created in Sprague Dawley rats by subcutaneous implantation of Alzet® osmotic pumps to continuously deliver scopolamine hydrobromide for 29 days. Five days post-pump implantation, rats were treated daily and bilaterally with topical instillation of vehicle, 5.26 µg/mL NGF, 4 mg/mL MIM-D3, 10 mg/mL MIM-D3, or 25 mg/mL MIM-D3 for 17 days with 5 rats per group. All animals were spared from treatments during the last week of the in-life phase. A naive group of 5 rats without scopolamine was also included as the control. Body weight and Schirmer test were evaluated prior to and post-scopolamine pump implantation. Tear breakup time (TBUT), corneal staining (CS) with fluorescein sodium and secreted mucin level in the tear fluid were evaluated weekly after pump implantation.
Clinical dry eye conditions were developed 5 days after subcutaneous implantation of the scopolamine pump in rats. They are characterized by a 52% decrease in tear production by Schirmer test, a 44-50% shortened TBUT and a 2-4 fold increase in CS with fluorescein sodium. Compare to the vehicle group, topical instillation of 10 mg/mL MIM-D3 for 17 days produced a statistically significant 2 fold decrease in CS (p<0.001) and an insignificant 31% increase in TBUT (p=0.06). These effects correlated with a statistically significant 4.5 fold increase of mucin secretion in the tear fluid from these animals over the controls (p<0.05). Topical application of NGF under the test concentration as well as 4 and 25 mg/mL MIM-D3 did not show statistical differences in the above clinical measurements or tear mucin level. Furthermore, tear production measured by Schirmer test remained unchanged in all treatment groups.
Topical instillation of MIM-D3, a small molecule NGF peptidomimetic, improved the clinical measurements of dry eye in an experimental model. The mechanism of action of MIM-D3 may be through upregulation of tear mucin secretion from conjunctival goblet cells, leading to an increase in tear film stability rather than enhancing aqueous tear production from the lacrimal glands. The pharmacological effect of MIM-D3 may also be tightly regulated by the pharmacokinetics and the receptor-binding selectivity of the drug, which warrants future investigations.
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