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William H Garner, Margaret Garner, Kathryn S Crawford, William Burns; Dioptin™ Eye Drop to Treat Presbyopia: corneal penetration and ocular pharmacokinetics. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3766.
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Aging of the human lens is accompanied by protein sulfhydryl groups oxidation (Takemoto). Disulfides may increase protein cross-linking to make the lens "stiff". Various compounds are known to reduce disulfides; but many are toxic to cells. Lipoic acid (LA) is a natural compound within pyruvate dehydrogenase complex. Encore Vision examined various esters of LA and discovered (US8410162B2) the choline ester of lipoic acid (LACE) demonstrates improved intraocular delivery.
LA is reduced by the endogenous antioxidants (NADPH/thioredoxin) to dihydrolipoic acid (DHLA). DHLA has been shown to reduce lens crystallin disulfides (Garner). Prior work (Cagini et al) has shown that LA does not significantly penetrate the cornea. Esters of lipoic acid were evaluated in rabbits for corneal penetration. Rabbits were also used to examine the metabolism, absorption, and distribution of LACE (LA prodrug) using HPLC-ESI/MS/MS (LOD > 2 ng/ml).
LACE was synthesized and found to improve penetration over LA. LACE is a cationic surfactant. A prototypic ocular eye drop formulation of LACE was tested as Dioptin™. It is rapidly degraded by endogenous butycholinesterases and provides elevated ocular tissue levels of LA. Lens DHLA (measured as LA) and LACE are both significantly elevated [P< 0.05] using 3% Dioptin™ treated compared to untreated contralateral eye; 22.6 +/- 9.1(5) and 142.3 +/- 31.9 (5) nM/L, respectively.
Dioptin™ can provide a delivery platform to reduce protein disulfides in order to soften the lens and restore accommodative amplitude. Helmholtz suggested (1855) that lens was responsible for accommodation, but prior to discovery of Dioptin™ nothing was available to test the hypothesis that reducing lens modulus could restore lost accommodation (average < +2 D @ > 47 yrs) when reading glasses are needed for near vision.
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