April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Dioptin™ Eye Drop to Treat Presbyopia: corneal penetration and ocular pharmacokinetics
Author Affiliations & Notes
  • William H Garner
    Research, Encore Vision, Fort Worth, TX
  • Margaret Garner
    Research, Encore Vision, Fort Worth, TX
  • Kathryn S Crawford
    Research, Encore Vision, Fort Worth, TX
    PharmOcu, Andover, MA
  • William Burns
    Research, Encore Vision, Fort Worth, TX
  • Footnotes
    Commercial Relationships William Garner, Encore Vision (C), Encore Vision (I), US8410162B2 (P); Margaret Garner, Encore Vision (C), Encore Vision (I); Kathryn Crawford, Encore Vision (C), Encore Vision (I), PharmOcu (E); William Burns, Encore Vision (E), Encore Vision (I)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 3766. doi:
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    • Get Citation

      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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

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.

 
Methods
 

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).

 
Results
 

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.

 
Conclusions
 

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.

 
 
Dioptin™ elevates LACE (prodrug) and LA (active) in ocular tissue samples (ESI/LC/MS/MS); importantly in the lens. Choline byproduct offers to maintain choline. Choline is a precursor for metabolites (methylation reactions). Methylation is an important component of LA tissue clearance as 6,8-bismethylthio-octanoic acid (BMOA).
 
Dioptin™ elevates LACE (prodrug) and LA (active) in ocular tissue samples (ESI/LC/MS/MS); importantly in the lens. Choline byproduct offers to maintain choline. Choline is a precursor for metabolites (methylation reactions). Methylation is an important component of LA tissue clearance as 6,8-bismethylthio-octanoic acid (BMOA).
 
Keywords: 404 accommodation • 653 presbyopia • 503 drug toxicity/drug effects  
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