September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Digoxin derivatives with selectivity for the α2β3 isoform of Na,K-ATPase potently reduce intraocular pressure
Author Affiliations & Notes
  • Dan Heller
    Department of ophthalmology, Assaf Harofe medical center, Rehovot, Israel
  • Arie Marcovich
    Department of ophthalmology, Kaplan medical center, Rehovot, Israel
  • Adriana Katz
    Deptartment of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
  • Daniel M. Tal
    Deptartment of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
  • Michael Habeck
    Deptartment of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
  • Efrat Ben Zeev
    Israel National Centre for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
  • Bilal Rabah
    Department of ophthalmology, Kaplan medical center, Rehovot, Israel
  • Yaniv Barkana
    Department of ophthalmology, Assaf Harofe medical center, Rehovot, Israel
  • Steven J.D. Karlish
    Deptartment of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
  • Footnotes
    Commercial Relationships   Dan Heller, Patent Yeda's ref. 2015-050 (P); Arie Marcovich, Patent Yeda's ref. 2015-050 (P); Adriana Katz, Patent Yeda's ref. 2015-050 (P); Daniel Tal, Patent Yeda's ref. 2015-050 (P); Michael Habeck, None; Efrat Ben Zeev, None; Bilal Rabah, Patent Yeda's ref. 2015-050 (P); Yaniv Barkana, Patent Yeda's ref. 2015-050 (P); Steven Karlish, Patent Yeda's ref. 2015-050 (P)
  • Footnotes
    Support  Israel Science Foundation (789/12) The Israel Ministry of Trade and Industry Kamin-Yeda programme (project 47146)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3017. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Dan Heller, Arie Marcovich, Adriana Katz, Daniel M. Tal, Michael Habeck, Efrat Ben Zeev, Bilal Rabah, Yaniv Barkana, Steven J.D. Karlish; Digoxin derivatives with selectivity for the α2β3 isoform of Na,K-ATPase potently reduce intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3017.

      Download citation file:


      © 2017 Association for Research in Vision and Ophthalmology.

      ×
  • Supplements
Abstract

Purpose : Glaucoma is associated with increased pressure in the eye, which can be alleviated by increasing outflow or reducing inflow of aqueous humor. The α2β3 isoform of Na,K-ATPase powers production of aqueous humor. We show that topical application of α2β3-selective derivatives of the classical Na,K-ATPase inhibitor, digoxin, to rabbit eyes efficiently reduce pharmacologically-raised or basal IOP.

Methods : IOP measurements were made with a Pneumatonometer (Model 30, Reichert technologies) in New-Zealand white rabbits after raising IOP with 4AP(40mg/ml) or on basal IOP after addition of one drop of 1mM digoxin derivatives to the right eye(RE) and one drop of PBS to the left eye(LE) as control. A local anesthetic, Oxybuprocaine HCl (0.4%, 25 μl) was applied to each cornea before IOP measurements. For comparison of DcB with Latanoprost, 3 groups of 5 rabbits were used. Rabbits treated with Latanoprost, received the medication daily for 5 days. On the day of the experiment rabbits were treated at 5 min interval with 1 drop of 1mM DcB, 1 drop of 0.005% Latanoprost, 1 drop each(RE) or normal saline(LE, Control). IOP was measured every hour for 12 hours and after 24 hours. Corneal thickness (μm) was measured using an ultrasonic pachometer(Sonogage, Cleveland, USA). For histologic examination animals were sacrificed, eyes were removed, fixed in 10% neutral buffered formalin, trimmed at 4µm and stained with hematoxylin and eosin.

Results : New digoxin derivatives, methylcyclopropyl and cyclobutyl (DMcP, DcB) have strong selectivity for α2β3 up to 22 and >33-fold compared to digoxin. ≥10μM concentrations of DMcP or DcB prevented 4AP-induced rise in IOP. Higher concentrations (0.1-0.3mM) reduced IOP below the starting value. Both Derivatives reduced basal IOP by 20-25%. Compared to Latanoprost, steady-state IOP was lower by 3.5±0.15, 2.6±0.11 and 3.44±0.39mmHg for DcB, Latanoprost and DcB+Latanoprost. Reduced IOP was maintained by DcB for about 8 hours. With DcB+Latanoprost low IOP was maintained for 24 hours. There was no detectable effect of either drug on corneal thickness. Histologic examination did not reveal significant damage to the anterior chamber or retina.

Conclusions : α2β3 plays a central role in production of aqueous humor. Digoxin derivatives such as DcB, might become interesting candidates for development as drugs for treatment of glaucoma.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×