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Effects of Topical alpha-Substituted Anandamides on Intraocular Pressure in Normotensive Rabbits

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Abstract

Purpose. Anandamides have been observed to lower intraocular pressure in the rabbit eye, preceded by a period of hypertension. Amidases are thought to catabolize these compounds into their component parts, including arachidonic acid. Direct application of arachidonic acid has been observed to cause a marked rise of intraocular pressure. Thus, anandamide analogs resistant to catabolism were thought possibly devoid of this initial hypertension, and their effects on rabbit IOP investigated.

Methods. A series of chiral alpha-substituted anandamides were synthesized and studied for their effect on the intraocular pressure (IOP) of normotensive pigmented rabbits. Each test compound was dissolved in an aqueous 2-hydroxypropyl-β-cyclodextrin solution (containing 3% polyvinyl alcohol) and administered (62.5 μg) unilaterally to the eye.

Results. The most promising compounds caused a statistically significant reduction of IOP (vs. vehicle) in the treated eyes. Of these, the R-alpha-isopropyl compound exhibited the best activity tested. Unlike the alpha-unsubstituted analogs previously studied, hypotensive effects were not preceded by an initial elevation of IOP and indomethacin pre-treatment (12.5 mg, s.c.) did not eliminate the IOP response, as demonstrated by administered R-alpha-isopropyl anandamide.

Conclusions. Catabolism of alpha-unsubstituted anandamides may account for their observed intraocular hypertensive effects. The physiological mechanism by which alpha-substituted anandamides work apparently differs from that of the more easily metabolized alpha-unsubstituted compounds.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, University of Kuopio, Finland

    David W. Pate, Pekka Jarho & Tomi Järvinen

  2. HortaPharm B.V., Schinkelhavenkade 6, 1075VS, Amsterdam, The Netherlands

    David W. Pate

  3. Department of Pharmaceutics, University of Kuopio, Finland

    Kristiina Järvinen & Arto Urtti

  4. Deva Biotech, Inc., Hatboro, Pennsylvania, USA

    Vaidyanath Mahadevan

Authors
  1. David W. Pate
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  2. Kristiina Järvinen
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  3. Arto Urtti
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  4. Pekka Jarho
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  6. Tomi Järvinen
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Correspondence to David W. Pate.

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Pate, D.W., Järvinen, K., Urtti, A. et al. Effects of Topical alpha-Substituted Anandamides on Intraocular Pressure in Normotensive Rabbits. Pharm Res 14, 1738–1743 (1997). https://doi.org/10.1023/A:1012131929940

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