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BMC Ophthalmology
Published in: BMC Ophthalmology 1/2017

Open Access 01-12-2017 | Research article

A novel TRPM8 agonist relieves dry eye discomfort

Authors: Jee Myung Yang, Fengxian Li, Qin Liu, Marco Rüedi, Edward Tak Wei, Michael Lentsman, Hyo Seok Lee, Won Choi, Seong Jin Kim, Kyung Chul Yoon

Published in: BMC Ophthalmology | Issue 1/2017

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Abstract

Background

Physical cooling of the eye surface relieves ocular discomfort, but translating this event to drug treatment of dry eye discomfort not been studied. Here, we synthesized a water-soluble TRPM8 receptor agonist called cryosim-3 (C3, 1-diisopropylphosphorylnonane) which selectively activates TRPM8 (linked to cooling) but not TRPV1 or TRPA1 (linked to nociception) and tested C3 in subjects with mild forms of dry eye disease.

Methods

A set of 1-dialkylphosphoryalkanes were tested for activation of TRPM8, TRPV1 and TRPA1 receptors in transfected cells. The bioactivity profiles were compared by perioral, topical, and intravenous delivery to anesthetized rats. The selected lead candidate C3 or vehicle (water) was applied with a cotton gauze pad to upper eyelids of patients with dry eye disease (n = 30). Cooling sensation, tear film break-up time (TBUT), basal tear secretion, and corneal staining were evaluated. C3 was then applied four times daily for 2 weeks to patients using a pre-loaded single unit applicator containing 2 mg/mL of C3 in water (n = 20) or water only. TBUT, basal tear secretion, and corneal staining, and three questionnaires surveys of ocular discomfort (VAS scale, OSDI, and CVS symptoms) were analyzed before and at 1 and 2 weeks thereafter.

Results

C3 was a selective and potent TRPM8 agonist without TRPV1 or TRPA1 activity. In test animals, the absence of shaking behavior after C3 perioral administration made it the first choice for further study. C3 increased tear secretion in an animal model of dry eye disease and did not irritate when wiped on eyes of volunteers. C3 singly applied (2 mg/ml) produced significant cooling in <5 min, an effecting lasting 46 min with an increase in tear secretion for 60 min. C3 applied for 2 weeks also significantly increased basal tear secretion with questionnaire surveys of ocular discomfort indices clearly showing improvement of symptoms at 1 and 2 weeks. No complaints of irritation or pain were reported by any subject.

Conclusions

C3 is a promising candidate for study of TRPM8 function on the eye surface and for relief of dry eye discomfort.

Trial registration

ISRCTN24802609 and ISRCTN13359367. Registered 23 March 2015 and 2 September 2015.
Appendix
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Metadata
Title
A novel TRPM8 agonist relieves dry eye discomfort
Authors
Jee Myung Yang
Fengxian Li
Qin Liu
Marco Rüedi
Edward Tak Wei
Michael Lentsman
Hyo Seok Lee
Won Choi
Seong Jin Kim
Kyung Chul Yoon
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Ophthalmology / Issue 1/2017
Electronic ISSN: 1471-2415
DOI
https://doi.org/10.1186/s12886-017-0495-2

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