Date of Award

January 2017

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Brian McAlvin

Second Advisor

Jessica Chow


Title: SITE 1 SODIUM CHANNEL BLOCKERS AND DEXMEDETOMIDINE AS A PROLONGED DURATION TOPICAL CORNEAL ANESTHETIC. Jenny C. Dohlman, James B. McAlvin, Changyou Zhan, Paraskevi E. Kolovou, Borja Salvador-Culla, and Daniel S. Kohane. Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Harvard Medical School, Boston Children’s Hospital, Boston, MA. (Sponsored by Jessica H. Chow, Department of Ophthalmology and Visual Sciences, Yale University School of Medicine).

Background: Conventional amino-ester and amino-amide local anesthetics used to treat ocular pain from corneal injury and ophthalmic surgery, such as the commonly used proparacaine, require repeated administration and may delay corneal healing with long-term use. An ocular anesthetic formulation with extended effect and minimal toxicity is needed. Here, we studied the corneal anesthetic effect of two site 1 sodium channel blockers, tetrodotoxin (TTX) and saxitoxin (STX), individually or in combination with 2-adrenergic receptor agonists (dexmedetomidine and clonidine), and compared them with proparacaine. Finally, we characterized the biocompatibility of each formulation through in vitro cytotoxicity studies and studied the effect of test solutions on corneal healing.

Methods: Solutions of TTX dexmedetomidine, TTX clonidine, STX dexmedetomidine, dexmedetomidine or proparacaine were topically applied to the rat cornea. The duration of corneal anesthesia was measured by recording the blink response to probing of the cornea using a Cochet-Bonnet esthesiometer. Cytotoxicity from anesthetic solutions was measured in vitro using human corneal limbal epithelial cells. The effect on corneal healing was measured in an in vivo rat model after corneal debridement followed by repeated drug administration.

Results: Addition of dexmedetomidine to TTX or STX significantly prolonged the duration of corneal anesthesia beyond that of either drug alone, whereas clonidine did not. Topical co-administration of either TTX or STX with dexmedetomidine resulted in two to three times longer corneal anesthesia than did proparacaine. Site 1 sodium channel blocker and dexmedetomidine formulations were not cytotoxic and corneal healing was not delayed significantly by any of the tested formulations.

Conclusions: Topical co-administration of site 1 sodium channel blockers with dexmedetomidine results in prolonged duration corneal anesthesia without delaying corneal wound healing. Such formulations may be useful for the management of acute surgical and nonsurgical corneal pain.


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