Efficacy of a novel synthetic topically applied tetrapeptide on eliciting corneal analgesia

1. Efficacy of a novel synthetic topically applied tetrapeptide on eliciting corneal analgesia subsequent to experimentally induced chemical corneal injury Bruce I. Gaynes, OD, Pharm D, Michael Russo, David Goldmeier Loyola University Chicago, Stritch School of Medicine, Department of Ophthalmology, Maywood, IL Introduction References Summary Methods Results Methods • SIS-ZEP04 appears to demonstrate efficacy in reducing pain and modifying pathways of nociception following chemical irritation in a capsaicin model of corneal insult. • As analgesic action was apparent in both treated and control eyes, it is unclear what effect, if any, the vehicle exerted in minimizing ocular pain or rather if a central action induced by systemic absorption of the peptide is in place. • The analgesic action appears to be a delayed action and occurs without reduction in corneal sensitivity. • Further study is required to clarify the mechanism by which this novel peptide appears to exert analgesia in the mammalian eye as well as ramifications of potential systemic absorption. • Currently, only limited medical alternatives are available to obtain adequate corneal analgesia following various corneal insults, either iatrogenic, traumatic or disease related. • Effective corneal analgesics must provide adequate pain relief without compromise of corneal sensitivity. • Interestingly, viper venom appears to demonstrate marked analgesic properties. Chromatographic fractionation of venoms demonstrated that low molecular weight fractions consist of peptides that impart significant analgesics properties. • Here we describe the action of the synthetic analogue of the low molecular weight venom fraction pGlu-Asn-Trp-Thr-OH (SIS-ZEP04) for topical use as a potential corneal analgesic. • Study Purpose: To ascertain efficacy of SIS-ZEP04 in reducing pain in a rat model of experimentally induced chemical corneal injury. • Administration of 20 µL of 0.01 mg/mL of tetrapeptide in 0.01% ethanol vehicle was applied to the right eye for 14 days. A negative control was employed in the fellow eye. • Capsaicin testing was performed at baseline, day 7 and 14. • The time required for recovery from capsaicin induced corneal insult, defined as blepharospasm, eye wiping, and squinting was recorded as a surrogate indicator of analgesic efficacy in relation to the control eye. Table 1. Descriptive values, blepharospasm recovery time (seconds+) Table 2. Power analysis* *G*Power v3.1.7 +GraphPad Prism v5.00 • Mean time (seconds) for recovery from capsaicin induced irritation in both right and left eyes at baseline was 38.0 +/- 7.8 and 52.2 +/- 9.8 seconds respectively. • Following SIS-ZEP04 treatment (at day 14) mean (SD) time for capsaicin induced irritation recovery was 12.8 +/-5.6 and 24.4 +/- 14.7 seconds for right and left eyes respectively (Tables 1 and 2). • A statistically significant reduction in mean time of capsaicin recovery was found for both right and left eyes (paired one way t test, p=0.0250 and 0.0072 respectively, Figure 1+). • Cochet-Bonnet aesthesiometry measurements did not deviate from baseline levels at day 7 or 14 for either eye. • Intermediate day 7 capsaicin results did not differ significantly between treatment and control groups. Farazifard R. Safarpour F, Sheibani V, Javan M. Eye-wiping test: a sensitive animal model for acute trigeminal pain studies. Brain Research Protocols. 2005;16:44-49 Bates, BD, Mitchell K, Keller MM, Chan CC, Swaim WD, Yaskovich R, Mannes AJ, Iadarola MJ. Prolonged analgesic response of cornea to topical resiniferatoxin., a potent TRPV1 agonist. Pain. 2010;149:522-528 • Five adult Sprague Dawley rats were utilized for study. All procedures were approved by the local animal use committee. The capsaicin eye wipe test was employed as a mechanism to ascertain analgesic efficacy.1,2 Acknowledgments: We would like to acknowledge the support of the Shulov Institute of Science (SIS) Ltd. Rehovot, Israel and the Richard A. Perritt Charitable Foundation in the conduct of this work. SIS ZEP04 was kindly provided by Dr. Naftali Primor of Shulov Institute of Science Ltd.