Comparison of Prostaglandin Analog Exposure on Wound Healing Response in the Porcine Model Mark McDermott, Fu-Shin X. Yu, Jia Yin, Ashok Kumar, Ke-Ping.

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Comparison of Prostaglandin Analog Exposure on Wound Healing Response in the Porcine Model Mark McDermott, Fu-Shin X. Yu, Jia Yin, Ashok Kumar, Ke-Ping Xu Kresge Eye Institute Wayne State University, Detroit, MI This study was funded by an unrestricted grant from Allergan, Inc. The authors have no financial relationships to disclose.

Abstract  Purpose: To determine the effect of prostaglandin analog exposure on corneal wound healing.  Methods: Standardized 5 mm epithelial wounds were made with ex vivo whole globe porcine eyes (n = 3). Globes were incubated for 24 hours in MEM before topical administration of 30 µL of test agents (saline control, toxic control [Triton], Travatan Z ®, Travatan ®, Lumigan ®, and Xalatan ® ). Wounds were exposed for 10 minutes to test agent, rinsed twice with 3 mL PBS, and subsequently 2 mL fresh MEM were added. Forty-eight hours postincision, wound healing response and epithelial defects were evaluated by staining (Richardson’s staining solution).  Results: Forty-eight hours after 5-mm incision, corneoepithelial wounds had a mean healed percentage of: baseline saline control = 96.89%, toxic control = 6.06%, Lumigan ® = 97.32%, Travatan ® = 84.76%, Travatan Z ® = 99.80%, and Xalatan ® = 80.51%. The wound size differences of Lumigan ®, Travatan ® and Travatan Z ® were not statistically significant from the saline control (P =.260, P =.141, P =.278 respectively). Xalatan ® statistically significantly delayed wound closure compared to saline control, Lumigan ®, and Travatan Z ® (P <.001 and P <.001, respectively).  Conclusion: The ex vivo porcine model permits the quantitative assessment of the impact of pharmaceutical agents on corneoepithelial wound healing. Lumigan ® and Travatan Z ® did not delay wound healing response rates. The effect of antihypertensive treatment on wound healing should be considered for patients following glaucoma filtration and/or cataract surgery.

Introduction  Exposure of corneal epithelial cells to irritants can trigger a cellular stress response, altering expression of factors involved in initiation of wound healing.  Ocular irritancy of ophthalmic medications in humans can be predicted using ex vivo models. 1 –In a bovine cornea model, benzalkonium chloride (BAK) and sodium dodecyl sulfate (SDS)  Induced tight junction disruption, increased permeability of corneal epithelium, and caused breakdown of epithelial barrier  Altered dose- and time-dependent binding activity of transcription factors (eg, AP-1 and NF  B)  A porcine cornea model is introduced to evaluate ophthalmic medication tolerability and toxicity on epithelial wound healing. 1. Xu et al. Toxicol Sci. 2000; 58:

Purpose  To determine the effect of prostaglandin analog exposure on corneal wound healing.

Methods  Standardized 5-mm epithelial wounds were made with ex vivo whole globe porcine eyes (n = 3).  Globes were incubated for 24 hours in minimum essential medium (MEM) before topical administration of 30 µL of test agents: –Saline control –Toxic control (Triton) –Travatan Z ® (travoprost 0.004%; sofZia TM ; Alcon Laboratories, Inc.; Fort Worth, TX) –Travatan ® (travoprost 0.004%; 0.015% BAK; Alcon Laboratories, Inc.; Fort Worth, TX) –Lumigan ® (bimatoprost 0.03%; 0.005% BAK; Allergan, Inc.; Irvine, CA) –Xalatan ® (latanoprost 0.005%; 0.02% BAK; Pfizer, Inc.; New York, NY)  Wounds were exposed for 10 minutes to test agent, rinsed twice with 3 mL PBS and subsequently 2 mL fresh MEM were added.  Wound healing response and epithelial defects were evaluated by staining (Richardson’s staining solution) 48 hours postincision.

Corneoepithelial Wound Healing Original wound 48 hours post-wounding ControlTriton X-100Lumigan ® Travatan ® Travatan Z ® Xalatan ®

Corneoepithelial Wound Healing  Wound healing with Lumigan ®, Travatan ®, and Travatan Z ® did not differ significantly from control. * *Significantly (P <.001) delayed healing compared with control, Lumigan ®, and Travatan Z ®. ControlTritonLumigan ® Travatan ® Travatan Z ® Xalatan ®

Discussion  Wound healing response in porcine eyes differs among the PGAs evaluated. –This may be dependent on a combination of the active ingredient and the preservative.

Conclusion  The ex vivo porcine model permits the quantitative assessment of the impact of pharmaceutical agents on corneoepithelial wound healing.  Lumigan ®, Travatan ®, and Travatan Z ® did not delay wound healing response rates, while wound healing was delayed with Xalatan ®.  The effect of IOP-lowering agents on wound healing may be a consideration for patients following glaucoma filtration or cataract surgery.