22 Feb Leg Wounds: Topical Timolol Accelerated Healing Times in Elderly Patients
MedicalResearch.com Interview with:
Chih-Shan Jason Chen, MD, PhD
Director, Dermatologic and Mohs Micrographic Surgery Unit
Memorial Sloan Kettering Skin Cancer Center at Hauppauge
Attending Mohs Surgeon, Dermatology Service
Memorial Sloan Kettering Cancer Center
Chief, Dermatologic Surgery Northport VA Medical Center
Associate Professor of Clinical Dermatology
Renaissance School of Medicine at Stony Brook University
MedicalResearch.com: What is the background for this study?
Response: Managing a surgical wound on the lower leg can be a challenge. Often, higher wound tension, atrophic skin, edema, and compromised circulation result in higher risks of wound dehiscence and infection, and significantly limit the capacity of wound closure post-surgically. Therefore, healing by secondary intention is a practical option for many lower leg Mohs defects. However, a secondary intention wound on the lower leg is expected to take a longer time to heal. Certain factors such as older age and health conditions of the host may adversely affect healing time.
Timolol is a nonselective beta-adrenergic receptor antagonist that has FDA approval for the treatment of glaucoma. In addition to this FDA-approved indication, topical timolol has several off-label uses in dermatology, such as for the treatment of infantile hemangiomas, venous stasis ulcers, and refractory wounds. Although timolol solution has been used in chronic wounds, knowledges of the efficacy and utility of timolol in an acute post-surgical wound setting is lacking.
MedicalResearch.com: What are the main findings?
Response: When comparing the group with anticipated poor wound healing in 2019 treated with the standard wound care regimen to the group with anticipated poor wound healing in 2020 treated with topical timolol, we saw a statistically significant difference in the time to complete re-epithelialization between these groups (p=0.0006). The group receiving topical timolol had quicker re-epithelialization, justifying the ability of topical timolol to significantly improve healing rates in this population. This is a significant finding that may help avoid the development of non-healing, chronic wounds following Mohs surgery. Under normal circumstances, acute wounds progress through an orderly process to rebuild and strengthen the wounded area. When this process is inhibited, wounds have the potential to become chronic; once a wound becomes chronic, it is associated with significant patient morbidity and elevated healthcare costs. We have observed that timolol improves acute wound healing, which may help avoid the development of chronic wounds.
MedicalResearch.com: Does timolol act as a vasodilator?
Response: Although timolol belongs to the class of beta-blocker pharmacologically, the mechanism of promoting wound healing may not be directly related to its vasodilator effect. There are various proposed mechanisms explaining the potential benefits of timolol on wound healing processes. Beta-2-adrenergic receptors (B2AR) are found on the surface of keratinocytes, and when bound to an agonist, there is decreased phosphorylation of MAPK pathways. This results in delayed keratinocyte migration and impaired keratinocyte proliferation, and thus poor wound healing. Cutaneous trauma causes local release of epinephrine and other B2AR agonists, which generates a poor wound healing microenvironment. Therefore, B2AR antagonists, such as timolol, can optimize wound healing by promoting keratinocyte and fibroblast migration, keratinocyte proliferation, and angiogenesis. Timolol also exhibits anti-inflammatory properties, by decreasing the release of proinflammatory cytokines and the migration of neutrophils and proinflammatory macrophages. Such anti-inflammatory effects regulate excess or prolonged inflammation in the tissue microenvironment. Inflammation plays a role in the earlier healing stage. Excess and prolonged inflammation inhibit normal progression of the healing process. Timolol may provide the benefit of steering the process back to normal.
MedicalResearch.com: What should readers take away from your report?
Response: Due to the expanding elderly population and the associated rise in skin cancer incidence, physicians continue to encounter complicated post-surgical lower leg wounds in the elderly with comorbidities. Traditionally, occlusion and compression are the main stay to facilitate healing of lower leg wounds. Our results suggest topical timolol does enhance wound healing by accelerating the healing time in those expected to have inadequate or prolonged healing. It provides a different and likely a simpler and less expensive option for clinicians who are managing difficult healing wounds on the lower leg.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: A limitation of this study is the small number of cases. Our results should now be validated by larger, prospective trials.
All authors report no conflict of interest.
Rachel Manci, Zaeem H. Nazir, Stephen W. Dusza, Chih-Shan Jason Chen
JAAD Published online: February 16, 2022
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