Use of Topical Timolol Maleate as Re-Epithelialization Agent for Treatment of Recalcitrant Wounds of Varying Etiologies

December 2020 | Volume 19 | Issue 12 | Editorials | 1252 | Copyright © December 2020


Published online December 1, 2020

Brian A Cahn MSa,c, Ramanjot Kaur MDb, Penelope A Hirt MDc, Catherine Tchanque-Fossuo MDb,d, Sara E Dahle DPM MPHc, Robert S Kirsner MD PhDc, Roslyn Rivkah Isseroff MDb,d, Hadar Lev-Tov MD MASc

aAlbert Einstein College of Medicine, Bronx, NY
bDermatology Section, Veterans Affairs Northern California Health Care System, Mather, CA
cDr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL
dDepartment of Dermatology, University of California, Davis, CA
ePodiatry Section, Veterans Affairs, Northern California Health Care System, Mather, CA

Abstract
Background: Chronic wounds remain a challenge for the clinician and healthcare system. It is therefore vital for additional therapies that target steps involved in wound recalcitrance. Recently, topical timolol has shown promising results for use in wound healing.

Objective: The goal of this study was to assess timolol’s effectiveness in healing wounds of varying etiologies.

Methods: This multi-center series took place from 2016¬–2019 at the wound healing centers at the University of Miami Health System and the Veterans Affairs Northern California Healthcare. We identified all wound patients who received treatment with topical timolol maleate 0.5% for at least 4 weeks after failing previous treatments. Timolol drops at a dose of 1 drop per cm2 of wound area were instilled with dressing changes twice a day, once a day, every other day, or continuous application. Once they began the study, they stopped all concurrent therapies aside from standard of care. Healing outcomes were classified into 3 categories: healed, defined as complete re-epithelialization of the wound and closure, improved, defined as decreasing wound size area (WSA), and worsening, defined as increasing WSA.

Results: We identified 39 patients, 32 males and 7 females that had a total of 55 chronic wounds of varying etiologies. Thirty-four of the wounds had completely healed, 15 wounds improved in WSA, 4 wounds were unchanged in WSA, and 2 wounds worsened in WSA.

Conclusions: In line with our previous experience, we found topical timolol to be a safe, cost-effective, and efficacious treatment for recalcitrant wounds of varying etiologies.

Introduction

Chronic wounds are a source of severe morbidity to patients.1 Wounds are also a notable burden on the healthcare system, with reported prevalence of 4.64% in the U.S. and an annual cost of over 25 billion dollars.2,3 Moreover, wounds are associated with >15% of all skin diseaserelated deaths4 and the 5 year mortality of some chronic wounds is greater than that of many cancers.5

Re-epithelialization and dermal proliferation are defining features of wound healing and must occur in order to restore the barrier function of the skin. However, many wounds fail to progress through these phases.6 Recent in-vitro and in-vivo studies7-11 as well as case reports,12-15 have demonstrated that beta-adrenergic receptor blockade with the β1 / β2 antagonist, timolol, either systemically administered or topically applied, promotes re-epithelialization and overall healing in chronic wounds. Timolol is a well-known, readily available and generic drug that has a cost ranging from 3 to 21 dollars.16 

Herein, we report a retrospective analysis of the effectiveness of topically applied timolol on 55 chronic wounds of varying etiologies in 39 patients.

METHODS

This multi-center, retrospective case-series study was conducted at the Wound Centers at the University of Miami Health System in Miami, Florida and Wound Clinics at the Veterans Affairs Health Care System of Northern California in Mather, California. We identified all wound patients from 2016 to 2018 who received treatment with topical timolol maleate 0.5% (timolol) for at least 4 weeks. Timolol drops at a dose of 1 drop per cm2 of wound area were instilled with dressing changes twice a day, once a day or every other day. Some patients received continuous application of timolol via a delivery system (Acton™ Topical Deliver System, Aplion Wound Care Technology®, Murfreesboro, TN). Timolol therapy was combined with standard of care.

From the patient’s medical records, we collected clinical data about wound etiology, duration, location, size and treatments as well as all other relevant history. Healing outcomes were classified into three categories: healed, defined as complete reepithelialization of the wound and closure, improved, defined as decreasing wound size area, and worsening, defined as increasing wound size area. This study was deemed exempt from the institutional review board at the University of Miami.

RESULTS

There was a total of 39 patients (32 males and 7 females) and 55 chronic wounds. Of the 55 wounds, the majority were venous leg ulcers (VLUs) (n=30) followed by traumatic wounds (n=8) as well as other wound etiologies (Table 1). The median duration of the wound before treatment was 118 days. Following treatment with topical timolol for different durations (Table 2), 34 wounds had healed, and 15 wounds decreased in wound area (Table 1). Two of the VLUs had increasing wound area.

In the healed group, the median treatment duration was 89.5 days, and the median healing rate was -0.25 cm2/week (Table 2). The majority of the wounds had timolol applied daily (Figure 1). Out of the 34 healed wounds, 3 wounds occurred at locations other than the leg (1 diabetic foot ulcer (DFU), 1 abdominal post-surgical wound). Etiologies in this subgroup included mostly VLUs and traumatic wounds (Table 1).

In the group with decreasing wound area, 8 were still receiving treatment at the time of analysis. The median treatment duration was 112 days, median healing rate was -0.24 cm2/week and the median percent decrease in wound size was 62% (Table 2). While the majority of wounds occurred on the leg (n=11), 4 occurred in other locations such as the scalp, abdomen and foot. The majority of the wounds in this subgroup were VLUs (Table 1).