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

fibroblasts²⁰ and melanocytes.²¹ Specifically, keratinocytes were discovered to have β2-ARs as the major class of expressed adrenergic receptors.²²

Initial in-vitro and in-vivo studies have demonstrated that the activation of β2-AR prevents migration of keratinocytes through various signaling mechanisms.²³ Additionally, the activation of β2-AR prevents the polarization of the keratinocyte and cytoskeleton organization that are key steps to initiate migration.²⁴ Interestingly, keratinocytes were also shown to express enzymes required for catecholamine synthesis, suggesting an autocrine signaling mechanism that activates the β2-AR in the event of wounding.⁹ This is in addition to circulating catecholamines that are present under organismal stress conditions, such as wounding.²⁴

Logically, subsequent studies examined the converse paradigm, and tested whether blockade of the receptor using β2-AR antagonists could act as a pro-motogenic agent to bring about wound healing. These reports demonstrated that β2- AR antagonists, such as timolol, enhanced wound healing by increasing the rate of keratinocyte migration.⁸ Furthermore, β2- AR antagonists accelerated skin re-epithelialization in a human skin model of a chronic wound.⁹

Timolol, a non-specific β blocker, has been anecdotally reported to safely promote re-epithelialization in chronic wounds.^12-14 In a recent retrospective case-controlled study timolol improved the healing of chronic leg ulcers.²⁵ However, many of these reports have focused on the use of timolol as a re-epithelialization agent solely for the treatment of VLUs.

In our analysis, we found topically applied timolol to be effective in healing recalcitrant wounds of varying etiologies. Specifically, timolol was effective in healing challenging wounds such as radiation dermatitis, pyoderma gangrenosum and malignancy related wounds amongst others.

Notably, the chronicity of many of these wounds was profound with a median duration of 118 days before treatment with timolol versus 89.5 days with timolol. Moreover, many of these wounds had demonstrated recalcitrance even when standard care and other advanced therapies such as skin substitutes were used by expert clinicians in interdisciplinary wound centers. Importantly, there were no reports of adverse reactions to timolol’s use. Within the VLU subgroup we found that 28 of the 30 venous leg ulcers responded to treatment with timolol, as has the previous observational study.¹² However, the novel findings here are the dose dependency of the response, whereby the highest rate of healing was in the patient that had continuous application of timolol. Yet, we found the slowest healing rate to be amongst those that applied timolol twice a day. These findings are likely related to the effectiveness of compression in the patient that received continuous timolol. By having timolol continuously applied to the wound, it afforded the patient the ability to remain in compression and not have to change the dressing as often. However, those that applied timolol twice a day probably did not achieve optimal compression.

Interestingly, and consistent with our previous experience,¹² time to response with timolol is about 3 months. This highlights the need to recognize that timolol is an adjunct to therapy at the current paradigm of use. Future research should focus on testing different dosing regimens and timolol concentrations. Regardless, this information is very useful for the design of future studies of timolol treatment as current healing outcomes in clinical trials of wounds end at 12 weeks. Alternatively, this may suggest that timolol should be introduced earlier in the treatment plan, perhaps before the pathologically hyperproliferative wound edge is established. Future clinical investigations into the use of timolol for chronic wounds should allow sufficient follow up time to capture the full healing effect and include early intervention arm. This need for randomized controlled trials with excellent confounder exclusion criteria can be highlighted by our results whereby, the overwhelming majority of the patients saw improvement or healing of their recalcitrant wounds, while the two patients who demonstrated worsening of their wounds had additional complex comorbidities and medical therapy that may have complicated, delayed or prevented wound healing.

Some limitations to this analysis are the lack of gender diversity, due to the majority of the patients being treated at the Veterans Association Health Care System where most patients are male. However, VLUs in men are more difficult to heal²⁶ and therefore our success is encouraging as a treatment option for this dif!cult population. Additionally, the uncontrolled nature of this study limited our ability to comment on causality.

Even with these limitations, our data suggests that topical timolol may be an effective and safe treatment for chronic wounds, especially those that seem to be stalled in the reepithelialization stage. Often, chronic wounds need multiple modalities in addition to standard of care to bring about healing. Timolol is an inexpensive and effective treatment in the armamentarium of the wound healing clinician.

The authors of this case series have no con"ict of interest to declare.

Hadar Lev-Tov MD hlevtov@med.miami.edu