Efficacy and Safety of 0.25% Timolol Gel in Healing Surgical Open Wounds

Healing of a cutaneous defect by second intention is a complex process. Migration of
fibroblasts, keratinocytes, and other cell types to the site of defect and their
proliferation under stimulation by cytokines and growth factors occur during this process.
The role of topical beta-blockers in promoting wound healing is currently emerging in the
international literature (1-3). β2-Adrenergic receptors (B2AR) are the only subtype of
beta-adrenoceptors expressed on skin (4-6). They can be found in secretory coil of apocrine
glands, keratinocytes, fibroblasts and melanocytes. The distribution of these receptors
provides insight on dermatological disorders that may be affected by β-blockers. Keratinocyte
migration occurs by the facilitation of chemotaxis, the polarization of cells, and activation
of extracellular signal-related kinases essential in the signaling of promigratory pathways.
The B2AR activation inhibits keratinocyte migration by activating the serine/threonine
phosphatase 2A, which downregulates phosphorylation of extracellular signal-related kinases
necessary for migration. Therefore, B2AR antagonists prevent the phosphorylation of
phosphatase 2A and have the downstream effect of extracellular signal-related kinase
promotion, inducing a promigratory pathway in keratinocytes (4-6). Keratinocyte migration
also occurs by galvanotaxis, a phenomenon in which cells migrate in response to electric
stimuli. Keratinocytes can be stimulated to migrate with the formation of electrical poles
and the application of electrical fields. The B2AR antagonists improve the ability of
keratinocytes to respond to such migratory cues, whereas the B2AR agonists decrease
keratinocytes' ability to respond, further implicating the use of topical timolol for
recalcitrant wounds (4-6). Angiogenesis and dermal fibroblast proliferation are also
regulated by B2ARs. The B2AR antagonists have been found to promote angiogenesis in chick
chorioallantoic membrane assays and in vivo murine wound models. Dermal fibroblast migration
is also increased (by 27%) when exposed to B2AR antagonists, and epidermal differentiation is
improved with B2AR antagonists and β1- and β2-receptor antagonists (5-10).

Topical beta-blockers have been gaining increasing popularity and evidence over the last few
years as enhancers of wound healing in acute and chronic open wounds. In particular, 0.25%
timolol gel may represent a commercially available, safe and simple, painless-though perhaps
moderately expensive-treatment for improving both acute and chronic open wounds, as well as
for improving long-term cosmetic outcomes.

To assess the efficacy and safety of topically applied 0.25% timolol gel in promoting wound
healing in surgical open wounds ≤1.5cm versus standard of care (SOC) by:

1. Evaluating healing in response to treatment with 0.25% topical timolol gel versus SOC in
terms of wound surface area reduction of open surgical wound;

2. Evaluating cosmetic outcomes of surgical wounds in terms of blinded physician (Vancouver
Scar Scale, VSS) and patient (Visual Analogue Scale, VAS) assessment at 3 and 6 months
follow up;

3. Evaluating patient discomfort during the healing process by means of a patient pain VAS;

4. Determining the side effects associated to 0.25% topical timolol versus SOC; and

5. Determining costs associated to the use of 0.25% topical timolol versus SOC.

Inclusion Criteria:

1. Age greater than 18 years

2. Open surgical wound ≤1.5cm

3. No hypersensitivity with use of 0.25% timolol gel

Exclusion Criteria:

1. Age less than 18 years of age

2. Open surgical wound >1.5cm

3. Pregnant women

4. Use of systemic retinoids within 1 month

5. Any hypersensitivity with use of 0.25% timolol gel