Beta-adrenergic antagonist for the healing of chronic diabetic foot ulcers: study protocol for a prospective, randomized, double-blinded, controlled and parallel-group study

Abstract

Background: Diabetic foot ulcers (DFUs) are the most common cause of leg amputations and their management is extremely challenging. Despite many advances and expensive therapies, there has been little success in improving outcomes of DFUs. In prior work our laboratory has examined the effects of beta-adrenergic antagonists (βAAs) on skin and skin-derived cells. We have shown that βAAs enhance the rate of keratinocyte migration, promote angiogenesis, and hasten wound healing in scratch wounds in vitro, in animal wound models, and in anecdotally reported cases of chronic wounds that healed successfully after topical application of the βAA timolol. Thus, we propose to test timolol directly on DFUs to determine if it improves healing above the current standard of care (SOC). This study will examine the efficacy and safety of topically applied beta-antagonist Timoptic-XE® (timolol maleate ophthalmic gel forming solution) in subjects with DFUs. Methods/design: This is a phase two, randomized, double-blinded, controlled, and parallel-group clinical trial with two treatment arms, SOC plus topical Timoptic-XE® and SOC plus a non-biologically active gel (hydrogel, as placebo drug). Study subjects with a DFU will be selected from the Veterans Affairs Northern California Health Care System (VANCHCS). Study duration is up to 31 weeks, with three phases (screening phase for two weeks, active phase for up to 12 weeks, with an additional second consecutive confirmatory visit after 2 weeks, and follow-up phase comprising monthly visits for 4 months). Subjects will apply daily either the topical study drug or the placebo on the foot ulcer for 12 weeks or until healed, whichever comes first. Measurements of wound size and other data will be collected at baseline, followed by weekly visits for 12 weeks, and then a monthly follow-up period.

Biotechnology in India: An Analysis of ‘Biotechnology Industry Research Assistance Council’ (BIRAC)‐Supported Projects

“…Esmolol hydrochloride (Galnobax gel formulation), initially developed as a cardioselective beta‐1 receptor blocker, completed Phase 3 studies for the treatment of diabetic foot ulcers. Beta blockers have been shown to enhance the rate of keratinocyte migration, promote angiogenesis, and hasten wound healing [73,74] …”

“…Beta blockers have been shown to enhance the rate of keratinocyte migration, promote angiogenesis, and hasten wound healing. [73,74] Under small-molecule-related synthesis and process R&D we have included synthetic chemistry as well as biotransformations, unless these provided merely access to early-stage starting materials, intermediates or chemicals with multiple applications, which were ranked under industrial biotechnology. Examples are deuterium-labelled glucuronides for metabolism studies, paclitaxel, deacetyl-cephalosporin, lipstatin, levodopa, and semi-synthetic artemisinin.…”

Utility of topical timolol in the management of chronic non-healing foot ulcers

“…10 Kaur et al showed that timolol was effective in chronic diabetic foot ulcers. 11 The studies of Braun et al and Vestita et al showed the efficacy of timolol in the management of chronic recalcitrant wounds. 12,13 Similarly, there have been many cases reported where chronic wounds were successfully treated with topical timolol.…”

Mechanism and application of β‐adrenoceptor blockers in soft tissue wound healing

“…Chronic wounds are typically characterized by delayed epithelialization, a persistent inflammatory response, infection, and impaired vascular‐neural function 90 . These pathological alterations prevent the damaged tissue from completing healing through the normal healing process, causing vascular ulcers, diabetic chronic ulcers, pressure wounds, and other complex wounds 91 . The formation of ulcers lengthens hospital stays, raises treatment costs, and results in significant physical, psychological, and financial burdens on patients 92 .…”