Abstract
Salbutamol is a well-established β2-adrenergic receptor agonist used clinically for the reversal of bronchospasm. A functional β2-adrenergic receptor agonist network exists in the skin, which can alter skin cell migration and proliferation, inhibit angiogenesis, and alter wound re-epithelialization, suggesting a potential role for a β2-adrenergic receptor agonist applied topically for the prevention and treatment of scarring. Reduced scarring has been observed in an in vivo pig model, whereby a 50% reduction in skin scar area and hyperpigmentation was observed after topical application of salbutamol. OBJECTIVES: We conducted a double-blind, placebo-controlled, randomized, dose-escalation clinical trial. This was designed to investigate both the safety and efficacy of topical salbutamol for the improvement of scar appearance when applied as a cutaneous gel to sutured wound margins on the arms of healthy volunteers. METHODS: In a phase I, single-center, double-blind, placebo (vehicle) controlled, randomized, dose-escalation trial on 45 healthy human volunteers, 1 ml salbutamol topical gel was administered once daily to one 2-cm full-thickness incision site on each arm of the trial participants for 60 days. Each participant was allocated to only 1 dosing group (group 1: 2.5 mM, group 2: 5 mM, and group 3: 10 mM). Pharmacokinetic and clinical assessments of safety and efficacy were performed over a 12-month period. Scarring was assessed by validated clinical scoring systems by both investigator and participant over 12 months. RESULTS: In healthy human volunteers, tolerability assessments indicated zero incidences of edema, exudate, bleeding, or infection at any salbutamol-treated site irrespective of dose. All participants at every time point had peak plasma levels of salbutamol below the prespecified limit of 30 ng/ml. In efficacy assessments of the scars, no statistically significant improvements were noted in the mean difference between salbutamol-treated scars at any dose compared with placebo at months 7, 9, or 12 for either the investigator or participants' assessments. CONCLUSIONS: There are no clinically significant safety signals after the cutaneous administration of salbutamol gel (0.2-10 mM) in humans either local to the site of injury and drug administration or arising from systemic exposure to salbutamol, but the extent of salbutamol absorption decreases as the wound heals, confirming that re-epithelialization of the wound limits the potential for systemic absorption. This trial was prospectively registered with the Medicines and Healthcare products Regulatory Agency with the European Union Drug Regulating Authorities Clinical Trials (EudraCT number: 2017-003118-15).