The development of topical Salbutamol to prevent human skin scarring and hyperpigmentation

全球每年有1.1亿例初级外科手术切开，其中那些在高紧张区域进行的切开特别容易留下疤痕。疤痕是伤口修复的自然过程的结果，由愈合伤口中过度的细胞行为产生。根据身体位置的不同，伤口的伤疤可能会在情感上(面部)和身体上(关节)虚弱。这对于一些患者来说尤其如此，他们的皮肤在受损部位明显变黑(过度色素沉着)，使任何伤害都特别具有创伤性。此外，伤口疤痕的护理给世界各地的医疗系统带来了沉重的财政负担。有效的疤痕预防治疗将造福于数以百万计的皮肤损伤患者，提高患者的健康和生活质量。目前还没有得到证实的治疗方法来防止伤口疤痕形成。沙丁胺醇是一种安全且耐受性良好的药物，自1968年以来一直是英国哮喘治疗的主要药物。普拉实验室和其他实验室的研究表明，沙丁胺醇可以调节伤口修复过程。独一无二的是，当沙丁胺醇应用于伤口部位时，它会改变伤口的愈合方式，抑制过度的细胞行为，并将愈合过程从疤痕转移到正常的皮肤再生。在猪创伤模型中，沙丁胺醇在创伤后56天减少了近50%的瘢痕面积和色素沉着，显著改善了疤痕外观。在这里，稳定的沙丁胺醇和安慰剂凝胶将根据良好的生产实践生产用于皮肤伤口的局部使用。非临床研究将根据良好的实验室实践在猪伤口模型中进行，以确保安全性(药代动力学(PK)研究和皮肤毒理学)，以满足法规要求，并在首个人类临床试验(CT)中确定防止皮肤疤痕的最佳1倍剂量。为了推进治疗的实施，I期CT被设计为一项志愿者内、双盲、随机、安慰剂控制的剂量递增试验。一项强有力的招募计划将招募45名健康志愿者，他们将被招募到三组，分别为0.5x、1x(从CT前选择)和2x沙丁胺醇配方，从最低剂量开始。这项研究将按照良好的临床实践进行，为期12个月。志愿者的每只手臂下将在相同的解剖位置做2厘米的线性切口，安慰剂和沙丁胺醇的剂量将在左臂和右臂之间随机分配。伤口将在60天内每天接受治疗。主要的试验目标是评估外用沙丁胺醇应用于直线切口的安全性和耐受性。术后第0/1天采集血样进行PK分析，以确定沙丁胺醇血药浓度峰值是否可接受。皮肤耐受性将每天在每个地点进行评估。不良事件将被记录下来。在0.5倍剂量后将提供中期安全性分析，以进展到更高的剂量。次要目标是确定沙丁胺醇改善瘢痕的最佳外用剂量。伤口愈合和疤痕评估将比较每位志愿者在创伤后6个月、9个月和12个月时配对的对侧瘢痕中的有效剂量和安慰剂，当疤痕被认为完全成熟时。数据将决定这项研究是否将为外科手术容易形成疤痕的患者进行进一步的CT检查铺平道路。除了对患者的好处外，这种治疗还将使外科医生和英国国民健康保险制度受益。患者会愈合得更好，更早出院，需要的疤痕修复手术更少，这将大大节省成本。已证明的预防皮肤疤痕的效果可以为使用沙丁胺醇预防皮肤过度疤痕(瘢痕疙瘩隆起，伤口部位逐渐扩大的疤痕)和其他组织的纤维化铺平道路。

One hundred and ten million primary surgical incisions occur globally every year, with those made in areas of high tension particularly prone to scarring. Scarring is the result of the natural process of wound repair, generated by excessive cell behaviour in the healing wound. Depending on the body location, wound scars can be emotionally (face) and physically (joint) debilitating. This is especially true for some patients who suffer significant darkening (hyperpigmentation) of the skin at the site of damage, making any injury particularly traumatic. In addition, the care of wound scars places a heavy financial burden on healthcare systems worldwide. An effective scar prevention treatment would benefit the millions of patients with skin injury, enhancing the patient's health and quality of life. There are currently no proven treatments available to prevent wound scarring. Salbutamol is a safe and well-tolerated pharmaceutical, which has been a mainstay of asthma therapy in the UK since 1968. Research in the Pullar lab and other labs has shown that salbutamol can modulate wound repair processes. Uniquely, when salbutamol is applied to the wound site, it alters the way the wound heals, curbing excessive cell behaviour and moving the healing process away from scarring and towards normal skin regeneration. In a pig wound model, salbutamol reduced scar area and hyperpigmentation by almost 50%, 56 days post-wounding, significantly improving scar appearance.Here, stable salbutamol and placebo gels will be manufactured for topical use in skin wounds in accordance with good manufacturing practices. Non-clinical studies will be performed in a pig wound model in accordance with good laboratory practices to ensure safety (pharmacokinetic (PK) studies and skin toxicology), to satisfy regulatory requirements and determine the optimum 1x dose for skin scar prevention in the first-in-human clinical trial (CT). To move towards therapeutic implementation, the phase I CT is designed as a within-volunteer, double-blind, randomised, placebo-controlled dose escalation trial. A robust recruitment plan will recruit 45 healthy volunteers who will be recruited into three groups of 0.5x, 1x (selected from the pre-CT) and 2x salbutamol formulation, starting with the lowest dose. The study, performed in accordance with good clinical practice, will be for 12 months. 2cm linear incisions will be made at the same anatomical location under each arm of volunteers and placebo and salbutamol dose will be randomised between left and right arms. Incisions will be treated daily for 60 days. The primarily trial objective will be to assess safety and tolerability of topical salbutamol when applied to linear incisions. Blood samples will be collected at day 0/1 after surgery to perform PK analysis to determine if peak salbutamol plasma levels are acceptable. Skin tolerance will be assessed at each site daily. Adverse events will be recorded. Interim analysis of safety will be provided after the 0.5x dose to progress to the higher dose. The secondary objective is to determine the optimal topical salbutamol dose for scar improvement. Wound healing and scar assessments will compare the active dose and placebo in each volunteer's paired, contralateral scars at 6, 9 and 12 months post-wounding, when scars are considered fully mature.The data will determine whether this study will pave the way for further CTs within patients with surgical procedures prone to scarring. In addition to the benefit to patients, this treatment would also benefit the surgeons and the NHS. Patients would heal better, leave hospital sooner and require less scar revision surgery, which would provide significant cost savings. Demonstrated efficacy in skin scar prevention could pave the way to the use of salbutamol to prevent excessive skin scarring (keloids - raised, progressively enlarging scars at the wound site) and fibrosis in other tissues.