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

全球每年有一亿一千万个初次手术切口，在高度紧张的地区特别容易留下疤痕。疤痕是伤口修复的自然过程的结果，由愈合伤口中的过度细胞行为产生。根据身体的位置，伤口疤痕可以在情感上（面部）和身体上（关节）使人衰弱。这对于一些在损伤部位皮肤显著变暗（色素沉着过度）的患者尤其如此，使任何损伤都特别具有创伤性。此外，伤口疤痕的护理给世界各地的医疗保健系统带来了沉重的经济负担。有效的疤痕预防治疗将使数百万皮肤损伤患者受益，提高患者的健康和生活质量。目前还没有有效的治疗方法来防止伤口疤痕。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支柱。Pullar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。独特的是，当沙丁胺醇应用于伤口部位时，它改变了伤口愈合的方式，抑制了过度的细胞行为，并使愈合过程远离疤痕，走向正常的皮肤再生。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过度，显著改善了瘢痕外观。在这里，将按照良好的生产规范生产稳定的沙丁胺醇和安慰剂凝胶，用于皮肤创伤局部使用。将根据药物非临床研究质量管理规范在猪伤口模型中进行非临床研究，以确保安全性（药代动力学（PK）研究和皮肤毒理学），满足监管要求，并确定首次人体临床试验（CT）中预防皮肤瘢痕的最佳1x剂量。为了实现治疗实施，I期CT设计为志愿者内、双盲、随机、安慰剂对照剂量递增试验。一个稳健的招募计划将招募45名健康志愿者，他们将被招募到三个组，分别为0.5x、1x（从CT前选择）和2x沙丁胺醇制剂，从最低剂量开始。本研究将按照药物临床试验质量管理规范进行，为期12个月。将在志愿者的每个手臂下的相同解剖位置处制作2cm线性切口，并且将在左臂和右臂之间随机分配安慰剂和沙丁胺醇剂量。每天处理切口，持续60天。主要试验目的是评估局部沙丁胺醇应用于线性切口时的安全性和耐受性。将在手术后第0/1天采集血样，进行PK分析，以确定沙丁胺醇血浆峰水平是否可接受。每天在每个研究中心评估皮肤耐受性。将记录不良事件。将在0.5x剂量后提供中期安全性分析，以进展至更高剂量。次要目的是确定改善瘢痕的最佳局部沙丁胺醇剂量。伤口愈合和疤痕评估将比较活性剂量和安慰剂在每个志愿者的配对，对侧疤痕在受伤后6个月，9个月和12个月，当疤痕被认为是完全成熟的。数据将决定是否这项研究将铺平道路，进一步CT在患者的外科手术容易形成疤痕。除了对患者有益外，这种治疗也将使外科医生和NHS受益。患者会愈合得更好，更快出院，需要更少的疤痕修复手术，这将大大节省成本。在皮肤瘢痕预防中证实的疗效可以为使用沙丁胺醇预防过度皮肤瘢痕形成（瘢痕疙瘩-在伤口部位逐渐扩大的瘢痕）和其他组织中的纤维化铺平道路。

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.