The role of topical timolol in wound healing and the treatment of vascular lesions: A narrative review
外用噻吗洛尔在伤口愈合和血管病变治疗中的作用：叙述性综述

acute wound, B blocker, beta-blocker, chronic wound, hemangioma, timolol, topical, wound, wound healing
急性伤口、B 受体阻滞剂、β 受体阻滞剂、慢性伤口、血管瘤、噻吗洛尔、局部用药、伤口、伤口愈合

Beta-adrenergic receptors are expressed in a wide range of body tissues and are known as fundamental regulators of the central nervous system, glands, vessels, lungs, and heart. Although the expression of these receptors in the human skin was first reported about 30 years ago, ${}^1$${}^1$^(1){ }^{1} the importance of their presence in this organ has recently been recognized. Beta-2 adrenergic receptors are the only subgroup of beta-adrenergic receptors expressed in the membrane of large cells, including skin keratinocytes, ${}^2$${}^2$^(2){ }^{2} fibroblasts, and melanocytes. Skin wound healing is a complex and highly regulated biological process that requires the coordinated migration and growth of keratinocytes and fibroblasts like other cells. Injury to the skin results in the stimulation of dermal and epidermal cells to produce cytokines, growth factors, and proteases and to build extracellular matrix components-all of which can regulate the migration and growth of keratinocytes that are required for epidermal regeneration. ${}^3$${}^3$^(3){ }^{3} After injury to the skin, cells migrate directly to the center of the wound bed to start restoration
β-肾上腺素能受体在人体多种组织中都有表达，是中枢神经系统、腺体、血管、肺和心脏的基本调节器。虽然这些受体在人体皮肤中的表达在大约 30 年前才首次被报道， ${}^1$${}^1$^(1){ }^{1} 但它们在这一器官中存在的重要性最近才被认识到。β-2肾上腺素能受体是唯一在大细胞膜上表达的β-肾上腺素能受体亚群，包括皮肤角质细胞、 ${}^2$${}^2$^(2){ }^{2} 成纤维细胞和黑色素细胞。皮肤伤口愈合是一个复杂而高度调节的生物过程，需要角质形成细胞和成纤维细胞像其他细胞一样协调迁移和生长。皮肤受伤会刺激真皮和表皮细胞产生细胞因子、生长因子和蛋白酶，并形成细胞外基质成分--所有这些都能调节表皮再生所需的角质形成细胞的迁移和生长。 ${}^3$${}^3$^(3){ }^{3} 皮肤受伤后，细胞会直接迁移到伤口床的中心，开始复原。
and restore the integrity of the epidermis. Many factors affect the injury-induced direct migration of keratinocytes, including chemotaxis and contact-induced inhibition. ${}^4$${}^4$^(4){ }^{4} In addition, the electrical environment plays an important role in the direct migration of keratinocytes and wound healing. ${}^{5,6}$${}^{5,6}$^(5,6){ }^{5,6} The use of beta receptor antagonists in wound healing was first proposed after their systemic administration in burn patients. ${}^7$${}^7$^(7){ }^{7} The first sign of the biological role of $\beta 2$$\beta 2$beta2\beta 2 adrenoreceptors in wound healing was revealed in a study that showed that $\beta 2$$\beta 2$beta2\beta 2 adrenoreceptor agonists lead to delayed wound healing in the organs of salamanders. ${}^8$${}^8$^(8){ }^{8} Nonetheless, subsequent studies on different epithelial cells yielded complex results. For instance, $\beta 2$$\beta 2$beta2\beta 2 adrenoreceptor agonists were reported to result in delays ${}^9$${}^9$^(9){ }^{9} or to speed up corneal wound healing. ${}^{10}$${}^{10}$^(10){ }^{10} It has recently been demonstrated that $\beta 2$$\beta 2$beta2\beta 2 adrenoreceptors can control the rate of epidermal barrier penetration by limiting epidermal water loss. ${}^{11}$${}^{11}$^(11){ }^{11} The wound healing process is a complex process and is influenced by several factors. The major growth factors and cytokines that participate in wound healing are EGF, FGF-2, TGF- $\beta$$\beta$beta\beta, PDGF, VEGF, IL-1, IL-6, and TNF- $\alpha$$\alpha$alpha\alpha. ${}^{12,13}$${}^{12,13}$^(12,13){ }^{12,13} At present, various topical
并恢复表皮的完整性。影响损伤诱导的角质形成细胞直接迁移的因素很多，包括趋化和接触诱导抑制。 ${}^4$${}^4$^(4){ }^{4} 此外，电环境在角质形成细胞的直接迁移和伤口愈合中也起着重要作用。 ${}^{5,6}$${}^{5,6}$^(5,6){ }^{5,6} β受体拮抗剂在伤口愈合中的应用是在烧伤患者全身用药后首次提出的。 ${}^7$${}^7$^(7){ }^{7} $\beta 2$$\beta 2$beta2\beta 2 肾上腺素受体在伤口愈合中的生物学作用的第一个迹象出现在一项研究中，该研究表明， $\beta 2$$\beta 2$beta2\beta 2 肾上腺素受体激动剂会导致蝾螈器官的伤口愈合延迟。 ${}^8$${}^8$^(8){ }^{8} 然而，随后对不同上皮细胞的研究得出了复杂的结果。例如， $\beta 2$$\beta 2$beta2\beta 2 肾上腺素受体激动剂据报道会导致 ${}^9$${}^9$^(9){ }^{9} 角膜伤口愈合延迟或加速。 ${}^{10}$${}^{10}$^(10){ }^{10} 最近有研究表明， $\beta 2$$\beta 2$beta2\beta 2 肾上腺素受体可以通过限制表皮失水来控制表皮屏障的渗透速度。 ${}^{11}$${}^{11}$^(11){ }^{11} 伤口愈合过程是一个复杂的过程，受到多种因素的影响。参与伤口愈合的主要生长因子和细胞因子有 EGF、FGF-2、TGF- $\beta$$\beta$beta\beta 、PDGF、VEGF、IL-1、IL-6 和 TNF- $\alpha$$\alpha$alpha\alpha 。 ${}^{12,13}$${}^{12,13}$^(12,13){ }^{12,13} 目前，各种外用
and systemic drugs and dressings are used to treat and accelerate the healing rate of various skin wounds. Timolol is one of drugs that use for treating different types of skin wounds. The topical and systemic use of timolol in the treatment of vascular disorders, especially neonatal hemangiomas, has already been investigated in various clinical trials. ${}^{14,15}$${}^{14,15}$^(14,15){ }^{14,15} This narrative review was written about the role of topical Timolol in hemangiomas and wound healing in the field of dermatology.
噻吗洛尔和全身用药及敷料用于治疗和加快各种皮肤伤口的愈合速度。噻吗洛尔是用于治疗各种皮肤伤口的药物之一。噻吗洛尔用于治疗血管疾病，特别是新生儿血管瘤的局部和全身用药已在各种临床试验中进行了研究。 ${}^{14,15}$${}^{14,15}$^(14,15){ }^{14,15} 这篇叙述性综述是关于外用噻吗洛尔在皮肤科领域的血管瘤和伤口愈合中的作用。

All the relevant articles in Pubmed, Scopus, and Google Scholar were reviewed for writing this narrative review article and the intended data were extracted.
为撰写这篇叙述性综述文章，我们查阅了 Pubmed、Scopus 和 Google Scholar 上的所有相关文章，并提取了预期数据。

The publication dates of the articles are from 2013 to 2019 and they are included case reports, case series, and randomized controlled trials.
文章的发表日期为 2013 年至 2019 年，包括病例报告、系列病例和随机对照试验。

The search terms were as follows: timolol AND (acute wound OR chronic wound OR [vascular tumors]). To find additional eligible studies, we manually searched the reference lists of all retrieved studies and published reviews and included all the identified relevant articles.
检索词如下：噻吗洛尔和（急性伤口或慢性伤口或[血管肿瘤]）。为了找到更多符合条件的研究，我们手动检索了所有检索到的研究和已发表的综述的参考文献目录，并纳入了所有已确定的相关文章。

Pullar et al ${}^{16}$${}^{16}$^(16){ }^{16} showed that specific $\beta 2$$\beta 2$beta2\beta 2 adrenoreceptor antagonists double the speed of surface wound healing in vitro and nonspecific antagonists also increase the healing rate. Plus, $\beta 2$$\beta 2$beta2\beta 2 adrenoreceptor antagonists increase the migration speed of keratinocytes. ${}^{16}$${}^{16}$^(16){ }^{16} They increase the phosphorylation of extracellular signal-regulated kinases (ERKs) significantly. ERKs play an important role in the signaling
Pullar等人 ${}^{16}$${}^{16}$^(16){ }^{16} 的研究表明，特异性 $\beta 2$$\beta 2$beta2\beta 2 肾上腺素受体拮抗剂能使体外表面伤口愈合速度加倍，非特异性拮抗剂也能提高愈合速度。此外， $\beta 2$$\beta 2$beta2\beta 2 肾上腺素受体拮抗剂还能提高角质形成细胞的迁移速度。 ${}^{16}$${}^{16}$^(16){ }^{16} 它们能显著增加细胞外信号调节激酶（ERKs）的磷酸化。ERKs在信号传导过程中发挥着重要作用。
pathways prior to migration (Figure 1) ${}^{17}$${}^{17}$^(17){ }^{17} and are critical for the repair of surface wounds in the form of a continuous monolayer of epidermal cells. ${}^{18}\beta 2$${}^{18}\beta 2$^(18)beta2{ }^{18} \beta 2 adrenoreceptor antagonists also improve keratinocytes’ migration by an electric field. ${}^{16}$${}^{16}$^(16){ }^{16} The electric field created immediately following skin injury is one of the first signals that cells receive to direct their migration to the wound bed. ${}^{19}$${}^{19}$^(19){ }^{19} Because the wound bed has negative charge relative to the wound edges and keratinocytes naturally tend to migrate to the negative pole (the cathode) in an electric field, the endogenous electric field created by the wound directs the keratinocytes’ movement toward the center of the wound. ${}^{20-22}\beta 2$${}^{20-22}\beta 2$^(20-22)beta2{ }^{20-22} \beta 2 adrenoreceptor antagonists speed up chronic wound healing by 66% in vitro. ${}^{16}$${}^{16}$^(16){ }^{16} Skin wound healing is accelerated by up to $72\mathrm{\%}$$72\mathrm{\%}$72%72 \% depending on its location, ${}^{11}$${}^{11}$^(11){ }^{11} the mechanism of which appears to entail blocking the internal $\beta 2$$\beta 2$beta2\beta 2 adrenoreceptor network, which reduces the migration speed and delays wound healing. ${}^{23,24}$${}^{23,24}$^(23,24){ }^{23,24} Topical timolol is now commonly used to treat infantile hemangiomas in neonates under 6 months without any significant complications, which demonstrates the low risk of its use. ${}^{25}$${}^{25}$^(25){ }^{25}
${}^{17}$${}^{17}$^(17){ }^{17} 迁移前的途径（图1），对表皮细胞以连续单层的形式修复表面伤口至关重要。 ${}^{18}\beta 2$${}^{18}\beta 2$^(18)beta2{ }^{18} \beta 2 肾上腺素受体拮抗剂也能通过电场改善角质形成细胞的迁移。 ${}^{16}$${}^{16}$^(16){ }^{16} 皮肤损伤后立即产生的电场是细胞接收到的引导其向伤口床迁移的第一信号之一。 ${}^{19}$${}^{19}$^(19){ }^{19} 由于伤口床相对于伤口边缘带负电荷，而角质形成细胞在电场中自然倾向于向负极（阴极）迁移，因此伤口产生的内源性电场会引导角质形成细胞向伤口中心移动。 ${}^{20-22}\beta 2$${}^{20-22}\beta 2$^(20-22)beta2{ }^{20-22} \beta 2 肾上腺素受体拮抗剂可使体外慢性伤口愈合速度加快66%。 ${}^{16}$${}^{16}$^(16){ }^{16} 皮肤伤口愈合的速度最多可加快 $72\mathrm{\%}$$72\mathrm{\%}$72%72 \% ，这取决于伤口的位置， ${}^{11}$${}^{11}$^(11){ }^{11} 其机制似乎需要阻断内部 $\beta 2$$\beta 2$beta2\beta 2 肾上腺素受体网络，从而降低迁移速度，延迟伤口愈合。 ${}^{23,24}$${}^{23,24}$^(23,24){ }^{23,24} 外用噻吗洛尔目前常用于治疗6个月以下新生儿的婴幼儿血管瘤，没有出现任何明显的并发症，这表明其使用风险较低。 ${}^{25}$${}^{25}$^(25){ }^{25}

A 67-year-old man with diabetes and chronic venous insufficiency had a $4.2{\mathrm{cm}}^2$$4.2{\mathrm{cm}}^2$4.2cm^(2)4.2 \mathrm{~cm}^{2} chronic wound in the left calf, which remained unhealed after 7 months of standard treatment. The wound margins’ biopsy indicated changes in favor of venous insufficiency and leukocytoclastic vasculitis. The patient was treated with timolol eye drop $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \%, three to four drops per day, and took 400 mg pentoxifylline tablets, thrice daily. The patient applied the timolol drop with cadexomer iodine gel on the wound and used Silva Sorb gel every other day.
一名患有糖尿病和慢性静脉功能不全的67岁男子左小腿上有一个 $4.2{\mathrm{cm}}^2$$4.2{\mathrm{cm}}^2$4.2cm^(2)4.2 \mathrm{~cm}^{2} 慢性伤口，经过7个月的标准治疗后仍未愈合。伤口边缘的活检结果表明，其变化有利于静脉功能不全和白细胞凝集性血管炎。患者接受了噻吗洛尔滴眼液 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% 的治疗，每天滴三到四滴，并服用 400 毫克喷托维林片，每天三次。患者将噻吗洛尔滴眼液与卡德索姆碘凝胶一起滴在伤口上，每隔一天使用一次席尔瓦-索布凝胶。

FIGURE 1 Keratinocyte Beta2 Adrenergic Receptor Signaling Pathways; A, cAMP-dependent signaling, B, PP2A-dependent pathway, C, IP3 and PKC-dependent pathway, and D, pathway for beta2 adrenergic receptor blockade
图 1 角质细胞 beta2 肾上腺素能受体信号传导途径；A，cAMP 依赖性信号传导，B，PP2A 依赖性途径，C，IP3 和 PKC 依赖性途径，D，β2 肾上腺素能受体阻断途径

Signs of a slight improvement appeared after 4 weeks. The patient then discontinued pentoxifylline because of its complications. During the next 83 days, the wound improved rapidly and was eventually completely epithelialized. ${}^{26}$${}^{26}$^(26){ }^{26} Braun et al ${}^{27}$${}^{27}$^(27){ }^{27} reported on an 80-year-old woman with a history of venous insufficiency who had underwent many treatments due to multiple painful wounds on both ankles caused by repeated traumas from a year before and had underwent one thigh z. Despite these treatments, the patient’s wound was still $3.2{\mathrm{cm}}^2$$3.2{\mathrm{cm}}^2$3.2cm^(2)3.2 \mathrm{~cm}^{2} after 6 months. She was treated with timolol $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% drop, one drop weekly per $2{\mathrm{cm}}^2$$2{\mathrm{cm}}^2$2cm^(2)2 \mathrm{~cm}^{2} of the wound edge, followed by dressing with silicone foam and a three-layer compress. All the patient’s wounds healed completely after 8 weeks. Another 70-year-old woman with a history of venous insufficiency, osteoporosis, and beta thalassemia presented with chronic wound on the back of her right leg from 3 months before. The patient’s wound was treated with standard dressings but no significant improvement was achieved. Timolol 0.5% drop was administered, one drop weekly per $2{\mathrm{cm}}^2$$2{\mathrm{cm}}^2$2cm^(2)2 \mathrm{~cm}^{2} of the wound, and then the wound was dressed with silicone foam and four-layer compress; this treatment improved the $1{\mathrm{cm}}^2$$1{\mathrm{cm}}^2$1cm^(2)1 \mathrm{~cm}^{2} wound within 7 weeks. Another female patient presented with a $4.8{\mathrm{cm}}^2$$4.8{\mathrm{cm}}^2$4.8cm^(2)4.8 \mathrm{~cm}^{2} wound due to a leftsided trauma of the back and recovered completely after treatment with timolol $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% drops daily for 8 weeks. Another woman with a wound due to pressure on the upper right thigh was treated with timolol daily for 4 weeks, and her wound size decreased from 2 to $0.6{\mathrm{cm}}^2$$0.6{\mathrm{cm}}^2$0.6cm^(2)0.6 \mathrm{~cm}^{2}. A man with a wound above the left inner ankle with sickle cell anemia and venous insufficiency was treated with timolol drops weekly for 8 weeks. He experienced $21\mathrm{\%}$$21\mathrm{\%}$21%21 \% improvement and a reduction in wound size from 3.6 to $2.9{\mathrm{cm}}^2{}^{27}$$2.9{\mathrm{cm}}^2{}^{27}$2.9cm^(2)^(27)2.9 \mathrm{~cm}^{2}{ }^{27} A 92-year-old woman with a history of ischemic heart disease with two chronic wounds on the left leg caused by venous insufficiency, which had not improved after 4 months of standard treatments, was treated with timolol eye drop $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \%, four drops daily, on one of the wounds. Both wounds were dressed with hydrocolloid film and silicone foam and were approximately $20{\mathrm{cm}}^2$$20{\mathrm{cm}}^2$20cm^(2)20 \mathrm{~cm}^{2} in size at the beginning. After 6 weeks, the wound treated with topical timolol reduced by $8{\mathrm{cm}}^2$$8{\mathrm{cm}}^2$8cm^(2)8 \mathrm{~cm}^{2} in size. After 12 weeks, it healed completely. No complications were observed with timolol treatment. ${}^{28}$${}^{28}$^(28){ }^{28} Tang et ${\mathrm{al}}^{29}$${\mathrm{al}}^{29}$al^(29)\mathrm{al}^{29} reported on a 43-year-old female patient who had presented due to a chronic left mid-back wound. The wound was $26{\mathrm{cm}}^2$$26{\mathrm{cm}}^2$26cm^(2)26 \mathrm{~cm}^{2} in size and 3.5 cm in depth and was created 15 months before due to thoracotomy for open heart surgery and the pipes inserted to discharge secretions. During this time, conservative treatments such as dressing with foam, negative pressure wound therapy and daily treatment with topical recombinant human platelet-derived growth factor for 3 weeks had not led to improvements. Due to the lack of desired results from different treatments, the patient began receiving treatment with timolol drops $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \%, three to four drops daily, on wounds dressed with a soft silicone. During the 8 weeks of treatment with timolol, the wound was completely epithelialized without any major complications. A 76-year-old man presented with a $10\times 11\mathrm{cm}$$10\times 11\mathrm{cm}$10 xx11cm10 \times 11 \mathrm{~cm} wound in the scalp region caused by removing squamous cell carcinoma by Mohs surgery. After 3 years of using standard treatments, a low vascular granulation tissue was created on his wound center. The patient was treated with topical timolol, three to four
4 周后，病情略有好转。随后，由于并发症的影响，患者停用了喷托昔林。在接下来的 83 天里，伤口迅速好转，最终完全上皮化。 ${}^{26}$${}^{26}$^(26){ }^{26} Braun等人 ${}^{27}$${}^{27}$^(27){ }^{27} 报告了一位有静脉功能不全病史的80岁妇女，由于一年前的多次外伤导致双脚踝多处伤口疼痛，她接受了许多治疗，并接受了一次大腿z治疗。她接受了噻吗洛尔 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% 滴剂治疗，每周每 $2{\mathrm{cm}}^2$$2{\mathrm{cm}}^2$2cm^(2)2 \mathrm{~cm}^{2} 伤口边缘滴一滴，然后用硅酮泡沫包扎，并进行三层热敷。所有患者的伤口均在 8 周后完全愈合。另一名 70 岁的妇女患有静脉功能不全、骨质疏松症和地中海贫血症，3 个月前右腿后部出现慢性伤口。患者的伤口接受了标准敷料治疗，但没有明显改善。患者使用了 0.5% 的噻吗洛尔滴剂，每周每 $2{\mathrm{cm}}^2$$2{\mathrm{cm}}^2$2cm^(2)2 \mathrm{~cm}^{2} 伤口滴一滴，然后用硅胶泡沫和四层敷料包扎伤口；这种治疗方法在 7 周内改善了 $1{\mathrm{cm}}^2$$1{\mathrm{cm}}^2$1cm^(2)1 \mathrm{~cm}^{2} 伤口。另一名女性患者因背部左侧外伤造成 $4.8{\mathrm{cm}}^2$$4.8{\mathrm{cm}}^2$4.8cm^(2)4.8 \mathrm{~cm}^{2} 伤口，在每天使用噻吗洛尔 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% 滴剂治疗8周后，伤口完全愈合。另一名妇女的伤口是由于右大腿上部受压造成的，每天使用噻吗洛尔治疗 4 周后，她的伤口面积从 2 mm 减小到 $0.6{\mathrm{cm}}^2$$0.6{\mathrm{cm}}^2$0.6cm^(2)0.6 \mathrm{~cm}^{2} 。一名男子因镰状细胞性贫血和静脉功能不全导致左内踝上方有伤口，他每周使用噻吗洛尔滴剂治疗8周。 一位 92 岁的妇女有缺血性心脏病史，左腿上有两处因静脉功能不全造成的慢性伤口，经过 4 个月的标准治疗后仍不见好转，她在其中一处伤口上滴了噻吗洛尔眼药水 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% ，每天 4 滴。两处伤口均使用水胶体薄膜和硅胶泡沫包扎，开始时伤口大小约为 $20{\mathrm{cm}}^2$$20{\mathrm{cm}}^2$20cm^(2)20 \mathrm{~cm}^{2} 。6 周后，使用局部噻吗洛尔治疗的伤口缩小了 $8{\mathrm{cm}}^2$$8{\mathrm{cm}}^2$8cm^(2)8 \mathrm{~cm}^{2} 。12 周后，伤口完全愈合。噻吗洛尔治疗未发现并发症。 ${}^{28}$${}^{28}$^(28){ }^{28} 唐等 ${\mathrm{al}}^{29}$${\mathrm{al}}^{29}$al^(29)\mathrm{al}^{29} 报告了一名43岁的女性患者，她因左背部中段的慢性伤口而就诊。伤口大小为 $26{\mathrm{cm}}^2$$26{\mathrm{cm}}^2$26cm^(2)26 \mathrm{~cm}^{2} ，深度为 3.5 厘米，是 15 个月前因开胸手术造成的，当时插入了管道以排出分泌物。在此期间，使用泡沫敷料、负压伤口疗法和每天使用重组人血小板衍生生长因子局部治疗 3 周等保守治疗方法均未见改善。由于不同的治疗方法都没有取得理想的效果，患者开始接受噻吗洛尔滴剂 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% 治疗，每天滴 3 到 4 滴，伤口用柔软的硅胶包扎。在使用噻吗洛尔治疗的 8 周内，伤口完全上皮化，没有出现任何重大并发症。一名 76 岁的男子因通过莫氏手术切除鳞状细胞癌而导致头皮部位出现 $10\times 11\mathrm{cm}$$10\times 11\mathrm{cm}$10 xx11cm10 \times 11 \mathrm{~cm} 伤口。经过 3 年的标准治疗，他的伤口中心出现了低血管肉芽组织。患者接受了外用噻吗洛尔治疗，用药三至四次。
drops twice daily, which was reduced to once a day due to stimulation, and then to every other day, and then to every 2 to 3 days. The granulation tissue was smoothed out and the wound was fully epithelialized after 4 months. ${}^{30}$${}^{30}$^(30){ }^{30} Two 1-year-old children with generalized junctional epidermolysis bullosa also presented with complaints about chronic wounds of the nail bed and the skin folds on the neck despite the topical application of corticosteroids and silicone dressing for over 2 months. After starting treatment with timolol eye drops 0.5%, under closed dressing, two drops twice daily for 3 weeks for the nail wounds and three drops twice daily for 8 weeks for the neck wounds, $100\mathrm{\%}$$100\mathrm{\%}$100%100 \% improvement was obtained for the nail wounds and 80% for the neck wounds. No complications were reported by the patients. ${}^{31}$${}^{31}$^(31){ }^{31} The use of topical timolol for the treatment of wounds caused by chronic diabetes and venous insufficiency has been reported to improve wound healing. One study examined 60 patients in two groups of 30 who were treated for chronic leg wounds due to diabetes and venous insufficiency. One group received topical timolol $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% along with the standard therapy and the other group received only standard treatment. Changes in the wounds at weeks 4, 8, and 12 were $25\mathrm{\%},44\mathrm{\%}$$25\mathrm{\%},44\mathrm{\%}$25%,44%25 \%, 44 \%, and $65\mathrm{\%}$$65\mathrm{\%}$65%65 \% in the patients receiving timolol and $12\mathrm{\%},22\mathrm{\%}$$12\mathrm{\%},22\mathrm{\%}$12%,22%12 \%, 22 \%, and $30\mathrm{\%}$$30\mathrm{\%}$30%30 \% in the control group, indicating accelerated healing as a result of topical timolol administration. ${}^{32}$${}^{32}$^(32){ }^{32} The effect of topical timolol on the healing process of a vasculitis wound was reported in a 40-year-old man with no history of underlying diseases who had presented because of a wound with a 5 cm diameter in the lower left limbs. The wound had formed 3 weeks before and vasculitis was reported in the wound biopsy. The patient was treated with systemic prednisolone, 60 mg daily for 1 month, followed by the coadministration of dapsone, 50 mg daily; however, no improvement was observed. Timolol eye drop $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% was prescribed for the patient, five drops thrice daily, on the center and edges of the wound. The wound improved significantly at the weekly follow-ups and healed after 6 weeks. ${}^{33}$${}^{33}$^(33){ }^{33}
每天滴两次，由于受到刺激，减少到每天一次，然后改为隔天一次，再后来改为每 2 至 3 天一次。4 个月后，肉芽组织被磨平，伤口完全上皮化。 ${}^{30}$${}^{30}$^(30){ }^{30} 两名患有全身交界性表皮松解症的 1 岁儿童也主诉甲床和颈部皮肤皱褶处有慢性伤口，尽管外用皮质类固醇激素和硅胶敷料已超过 2 个月。在开始使用0.5%噻吗洛尔滴眼液治疗后，在封闭敷料下，指甲伤口每天两次，每次两滴，连续使用3周；颈部伤口每天两次，每次三滴，连续使用8周， $100\mathrm{\%}$$100\mathrm{\%}$100%100 \% 指甲伤口和颈部伤口的改善率分别为80%。患者未报告任何并发症。 ${}^{31}$${}^{31}$^(31){ }^{31} 据报道，使用局部噻吗洛尔治疗慢性糖尿病和静脉功能不全引起的伤口可改善伤口愈合。一项研究对60名患者进行了检查，这些患者分为两组，每组30人，他们都因糖尿病和静脉功能不全导致慢性腿部伤口而接受治疗。其中一组在接受标准治疗的同时还接受了局部噻吗洛尔 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% 治疗，另一组只接受了标准治疗。在第 4、8 和 12 周，接受噻吗洛尔治疗的患者的伤口变化分别为 $25\mathrm{\%},44\mathrm{\%}$$25\mathrm{\%},44\mathrm{\%}$25%,44%25 \%, 44 \% 和 $65\mathrm{\%}$$65\mathrm{\%}$65%65 \% ，而对照组的伤口变化分别为 $12\mathrm{\%},22\mathrm{\%}$$12\mathrm{\%},22\mathrm{\%}$12%,22%12 \%, 22 \% 和 $30\mathrm{\%}$$30\mathrm{\%}$30%30 \% ，这表明外用噻吗洛尔可加速伤口愈合。 ${}^{32}$${}^{32}$^(32){ }^{32} 有报道称，局部使用噻吗洛尔对脉管炎伤口愈合过程有影响，患者为一名40岁的男性，无基础疾病史，因左下肢直径5厘米的伤口就诊。 伤口是在 3 周前形成的，伤口活检结果显示患有血管炎。患者接受了每天 60 毫克的泼尼松龙全身用药治疗 1 个月，随后又联合使用了每天 50 毫克的地塞米松，但病情未见好转。医生给患者开了噻吗洛尔滴眼液 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% ，每天三次，每次五滴，滴在伤口中央和边缘。每周复查时，伤口明显好转，6 周后痊愈。 ${}^{33}$${}^{33}$^(33){ }^{33}

In a study conducted on six patients, Dabiri et al ${}^{34}$${}^{34}$^(34){ }^{34} investigated the effect of topical timolol for the treatment of acute wounds caused by surgical excision in nonmelanoma skin cancers. This study was conducted on four female and two male patients with a mean age of 70 years and a mean wound size of $4{\mathrm{cm}}^2$$4{\mathrm{cm}}^2$4cm^(2)4 \mathrm{~cm}^{2} and depth of 1 mm . Three patients were treated with timolol and three with saline. The results showed that the use of topical timolol on acute wounds improved the aesthetic results twice more in the wound site. Summary of studies used topical timolol for dermatologic indications especially for wound healing have been showed in Table 1. ${}^{26-34}$${}^{26-34}$^(26-34){ }^{26-34} To assess the impact of topical timolol after destructive CO2 laser, laser was applied on two areas of $1.5{\mathrm{cm}}^2$$1.5{\mathrm{cm}}^2$1.5cm^(2)1.5 \mathrm{~cm}^{2} on the volar part of each forearm in a 68-year-old woman with Fitzpatrick skin color type 2. All four areas were treated twice daily with a solution of vinegar diluted in water and then hydrating ointment was applied. One drop of timolol $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% drop was applied to one of the areas in each part before applying the hydrating ointment. In the first week of treatment, areas where timolol was applied
在一项针对六名患者的研究中，Dabiri 等人 ${}^{34}$${}^{34}$^(34){ }^{34} 调查了外用噻吗洛尔治疗非黑色素瘤皮肤癌手术切除引起的急性伤口的效果。这项研究的对象是四名女性和两名男性患者，他们的平均年龄为 70 岁，平均伤口大小为 $4{\mathrm{cm}}^2$$4{\mathrm{cm}}^2$4cm^(2)4 \mathrm{~cm}^{2} ，深度为 1 毫米。三名患者接受了噻吗洛尔治疗，三名患者接受了生理盐水治疗。结果表明，在急性伤口上局部使用噻吗洛尔可使伤口部位的美观效果提高两倍。表 1 列出了将局部噻吗洛尔用于皮肤科适应症，尤其是伤口愈合的研究摘要。 ${}^{26-34}$${}^{26-34}$^(26-34){ }^{26-34} 为了评估外用噻吗洛尔在破坏性 CO2 激光治疗后的影响，我们在一名 68 岁的菲茨帕特里克肤色 2 型女性的前臂两侧 $1.5{\mathrm{cm}}^2$$1.5{\mathrm{cm}}^2$1.5cm^(2)1.5 \mathrm{~cm}^{2} 的两个区域使用了激光。每天用稀释在水中的醋溶液治疗所有四个区域两次，然后涂上保湿软膏。在涂抹保湿软膏之前，在每个部位的其中一个部位滴一滴噻吗洛尔 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% 滴剂。在治疗的第一周，使用噻吗洛尔的部位
TABLE 1 Summary of studies which have used topical timolol for dermatologic indications especially for wound healing
表 1 将局部噻吗洛尔用于皮肤病适应症（尤其是伤口愈合）的研究综述

were less inflamed. The transepidermal water loss (TEWL) was measured using a VapoMeter. This value was significantly lower for the timolol-treated areas in the first week and during the study, indicating the faster rate of recovery in these areas. Over time, TEWL levels became similar to that of normal skin, which was faster in areas treated with timolol. That study showed an increase in the rate of wound healing caused by destructive ${\mathrm{CO}}_2$${\mathrm{CO}}_2$CO_(2)\mathrm{CO}_{2} laser using topical timolol. ${}^{35}$${}^{35}$^(35){ }^{35}