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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

Azadeh Goodarzi 1 1 ^(1){ }^{1} | Samaneh Mozafarpoor 2 2 ^(2){ }^{2} | Milad Dodangeh 3 3 ^(3){ }^{3} | Farnoosh Seirafianpour 3 3 ^(3){ }^{3} | Mohamad Hasan Shahverdi 1 1 ^(1){ }^{1} ()
Azadeh Goodarzi 1 1 ^(1){ }^{1} | Samaneh Mozafarpoor 2 2 ^(2){ }^{2} | Milad Dodangeh 3 3 ^(3){ }^{3} | Farnoosh Seirafianpour 3 3 ^(3){ }^{3} | Mohamad Hasan Shahverdi 1 1 ^(1){ }^{1} ()

1 1 ^(1){ }^{1} Department of Dermatology, Rasool Akram
1 1 ^(1){ }^{1} 拉苏尔-阿克拉姆皮肤科Medical Complex, Iran University of Medical Sciences (IUMS), Tehran, Iran
伊朗，德黑兰，伊朗医学科学大学（IUMS）医疗大楼 2 2 ^(2){ }^{2} Department of Dermatology, Skin Disease and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
2 2 ^(2){ }^{2} 伊朗伊斯法罕，伊斯法罕医科大学皮肤病与利什曼病研究中心皮肤病学系 3 3 ^(3){ }^{3} Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
3 3 ^(3){ }^{3} 伊朗德黑兰，伊朗医学科学大学医学院学生研究委员会\section*{Correspondence}
\小节*{通信｝Mohamad Hasan Shahverdi and Farnoosh Seirafianpour, Nyayesh Street, Sattarkhan Avenue, Rasool Akram Medical Complex, Tehran, Iran.
Mohamad Hasan Shahverdi 和 Farnoosh Seirafianpour，伊朗德黑兰，Rasool Akram 医疗中心，Sattarkhan 大道，Nyayesh 街。Email: shahverdy@gmail.com (M.H.S.) and farnoosh.se@gmail.com (F.S.)
电子邮件：shahverdy@gmail.com (M.H.S.) 和 farnoosh.se@gmail.com (F.S.)

Abstract 摘要

Beta-2 adrenergic receptors are the only subgroup of beta-adrenergic receptors expressed in the membrane of large cells, including skin keratinocytes, fibroblasts, and melanocytes. Alterations in the function or concentration of β 2 β 2 beta2\beta 2 adrenoreceptors related to keratinocytes are associated with some skin conditions. Some findings suggest the role of β 2 β 2 beta2\beta 2 adrenoreceptors in maintaining the function and integrity of the epidermis. Beta-receptor antagonists can be systemically and topically effective in healing hemangioma, paronychia, vasculitis ulcer, tufted angioma, acute and chronic wounds. Most studies with a strong design on this subject deal with the systemic form, but recently, numerous case and group reports and smaller studies have focused on topical forms, especially topical timolol. The present comprehensive review study surveys the role of topical timolol in acute and chronic wound healing in the field of dermatology.
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、成纤维细胞和黑色素细胞。与角朊细胞有关的 β 2 β 2 beta2\beta 2 肾上腺素受体的功能或浓度的改变与某些皮肤病有关。一些研究结果表明， β 2 β 2 beta2\beta 2 肾上腺素受体在维持表皮的功能和完整性方面发挥作用。β-受体拮抗剂对治疗血管瘤、脓疱疮、血管炎溃疡、簇状血管瘤、急性和慢性伤口有全身和局部疗效。有关这一主题的大多数研究都是针对全身用药的，但最近，许多病例和小组报告以及较小规模的研究都侧重于局部用药，尤其是局部噻吗洛尔。本综述研究调查了外用噻吗洛尔在皮肤科急慢性伤口愈合中的作用。

KEYWORDS 关键词

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

1 | INTRODUCTION 1 简介

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 β 2 β 2 beta2\beta 2 adrenoreceptors in wound healing was revealed in a study that showed that β 2 β 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, β 2 β 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 β 2 β 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- β β beta\beta, PDGF, VEGF, IL-1, IL-6, and TNF- α α 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} β 2 β 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， β 2 β 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， β 2 β 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， β 2 β 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- β β beta\beta 、PDGF、VEGF、IL-1、IL-6 和 TNF- α α 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。

2 | METHODS AND MATERIALS
2 方法和材料

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。

3 | DISCUSSION AND CONCLUSION
3 讨论和结论

Pullar et al 16 16 ^(16){ }^{16} showed that specific β 2 β 2 beta2\beta 2 adrenoreceptor antagonists double the speed of surface wound healing in vitro and nonspecific antagonists also increase the healing rate. Plus, β 2 β 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 β 2 β 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， β 2 β 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 β 2 18 β 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 β 2 20 − 22 β 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 % 72 % 72%72 \% depending on its location, 11 11 ^(11){ }^{11} the mechanism of which appears to entail blocking the internal β 2 β 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 β 2 18 β 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 β 2 20 − 22 β 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 % 72 % 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 β 2 β 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}

4 | TIMOLOL WOUND HEALING
4 | 噻吗洛尔伤口愈合

4.1 | Chronic wounds 4.1 | 慢性伤口

A 67-year-old man with diabetes and chronic venous insufficiency had a 4.2 cm 2 4.2 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 % 0.5 % 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 cm 2 4.2 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 % 0.5 % 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 cm 2 3.2 cm 2 3.2cm^(2)3.2 \mathrm{~cm}^{2} after 6 months. She was treated with timolol 0.5 % 0.5 % 0.5%0.5 \% drop, one drop weekly per 2 cm 2 2 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 cm 2 2 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 cm 2 1 cm 2 1cm^(2)1 \mathrm{~cm}^{2} wound within 7 weeks. Another female patient presented with a 4.8 cm 2 4.8 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 % 0.5 % 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 cm 2 0.6 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 % 21 % 21%21 \% improvement and a reduction in wound size from 3.6 to 2.9 cm 2 27 2.9 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 % 0.5 % 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 cm 2 20 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 cm 2 8 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 al 29 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 cm 2 26 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 % 0.5 % 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 × 11 cm 10 × 11 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 % 0.5 % 0.5%0.5 \% 滴剂治疗，每周每 2 cm 2 2 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 cm 2 2 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 cm 2 1 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 cm 2 4.8 cm 2 4.8cm^(2)4.8 \mathrm{~cm}^{2} 伤口，在每天使用噻吗洛尔 0.5 % 0.5 % 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 cm 2 0.6 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 % 0.5 % 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 cm 2 20 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 cm 2 8 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 al 29 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 cm 2 26 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 % 0.5 % 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 × 11 cm 10 × 11 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 % 100 % 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 % 0.5 % 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 % , 44 % 25 % , 44 % 25%,44%25 \%, 44 \%, and 65 % 65 % 65%65 \% in the patients receiving timolol and 12 % , 22 % 12 % , 22 % 12%,22%12 \%, 22 \%, and 30 % 30 % 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 % 0.5 % 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 % 100 % 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 % 0.5 % 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 % , 44 % 25 % , 44 % 25%,44%25 \%, 44 \% 和 65 % 65 % 65%65 \% ，而对照组的伤口变化分别为 12 % , 22 % 12 % , 22 % 12%,22%12 \%, 22 \% 和 30 % 30 % 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 % 0.5 % 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}

4.2 | Acute wounds 4.2 | 急性伤口

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 cm 2 4 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 cm 2 1.5 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 % 0.5 % 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 cm 2 4 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 cm 2 1.5 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 % 0.5 % 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
Type/design 类型/设计 Study, year 研究，年份 Duration of therapy 治疗持续时间 Intervention 干预措施 Dose 剂量 Failed treatments/duration
治疗失败/持续时间		 Pts 分 Sites 网站 Outcomes 成果
Chronic wound/CR 慢性伤口/CR Lev-Tov H , 2013 26  Lev-Tov  H , 2013 26 {:[" Lev-Tov "],[H","2013^(26)]:}\begin{aligned} & \text { Lev-Tov } \\ & \mathrm{H}, 2013^{26} \end{aligned} 3 months 3 个月 Timolol eye drop 0.5% 400 mg pentoxifylline tablets
噻吗洛尔滴眼液 0.5% 400 毫克 戊氧地胆草碱片		 3 to 4 drops daily thrice daily
每日 3 至 4 滴，每日三次		 Daily iodine gel, collagenase ointment, compression, weekly debridement/7 months
每日碘凝胶、胶原酶软膏、加压、每周清创/7 个月		 1 Calf 小牛 Completely epithelialized
完全上皮化
Chronic wound/CR 慢性伤口/CR Braun  棕色 LR,2013 27  LR,2013  27 " LR,2013 "^(27)\text { LR,2013 }{ }^{27} 8 weeks 8 周 Timolol eye drop 0.5% silicone foam three-layer compress
噻吗洛尔滴眼液 0.5% 硅胶泡沫三层敷料		 1 drop weekly per 2 cm 2 2 cm 2 2cm^(2)2 \mathrm{~cm}^{2}
2 cm 2 2 cm 2 2cm^(2)2 \mathrm{~cm}^{2} 每周 1 滴		 Compression bandages, foam dressing, porcine small intestine, bilayered living skinequivalent, graft/6 months
压缩绷带、泡沫敷料、猪小肠、双层活体等效皮肤、移植/6 个月		 1 Ankles 脚踝 Completely healed 完全痊愈
Chronic wound/CR 慢性伤口/CR Braun  棕色 LR,2013 27  LR,2013  27 " LR,2013 "^(27)\text { LR,2013 }{ }^{27} 7 weeks 7 周 Timolol 0.5% drop silicone foam four-layer compress
噻吗洛尔 0.5% 滴剂硅酮泡沫四层敷料		 1 drop weekly per 2 cm 2 2 cm 2 2cm^(2)2 \mathrm{~cm}^{2}
2 cm 2 2 cm 2 2cm^(2)2 \mathrm{~cm}^{2} 每周 1 滴		 Compression bandages, foam dressings, skin equivalent
压缩绷带、泡沫敷料、皮肤等效物		 1 Back of leg 脚背 Improved the 1 cm 2 cm 2 cm^(2)\mathrm{cm}^{2} wound
改进了 1 cm 2 cm 2 cm^(2)\mathrm{cm}^{2} 伤口
Chronic wound/CR 慢性伤口/CR Manahan MN,2014 28 28 ^(28){ }^{28} 12 weeks 12周 Timolol 0.5% drops dressed with hydrocolloid film and silicone foam
噻吗洛尔 0.5%滴眼液，敷有水胶体薄膜和硅胶泡沫		 4 drops daily 每日 4 滴 Antibiotics, alginate and foam dressings, Ultra-sonic wound debridement/4 months
抗生素、藻酸盐和泡沫敷料、超音波伤口清创/4 个月		 1 Leg 腿部
 完全痊愈
Healed
completely
Healed completely| Healed | | :--- | | completely |
Chronic wound/CR 慢性伤口/CR Tang JC,2012  Tang   JC,2012  {:[" Tang "],[" JC,2012 "]:}\begin{aligned} & \text { Tang } \\ & \text { JC,2012 } \end{aligned} 8 weeks 8 周 Timolol 0.5% drops soft silicone dressing
噻吗洛尔 0.5% 滴剂软硅胶敷料		 3-4 drops daily 每天 3-4 滴 Dressing with foam, negative pressure and daily topical recombinant human platelet-derived growth factor/3 weeks
用泡沫、负压和每日局部重组人血小板衍生生长因子包扎 3 周		 1 Mid-back wound 中背部伤口 Epithelialized completely
完全上皮化
Chronic wound/CR 慢性伤口/CR Beroukhim  贝鲁吉姆 K , 2014 30 K , 2014 30 K,2014^(30)\mathrm{K}, 2014^{30} 4 months 4 个月 Timolol 0.5% 噻吗洛尔 0.5% 3-4 drops twice daily 每日两次，每次 3-4 滴 Standard treatments / 3 / 3 //3/ 3 years
标准治疗 / 3 / 3 //3/ 3 年		 1 Scalp 头皮 Fully epithelialized 完全上皮化
Chronic wound/CS 慢性伤口/CS Chiaverini C,  Chiaverini C、 2016 31 2016 31 2016^(31)2016^{31}

3周/指甲 8周/颈部
3 weeks/nail
8 weeks/ neck
3 weeks/nail 8 weeks/ neck| 3 weeks/nail | | :--- | | 8 weeks/ neck |
 Timolol 0.5%, closed dressing
噻吗洛尔 0.5%，封闭式敷料

每日两次，每次 2 滴/指甲 每日两次，每次 3 滴/颈部
2 drops twice daily/nail
3 drops twice daily/neck
2 drops twice daily/nail 3 drops twice daily/neck| 2 drops twice daily/nail | | :--- | | 3 drops twice daily/neck |
 Topical corticosteroids, silicone dressing/2 months
外用皮质类固醇、硅胶敷料/2 个月		 2 Nail bed,Neck skin fold 甲床、颈部皮肤褶皱

指甲的改善率为 100%，颈部的改善率为 80
100%
improvement for the nail, 80% for the neck
100% improvement for the nail, 80% for the neck| 100% | | :--- | | improvement for the nail, 80% for the neck |
Chronic wound/RCT 慢性伤口/RCT Thomas B,  Thomas B、 2017 32 2017 32 2017^(32)2017^{32} 12 weeks 12周 Timolol 0.5%, standard therapy
噻吗洛尔 0.5%，标准疗法		 1 drop for every 2 cm of wound daily
每天每 2 厘米伤口 1 滴		 Standard therapy: antibiotics, glycemic con-trol, absorbent dressing, debridement
标准疗法：抗生素、血糖控制、吸水敷料、清创		 30 Lower extremity 下肢

改进幅度是对照组的两倍
The
improvement was twice that of the control group
The improvement was twice that of the control group| The | | :--- | | improvement was twice that of the control group |
Vasculitis wound/CR 血管炎伤口/CR Alsaad AMS,  Alsaad AMS、 2019 33 2019 33 2019^(33)2019^{33} 6 weeks 6 周 Timolol 0.5%, 噻吗洛尔 0.5%、 5 drops thrice daily 每日三次，每次 5 滴 Systemic prednisolone, dapsone/3 weeks
全身泼尼松龙、达泊松/3 周		 1 Lower limbs 下肢 Healed completely 完全痊愈
Acute wound/RCT 急性伤口/RCT Dabiri G,  Dabiri G、 2017 34 2017 34 2017^(34)2017^{34} 13 weeks 13周 Timolol 0.5% 噻吗洛尔 0.5% - - 3 Below the patella 髌骨下方

疤痕更美观
More
cosmetically favorable scars
More cosmetically favorable scars| More | | :--- | | cosmetically favorable scars |
Type/design Study, year Duration of therapy Intervention Dose Failed treatments/duration Pts Sites Outcomes Chronic wound/CR " Lev-Tov H,2013^(26)" 3 months Timolol eye drop 0.5% 400 mg pentoxifylline tablets 3 to 4 drops daily thrice daily Daily iodine gel, collagenase ointment, compression, weekly debridement/7 months 1 Calf Completely epithelialized Chronic wound/CR Braun " LR,2013 "^(27) 8 weeks Timolol eye drop 0.5% silicone foam three-layer compress 1 drop weekly per 2cm^(2) Compression bandages, foam dressing, porcine small intestine, bilayered living skinequivalent, graft/6 months 1 Ankles Completely healed Chronic wound/CR Braun " LR,2013 "^(27) 7 weeks Timolol 0.5% drop silicone foam four-layer compress 1 drop weekly per 2cm^(2) Compression bandages, foam dressings, skin equivalent 1 Back of leg Improved the 1 cm^(2) wound Chronic wound/CR Manahan MN,2014 ^(28) 12 weeks Timolol 0.5% drops dressed with hydrocolloid film and silicone foam 4 drops daily Antibiotics, alginate and foam dressings, Ultra-sonic wound debridement/4 months 1 Leg "Healed completely" Chronic wound/CR " Tang JC,2012 " 8 weeks Timolol 0.5% drops soft silicone dressing 3-4 drops daily Dressing with foam, negative pressure and daily topical recombinant human platelet-derived growth factor/3 weeks 1 Mid-back wound Epithelialized completely Chronic wound/CR Beroukhim K,2014^(30) 4 months Timolol 0.5% 3-4 drops twice daily Standard treatments //3 years 1 Scalp Fully epithelialized Chronic wound/CS Chiaverini C, 2016^(31) "3 weeks/nail 8 weeks/ neck" Timolol 0.5%, closed dressing "2 drops twice daily/nail 3 drops twice daily/neck" Topical corticosteroids, silicone dressing/2 months 2 Nail bed,Neck skin fold "100% improvement for the nail, 80% for the neck" Chronic wound/RCT Thomas B, 2017^(32) 12 weeks Timolol 0.5%, standard therapy 1 drop for every 2 cm of wound daily Standard therapy: antibiotics, glycemic con-trol, absorbent dressing, debridement 30 Lower extremity "The improvement was twice that of the control group" Vasculitis wound/CR Alsaad AMS, 2019^(33) 6 weeks Timolol 0.5%, 5 drops thrice daily Systemic prednisolone, dapsone/3 weeks 1 Lower limbs Healed completely Acute wound/RCT Dabiri G, 2017^(34) 13 weeks Timolol 0.5% - - 3 Below the patella "More cosmetically favorable scars"| Type/design | Study, year | Duration of therapy | Intervention | Dose | Failed treatments/duration | Pts | Sites | Outcomes | | :---: | :---: | :---: | :---: | :---: | :---: | :---: | :---: | :---: | | Chronic wound/CR | $\begin{aligned} & \text { Lev-Tov } \\ & \mathrm{H}, 2013^{26} \end{aligned}$ | 3 months | Timolol eye drop 0.5% 400 mg pentoxifylline tablets | 3 to 4 drops daily thrice daily | Daily iodine gel, collagenase ointment, compression, weekly debridement/7 months | 1 | Calf | Completely epithelialized | | Chronic wound/CR | Braun $\text { LR,2013 }{ }^{27}$ | 8 weeks | Timolol eye drop 0.5% silicone foam three-layer compress | 1 drop weekly per $2 \mathrm{~cm}^{2}$ | Compression bandages, foam dressing, porcine small intestine, bilayered living skinequivalent, graft/6 months | 1 | Ankles | Completely healed | | Chronic wound/CR | Braun $\text { LR,2013 }{ }^{27}$ | 7 weeks | Timolol 0.5% drop silicone foam four-layer compress | 1 drop weekly per $2 \mathrm{~cm}^{2}$ | Compression bandages, foam dressings, skin equivalent | 1 | Back of leg | Improved the 1 $\mathrm{cm}^{2}$ wound | | Chronic wound/CR | Manahan MN,2014 ${ }^{28}$ | 12 weeks | Timolol 0.5% drops dressed with hydrocolloid film and silicone foam | 4 drops daily | Antibiotics, alginate and foam dressings, Ultra-sonic wound debridement/4 months | 1 | Leg | Healed <br> completely | | Chronic wound/CR | $\begin{aligned} & \text { Tang } \\ & \text { JC,2012 } \end{aligned}$ | 8 weeks | Timolol 0.5% drops soft silicone dressing | 3-4 drops daily | Dressing with foam, negative pressure and daily topical recombinant human platelet-derived growth factor/3 weeks | 1 | Mid-back wound | Epithelialized completely | | Chronic wound/CR | Beroukhim $\mathrm{K}, 2014^{30}$ | 4 months | Timolol 0.5% | 3-4 drops twice daily | Standard treatments $/ 3$ years | 1 | Scalp | Fully epithelialized | | Chronic wound/CS | Chiaverini C, $2016^{31}$ | 3 weeks/nail <br> 8 weeks/ neck | Timolol 0.5%, closed dressing | 2 drops twice daily/nail <br> 3 drops twice daily/neck | Topical corticosteroids, silicone dressing/2 months | 2 | Nail bed,Neck skin fold | 100% <br> improvement for the nail, 80% for the neck | | Chronic wound/RCT | Thomas B, $2017^{32}$ | 12 weeks | Timolol 0.5%, standard therapy | 1 drop for every 2 cm of wound daily | Standard therapy: antibiotics, glycemic con-trol, absorbent dressing, debridement | 30 | Lower extremity | The <br> improvement was twice that of the control group | | Vasculitis wound/CR | Alsaad AMS, $2019^{33}$ | 6 weeks | Timolol 0.5%, | 5 drops thrice daily | Systemic prednisolone, dapsone/3 weeks | 1 | Lower limbs | Healed completely | | Acute wound/RCT | Dabiri G, $2017^{34}$ | 13 weeks | Timolol 0.5% | - | - | 3 | Below the patella | More <br> cosmetically favorable scars |
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 CO 2 CO 2 CO_(2)\mathrm{CO}_{2} laser using topical timolol. 35 35 ^(35){ }^{35}
炎症较轻。使用 VapoMeter 测量了经表皮失水（TEWL）。在第一周和研究期间，噻吗洛尔治疗区域的该值明显较低，这表明这些区域的恢复速度较快。随着时间的推移，TEWL 水平变得与正常皮肤相似，而使用噻吗洛尔治疗的部位恢复得更快。该研究表明，局部使用噻吗洛尔的破坏性 CO 2 CO 2 CO_(2)\mathrm{CO}_{2} 激光可提高伤口愈合率。 35 35 ^(35){ }^{35}

5 | TIMOLOL IN TREATING VASCULAR LESIONS
5 治疗血管病变的噻吗洛尔

5.1 | Pyogenic granuloma 5.1 | 化脓性肉芽肿

To investigate the effect of topical timolol on the treatment of pyogenic granuloma caused by EGFR-inhibitor drugs, Sollena et al 36 36 ^(36){ }^{36} reported on six women and three men with 25 injuries who were treated with topical timolol gel twice daily until the time of recovery or at most for 4 weeks. Among these, 13 lesions recovered completely, nine showed partial improvement, and three lesions belonging to the same patient remained unimproved. With a mean follow-up of 7 months, no relapse was reported in the fully recovered lesions. Gupta et al 37 al 37 al^(37)\mathrm{al}^{37} reported on 10 patients with pyogenic granuloma treated with timolol eye drop 0.5 % 0.5 % 0.5%0.5 \%, four times daily with two drops each time. Complete response was in the form of recovery of the lesions, partial response as decreased size and number of lesions, and no response as no change in the size and number of the lesions. Four patients showed complete response within three to 24 days and showed no relapse at the 3-month follow-up. Three patients had partial response and three patients had none. The review of similar articles on the use of beta adrenoreceptor antagonists in the treatment of pyogenic granuloma caused by EGFR inhibitors conducted by Sollena et al yielded four articles on a total of 34 patients. Piraccini et al 38 al 38 al^(38)\mathrm{al}^{38} treated 10 patients using propranolol ointment 1%, applied once daily for a maximum of 45 days. Complete response was observed in three patients, and seven patients did not respond to the treatment. In two relatively similar studies, Cubiró et al reported on 10 patients and Sibaud et al on 13 patients who were treated with timolol eye gel 0.5 % 0.5 % 0.5%0.5 \%, used twice daily under the dressing for up to a month. Eleven patients recovered, seven partially recovered, and five patients did not recover at all. 39 , 40 39 , 40 ^(39,40){ }^{39,40} Yen et al 41 al 41 al^(41)\mathrm{al}^{41} treated one patient fully with Betaxolol eye drop 0.25 % 0.25 % 0.25%0.25 \%, used under the dressing for 1 month.
为了研究外用噻吗洛尔对表皮生长因子受体抑制剂药物引起的化脓性肉芽肿的治疗效果，Sollena 等人 36 36 ^(36){ }^{36} 报道了 6 名女性和 3 名男性的 25 例损伤，他们接受了外用噻吗洛尔凝胶的治疗，每天两次，直到痊愈或最多持续 4 周。其中，13 例皮损完全恢复，9 例部分改善，3 例属于同一患者的皮损仍未改善。在平均 7 个月的随访中，完全康复的皮损没有复发的报告。Gupta等人 al 37 al 37 al^(37)\mathrm{al}^{37} 报告了10名化脓性肉芽肿患者使用噻吗洛尔滴眼液 0.5 % 0.5 % 0.5%0.5 \% 治疗的情况，每天四次，每次两滴。完全反应是指病变恢复，部分反应是指病变的大小和数量减少，无反应是指病变的大小和数量没有变化。四名患者在三至二十四天内出现了完全反应，并且在三个月的随访中没有复发。3 名患者有部分反应，3 名患者没有反应。Sollena等人对使用β肾上腺素受体拮抗剂治疗表皮生长因子受体抑制剂引起的化脓性肉芽肿的类似文章进行了回顾，共收到4篇文章，涉及34名患者。Piraccini等 al 38 al 38 al^(38)\mathrm{al}^{38} 使用1%普萘洛尔软膏治疗了10名患者，每天涂抹一次，最长持续45天。3名患者观察到完全反应，7名患者对治疗没有反应。在两项相对类似的研究中，Cubiró等人报告了10名患者的情况，Sibaud等人报告了13名患者的情况，他们使用噻吗洛尔眼用凝胶 0.5 % 0.5 % 0.5%0.5 \% 进行治疗，每天两次，在敷料下使用，最长持续一个月。11名患者痊愈，7名患者部分痊愈，5名患者完全没有痊愈。 39 , 40 39 , 40 ^(39,40){ }^{39,40} Yen等 al 41 al 41 al^(41)\mathrm{al}^{41} 用倍他洛尔滴眼液 0.25 % 0.25 % 0.25%0.25 \% 完全治疗了一名患者，并在敷料下使用了1个月。

5.2 | Infantile hemangioma
5.2 | 婴儿血管瘤

In a meta-analysis, Zheng et al 42 al 42 al^(42)\mathrm{al}^{42} investigated the response rate and the effects of topical timolol in the treatment of infantile hemangiomas. They examined 10 studies with 887 patients. The rate of recovery with topical timolol was assessed compared to laser therapy, placebo, propranolol administration, and observation in eight
Zheng等人在一项荟萃分析中研究了外用噻吗洛尔治疗婴儿血管瘤的反应率和效果。他们对10项研究的887名患者进行了研究。与激光治疗、安慰剂、普萘洛尔用药和观察相比，评估了八项研究中局部使用噻吗洛尔的痊愈率。
studies with a total of 569 patients. Except for propranolol, which showed no significant differences, the improvement rate with timolol had a significant difference with the other treatments. Timolol complications were examined in nine studies with 677 patients and were shown to be much less than the complications of laser therapy, placebo and observation but similar to those of propranolol. Wu et al 43 43 ^(43)^{43} treated 321 patients with Superficial Infantile Hemangioma using a new formulation of timolol in the form of hydrogel. The treatment sequence was three times per day, each time applied as a thin layer over the entire hemangioma surface, until the lesion development stopped; then, it was applied twice daily for 2 weeks, and then tapered to once a day over 2 weeks. Forty percent of the patients had an excellent response, 50% good response, 10% moderate response, and 1 % 1 % 1%1 \% poor response. Clinical improvement was characterized by blanching and softening of the lesion surface after the initiation of treatment.
共有 569 名患者接受了研究。除普萘洛尔无显著差异外，噻吗洛尔的改善率与其他疗法有显著差异。9项研究共对677名患者进行了噻吗洛尔并发症检查，结果显示，噻吗洛尔的并发症远低于激光疗法、安慰剂和观察法，但与普萘洛尔的并发症相似。Wu等人 43 43 ^(43)^{43} 使用水凝胶形式的噻吗洛尔新配方治疗了321名浅表性婴儿血管瘤患者。治疗顺序为每天三次，每次在整个血管瘤表面薄薄地涂抹一层，直到病变停止发展；然后，每天涂抹两次，持续两周，再逐渐减少到每天一次，持续两周。40%的患者反应极佳，50%反应良好，10%反应中等， 1 % 1 % 1%1 \% 反应较差。临床改善的特点是治疗开始后皮损表面变白和软化。

5.3 | Tufted anioma 5.3 | 簇绒肛门瘤

Zhang et al 44 al 44 al^(44)\mathrm{al}^{44} reported on a case of tufted angioma treatment with topical timolol. A 5-year-old girl with a 4-year history of tufted angioma in the right arm was treated with timolol eye solution 0.5 % 0.5 % 0.5%0.5 \% twice daily. After 18 months, the lesion and its associated pain were completely resolved and no complications were observed during the treatment.
Zhang等 al 44 al 44 al^(44)\mathrm{al}^{44} 报道了一例用局部噻吗洛尔治疗丛生血管瘤的病例。一名 5 岁女孩的右臂有长达 4 年的簇状血管瘤病史，她接受了噻吗洛尔眼液 0.5 % 0.5 % 0.5%0.5 \% 的治疗，每天两次。18 个月后，病变和相关疼痛完全消失，治疗期间未发现任何并发症。

5.4 | Kaposi sarcoma 5.4 | 卡波西肉瘤

Nine cases of treatment of Kaposi’s sarcoma with topical timolol have been reported. The duration of the treatment varied from 4 to 24 weeks and the patients ranged from 52 to 94 years in age. Except for one case where treatment failed and two cases where the lesion remained macular, all the patients recovered fully. 45 45 ^(45){ }^{45}
据报道，用局部噻吗洛尔治疗卡波西肉瘤的病例有 9 例。治疗时间从 4 周到 24 周不等，患者年龄从 52 岁到 94 岁不等。除一例治疗失败和两例病变仍为黄斑外，所有患者均完全康复。 45 45 ^(45){ }^{45}

6 | SIDE EFFECTS AND CONTRAINDICATIONS
6 副作用和禁忌症

With several guidelines, the severity of side effects can be significantly reduced. Before starting treatment, all patients who will use timolol should be screened for risk factors and contraindications such as severe asthma, chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrio-ventricular block, cardiac failure, ischemic heart disease, or venous obstruction. However, optimal dosing of topical timolol is not yet known, patients should be started and maintained with the lowest concentration of timolol. After starting treatment, patients should be questioned about their adverse experiences in each visit. Besides, all patients should note that if they have a problem, they should see a doctor immediately. By awareness of physicians of potential side effects, serious morbidity, and mortality can be prevented with this effective drug.
通过一些指导原则，可以大大降低副作用的严重程度。在开始治疗前，所有使用噻吗洛尔的患者都应接受风险因素和禁忌症筛查，如严重哮喘、慢性阻塞性肺病、窦性心动过缓、二度或三度房室传导阻滞、心力衰竭、缺血性心脏病或静脉阻塞。然而，外用噻吗洛尔的最佳剂量尚不清楚，患者应从最低浓度的噻吗洛尔开始用药并维持用药。开始治疗后，每次就诊时都应询问患者的不良反应。此外，所有患者都应注意，如果出现问题，应立即就医。通过提高医生对潜在副作用的认识，这种有效的药物可以避免严重的发病率和死亡率。
Topical timolol can have many side effects in case of systemic absorption, but in published articles about the use of ocular timolol 0.5 % 0.5 % 0.5%0.5 \%, no serious side effects have been reported. 14 , 46 14 , 46 ^(14,46){ }^{14,46}
外用噻吗洛尔在全身吸收的情况下会产生许多副作用，但在已发表的关于使用眼用噻吗洛尔的文章 0.5 % 0.5 % 0.5%0.5 \% 中，没有关于严重副作用的报道。 14 , 46 14 , 46 ^(14,46){ }^{14,46}

7 | CONCLUSION 7 结论

Given the increasing successful reports on the effectiveness of topical timolol in healing acute and chronic wounds and skin vascular lesions and the proper and even better safety profile compared to the systemic forms of beta receptor antagonists, the prospects for topical timolol use for different therapeutic dermatologic indications are very clear and require further studies with more robust designs for more practical assessment of the case.
鉴于越来越多关于外用噻吗洛尔对急慢性伤口和皮肤血管病变愈合有效的成功报道，以及与全身用β受体拮抗剂相比适当甚至更好的安全性，外用噻吗洛尔用于不同皮肤病治疗适应症的前景非常明显，需要进一步开展设计更合理的研究，以便对病例进行更实际的评估。

ACKNOWLEDGMENT 致谢

The authors would like to thank Rasool Akram Medical Complex Clinical Research Development Center (RCRDC) for its technical and editorial assist.
作者感谢拉苏尔-阿克拉姆医疗中心临床研究发展中心（Rasool Akram Medical Complex Clinical Research Development Center，RCRDC）提供的技术和编辑协助。

AUTHOR CONTRIBUTIONS 作者贡献

Study concept and design: Azadeh Goodarzi, Samaneh Mozafarpoor; Acquisition of data: Mohamad Hasan Shahverdi; Analysis and interpretation of data: Milad Dodangeh, Farnoosh Seirafianpour, Mohamad Hasan Shahverdi; Drafting of the manuscript: Azadeh Goodarzi, Samaneh Mozafarpoor; Critical revision of the manuscript for important intellectual content: Azadeh Goodarzi, Samaneh Mozafarpoor, Milad Dodangeh, Farnoosh Seirafianpour, and Mohamad Hasan Shahverdi; Statistical analysis: Milad Dodangeh, Farnoosh Seirafianpour, and Mohamad Hasan Shahverdi; substantively revision of the final revised paper: Azadeh Goodarzi, Milad Dodangeh, Samaneh Mozafarpoor, Mohamad Hasan Shahverdi, and Farnoosh Seirafianpour; Administrative, technical, and material support and study supervision: Azadeh Goodarzi and Samaneh Mozafarpoor. All authors read and approved the final manuscript.
研究概念与设计Azadeh Goodarzi、Samaneh Mozafarpoor；数据采集：Mohamad Hasan Shahverdi；分析和解释数据：Milad Dodangeh、Farnoosh Seirafianpour、Mohamad Hasan Shahverdi；手稿起草：Azadeh Goodarzi、Samaneh Mozafarpoor；对手稿中重要的知识性内容进行了严格的修改：Azadeh Goodarzi、Samaneh Mozafarpoor、Milad Dodangeh、Farnoosh Seirafianpour 和 Mohamad Hasan Shahverdi；统计分析：Milad Dodangeh、Farnoosh Seirafianpour 和 Mohamad Hasan Shahverdi；对最终修订论文进行实质性修改：Azadeh Goodarzi、Milad Dodangeh、Samaneh Mozafarpoor、Mohamad Hasan Shahverdi 和 Farnoosh Seirafianpour；行政、技术、材料支持和研究监督：Azadeh Goodarzi 和 Samaneh Mozafarpoor。所有作者阅读并批准了最终手稿。

CONFLICTS OF INTEREST 利益冲突

The authors declare no conflict of interest.
作者声明没有利益冲突。

DATA AVAILABILITY STATEMENT
数据可用性声明

Our data are in form of table which is within the manuscript. The data is available by corresponding author with reasonable request.
我们的数据以表格的形式载于手稿中。如果提出合理要求，相应作者可提供这些数据。

ORCID

Mohamad Hasan Shahverdi (iD https://orcid.org/0000-0003-18026252
Mohamad Hasan Shahverdi (iD https://orcid.org/0000-0003-18026252)

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How to cite this article: Goodarzi A, Mozafarpoor S, Dodangeh M, Seirafianpour F, Shahverdi MH. The role of topical timolol in wound healing and the treatment of vascular lesions: A narrative review. Dermatologic Therapy. 2021;34:
本文引用方式Goodarzi A, Mozafarpoor S, Dodangeh M, Seirafianpour F, Shahverdi MH.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。皮肤病治疗》。2021;34:
e14847. https://doi.org/10.1111/dth. 14847
e14847.https://doi.org/10.1111/dth.14847