0.0584%氢化可的松醋丙酯喷雾剂对特应性皮炎犬的临床症状和皮肤 ...

王帆

 

Evaluation of the effect of a 0.0584% hydrocortisone aceponate spray on clinical signs and skin barrier function in dogs with atopic dermatitis

0.0584%氢化可的松醋丙酯喷雾剂对特应性皮炎犬的临床症状和皮肤屏障功能的影响评估

 

翻译：王帆

 

The purpose of this study was to evaluate the effects of a topical spray containing 0.0584% hydrocortisone aceponate (HCA) on canine atopic dermatitis (CAD) and to evaluate the skin barrier function during the treatment of CAD. Twenty-one dogs that fulfilled the diagnostic criteria for CAD were included in this study. The HCA spray was applied once a day to the lesions of all dogs for 7 or 14 days. Clinical assessment was performed before (day 0) and after treatment (day 14), and clinical responses were correlated with changes in skin barrier function. CAD severity significantly decreased after 14 days of HCA treatment based on the lesion scores (p ＜ 0.0001), which were determined using the CAD extent and severity index (CADESI-03) and pruritus scores (p ＜ 0.0001) calculated using a pruritus visual analog scale. Transepidermal water loss, a biomarker of skin barrier function, was significantly reduced compared to baseline (day 0) measurements (p ＝ 0.0011). HCA spray was shown to be effective for significantly improving the condition of dogs suffering from CAD. This treatment also significantly improved cutaneous hydration and skin barrier function in the animals.

本研究的目的是评价含0.0584%氢化可的松醋丙酯（HCA）的外用喷雾剂对犬特应性皮炎（CAD）的影响，并评估CAD治疗期间的皮肤屏障功能。本研究共纳入了21只符合CAD诊断标准的犬。HCA喷雾剂每天对所有犬的病变使用一次，持续7或14天。在治疗前（第0天）和治疗后（第14天）进行临床评估，临床反应与皮肤屏障功能的变化相关。根据病变评分（p < 0.0001），HCA治疗14天后CAD严重程度显著降低，使用CAD程度和严重程度指数（CADESI-03）和瘙痒视觉模拟量表计算的瘙痒评分（p < 0.0001）确定。与基线（第0天）测量值相比，皮肤屏障功能的生物标志物、经表皮水分流失显著减少（p = 0.0011）。HCA喷雾剂可显著改善CAD犬的病情状况。这种治疗也显著改善了动物的皮肤水合作用和皮肤屏障功能。

Keywords: atopic dermatitis, canine, hydrocortisone aceponate, transepidermal water loss

关键词：特应性皮炎，犬，氢化可的松醋丙酯，经表皮失水量

 

Introduction

介绍

Canine atopic dermatitis (CAD) is a chronic pruritic skin disorder with characteristic clinical features associated with the production of IgE antibodies against environmental allergens . The pathogenesis of CAD is not fully understood but this is a complex, multifactorial disease involving interactions between environmental factors, immunologic abnormalities, and skin barrier defects . Treatment options include allergen avoidance, allergen-specific immunotherapy, topical and systemic treatments such as administration of glucocorticoids, cyclosporine, anti-histamines, or essential fatty acids, and management of secondary bacterial or yeast infections .

犬特应性皮炎（CAD）是一种慢性瘙痒性皮肤病，其临床特征与针对环境过敏原的IgE抗体的产生有关。CAD的发病机制尚不完全清楚，但这是一种复杂的、多因素的疾病，涉及环境因素、免疫异常和皮肤屏障缺陷之间的相互作用。治疗方案包括避免过敏原、过敏原特异性免疫治疗、外用和全身治疗，如给予糖皮质激素、环孢素、抗组胺药或必需脂肪酸，以及继发性细菌或酵母菌感染的管理。

 

Glucocorticoids are the most commonly used drugs for treating a variety of inflammatory skin diseases including CAD . However, the adverse effects of glucocorticoids such as skin atrophy and iatrogenic Cushing’s syndrome has limited the use of these compounds. Topical glucocorticoids are an attractive treatment option since the drug can be directly absorbed at the site of inflammation, thereby avoiding systemic exposure. However, this mode of application is not recommended in veterinary dermatology due to a lack of penetration into the skin through the hair coat and concerns regarding the ingestion of the product. Although ideal topical glucocorticoids with high potency and a low risk of side effects have not yet been synthesized, esterification to a hydrocortisone template molecule was performed to produce new glucocorticoid products with significant anti-inflammatory effects and minimal adverse effects. Diester molecules can rapidly penetrate the stratum corneum and undergo metabolism within the dermis, thus mitigating local and systemic side effects . These compounds are widely used for treating atopic dermatitis and other forms of eczema in humans . Recently, a new generation of topical glucocorticoids with excellent pharmacological activities and low benefit-risk ratios was developed for use in veterinary dermatology. The purpose of this study was to evaluate the effects of a topical diester formula spray containing 0.0584% hydrocortisone aceponate (HCA) on canines with CAD, and to evaluate skin barrier function during the treatment of CAD by measuring transepidermal water loss (TEWL).

糖皮质激素是治疗包括特应性皮炎在内的多种炎症性皮肤病最常用的药物。然而，糖皮质激素的不良反应，如皮肤萎缩和医源性库欣综合征，限制了这些化合物的使用。外用糖皮质激素是一种有吸引力的治疗选择，因为该药物可以直接在炎症部位被吸收，从而避免全身暴露。然而，这种应用模式不推荐在兽医皮肤科，因为缺乏通过被毛穿透皮肤和担心摄入产品。虽然尚未合成理想的高效、低副作用风险的外用糖皮质激素，但将氢化可的松模板分子酯化，以产生具有显著抗炎作用和最小副作用的新糖皮质激素产物。双酯分子可以迅速穿透角质层，在真皮内进行代谢，从而减轻外用和全身的副作用。这些化合物被广泛用于治疗人类特应性皮炎和其他形式的湿疹。最近，新一代的外用糖皮质激素具有良好的药理活性和低效益-风险比，被开发用于兽医皮肤科。本研究的目的是评价含0.0584%氢化可的松醋丙酯（HCA）的外用二酯配方喷雾剂对犬的影响，并通过测量经皮失水（TEWL）来评估CAD治疗过程中的皮肤屏障功能。

 

Materials and Methods

材料和方法

Study population

研究对象

The CAD dogs used in the study were recruited from the Seoul National University Hospital for Animals (Korea) between June 2009 and April 2010. CAD was diagnosed based on the animal’s history, clinical findings, positive results of a serum allergen-specific IgE test and/or intradermal skin test, and exclusion of ectoparasites and skin infections. A food elimination trial using a commercial single protein diet (Natural Balance Potato and Duck formula; Natural Balance Pet Foods, USA) or a commercial hydrolyzed hypoallergenic diet (Royal Canin Hypoallergenic; Royal Canin, France) for a minimum of 6 weeks was performed to rule out adverse food reactions, and dogs with a partial or complete resolution of clinical signs while being fed the diet were excluded.

本研究中使用的CAD犬于2009年6月至2010年4月期间从首尔国立大学动物医院（韩国）招募。CAD的诊断是基于动物的病史、临床表现、血清过敏原特异性IgE试验和/或皮内皮肤试验的阳性结果，并排除了体外寄生虫和皮肤感染。使用商业单一蛋白质饮食（天然平衡马铃薯和鸭配方；美国天然平衡宠物食品）或商业水解低过敏性饮食（皇家犬低过敏性；法国皇家犬）进行至少6周的食物排查试验，以排除食物不良反应，排除在喂食饮食时临床症状部分或完全缓解的犬。

 

Study protocol

研究方案

The 0.0584% HCA spray (Cortavance; Virbac, France) was applied to all atopic dogs once a day for 7 or 14 days. The spray was administered according to the manufacturer’s instruction. The owners applied two pumps of the spray over the severe skin lesions (a surface area of 100 cm2 ) from a distance of 10 cm. A clinician (C.Y. Hwang, Seoul National University, Korea) conducted an assessment of the animals on days 0 and 14 as described below.

0.0584% HCA喷雾剂（皮乐美）应用于所有特应性皮炎患犬，每天一次，持续7或14天。喷雾剂是根据制造商的说明进行的。宠主在距离皮肤10厘米处，在严重的皮肤病变（表面积为100厘米2）上使用按压两次喷雾泵。一名临床医生（韩国首尔国立大学黄教授）在第0天和第14天对这些动物进行了评估，如下所述。

 

Lesion scores

病变评分

To estimate the clinical severity of the lesions at the spray application sites, the clinician used a modified lesion scoring system based on the CAD extent and severity index (CADESI-03) . This approach evaluated four clinical factors (erythema, excoriation, lichenification, and selfinduced alopecia) that were graded from 0 (normal) to 5 (most severe), thereby yielding a score of 0 ~ 20 for each body site examined.

为了评估喷雾剂应用部位病变的临床严重程度，临床医生使用了基于CAD范围和严重程度指数（CADESI-03）的改良病变评分系统。该方法评估了4个临床因素（发红、抓痕、苔藓化和自损性脱毛），从0（正常）到5（最严重），因此每个机体部位的评分为0 ~ 20。

 

Pruritus scores

瘙痒评分

The owners were asked to evaluate the degree of their dog’s pruritus using a pruritus visual analog scale . This scale consisted of an 11-point linear scale with which the condition of the animals was graded from 0 (not itchy: no scratching, chewing, rubbing, or licking observed) to 10 (extremely itchy: scratching, chewing, rubbing, or licking constantly).

主人被要求使用瘙痒视觉模拟量表来评估他们的犬的瘙痒程度。这个量表由一个11分的线性量表组成，动物的状况从0（不痒：不抓、啃咬、摩擦、舔）到10（非常痒：抓、啃咬、摩擦或不断舔）。

 

TEWL assessment

TEWL评估

TEWL, a marker of epidermal barrier function, was measured in lesions of the CAD dogs using a VapoMeter (Delfin Technologies, Finland), a hand-held, closed chamber evaporimeter, according to the manufacturer’s instructions. All dogs were allowed to acclimate to an environmentally controlled room maintained at 20 ~ 22o C with 40 ~ 60% relative humidity for at least 10 min prior to testing. TEWL was measured three times at the spray application sites.

TEWL是一种表皮屏障功能的标记物，根据制造商的说明，使用VapoMeter对CAD犬的病变进行测量。在测试前，所有的犬都被允许适应环境控制的房间，保持在20~22℃，相对湿度40 ~60%至少10 min。TEWL在喷雾应用部位被测量了3次。

 

Assessment of the HCA spray safety

对HCA喷雾剂的安全性进行评估

Clinicians (C.Y. Hwang and E.H. Nam, Seoul National University, Korea) evaluated any adverse events by performing thorough clinical examinations at each visit. On days 0, 14, and 28 of the study, blood samples for complete blood cell count and biochemical analysis of hepatic enzyme activities were taken, and adrenocorticotrophic hormone (ACTH) stimulation tests were performed. Briefly, serum was collected for cortisol assay before and 1 h after administration of synthetic ACTH 0.25 mg/dog, IV (Synacthen; Alliance Pharmaceuticals, UK).

临床医生通过在每次就诊时进行彻底的临床检查来评估任何不良事件。在研究的第0、14和28天，采集血样进行全血细胞计数和肝酶活性生化分析，并进行促肾上腺皮质激素（ACTH）刺激试验。简单地说，在静脉给药合成的ACTH0.25mg/犬前和使用后1小时收集血清进行皮质醇测定。

 

Statistical analysis

统计分析

Results of the clinical evaluation (lesion score, pruritus score, and TEWL findings) were compared to the data obtained before treatment. Statistical comparisons were performed using a paired Student’s t-test and Wilcoxon signed rank test depending on the validity of the assumptions. All data were analyzed using the SPSS statistical software package (ver. 12.0; SPSS, USA). Data are presented as the mean ± SD. p-values < 0.05 were considered statistically significant.

将临床评价结果（病变评分、瘙痒评分、TEWL结果）与治疗前获得的数据进行比较。根据假设的有效性，使用配对的学生t检验和Wilcoxon符号秩检验进行统计比较。所有数据均采用SPSS统计软件包。数据以平均±标准差表示。p值<0.05被认为有统计学意义。

 

Results

结果

Twenty-one dogs with CAD were enrolled in this study (Table 1). The study group included three intact males, six castrated males, six intact females, and six spayed females. The mean age of the animals was 8.5 years (range: 5∼13 years). The breeds of the dogs were Shih Tzu (n = 10), mixed (n = 3), Maltese (n = 2), Yorkshire Terrier (n = 1), Cocker Spaniel (n = 1), Beagle (n = 1), Pomeranian (n = 1), Schnauzer (n = 1), and Pekingese (n = 1).

本研究共纳入21只CAD犬（表1）。研究小组包括3只未去势雄性，6只已去势雄性，6只未绝育雌性，和6只已绝育雌性。这些动物的平均年龄为8.5岁（范围：5∼13岁）。这些犬的品种是西施犬（n = 10），杂交犬（n = 3）、马尔济斯犬（n = 2）、约克夏犬（n = 1）、可卡犬（n = 1）、比格犬（n = 1）、博美犬（n = 1）、雪纳瑞犬（n = 1）和北京犬（n = 1）。

 

Lesion scores

病变评分

The lesion scores at the spray application sites significantly decreased by day 14 (mean: 5.5 ± 3.7, range: 3∼17) after HCA treatment compared to day 0 (mean: 11.9 ± 4.1, range: 0 ~ 12; p ＜ 0.0001, Fig. 1). The lesion scores for 15 of the 21 atopic dogs were reduced by 50% or more following HCA treatment compared to the day 0 scores.

与第0天（平均11.9 ± 4.1，范围： 0 ~ 12）相比，HCA治疗后第14天（平均5.5±3.7，范围：3∼17)显著下降（p < 0.0001，图1）。在HCA治疗后，21只特应性皮炎犬中的15只的病变评分比第0天的评分降低了50%或更多。

 

Pruritus scores

瘙痒评分

The pruritus scores were significantly lower on day 14 (mean: 2.4 ± 1.4, range: 0∼6) after HCA treatment compared to day 0 (mean: 6.8 ± 1.5, range: 3∼8; p ＜ 0.0001, Fig. 2). The scores for 16 of the 21 atopic dogs improved by 50% or more following HCA treatment.

HCA治疗后第14天瘙痒评分（平均2.4 ± 1.4，范围：0∼6）明显低于第0天（平均6.8 ± 1.5，范围：3∼8；p < 0.0001，图2）。21只特应性皮炎犬中的16只在接受HCA治疗后，得分改善了50%或更多。

 

TEWL findings

TEWL结果

To evaluate the effect of the HCA spray treatment on skin barrier function, TEWL was measured in the lesions of the CAD dogs. Post-treatment TEWL values (mean: 17.5 ± 6.9 g/m2 /h, range: 9.5∼29.8 g/m2 /h) were significantly lower than the pre-treatment values (mean: 48.7 ± 42.4 g/m2 /h, range: 12.9∼211.0 g/m2 /h; p = 0.0011, Fig. 3). Reductions in TEWL values of 50% or more were observed in 13 of the 21 atopic dogs following HCA treatment.

为了评估HCA喷雾剂治疗对皮肤屏障功能的影响，我们测量了CAD犬病变中的TEWL。处理后TEWL值（平均17.5 ± 6.9 g/m2 /h，范围9.5∼29.8g/m2/h）显著低于处理前值（平均48.7 ± 42.4 g/m2 /h，范围12.9∼211.0g/m2/h；p = 0.0011，图3）。在HCA治疗后的21只特应性皮炎犬中，有13只的TEWL值降低了50%或更多。

 

Adverse events

不良事件

No adverse events were observed in any of the 21 dogs during the study period by the owners or clinicians.

在研究期间，宠主或临床医生没有在这21只犬中观察到任何一只发生不良事件。

 

                   

    

                                 

       

Fig. 1. Changes in lesion scores during treatment with 0.0584% hydrocortisone aceponate (HCA) spray (n = 21). A statistically significant difference in lesion scores was observed between day 0 and day 14 (p ＜ 0.0001). Box and whisker plots show the median, 25th and 75th percentiles, and range of the scores.

图1. 使用0.0584%氢化可的松醋丙酯（HCA）喷雾剂治疗期间病变评分的变化（n = 21）。第0天和第14天之间的病变评分差异有统计学意义（p < 0.0001）。框图和箱线图显示了中位数，第25和第75百分位数，以及分数的范围。

 

Fig. 2. Changes in pruritus scores during treatment with 0.0584% HCA spray (n = 21). A statistically significant difference in pruritus scores was observed between day 0 and day 14 (p ＜ 0.0001). The box represents the 25th and 75th percentiles with the bold lines indicating the median. The whiskers indicate the range. Outliers (asterisks) are also indicated.

图2. 使用0.0584% HCA喷雾剂治疗期间瘙痒评分的变化（n = 21）。第0天和第14天之间的瘙痒评分差异有统计学意义（p < 0.0001）。框图表示第25个和第75个百分位数，粗体线表示中位数。箱线图表示这个范围。同时还显示了异常值（星号）。

 

 

 

Fig. 3. Changes in transepidermal water loss (TEWL) during treatment with 0.0584% HCA spray (n = 21). TEWL values differed significantly between day 0 and day 14 (p = 0.0011). Box and whisker plots show the median, 25th and 75th percentiles, and range of the TEWL values. Outlier (asterisk) are also indicated.

图3. 用0.0584% HCA喷雾剂（n = 21）处理期间，经表皮失水量（TEWL）的变化。TEWL值在第0天和第14天之间差异显著（p = 0.0011）。框图和箱线图显示了TEWL值的中位数、第25和第75百分位数以及TEWL值的范围。同时还表示了异常值（星号）。

 

Discussion

讨论

CAD is a multigenetic and multifactorial disease caused by various factors including pharmacologic and immunologic abnormalities, and skin barrier defects . Currently, there is evidence indicating that abnormal skin barrier function contributes to the pathogenesis of CAD, which is similar to that seen in human with atopic dermatitis. The skin barrier is located in the stratum corneum of the epidermis. This barrier controls percutaneous absorption of external irritants and allergens, and regulates TEWL . Impairment of the skin barrier can be caused by a primary defect or is a consequence of inflammation. Once the barrier function has been impaired, progressive worsening of this function occurs. Thus, impaired barrier function might play a key role in the development and aggravation of the clinical signs of CAD. Recent studies have revealed that there is a correlation between improved skin barrier function and alleviation of CAD symptoms. Therefore, it was suggested that skin barrier function is crucial for the successful treatment of CAD.

CAD是一种由多种因素引起的多基因和多因素的疾病，包括药理和免疫异常，以及皮肤屏障缺陷。目前，有证据表明，异常的皮肤屏障功能是CAD的发病机制之一，这与人类特应性皮炎相似。皮肤屏障位于表皮的角质层中。这种屏障控制着外部刺激物和过敏原的经皮吸收，并调节TEWL。皮肤屏障的损害可能是由原发性缺陷或炎症引起的结果。一旦屏障功能受损，这一功能就会逐渐恶化。因此，屏障功能受损可能在CAD临床症状的发展和加重中起关键作用。最近的研究表明，皮肤屏障功能的改善与CAD症状的缓解之间存在相关性。因此，我们提示皮肤屏障功能是CAD成功治疗的关键。

 

The present study was carried out to examine the potential beneficial role of skin barrier function as well as the efficacy of a 0.0584% HCA spray for treating CAD. We found that application of the HCA spray significantly improved both pruritus and other clinical signs associated with CAD in atopic dogs. After 14 days, scores for lesion severity (calculated according to the modified CADESI-03) and pruritus at the spray application sites were reduced from the baseline values by an average of 54.63% and 60.57%, respectively, with the majority of atopic dogs achieving more than a 50% reduction. To evaluate skin barrier function, TEWL, which is defined as the total amount of water loss that occurs by passive diffusion through the epidermal layer, was measured . Measurement of TEWL values, which increase with progressive damage to the skin, is one of the most commonly used noninvasive methods to assess skin barrier function. In our study, significant improvement in TEWL values was observed for the skin of atopic dogs following HCA spray treatment. The mean reduction in TEWL scores was 47.43%, and the TEWL values for 13 of the 21 dogs decreased by more than 50%. HCA has been show to exert potent anti-inflammatory effects in the skin with few adverse side effects. HCA, which is derived from the esterification of C21-acetate and C17-propionate, has increased hydrophilicity and lipophilicity compared to the parent drugs. This enhances its accumulation in the epidermis-dermis without entering the blood circulation . In recent studies, HCA was show to be very well tolerated and the repeated use of the HCA had no observable adverse reactions over 70 days in dogs. As shown in the present study, 7-day treatment with the HCA spray may be sufficient for reducing the severity of pruritus and skin lesions although long-term use of this product will be required to control the clinical signs of CAD. It may also be possible that the dose and frequency of administration can be reduced when using the HCA spray relative to systemic glucocorticoids and calcineurin inhibitors. Therefore, HCA may be more effective and safer than traditional topical glucocorticoids for treating CAD and other forms of pruritic dermatitis.

本研究旨在研究皮肤屏障功能的潜在有益作用，以及0.0584% HCA喷雾剂治疗CAD的疗效。我们发现，应用HCA喷雾剂显著改善了瘙痒症和其他与CAD相关的临床症状特应性皮炎犬。14天后，病变严重程度（根据改良的CADESI-03计算）和喷雾部位瘙痒评分较基线值分别降低了54.63%和60.57%，大多数特应性皮炎犬的评分降低了50%以上。为了评估皮肤屏障功能，我们测量了TEWL，其定义为通过表皮层被动扩散发生的失水总量。TEWL值的测量是评估皮肤屏障功能最常用的无创方法之一，它会随着皮肤的进行性病变而增加。在我们的研究中，观察到HCA喷雾治疗后特应性皮炎犬皮肤的TEWL值显著改善。TEWL评分平均下降了47.43%，21只犬中有13只犬的TEWL值下降了50%以上。HCA已被证明在皮肤中发挥强大的抗炎作用，但副作用很少。HCA是由c21-乙醋酸和c17-丙酸酯化而成，与母药相比，它具有更高的亲水性和亲脂性。这增强了它在表皮-真皮层的蓄积，而不进入血液循环。在最近的研究中，HCA对犬耐受是非常好的，犬重复使用超过70天内没有明显的不良反应。如本研究所示，使用HCA喷雾剂进行7天的治疗可能足以减轻瘙痒和皮肤病变的严重程度，但需要长期使用该产品来控制CAD的临床症状。相对于全身糖皮质激素和钙调神经磷酸酶抑制剂，使用HCA喷雾剂也有可能可以减少给药的剂量和频率。因此，HCA可能比传统的外用糖皮质激素治疗CAD和其他形式的瘙痒性皮炎更有效、更安全。

 

In conclusion, our findings suggest that daily application of a 0.0584% HCA spray not only provided short-term alleviation of clinical signs associated with CAD, but also improved skin barrier function, which is associated with the pathogenesis of CAD. Further investigation is required to monitor adverse effects resulting from the prolonged use of this product although no adverse effects following treatment for up to 70 days were observed in a previous study.

总之，我们的研究结果表明，每天使用0.0584%的HCA喷雾剂，不仅能短期缓解与CAD相关的临床症状，而且还能改善与CAD的发病机制相关的皮肤屏障功能。虽然在之前的研究中未观察到治疗后长达70天的不良反应，但仍需要进一步调查来监测长期使用该产品造成的不良反应。

 

 

杨先生

zhangenzyme