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犬异位性皮炎的治疗:最新进展 Therapies in Canine AtopicDermatitis: An Update
作者：Domenico Santoro, DVM, MS, DrSc, PhD 翻译：张亚飞 校对：王帆
关键词•异位性皮炎•犬•治疗•综述
重点 •犬异位性皮炎是一种涉及到多方面的慢性疾病，治疗方案需要量身定制。 •针对犬异位性皮炎已有新的治疗方法。 •辅助治疗和外部治疗是犬异位性皮炎的基础治疗。 •未来的治疗方法可能包括更多的生物制剂和根据单个病例临床表现量身定制的治疗方案。
KEYWORDS•Atopic dermatitis•Dog•Therapy•Review
KEY POINTS •Canine atopic dermatitis is a multifaceted chronic disease requiring a tailored therapeutic approach. •New therapies have been designed for canine atopic dermatitis. •Alternative and topical therapies are fundamental in the management of canine atopic dermatitis. •Future therapies may include more biologics and more tailored treatments based on the individual clinical presentation. 介绍INTRODUCTION
异位性皮炎(AD)是犬最常见的皮肤炎症和瘙痒性疾病之一。AD是一种具有遗传性炎性反应和瘙痒性皮肤病，伴有明显的临床表现，以及有针对环境过敏原的免疫球蛋白(Ig)E。异位样皮炎(ADL)是一种与AD有相同临床症状，但没有IgE介导的疾病。这两种疾病主要区别在于，在ADL中不会检测到IgE，不能进行过敏原特异性免疫治疗(ASIT)。ADL的真实发病率尚不清楚，使用治疗AD的常用方法的效果也未知。Prelaud和Cochet-Faivre在法国进行的一项未发表的研究中报道，25.6%的犬被诊断为ADL。最近美国的一项研究中的比例也相似(14.6%)。其中一项研究也怀疑英国斗牛犬具有品种倾向性。此外，环孢菌素(CsA)对这类患犬的疗效存在争议。虽然在第一项研究中，ADL的有效率低于AD患犬(50% 比 92%)，但是在其他研究中，已证明CsA对ADL患犬有效。最近的药物对ADL的效果尚不清楚。治疗AD/ ADL患犬的困难还在于，已知的两种AD临床表现和治疗效果的多样性。正因为这种巨大的多样性，所以最近认为应该向人AD提出的那样，将犬AD归为一种综合征，而不是一种典型的、单一的皮肤炎性疾病。Atopic dermatitis (AD) is one of the most common cutaneous inflammatory and pruritic diseases in dogs. AD is a genetically predisposed inflammatory and pruritic skin disease associated with well-defined clinical signs and immunoglobulin (Ig)E directed against environmental allergens. Atopiclike dermatitis (ADL) is a disease characterized by the same clinical signs of AD in absence of demonstrable IgE. The major difference between these 2 entities resides in the impossibility to demonstrate IgE in ADL, making it impossible to formulate an allergen-specific immunotherapy (ASIT). The true incidence of ADL is unknown, and the therapeutic response to the common therapies for AD is also unknown. In one unpublished study performed in France by Prelaud and Cochet-Faivre, 25.6% of dogs enrolled were diagnosed with ADL. A similar percentage (14.6%) was present in a more recent study in the United States. A breed predisposition for English bulldogs was also suspected in one of these studies. In addition, the efficacy of cyclosporine (CsA) for such patients is controversial. In the first study, a lower efficacy rate was seen in ADL compared with AD dogs (50% vs 92%); although in other studies, CsA has been shown to be effective in ADL dogs. The effect of more recent drugs on ADL is unknown. The difficulty to treat AD/ ADL dogs resides also in the well-known diversity in clinical presentation and response to treatments within the 2 AD entities. Because of this enormous diversity, canine AD has been recently suggested to be classified as a syndrome more than a well-defined single cutaneous inflammatory entity, as proposed in human AD. 犬异位性皮炎:临床表现与发病机制概况CANINE ATOPIC DERMATITIS: CLINICAL AND PATHOGENETIC SYNOPSIS AD在犬中非常常见，发病率在整体犬群中为3%至15%，在皮肤病患犬中超过58%。典型发病年龄在6月龄至6岁之间。但是，超过70%的AD患犬在1到3岁之间出现临床症状。许多品种都易患AD，最常见于㹴类犬、巡回猎犬和短头犬。 AD is extremely common in dogs, affecting between 3% and 15% of the canine population or up to 58% of dogs affected by skin diseases. The age of onset typically spans between 6 months and 6 years; however, more than 70% of AD dogs develop clinical signs between 1 and 3 years of age. Many breeds have been associated with AD, with terriers, retrievers, and brachycephalic dogs most commonly affected.
临床上，犬AD的特征是慢性皮肤炎症、瘙痒和复发性皮肤感染。最常见的临床症状包括全身性瘙痒(季节性、全年或全年伴季节性加重)、红斑、丘疹、脓疱、结痂和抓痕。最常见的发病部位一般出现在头部(嘴周、眼周和耳部)、肘关节、腕关节和跗关节屈曲面、爪子(趾部、爪垫和趾间)、侧腹部、会阴部和尾巴腹侧。但西高地白㹴犬、沙皮犬和德国牧羊犬除外。犬AD的诊断基于临床症状，以及排除其他瘙痒性疾病(如食物过敏、蠕形螨病、疥螨病)。 Clinically, canine AD is characterized by chronic skin inflammation, pruritus, and recurrent skin infections. The most common clinical signs include generalized pruritus (seasonal, nonseasonal, or nonseasonal with seasonal worsening), erythema, papules, pustules, crusts, and excoriations. Head (perioral, periocular, and ears), flexor aspect of elbows, carpal and tarsal joints, paws (digits, claws, and interdigital aspects), ventral abdomen, perineum, and ventral tail are most commonly affected. However, few exceptions have been reported in West Highland white terriers, sharpeis, and German shepherds.The diagnosis of canine AD is based on characteristic clinical signs and by excluding other pruritic diseases (eg, food allergy, demodicosis, scabies).
AD的发病机制十分复杂，尚未完全阐明。遗传因素和环境因素共同导致临床疾病的发生，同时伴有I型和IV型超敏反应。过程分别是，AD发展的第一步是致敏作用，即环境过敏原(如户尘螨)穿过皮肤(为主)，能通过与IgE结合导致募集和活化炎症细胞，以及导致肥大细胞脱颗粒。在激活过程中，多种炎症介质，包括细胞因子(特别是2型和促炎因子)和趋化因子被分泌出来，决定了疾病的进程。随着转为慢性病变，以1型炎症反应为主。最后，过敏原通过皮肤的高渗透性和炎症反应的加剧致使表皮屏障缺陷。然而，这种缺陷是原发的还是继发的，仍然存在争议。其他主要导致恶化因素包括细菌(假中间型葡萄球菌)和真菌(马拉色菌皮炎)感染，以及心理和环境因素(如湿度)。最近发表了一系列综述性文章。这些文章对犬AD的发病机制进行了广泛性概述。因此，为了获得更深入的信息，作者建议读者阅读这类综述性文章。 The pathogenesis of AD is very complex and not completely elucidated. Both genetic and environmental factors are involved in the development of the clinical disease, with both types I and IV hypersensitivity reactions demonstrated. Classically, the first step involved in the development of AD is a sensitization to environmental allergens (eg, house dust mites) penetrating through the skin (mainly) able to lead to recruitment and activation of resident inflammatory cells and degranulation of mast cells via binding to IgE. On activation, multiple inflammatory mediators, including cytokines (specifically type 2 and proinflammatory) and chemokines are secreted, determining the course of the disease. With the chronicity of the lesions, a type 1 inflammatory response predominates. Last, a defect in the epidermal barrier is associated to a higher penetration of allergens through the skin and exacerbation of the inflammatory response. However, if such defect is primary or secondary is still controversial. Other major exacerbating factors include bacterial (Staphylococcus pseudintermedius) and fungal (Malassezia pachydermatis) infections along with psychogenic and environmental (eg, humidity) factors. Very recently, a series of review articles has been published. The series represents an extensive review on the current knowledge on the pathogenesis of canine AD. Thus, for more in-depth information, the author refers the reader to such review articles. 因为参与犬AD发病机制的表现多样性，以及各种临床症状，所以需要对每只患犬采取更合理、更有针对性的治疗方法。这些治疗方案应根据每只异位性皮炎患犬进行定制，并考虑到每只犬的需要(例如：药物用量、不良反应、临床症状的严重程度、治疗的容易程度)和犬主人(例如，经济状况、期望、生活质量、时间)。 Due to the diversity of the phenomena involved in the pathogenesis of canine AD and the variety of clinical presentations, a more rational and tailored therapeutic approach is required for each patient. Such therapeutic options should be customized for each atopic dog, keeping in consideration the needs of each dog (eg, amount of drugs, side effects, severity of the clinical signs, easy administration of treatments) and the dog’s owners (eg, financial circumstances, expectations, quality of life, time). 治疗概述 TREATMENT OVERVIEW 犬AD的治疗主要集中在4个方面:时间(慢性和急性病变)、瘙痒、炎症和感染。慢性病变及其严重程度决定短期给药(如：急性发病)和长期给药的选择，同时要考虑副作用、疗效和成本。最后，皮肤感染，细菌和/或真菌，是主要的恶化因素，因此需要正确地治疗。外部和全身治疗选择治疗AD的现有产品。本综述的目的是，仅深入探讨对犬可行的治疗方法。最后，关于ASIT的讨论，皮下注射方法或舌下给药方法，未列入本文范围。 The treatment of canine AD is mainly centered on 4 factors: time (chronic vs acute lesions), presence of pruritus, inflammation, and infections. The chronicity of the lesions and their severity will determine the choice of short-term (eg, flare) versus long-term medications, keeping in mind side effects, efficacy, and costs. Finally, cutaneous infections, bacterial and/or fungal, are major exacerbators, and as such need to be properly treated. Topical and systemic options are commercially available to treat AD. For the purpose of this review, only therapies that are available for dogs are discussed in depth. Finally, a discussion on ASIT, injectable or sublingual, is beyond the scope of this review. 外部治疗 TOPICAL THERAPIES
最近，两篇强调犬AD治疗指南的文献表明，改善皮肤及被毛的卫生和护理是异位性皮炎患犬的治疗基础。皮肤护理可以有多种方式，通过使用不同的产品达到皮肤保湿、减少炎症和/或瘙痒反应，修复皮肤屏障的目的。 Recently, 2 documents highlighting the guidelines for the treatment of canine AD have shown that the improvement of the skin, and coat hygiene and care is fundamental in treating atopic dogs. The skin care can be achieved in several ways by using different products with the goal of moisturizing the skin, reducing the inflammatory and/or pruritic response, and repairing the skin barrier. 保湿剂 MOISTURIZERS保湿剂(润肤剂和/或保湿剂)有多种功能。最重要的作用是通过阻断剂(例如：油类)或使用锁水因子来减少经表皮水分流失量(TEWL)，从而增加皮肤水分含量。后者起着隔离剂的作用，从环境和/或真皮/皮下组织吸收水分(如燕麦)。仅增加水合作用就能显著减少瘙痒和止痒药用量。每周使用爱乐美香波（含脂类、复合糖类和防腐剂），连续3至4周，可显著降低大多数犬的瘙痒和病变评分。 Moisturizers (emollients and/or humectants) have multiple functions. The most important action is increasing the amount of water in the skin by reducing the transepidermal water loss (TEWL) via blocking agents (ie, oils) or using hygroscopic molecules. These latter act as occlusive agents and attract water from the environment and/or from the dermis/subcutaneous tissues (eg, oatmeal). The increase of hydration alone is able to significantly reduce the pruritus and the need of antipruritic drugs; weekly Allermyl shampoo (containing lipids, complex sugars, and antiseptics) for 3 to 4 weeks significantly decreases pruritus and lesional score in most dogs.
抗炎/止痒 ANTI-INFLAMMATORY/ANTIPRURITIC
最重要的外用抗炎药包括糖皮质激素(GCs)和钙调蛋白抑制剂(CIs)。然而，犬使用抗组胺药和局麻药也有一定效果。 The most important topical anti-inflammatory drugs include glucocorticoids (GCs) and calcineurin inhibitors (CIs); however, antihistamines and local anesthetics have been used in dogs with some success.
GCs是一种非常有效和用途广泛的药物，可全身使用或外用。它们通常能明显缓解炎症反应和瘙痒。它们的作用机制非常广泛、复杂，而且尚不完全明确。在过敏性疾病中，它们似乎会干扰促炎因子和致痒因子、炎性细胞迁移和功能，以及与炎症相关的神经高敏反应。 GCs are extremely potent and versatile compounds that can be used either systemically or topically. They are generally associated to a significant reduction in both inflammation and pruritus. Their mechanism of action is very broad, complex, and not completely understood. In allergic diseases, they seem to interfere with proinflammatory and pruritogenic mediators, inflammatory cell migration and function, and with inflammation-associated nerve hypersensitivity.
与口服GCs相比，在过去几十年间，为了减少全身副反应(如多尿、多饮、多食、尿道感染和肌肉萎缩)，外用GCs被广泛应用。但是，皮肤萎缩、粉刺和皮肤钙质沉着是一些外用GCs潜在的副反应。根据其化学结构，外应GCs可分为“传统”和“新型”。前者包括氢化可的松、泼尼松龙、曲安奈德、倍他米松和地塞米松。新一代包括外用双酯GCs，如糠酸莫米松、氢化可的醋丙酯和泼尼卡酯。后者在皮肤上代谢成失活分子，明显降低全身副反应。
Topical GCs have been largely used during the past decades for the reduced presence of systemic side effects (eg, polyuria, polydipsia, polyphagia, urinary tract infections, and muscle wasting) compared with oral GCs; however, cutaneous atrophy, comedones, and calcinosis cutis are potential side effects for some topical GCs. Based on their chemical structure, topical GCs can be divided into “old” and “new” generation. To the former belong compounds like hydrocortisone, prednisolone, triamcinolone acetonide, betamethasone, and dexamethasone. The new generation includes diester topical GCs, like mometasone furoate, hydrocortisone aceponate, and prednicarbate. These latter are metabolized in situ into inactive molecules,dramatically reducing the presence of systemic side effects.
曲安奈德(0.015%, Genesis; Virbac, Fort Worth, TX)喷雾是唯一被证明在治疗犬AD的高度有效的“传统”GC，。在一项多中心、随机、双盲、安慰剂组/药物治疗组临床对照试验(RDBPCT)中，用曲安奈德喷雾剂以逐渐减少的频率治疗过敏犬4周。在研究结束时，与无临床症状和轻度血液学副反应(治疗后总白细胞、淋巴细胞和嗜酸性粒细胞数量轻度下降)的犬相比，用曲安奈德治疗犬的瘙痒程度、临床症状和整体评估均有显著改善。
Triamcinolone acetonide (0.015%, Genesis; Virbac, Fort Worth, TX) spray is the only “old” GC that has been shown to be highly efficacious in the treatment of canine AD. In a multicenter, randomized, double-blinded, placebo/vehicle-controlled clinical trial (RDBPCT), triamcinolone acetonide spray was applied to allergic dogs for 4 weeks at tapered frequency. At the end of the study, a significant improvement in pruritus, clinical signs, and overall assessment was present when compared with vehicle in absence of clinical and minor hematological adverse effects (slightly lower total leukocyte, lymphocyte, and eosinophil counts after treatment). 在欧洲和韩国，已使用效果相似的氢化可的松醋丙酯（0.0584％，皮乐美; Virbac），一种“新型”GC，进行了少量的RDBPCTs试验。在第一次临床试验中，皮乐美以逐渐减量的频率控制轻度AD患犬，使用了70天。治疗28天后，73.0%和46.6%的犬的临床评分和瘙痒症状程度各自下降了50%。这些结果在第二次研究中得到了证实，比较了84天内每日使用皮乐美和环孢菌素的效果。这项研究表明，在没有临床、血液学或激素异常的情况下，皮乐美和CsA具有临床等效性。同样，第三次使用皮乐美 14天的研究显示，在没有副反应的情况下，临床症状、瘙痒和TEWL显著下降，这表明醋丙氢可的松对皮肤屏障功能有积极作用。另一项RDBPCT表明皮乐美作为预防性治疗具有良好效果(每周两次)，能够延长异位性皮炎患犬的缓解时间。最后，最近在美国和日本进行的另外两项研究中也评估了皮乐美的免疫效果。在第一项研究中，研究人员发现，连续14天每天使用一次皮乐美喷雾剂会干扰犬的皮内测试(IDT)，至少需要2周时间才能避免这种影响。此外，这是第一个研究表明，皮乐美可能在组织学上能够诱导，使真皮厚度显著减少。此外，在每日使用连用3周后，皮乐美还可诱导促肾上腺皮质激素皮质醇水平显著降低(36.0%降低)。但皮乐美对外周血CCR41CD41T淋巴细胞无任何影响。总之，这些研究表明，皮乐美作为一种预防或管理疗法，对轻度犬AD的治疗具有显著的临床疗效。此外，在犬AD的短期和长期治疗中，皮乐美均显示出较大的安全性。
Similar response has been documented for hydrocortisone aceponate (0.0584%, Cortavance; Virbac), a “new” GC, through few RDBPCTs trials in Europe and Korea. In the first clinical trial, Cortavance was administered to dogs with mild AD for 70 days at tapered frequency. After 28 days of treatment, 73.0% and 46.6% of dogs achieved a reduction of 50% in clinical score and pruritus, respectively. These results were confirmed by a second study comparing the efficacy of daily Cortavance with cyclosporine over 84 days. This study showed the clinical equivalence between Cortavance and CsA in absence of clinical, hematological, or hormonal abnormalities. Similarly, a third study using Cortavance for 14 days showed a significant decrease in clinical signs, pruritus, and TEWL in absence of side effects, suggesting a positive effect of hydrocortisone aceponate on skin barrier function. Another RDBPCT showed promising effects of Cortavance as prophylactic treatment (twice weekly), able to prolong the remission time in atopic dogs. Finally, more recently, the immunologic effects of Cortavance have also been assessed in 2 other studies performed in the United States and Japan. In the first study, the investigators showed that once-daily Cortavance spray for 14 days is able to interfere with intradermal testing (IDT) in dogs, and a minimum of 2 weeks is necessary to avoid such effect on IDT. In addition, this was the first study showing that Cortavance may be able to induce, histologically, a significant decrease in dermal thickness that may be present. In addition, Cortavance may also induce, when used daily for 3 weeks, a significant reduction (36.0% decrease) in the post–adrenocorticotropic hormone cortisol level. However, Cortavance did not have any effect on peripheral CCR41CD41 T-lymphocytes. Altogether, these studies showed a significant beneficial clinical effect of Cortavance in the treatment of mild canine AD as preventive or as management therapy. In addition, they show a large margin of safety of Cortavance in both short-term and long-term treatment of canine AD. 外用GCs的替代品是CIs(他克莫司和环孢菌素)。仅有3篇关于他克莫司用于犬AD局部病变RDBPCTs的研究发表，其中2篇研究了0.1%和1篇研究了0.3%制剂的使用情况。在所有3项研究中，使用他克莫司虽然昂贵，但在治疗局部病变方面具有非常好的前景，副反应最小。在所有的研究中，大多数被纳入研究的犬都能够在4或12周的治疗后获得治疗成功(定义为临床症状比治疗前减少50%)。少数病例在使用后出现轻微刺激，并未发生血常规和生化指标改变。在研究结束时，血液中有检测到他克莫司。但是，他克莫司浓度低于中毒剂量。当使用0.3%他克莫司软膏时，使用0.3%他克莫司软膏的犬的血液中他克莫司浓度增加了四倍。因为效果相同，以及血药浓度较低，所以建议使用0.1%的软膏作为更安全的选择。环孢菌素，是另一种钙调神经磷酸酶抑制剂，最近作为犬AD的外部治疗的研究。在一项安慰剂对照组的临床研究中，研究人员发现，纳米技术的环孢菌素制剂具有显著的临床效果(对于中度-重度AD的局部病变)和疗程中间值为(21天)，该制剂能够穿透表皮，保证良好的吸收和真皮作用。治疗后第21天和第45天，治疗组的临床和瘙痒评分明显低于安慰剂组，显示纳米复合物在没有副反应的情况下具有快速有效的作用。然而，还需要更多的研究来证实这种制剂对患犬的效果。
An alternative to topical GCs is CIs (tacrolimus and cyclosporine). Only 3 RDBPCTs have been published on the use of tacrolimus for localized lesions of AD in dogs, 2 of which investigated the use of the 0.1% and 1 the 0.3% formulation. In all 3 studies, the use of tacrolimus, although expensive, was very promising in treating localized atopic lesions with minimal side effects. In all studies, most dogs enrolled were able to achieve a treatment success (defined as 50% reduction in clinical signs from baseline) after 4 or 12 weeks of treatment. Mild irritation was noticed in a minority of cases after application and a lack of hematological and biochemical changes was reported. Detectable levels of tacrolimus were present in the blood at the end of the study; however, tacrolimus concentration was below toxicity limits. When 0.3% tacrolimus ointment was used, a fourfold increase in tacrolimus concentrations was observed in the blood of dogs using 0.3% ointment. Due to equal efficacy and lower blood levels of tacrolimus, the 0.1% ointment is recommended as a safer choice. Cyclosporine, another calcineurin inhibitor, has been recently investigated as a topical treatment option for canine AD. In a placebo-controlled clinical study, the investigators showed a significant clinical efficacy (localized lesions of moderate-severe AD) and moderate speed of action (21 days) of a nanotechnology pharmaceutical formulation of cyclosporine able to penetrate the epidermis, guaranteeing good absorption and dermal action. On days 21 and 45 after treatment, a significant reduction in clinical and pruritus score was seen in the treatment group compared with placebo, showing a rapid and effective action of the nano-compound in absence of side effects. However, more studies are needed to confirm the beneficial effect of this formulation in affected dogs. 毫无疑问，新型GCs和CIs是治疗犬AD最有效的外用抗炎药。它们不仅能干扰不同级别的炎症反应，还能减少瘙痒。但是，由于成本或潜在的副反应，它们的使用可能有局限性。局部抗组胺药物、局部麻醉剂和皮肤屏障修复剂，可作为糖皮质激素喷剂的良好替代药物。
Without a doubt, new-generation GCs and CIs are the most effective topical antiinflammatory drugs used in canine AD. They are not only able to interfere with the inflammatory cascade, but also decrease pruritus. However, due to cost or potential side effects, their use may be limited. Good alternative medications that can be used as glucocorticoid-sparing drugs include topical antihistamines, local anesthetics, and skin barrier–repairing agents. 抗组胺药物(H1受体拮抗剂)作用于组胺受体，竞争性地阻断组胺受体复合物的形成。因此，它们抑制组胺释放后的由组胺引起的一系列反应，一些抗组胺药也能抑制肥大细胞脱颗粒。常用的抗组胺药包括苯海拉明、羟嗪和西替利嗪。尽管价格低廉且极其安全，但它们在治疗犬的过敏症状方面的效果一直不好;抗组胺药物在犬AD中缺乏疗效，可能是因为组胺并不是异位性皮炎的皮肤炎症反应的主要原因，也可能是因为一旦组胺与受体结合，抗组胺药就不能把组胺从受体中清除。不幸的是，近期的研究显示，外部使用H1(苯海拉明)和H4 (JNJ7777120和JNJ28307474)拮抗剂的疗效较低。外部使用苯海拉明仅能在使用28天和56天后分别减少AD约20%至38%的临床症状。同样，H4拮抗剂也不能预防模型AD犬的皮肤病变。这两项研究表明外用抗组胺药在犬AD中的潜在应用，尽管还需要更多的研究来充分评估此类药在犬AD中的有效性。 Antihistamines (H1 receptor antagonists) acts on histamine receptors, competitively blocking the formation of histamine-receptor complex. Thus, they inhibit the histaminic cascade after histamine is released, with some antihistamines able to inhibit mast cell degranulation as well. Common antihistamines used in veterinary dermatology include diphenhydramine, hydroxyzine, and cetirizine. Although inexpensive and extremely safe, their efficacy has been historically low in treating allergic conditions in dogs; however, the lack of efficacy of antihistamine in canine AD may be because histamine is not the major player in cutaneous inflammation in atopic dogs and also because antihistamines are not able to dislodge histamine from its receptors once they are bound. Unfortunately, the efficacy of topical H1 (diphenhydramine) and H4 (JNJ7777120 and JNJ28307474) antagonists has been shown to be low in recent studies. Topical diphenhydramine was able to reduce clinical signs of AD only approximately 20% to 38% after 28 and 56 days of use, respectively. Similarly, H4 antagonists, were not able to prevent skin lesions in a canine model of AD. These 2 studies indicate a potential use of topical antihistamines in canine AD, although more studies are needed to fully evaluate the usefulness of such mediations in canine AD. 临床上使用局麻药可以减轻犬过敏性皮肤病的临床症状。特别是，虽然经常使用普莫卡因作为香波或润丝膏，但是关于对犬应用效果的临床试验发表的并不多。只有一项交叉开放临床试验，评估了两种外用的普莫卡因润丝膏（Relief，Bayer，Shawnee，KS，USA; Derma-Soote，Vetoquinol，Fort Worth，Tx，USA）对异位性皮炎患犬连用4周的效果。在研究结束时，41%的主人认为普莫卡因有效(瘙痒程度下降51%-75%)。治疗后止痒效果持续48小时。 Local anesthetics have been used in clinical practice to alleviate the clinical signs of allergic dermatoses in dogs. In particular, the use of pramoxine as shampoo or cream rinse is of common use, although not many clinical trials have been published on its efficacy in dogs. Only 1 crossover open clinical trial has evaluated the efficacy of 2 topical formulations of pramoxine cream rinse (Relief, Bayer, Shawnee, KS, USA; Derma-Soote, Vetoquinol, Fort Worth, Tx, USA) in atopic dogs for a total of 4 weeks. At the end of the study, pramoxine was judged effective (51%–75% reduction in pruritus) by 41% of the owners. The pos-treatment antipruritic effects lasted for 48 hours.
皮肤屏障修复剂 SKIN BARRIER–REPAIRING AGENTS 在治疗过敏症患犬时，必不可少要使用外用抗炎/止痒药。但是，最近的研究表明，人和犬的异位性皮炎都存在原发性和/或继续性皮肤屏障改变。这些结果使得研究人员和临床医生开始关注改善过敏症病例的皮肤屏障缺陷的治疗方法。特别是，外用脂肪酸和(前体)神经酰胺已被广泛用于犬AD的辅助治疗。一些研究表明，外用皮肤屏障修复剂能使表皮脂质层和皮脂正常化。但是，此类产品的临床效果仅在少数临床试验中得到证实，总体表现为轻度至中度有效。
The use of anti-inflammatory/antipruritic topical mediations is essential in the treatment of allergic conditions in dogs. However, recent studies have shown that a skin barrier alteration, primary and/or secondary in nature, is present in both human and canine atopic skin. These results have led researchers and clinicians to look into therapies focused on ameliorating the skin barrier defect in allergic patients. In particular, topical fatty acids and (pro)ceramides have been largely used as adjuvant therapies for the treatment of canine AD. A few studies have been published on the effects of topical skin barrier–repairing agents showing a normalization of the epidermal lipid lamellae and skin lipids. However, the clinical effects of such products have been demonstrated in only a few clinical trials, showing an overall mild to moderate efficacy. 必需脂肪酸(EFAs)作为过敏性皮肤病和皮肤干燥的辅助治疗方法，在临床上已经应用了几十年。必需脂肪酸，以ω-3和/或ω-6的形式，已作为口服或通过商品化的富含EFA的粮食补充。直到最近，外用精油产品才被认为是为患犬皮肤提供不饱和脂肪酸的一种潜在的替代治疗。2011年，在德国进行了为期8周的RDBPCT试验，对含有精油和不饱和脂肪酸的皮肤滴剂（Dermoscent Essential 6 spot-on, Adventix, Burlington, ON, Canada）和一个成分相似，但精油和脂肪酸不同的喷剂(Dermoscent Atop 7 spray)进行临床效果对比。测量结果包括在研究开始和结束时的临床评估、瘙痒评分和皮肤屏障评估(TEWL)。在研究结束时，临床症状(滴剂和喷剂分别改善40%和79%)、瘙痒评分(32%和43%)和TEWL(喷雾制剂)都得到明显改善。最后，未发现任何治疗副反应。同一个研究小组进行了另一项RDBPCT分析，在8周的时间里，使用安慰剂滴剂的效果。患犬被分为轻度或中度/严重异位性皮炎患犬。研究结束时，治疗组的临床症状和瘙痒程度明显改善。最近，另一个RDBPCT评估了含有神经酰胺、脂肪酸和18-b-甘草次酸的外用脂质乳液在3个月内的使用情况。首次治疗一个月后，50%患犬的瘙痒评分降低超过50%。但是，这种改善效果在3个月后就消失了。
The use of essential fatty acids (EFAs), as adjuvant therapy for allergic skin conditions and dry skin, has been adapted in the clinical practice for decades. Essential fatty acids, in form of ω-3 and/or ω-6, have been administered as oral supplementation or through commercially available EFA-enriched diets. Only recently, the use of essential oil topical products has been considered as a potential alternative for delivering unsaturated EFA to affected skin. In 2011, an 8-week RDBPCT was performed in Germany comparing the clinical effects of a spot-on formulation containing essential oils and unsaturated fatty acids (Dermoscent Essential 6 spot-on, Adventix, Burlington, ON, Canada) with a spray containing similar, although different, oils and fatty acids (Dermoscent Atop 7 spray). The outcomes measured included a clinical assessment, pruritus score, and skin barrier assessment (TEWL) at the beginning and at the end of the study. At the end of the study, there was a significant reduction in clinical signs (40% and 79% for spot-on and spray, respectively), pruritus score (32% and 43%), and TEWL (spray formulation). Finally, no side effects were reported for any of the treatments. The same research group performed another RDBPCT analyzing the effects of the spot-on formulation against placebo over an 8-week period. The dogs were divided in mildly or moderately/severely affected atopic dogs. At the end of the study, a significant improvement of clinical signs and pruritus was seen in the treatment group. More recently, another RDBPCT evaluating the use of a topical lipid emulsion containing ceramides, fatty acids, and 18-b-glycyrrhetinic acid over a 3-month period was published. After the first month, a reduction of ≥50% in pruritus score was achieved in 50% of dogs; however, this beneficial effect was lost at the 3-month mark. 一种替代精油和脂肪酸外用制剂的方法是使用含有神经酰胺、胆固醇和脂肪酸的外用产品。事实上，早期对人的研究表明，含有一定比例的神经酰胺、胆固醇和脂肪酸(3:1:1)的产品，模拟皮肤中本身存在的比例，对改善异位性皮炎病例的皮肤病变非常有效。在兽医领域，2008年发表的一项研究显示，含有这种比例的滴剂产品有效。在那项研究中，研究人员连续6次，每3天使用一种滴剂产品(Allerderm spot-on by Virbac)。6次治疗后，角质层内脂质明显发生改善，因为皮肤角质层内的脂质的产生和分泌可能有所增加。在数年后进行了另一项概念验证研究，分析使用6次爱乐滴前后，异位性皮炎患犬的皮肤角质层神经酰胺、胆固醇和脂肪酸的表达。在研究结束时，研究人员报告了与治疗前相比神经酰胺含量的显著增加，角质层的脂质蛋白含量分布更加均匀。在这些研究之后，进行了两项临床试验，评估爱乐滴对异位性皮炎患犬的临床治疗效果。两项研究得出了相似的结果。与用药前评分相比，每周两次、连续4至12周使用爱乐滴，临床症状明显变轻。但是，对瘙痒程度和屏障功能(TEWL)未发现明显改变。这些研究表明，使用该产品能改善脂质合成和在角质层分布，从而改善皮肤屏障，但其临床应用价值还有待进一步研究。
An alternative to essential oils and fatty acid topical formulations is the use of topical products containing a combination of ceramides, cholesterols, and fatty acids. In fact, early studies in people showed that products containing a specific molar ratio of ceramide, cholesterol, and fatty acids (3:1:1) to mimic the ratio naturally present in the skin were highly beneficial to improve skin lesions in atopic patients. In veterinary medicine, the first study showing a beneficial effect of a spot-on product containing such molar ratio was published in 2008. In that study, the investigators used a spot-on formulation (Allerderm spot-on by Virbac) every 3 days for 6 consecutive times. After 6 treatments, a significant reorganization of the intracorneal lipids, due to a possible increase in production and secretion of endogenous stratum corneum lipids, was seen. Another proof-of-concept study was performed a few years later analyzing the expression of ceramides, cholesterol, and fatty acids in the stratum corneum of atopic dogs before and after 6 applications of Allerderm spot-on. At the end of the study, the investigators reported a significant increase in ceramide content and a more homogeneous distribution of proteinbound lipid content in the stratum corneum compared with before treatment. These studies were followed by 2 clinical trials evaluating the clinical benefits of Allerderm spot-on on atopic dogs; both studies gave similar results. The use of Allerderm spot-on, applied twice weekly for 4 to 12 weeks, was associated with a significant decrease in clinical signs compared with baseline scores; however, no benefits were seen for pruritus and barrier function (TEWL). These studies demonstrated that the application of such products might improve the lipid biosynthesis and distribution in the stratum corneum ameliorating the skin barrier, however, its usefulness in clinical practice still needs additional studies. 最近的一项研究，使用28天神经酰胺类保湿剂，评估使用前后的异位性皮炎患犬的临床表现和超微结构变化，证实了爱乐滴的效果。治疗包括每天使用含有神经酰胺、胆固醇和脂肪酸的保湿霜(比例为3:1:1)(Atobarrier Cream，Aestura, Hangang-daero, Yongsan-gu, Seoul, Seoul, Korea)，联合每周使用保湿香波(Dermally shampoo, Dechra, Laewood, KS, USA)。在研究结束时，据报道，临床症状、瘙痒程度和TEWL显著改善，以及增加了皮肤水合作用。超微结构研究表明，脂质双分子层的厚度和连续性明显增加。 The results obtained by Allerderm spot-on were confirmed by a more recent study assessing the clinical and ultrastructural changes in atopic dogs before and after application of ceramide-based moisturizers for 28 days. The treatment involved the daily use of a moisturizing cream containing ceramide, cholesterol, and fatty acids (ration 3:1:1) (Atobarrier Cream, Aestura, Hangang-daero, Yongsan-gu, Seoul, Seoul, Korea) associated with a weekly moisturizing shampoo (Dermally shampoo, Dechra, Laewood, KS, USA). At the end of the study, a significant decrease in clinical signs, pruritus, and TEWL associated with an increase in skin hydration was reported. As far as the ultrastructural study, it showed a significant increase in thickness and continuity of the lipid bilayer. 在过去几年里，其他皮肤屏障修复产品越来越受欢迎，包括含有植物鞘氨醇(植物鞘氨醇)的外用产品。鞘氨醇是神经酰胺的天然衍生物，具有显著的抗炎、抗菌和屏障修复活性。法国最近的一项研究评估了一种含有植物鞘氨醇、覆盆子油和脂类的摩丝(Douxo Calm mousse, Ceva, Paris, France)在实验犬模型中的屏障修复活性。研究结束时，TEWL或pH值无明显变化。但是，与未治疗组皮肤相比，治疗组皮肤的增殖标志物(ki-67)、B淋巴细胞和树突状细胞(BLA36)显著减少，表明植物鞘氨醇明显影响了皮肤炎症反应和增殖。 Other skin barrier–repairing products that have increased in popularity in the past few years are topicals containing plant-derived sphingosines (phytosphingosines). Sphingosines are natural derivates of ceramides that have been associated with significant anti-inflammatory, antimicrobial, and barrier-repairing activity. A recent study in France evaluated the barrier-repairing activity of a mousse containing phytosphingosines, raspberry oil, and lipids (Douxo Calm mousse, Ceva, Paris, France) in an experimental canine model. At the end of the study, there were no significant changes in TEWL or pH; however, a significant reduction of proliferation markers (ki-67) and B-lymphocytes and dendritic cells (BLA36) was seen in the treated compared with the untreated skin, suggesting a significant effect of phytosphingosines on inflammation and proliferation. 总之，这些研究表明，外用皮肤屏障修复剂对治疗犬AD有显著优势。特别是，它们能够降低皮肤炎症反应和使角质层内脂质恢复正常化，使异位性皮炎患犬皮肤屏障正常化。 Altogether, these studies have shown that topical skin barrier–repairing agents have a significant benefit in treating canine AD. In particular, they are able to reduce cutaneous inflammation and restore intracorneal lipids normalizing the skin barrier of atopic dogs.
替代疗法 ALTERNATIVE THERAPIES 在过去的十年中，治疗犬AD的替代疗法的研究有了巨大进步。特别是，研究人员已经在寻找更多的天然化合物、副反应更少、能够减少或完全消除对AD全身性药物(如GC、环孢菌素、奥拉替尼)的需求。最早和最重复的尝试是研究益生菌，作为一种潜在能减少或预防犬AD临床症状的方法。特别是，使用鼠李糖乳杆菌已被证明在子宫内给药(从怀孕第三周至出生)，并给出生后的幼犬从三周至六个月龄继续使用，能有效地预防发生犬AD。经过3年治疗发现，在免疫和结构方面(皮肤屏障功能)具有明显优势。最近，一项比较西替利嗪和副干酪乳杆菌K71的研究显示，在12周的治疗中，轻度AD患犬的临床症状(38.1%对45.8%)和瘙痒(38.1%对26.8%)评分有类似的降低。使用乳酸菌sakei probio-65治疗严重AD患犬8周后，也得出同样结果。总之，这些研究表明，益生菌的应用可能有助于预防或减少犬AD的临床症状(和药物剂量)。然而，一定要记住，并不是所有的细菌都是益生菌，而且需要特别注意选择要使用的益生菌，以优化其效果。 The research of alternative therapies to treat canine AD has seen a tremendous increase in the past decade. In particular, researchers have invested in searching for more natural compounds with fewer side effects able to reduce or completely eliminate the needs of medications generally used for AD (eg, GC, cyclosporine, oclacitinib). The earliest and most repeated attempt was done looking into probiotics as a potential tool to reduce or prevent clinical signs of AD in dogs. In particular, the use of Lactobacillus rhamnosus has been shown to be effective in preventing the development of AD in a canine model when given in utero (from the third week of gestation until lactation) and continued in the offspring from the third week to 6 months of age. Immunologic and structural (skin barrier function) benefits were still evident after 3 years from the administration. More recently, a study, comparing cetirizine with Lactobacillus paracasei K71, showed a similar reduction in clinical signs (38.1% vs 45.8%) and pruritus (38.1% vs 26.8%) scores in mild cases of AD over 12 weeks of treatment. Similar results were confirmed by using Lactobacillus sakei probio-65 after 8 weeks in dogs with severe AD. Altogether, these studies suggest that the administration of probiotics could be beneficial in preventing or reducing the clinical signs (and drugs) of AD in dogs. However, it is essential to keep in mind that not all bacteria act as probiotics, and particular attention needs to be applied to the choice of probiotics to be administered to optimize their beneficial effects. 据报道，为了降低异位性皮炎的临床症状或药物治疗剂量，其他治疗方法已有研究。特别是口服维生素E和非索非那丁，在治疗8周后，与安慰剂联合非索非那丁治疗组相比，对中度AD患犬的临床症状有显著降低作用(分别为96%和89%)。研究人员还报告了循环维生素E的增加和总抗氧化能力的增加。同样，口服维生素D在轻度至中度AD患犬中使用8周，已被证明结果值得期待。在维生素E的研究中，检测到循环维生素D的增加。在这两项研究中，都没有发现副反应。 Other treatments reported to be useful in reducing the clinical signs or the need of drugs to treat atopic dogs have been studied. In particular, oral vitamin E, associated with fexofenadine, has been shown to be highly effective in reducing clinical signs in moderate cases of AD after 8 weeks of treatment when compared with placebo plus fexofenadine (96% vs 89%, respectively). The investigators also reported an increase in circulating vitamin E and an increase in total antioxidant capacity. Similarly, the use of oral vitamin D has been shown to be promising when used in mild to moderate cases of AD for 8 weeks. As in the vitamin E study, an increase in circulating vitamin D was detected. In both studies, a lack of side effects was reported. 在治疗犬AD中证明有效的其他替代疗法，包括使用普鲁卡因（神经疗法）、超纯水、己酮可可碱加多不饱和脂肪酸（PUFA）和内源性大麻素，但是其他方法对犬AD不能带来明显改善或疑似改善（例如，冷激光疗法、顺势疗法、氟西汀、CCR4抑制剂、氨基喋呤），或带来中度至重度副作用（例如，马赛替尼）。 Other alternative therapies shown to be effective in the treatment of canine AD include the use of procaine (neural therapy), ultrapure water, pentoxifylline plus polyunsaturated fatty acids (PUFAs), and endocannabinoids, whereas other options have not been associated with a significant or questionable improvement of canine AD (eg, cold laser therapy, homeopathy, fluoxetine, CCR4 inhibitors, aminopterin) or associated with moderate to severe side effects (eg, masitinib). 简而言之，静脉注射普鲁卡因和皮内注射普鲁卡因(在病变部位）的临床症状和瘙痒评分显著降低了82.6%和77.4%，88%的犬在没有副反应的情况下，治疗13周后，这两项评分的降低都超过了50%。此外，自上次注射后19周，55%的犬的临床症状得到持续改善。 Briefly, the use of procaine intravenously and intradermally (in affected areas), showed a significant reduction of 82.6% and 77.4% in clinical signs and pruritus score with 88% of dogs reaching a reduction of both scores of ≥50% after 13 weeks of treatment in absence of side effects. Furthermore, a maintained improvement of the clinical signs was seen in 55% of the dogs enrolled after 19 weeks from last injection. 最近，一项安慰剂对照临床试验评估了每周使用超纯软水和爱乐美香波(神经酰胺和EFAs)与每周使用自来水和爱乐美香波，在4周内治疗中度犬AD。与自来水相比，超纯软水具有硬度低、钙镁含量低、钠含量高的特点。研究显示，与对照组相比，治疗组的临床症状(21%对0.45%)、瘙痒程度(24.0%对3.6%)和TEWL(46.4%对6.0%)都显著下降。 Recently, a placebo-controlled clinical trial evaluated the efficacy of weekly Allermyl shampoo (ceramides and EFAs) using ultrapure soft water compared with Allermyl shampoo using tap water in moderate cases of canine AD over a 4-week period. Ultrapure soft water is characterized by low hardness, low calcium and magnesium, and high sodium compared with tap water. The study showed a significant decrease in clinical signs (21% vs 0.45%), pruritus (24.0% vs 3.6%), and TEWL (46.4% vs 6.0%) for the treatment group compared with the control. 己酮可可碱是一种非选择性磷酸二酯酶抑制剂，可降低纤维蛋白、促炎细胞因子的产生和白细胞对白细胞介素的反应，破坏T淋巴细胞与角质细胞的结合，降低成纤维细胞活性，长期使用可降低纤维化。虽然临床上已使用很久，但只有1篇安慰剂对照的随机研究评估其对犬AD疗效的文章。单独(I组)或与口服PUFAs(II组)联合口服己酮可可碱，剂量为每8小时20 mg/kg，口服60天。在第30天和第60天，与安慰剂组(第三组)和基线相比，两组患犬的临床症状和瘙痒评分均显著降低。然而，联合使用己酮可可碱和PUFAs比单独使用己酮可可碱更有效。 Pentoxifylline is a nonselective phosphodiesterase enzyme inhibitor able to decrease fibronectin, production of proinflammatory cytokines, and leukocyte response to interleukins, and impairs T-lymphocyte binding to keratinocytes, decreases fibroblastic activity, and with long-term use, may decrease fibrosis. Although clinically used, only 1 placebo-controlled, randomized study has been published assessing its efficacy in treating canine AD. Pentoxifylline was administered orally at the dosage of 20 mg/kg every 8 hours, alone (group I) or in combination with oral PUFAs (group II), for 60 days. On days 30 and 60, a significant reduction in both clinical signs and pruritus scores was seen in both treatment groups compared with placebo (group III) and with baseline. However, the combination of pentoxifylline and PUFAs was more efficacious than pentoxifylline alone. 最后，研究了口服天然生物活性脂类内源性大麻素类化合物对AD患犬的影响。特别值得注意的是，一项使用超微粉化棕榈酰乙醇酰胺的开放标签临床试验显示，连续8周，每天10.9 mg/kg的剂量，显著降低了临床症状(第28天:31.6%;第56天:48.2%)和瘙痒(第28天:26%;第56天:36.8%)，以及生活质量的提高。这项研究，虽然是第一次在犬身上发表，但非常有前景。 Last, the oral use of naturally occurring bioactive lipid endocannabinoidlike compounds has been investigated in dogs affected by AD. In particular, an open-label clinical trial using ultra-micronized palmitoylethanolamide at 10.9 mg/kg per day for 8 weeks showed a significant reduction in both clinical signs (day 28: 31.6%; day 56: 48.2%) and pruritus (day 28: 26%; day 56: 36.8%), and an increase in quality of life. This study, although it is the first one published in dogs, is very promising. 至于治疗犬AD的顺势疗法而言，只有一项小规模的试点研究显示，个体化疗法对犬AD有潜在的好处。然而，由于入选的犬的数量非常少，而且缺乏对照、盲法、随机临床试验，目前使用顺势疗法并不合理。在安慰剂对照的临床试验中，研究了冷激光治疗的应用。然而，在治疗5周后，低强度激光治疗(冷激光)和安慰剂在临床症状和瘙痒方面没有差异。最后，一项为期2个月的双盲、安慰剂对照交叉临床试验评估了氟西汀治疗重度AD的疗效，结果显示氟西汀治疗2个月后无效。 As far as homeopathic remedies for treating AD in dogs, only 1 small pilot study showed a potential benefit of individualized remedies in canine AD. However, due to the very low number of dogs enrolled and the lack of a controlled, blinded, randomized clinical trial, the use of homeopathy is not justified at the moment. The use of cold laser therapy was investigated in a placebo-controlled, clinical trial. However, after 5 weeks of treatment, no difference in clinical signs and pruritus was present between low-level laser therapy (cold laser) and placebo. Finally, a double-blinded, placebocontrolled crossover 2-month clinical trial evaluated the efficacy of fluoxetine for severe AD, showing no efficacy after 2 months of fluoxetine. 未来的治疗
FUTURE THERAPIES 展望未来，更安全、更有针对性的化合物将有可能用于犬AD。具体来说，可使用生物靶向分子治疗特定的AD临床亚型。另一方面，使用病毒颗粒结合细胞因子或细菌素也被研究作为治疗动物过敏症的潜在方法。它们的疗效不定，但副反应轻微，有一定前景。其中，针对IL-4、IL-13、IL-17和IL-22的人源化抗白介素抗体已被研究，或正在评估用于治疗人AD。除了抗白介素抗体外，抗人IgE和抗IL-31受体抗体的应用前景广阔。在兽医学中，唯一被批准的生物制剂是lokivetmab（洛基维特单克隆抗体）。我们有理由假设，在不久的将来会有更多的生物制剂问世。但是，基于异位性皮炎的复杂性，也许使用单克隆抗体的混合疗法可以取代单一单克隆抗体，提高该治疗方案的疗效。 Looking at the future, it is possible that safer and more targeted compounds will be available for canine AD. Specifically, biologics targeting molecules involved in the treatment of specific clinical subtypes of AD are desirable. On the other hand, the use of viral-particle-associated cytokines or bacterins have also been studied as potential treatments for allergies in animals. Their efficacy is variable but promising in the face of mild side effects. Among others, humanized anti-interleukin antibodies (targeting IL-4, IL-13, IL-17, and IL-22) have been studied, or are currently under evaluation, for the treatment of human AD. Along with anti-interleukin antibodies, the use of anti-human IgE and anti–IL-31 receptor antibodies have been highly promising as well. In veterinary medicine, the only biologic approved is lokivetmab. It is plausible to assume that more biologics will be readily available in the near future; however, based on the complexity of the atopic disease, instead of a single monoclonal antibody, maybe the use of cocktails of monoclonal antibodies may increase the efficacy of this therapeutic option.
总结 SUMMARY 综上所述，犬AD是一种极其复杂的临床综合征，临床表现和治疗反应各不相同。由于其复杂性，对多种治疗方法在不同的临床表现中进行评估，有时会产生相反的结果。目前，少数化药代表了治疗犬AD的“核心”选择(如GC、环孢菌素、奥拉替尼)。然而，替代药物和外部治疗由于其低毒性和高疗效，尤其是与“核心”药物相关的药物，已经引起了越来越多的关注。此外，重要的是要记住，作为预防性药物的化合物，争取的是延迟而不是治疗异位性皮炎犬的急性发作和皮肤感染。此外，重要的是，要认识到更适合治疗急性发病的药物和更有效预防急性发病的药物之间的差异。治疗方案应根据病例及其主人的具体需要定期重新评估和调整。成功治疗犬AD的关键往往是高疗效、低成本和低副反应。 In conclusion, canine AD is an extremely complex clinical syndrome characterized by different clinical manifestations and therapeutic response. Because of its complexity, multiple therapies have been evaluated in different clinical subtypes, with sometimes contrasting results. At the moment, a pool of few compounds represent the “core” of treatment options for canine AD (eg, GC, cyclosporine, oclacitinib). However, alternative drugs and topical therapies have been looked at with increased interest due to their low toxicity and high efficacy, specifically if associated with “core” medications. Furthermore, it is fundamental to remember to strive for preventive medicine using compounds able to delay rather that treat flares and skin infections in atopic dogs. In addition, it is important to recognize the difference in drugs more suited for treating flares and drugs more effective in preventing the flares. Treatment options should be regularly reassessed and adjusted based on the specific needs of patients and their owners. The key of a successful treatment for canine AD often combines high efficacy with low cost and mild side effects.
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发表于 2019-7-2 23:33:17
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