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Efficacy of APOQUEL® for the Control of Otitis Externa Secondary to Allergic Skin Disease in Client-Owned Dogs
爱波克控制家养犬过敏性皮肤病继发的外耳炎的效果
作者：Gotthelf LN
翻译：王帆
摘要
Abstract
背景：这项目标单一、无隐藏、病变部位单一的研究，目的是评估每日两次，连用14天的奥拉替尼（爱波克）对过敏性皮肤病患犬继发外耳炎时的局部抗感染效果。研究记录了13只宠物犬，有3只犬因为主人不服从管理而退出研究。患犬要求年龄大于1岁，体重是3-80kg，调查人员认为是由于过敏性皮肤病导致的单纯性外耳炎，外耳炎指数评分≥6分，且有全身或外部止痒药、抗炎或抗感染药物等，可能对评估有干扰的治疗将退出研究。采集每只耳朵的样本进行细胞学检查。对有外耳炎的耳朵进行清洁和记录。每天两次口服奥拉替尼，有感染提示的患犬，患耳外用恩诺沙星/磺胺嘧啶银（Baytril® Otic）每日两次。宠物主人每日进行评估，调查人员第7天和第14天进行评估。
结果：共有7只母犬和3只公犬完成了此项研究。年龄在3-12岁之间，体重在3.6-47kg之间。使用奥拉替尼和恩诺沙星/磺胺嘧啶银耳药每日两次，连用14天后，调查人员进行耳炎评分，平均分从第0天的19.7分到第14天改善至3.4分，平均分降低了81.7%。在14天的研究中，宠物主人评估的平均分分别改善了94.7%（左耳）和80.6%（右耳）。细胞学检查的记录是有7只左耳和7只右耳有细菌，第14天对比时只有1只左耳有细菌，右耳没有。开始时有一只犬没有细菌或酵母菌感染，第14天时有9只犬没有细菌感染。有2只左耳和2只右耳记录发现了酵母菌，在第14天时仅有1只右耳有酵母菌。
结论：这项目标单一、病变部位单一、无隐藏的研究结果表明，口服奥拉替尼联合患耳外用抗感染耳药，每日两次，连用14天，对过敏性皮肤病患犬的继发性外耳炎的管理有效。
Background: This single-arm, unmasked, single-site study was conducted to evaluate the efficacy of oclacitinib (APOQUEL®) administered twice daily for 14 days with a topical anti-infective, when indicated, for the control of otitis externa secondary to allergic skin disease in dogs. Thirteen (13) client-owned dogs were enrolled; three (3) dogs were withdrawn for owner non-compliance. Dogs were required to be ≥1 year old, weigh 3.0-80.0 kg, have uncomplicated otitis externa that the Investigator attributed to allergic skin disease, have an Otitis Index Score of ≥6 and been withdrawn from any systemic or topical treatments with antipruritic, anti-inflammatory or anti-infective properties that could interfere with assessments. Cytology samples were collected from each ear. Ears with otitis externa were cleaned at enrollment. Oclacitinib was administered orally twice daily; in dogs with evidence of infection, enrofloxacin/silver sulfadiazine (Baytril® Otic) was administered topically twice daily in affected ears. Owner assessments were performed daily and Investigator assessments were performed on Days 7 and 14.
Results: Seven (7) female and three (3) male dogs completed the study. Ages ranged from 3.0-12.0 years and body weight ranged from 3.6-47.0 kg. Administration of oclacitinib and enrofloxacin/silver sulfadiazine twice daily for 14 days resulted in mean Investigator otitis scores improving from 19.7 on Day 0 to 3.4 by Day 14, for a mean reduction of 81.7%. Mean owner assessment improved by 94.7% (left ear) and 80.6% (right ear) during the 14-day study. Cytologic examination of the ears showed bacteria in seven left ears and seven right ears at enrollment compared to only one left ear and no right ears on Day 14. One dog had no bacteria or yeast on Day 0 compared to nine dogs with no bacteria on Day 14. Yeast was present in two left and two right ears at enrollment and in only one right ear on Day 14.
Conclusions: The results of this single-arm, single-site, unmasked study suggest that oral administration of oclacitinib with a topical anti-infective applied to affected ears twice daily for 14 days is effective for the management of otitis externa secondary to allergic skin disease in dogs.
关键词：外耳炎；犬；奥拉替尼；爱波克
缩写：ND（不用）；NSAID（非甾体抗炎药）；OTIS（耳炎指数评分）；USA（美国）；VAS（视觉模拟评分）
Keywords: Otitis Externa; Canine; Oclacitinib; APOQUEL.
Abbreviations: ND (Not Done); NSAID (Non-Steroidal Anti-Inflammatory); OTIS (Otitis Index Score); USA (United States of America); VAS (Visual Analog Scale).
背景
Background
外耳炎是外耳道皮肤的一种炎性反应，是家养犬的一种常见疾病。外耳炎的临床症状包括：皮肤发红、水肿、异味、瘙痒、甩头和抓痕。在兽医诊所提交的病例中，预计外耳炎的患病率在7.3%到10.2%之间。犬外耳炎的原发诱因包括：特应性皮炎、食物过敏、寄生虫和异物，而易感因素包括耳部构造、导致耳道内水分过多的生活方式以及不恰当的治疗。在一项回顾性研究中，我们评估了来兽医院就诊的外耳炎病例的原发病因，过敏性皮肤病是最常见的原发诱因，且占评估的外耳炎病例的43%。一项类似的研究发现。60%的过敏性皮肤病患犬都有外耳炎。与外耳炎有关的细菌感染通常被认为是机会性感染，不是原发性致病菌，如果治疗不当将会成为外耳炎持久因素。外耳炎的治疗历来侧重于控制导致动物个体疾病的病因。由于过敏性皮肤病患犬在外耳炎患犬占的比例很大，所以控制过敏性皮肤病在外耳炎管理中显得尤为重要。
Otitis externa, an inflammation of the skin of the external ear canal, is a common problem in domestic dogs. Clinical signs of otitis externa include erythema, edema, pain, odor, pruritus, head shaking and excoriations. The prevalence of otitis externa has been estimated to be between 7.3 and 10.2% of cases presenting to veterinary clinics. Primary triggers for otitis externa in dogs include atopic dermatitis, food allergy, parasites and foreign bodies, while predisposing factors include conformation of the ear, lifestyle factors causing excessive moisture in the ear canal and inappropriate treatment. In a retrospective study that evaluated primary causative factors for otitis externa in patients presented to a veterinary school, allergic dermatitis was the most common primary factor and was observed in 43% of the otitis externa cases evaluated. A similar study found that 60% of dogs presenting with atopic dermatitis had otitis externa. Bacterial infections associated with otitis externa are generally considered opportunistic and not primary pathogens and can become perpetuating factors in otitis externa if not appropriately treated. Treatment of otitis externa has historically focused on controlling the causative factors contributing to the individual animal’s condition. Since dogs with allergic skin disease make up a large proportion of the dogs with otitis externa, controlling allergic skin disease becomes important in the management of otitis externa.
奥拉替尼（爱波克）是一种新型Janus激酶（JAK）抑制剂，可以抑制与瘙痒（IL-31）、过敏症和炎性反应（IL-2、IL-4和IL-13）有关的细胞因子。奥拉替尼目前被批准用于控制与过敏性皮肤病有关的瘙痒，以及用于控制大于12月龄的特应性皮炎患犬。奥拉替尼已被证实在特应性皮炎和过敏性皮肤病患犬上长期使用是安全有效的。本研究旨在评估奥拉替尼对控制过敏性皮肤病患犬的外耳炎的潜在作用。因为要想成功治疗外耳炎控制继发的细菌感染很重要，所以在本研究中如果发生感染，则包括被感染耳道每日两次使用抗感染耳药管理。
Oclacitinib (APOQUEL®) is a novel Janus kinase (JAK) inhibitor that has been shown to inhibit cytokines involved in pruritus (IL-31) and allergy and inflammation (IL-2, IL-4, IL-6 and IL13). Oclacitinib is currently approved for the control of pruritus associated with allergic dermatitis and for the control of atopic dermatitis in dogs that are at least 12 months of age. Oclacitinib has been shown to be safe and effective for long-term use in dogs with atopic and allergic skin disease. The present study was designed to evaluate the potential for oclacitinib to aid in the control of otitis externa in dogs with allergic skin disease. Due to the importance of controlling secondary bacterial infections in successful treatment of otitis externa, the present study included twice daily administration of an anti-infective in the affected ears if infection was present.
方法
Methods
单一部位研究是一种探索性研究，临床研究评估奥拉替尼（爱波克）与外用抗感染耳药（恩诺沙星/磺胺嘧啶银；Baytril® Otic）联合使用时，对控制过敏性皮肤病患犬继发的外耳炎的效果。这项研究是在美国阿拉巴马州的蒙哥马利市的一家私人兽医诊所对家养犬进行的分析，在对犬进行任何研究操作之前，已征得每位主人的书面同意。该协议于2015年4月在该研究开始前已被硕腾公司伦理审查委员会批准。
This single-site study was conducted as an exploratory, clinical study to assess the efficacy of oclacitinib (APOQUEL®) for the control of otitis externa secondary to allergic skin disease in dogs, when administered in combination with a topical anti-infective (enrofloxacin/silver sulfadiazine; Baytril® Otic). The study was conducted in client-owned dogs at a private veterinary practice in Montgomery, Alabama, USA, and each owner provided written informed consent before any study procedures were performed on their dog. The protocol was approved by the Zoetis Ethical Review Board in April 2015 before the start of the study.
调查人员会对任何性别、品种或杂交品种的健康犬，出现的由过敏性皮肤病外耳炎进行评估和记录。可能是一只耳朵有外耳炎，也可能是两只耳朵都有。患犬不能怀孕或正在哺乳、正用于繁殖，并且体重必须在3-80kg之间，年龄至少是12个月。在登记当天，患犬要进行全面的体检，包括对鼓膜的评估。调查人员要对每只耳朵的水平和垂直耳道的皮肤发红、水肿/异味、糜烂/溃疡以及分泌物，分别以0-3分进行评估，从而进行耳炎指数评分（OTIS）。调查人员也要对每只耳朵的气味、疼痛和外耳炎严重程度进行评估。登记时至少需要一只患耳的总分是6分。在登记时，教会主人使用视觉模拟评分（VAS）来评估耳炎的严重程度。临床症状包括：异味、分泌物、变红、变热、疼痛、肿胀、瘙痒、刺激、结痂/皮屑、抓挠和/或摩擦。每只耳朵记录表上都有一个垂直线，主人需要在这条垂线上的最能反应这只耳朵情况的点上作一个水平十字标记。完成评估后，在每只有外耳炎症状的患耳，采集耳道细胞学检查的样本在临床实验室进行评估。使用独立包装的无菌棉签给每只耳朵进行采样。立即制片即在事先准备好的干净的长方形载玻片上滚动棉签。左耳样本放在玻片一侧，右耳样本放在另一侧。玻片上用铅笔标记R、L和患犬姓名。每张玻片要热固定1分钟，然后用Diff Quick染液（Jorgensen Labs）按说明染色。用油镜检查染片，在高倍镜下每只耳朵随机检查5个视野，并记录下是否发现细菌和/或酵母菌。完成细胞学采样后，使用耳道清洁剂（Epi-Otic®, Virbac）清洁患耳。
Healthy dogs of any gender, breed or mix of breeds presenting with otitis externa that the investigator determined was secondary to allergic skin disease were evaluated for enrollment. The otitis externa could be in one or both ears. Dogs could not be pregnant or lactating, intended for breeding, and had to weigh 3.0-80.0 kg and be at least 12 months of age. On the day of enrollment, a thorough physical examination was performed, including an assessment of the tympanic membrane. The Investigator determined the Otitis Index Score (OTIS) by assessing the horizontal and vertical ear canals in each ear for erythema, edema/ swelling, erosion/ulceration and exudate using a 0-3 scale for each variable. The odor, pain and severity of otitis externa were also assessed by the investigator for each ear. A total score of 6 in at least one ear was required for enrollment. At enrollment, the owner was instructed on the use of a visual analog scale (VAS) for the severity of otitis. The clinical signs considered included odor, discharge, redness, heat, pain, swelling, itching, irritation, crusts/scales, scratching and/or rubbing. A vertical line was present on the form for each ear, and the owner was to mark a single horizontal cross mark on the vertical line at the point at which the owner thought best reflected the condition of that ear. After the assessments were completed, an ear cytology sample was collected from each ear with clinical signs of otitis externa for evaluation in the clinic’s laboratory. Separate non-sterile cottontipped applicators were used to collect a sample from each ear. Slides were prepared immediately by rolling the swab on a new pre-cleaned slide lengthwise. The left ear sample was placed on one side of the slide and the right ear sample was placed on the other side of the slide. The slides were appropriately labeled R, L and the name of the patient with pencil. Each slide was heat fixed for 1 minute and then stained with Diff Quick solution (Jorgensen Labs) according to manufacturer’s instructions. Slides were evaluated under immersion oil and the presence or absence of bacteria and/or yeast was recorded for each of five random high power fields for each ear. After cytology sample collection was complete, the affected ears were cleaned using an ear cleanser solution (Epi-Otic®, Virbac).
如果患犬在登记前用相同方法至少治疗了6周（包括低过敏饮食），并且在研究期间持续进行这种治疗/饮食，那么需要在健康情况上进行备注，并允许登记治疗。所有犬都没有跳蚤感染记录，且不限制使用控制跳蚤的产品。本研究登记的犬没有进行特异性过敏原免疫治疗。对使用能干扰过敏性皮肤病继发外耳炎评估的，任何已知的全身或外用治疗，或疑似止痒和/或抗炎药物的，在进入研究之前都会被禁止或停药一段时间，类似于在皮内试验前建议停药。先前接受过奥拉替尼治疗的犬将不被研究。
Dogs with incidental health conditions requiring treatment were alloweto enroll if they had been on the same treatment regimen (including hypoallergenic diets) for at least 6 weeks before enrollment and continued those treatments/diets throughout the study. All dogs were free of fleas at enrollment, and there was no restriction on administration of flea control products. No dogs enrolled in this study were receiving allergen-specific immunotherapy. Any systemic or topical treatments with known or suspected antipruritic and/or anti-inflammatory properties that could confound the assessment of the otitis externa secondary to allergic skin disease were prohibited or discontinued for periods prior to entry into the study similar to those recommended for drug withdrawal prior to intradermal testing . Dogs that had previously been treated with oclacitinib were excluded.
在本研究中，奥拉替尼和恩诺沙星/磺胺嘧啶银都是按说明剂量使用。奥拉替尼剂量是（0.4-0.6mg奥拉替尼/kg体重，每天两次）按包装上说明书的剂量图使用的。直接口服奥拉替尼或与少量食物一起口服。根据包装说明书，恩诺沙星/磺胺嘧啶银的剂量是体重小于等于35磅（15.9kg）的犬，每次用量5-10滴，体重大于35磅的犬，每次用量10-15滴，每日两次。使用后轻轻按摩耳部，以确保耳药均匀分布在整个外耳道。登记时，药剂师会按正确规格（3.6 mg, 5.4 mg or 16 mg）把14 (±2) 天剂量的奥拉替尼药片放到药瓶里，连同一瓶恩诺沙星/磺胺嘧啶银一起给主人。并指导主人如何使用奥拉替尼（口服）和恩诺沙星/磺胺嘧啶银（耳部外用）。同时指导主人如何记录使用剂量，以及提供剂量用表和VAS评估数据。健康的任何异常情况都要记录上。
Oclacitinib and enrofloxacin/silver sulfadiazine were both administered at the approved label doses in this study. The dose of oclacitinib (0.4 to 0.6 mg oclacitinib/kg body weight twice daily) was determined using the dosing chart on the package insert. The oclacitinib dose was administered directly into the mouth or in a small amount of food. The enrofloxacin/silver sulfadiazine dose was 5-10 drops/treatment for dogs weighing 35 lb (15.9 kg) or less and 10-15 drops/treatment for dogs weighing more than 35 lb twice daily, according to the package insert. Following treatment, the ear was gently massaged to ensure complete and uniform distribution of the medication throughout the external ear canal. At enrollment, the dispenser placed the appropriate number of the correct size oclacitinib tablets (3.6 mg, 5.4 mg or 16 mg) for 14 (±2) days of dosing into a pill container which was dispensed to the owner, along with a bottle of enrofloxacin/ silver sulfadiazine. The owner was provided instructions on how to administer the oclacitinib (orally) and the enrofloxacin/silver sulfadiazine (topically in the ear). The owner was also instructed on how to record dose administration and was provided with the appropriate forms for recording dosing and VAS assessment data. Any abnormal health events were to be documented.
调查人员在第7(±2 )天进行体格检查、每只耳朵都要完成OTIS评分、细胞学检查和就诊登记，并且用耳道清洁剂（EpiOtic®）对患耳进行清洁。在第14(±2 )天进行最后一次研究评估。调查人员进行体格检查、确定每只耳朵的OTIS评分和采集每只耳朵的细胞学检测样本，同时进行就诊登记。主人归还所有研究表格和剩余的研究用药。再次对主人的表格和药物进行审核。
At the Day 7 (±2 days) evaluation, the investigator performed a physical examination, completed an OTIS score for each ear, performed cytology as described for the enrollment visit, and affected ears were cleaned with an ear cleansing solution (EpiOtic®). Day 14 (±2 days) was the final study evaluation. The Investigator performed a physical examination, determined the OTIS score for each ear and collected a cytology sample from each ear as described for the enrollment visit. The owner returned all study forms and remaining study medications. Owner forms and drug accountability were reviewed.
计算性别、绝育/去势和品种的分布频率。计算每个时间点的年龄和体重，进行统计性描述。计算完成研究的分布频率。疗效变量是调查人员的OTIS评分和主人的VAS。确定每只犬每个变量的低于基线的百分比。仅对就诊登记时最严重的耳道使用OTIS总结。计算每个时间点的所有四个疗效变量，进行统计性描述。
Frequency distributions of gender, spayed/neutered and breed were calculated. Descriptive statistics were calculated for age and body weight at each time point. A frequency distribution of study completion was calculated. The efficacy variables were the Investigator OTIS score and the Owner VAS. The percent reduction from baseline for each variable was determined for each dog. Only the most severely affected ear at the enrollment visit was used for the OTIS summaries. Descriptive statistics were calculated for all four efficacy variables at each time point.
结果
Results
研究对象
Study Population
共有13只犬参加此项研究。有三只犬的主人在登记后没有来复诊，这三例视为随访失败。收集完成研究的10只犬的数据进行数据总结。代表性品种包括：杂交品种（n=4），腊肠犬(n=2)，拉布拉多犬(n=2)，比特犬（n=1）和西高地白梗（n=1）。有四只已绝育母犬、三只未绝育母犬、一只已去势公犬和两只未去势公犬。完成研究的犬年龄在3到12岁之间（平均值=6.7岁；中间值=6岁），体重登记范围在3.6到47kg（平均体重=19.7kg；中间体重=14kg）。第7天和第14天的就诊时间分别为第5-12天（平均7.5天）和第14-26天（平均15.7天）。
A total of 13 dogs were enrolled in this study. The owners of three of the dogs did not return for subsequent visits after the enrollment visit, and these three cases were considered lost to follow-up. The data summaries include data from the 10 dogs that completed the study. Breeds represented include mixed breed (n=4), dachshund (n=2), Labrador retriever (n=2), pit bull (n=1) and West Highland white terrier (n=1). There were four spayed females, three intact females, one neutered male and two intact males. The ages of the dogs that completed the study ranged from 3 to 12 years (mean=6.7 years; median=6.0 years) and the body weights at enrollment ranged from 3.6 kg to 47 kg (mean body weight=19.7 kg; median body weight =14.0 kg). The Day 7 and Day 14 visits occurred between Days 5-12 (mean day 7.5) and Days 14-26 (mean day 15.7), respectively.
临床检查
Physical Examination Findings
所有参与本项研究的犬都表现出过敏性皮肤病继发外耳炎的临床症状。登记中，可观察到的过敏性外耳炎的临床症状包括：瘙痒、耵聍腺增生、蜡样耳垢、皮肤发红和耳道狭窄。到第7天，有5只犬的外耳炎临床症状得到改善，有3只犬症状完全消失。研究结束时，10只犬中有7只的外耳炎临床症状完全消失。
All dogs enrolled in this study showed clinical signs of otitis externa secondary to active allergic skin disease. At enrollment, clinical signs of allergic otitis externa observed included pruritus, hyperplasia, wax accumulation, erythema and stenosis. Clinical signs of otitis externa improved in five dogs by Day 7 and had completely resolved in three dogs at that time. By the end of the study, clinical signs of otitis externa had completely resolved in seven of the 10 dogs.
调查人员耳炎指数评分(OTIS)
Investigator Otitis Index Scores (OTIS)
每个动物最严重的第0天的耳朵OTIS评分和从第0开始的下降比例见表1。从第0天到第7天，所有犬的OTIS都下降了，下降比例范围从20%到100%。从第7天到第14天，有8只犬的OTIS分数降低了，但剩余2只犬的分数升高了。这2只犬的第14天的OTIS分数比第0天的分数低，这表明它们比基础水平有进步。第14天OTIS分数比第0天分数下降比例范围从13.6%到100%。
The individual animal OTIS scores for the ear that was most severely affected on Day 0 and the percent reduction in score from Day 0 are presented in Table 1. From Day 0 to Day 7, the OTIS scores decreased for all dogs, with the percent reduction in score ranging from 20.0 to 100%. From Day 7 to Day 14, the OTIS scores decreased for eight dogs, but increased for the remaining two dogs. The Day 14 OTIS scores for these two dogs were numerically lower than their Day 0 scores, indicating improvement from baseline. The percent reduction in Day 14 OTIS scores compared to the Day 0 scores ranged from 13.6% to 100%.
宠物主人VAS评分
Owner VAS Scores
在研究过程中，每只犬的主人都分别对犬的两只耳朵进行了VAS评分（表2）。在整个研究过程中，每只犬的左耳VAS评分平均值每天都在下降，而右耳的平均值除了第6天和第8天以外，也每天都在下降。主人的VAS评分下降比例总结见表2。在第4天，左耳的VAS评分降低了50%；直到第10天才看到右耳VAS评分下降50%。在第14天，主人给出的左耳和右耳的VAS评分分别降低了94.7%和80.6%。
Each owner assigned VAS scores for each of their dog’s ears daily during the study (Table 2). Mean owner VAS scores for the left ear decreased each day throughout the study, while the mean scores for the right ear decreased daily except for Day 6 and 8. A summary of the percentage reduction in owner VAS scores is presented in Table 2. A 50% reduction in the owner VAS scores for the left ear was achieved on day 4; a 50% reduction in the owner VAS score for the right ear was not observed until Day 10. On Day 14, owner VAS scores were reduced 94.7% for the left ear and 80.6% for the right ear.
耳道细胞学检查
Ear Cytology
细胞学发现的总结见表3。登记中，10只左耳中有7只左耳和9只右耳中有7只右耳仅发现了细菌，而10只左耳中有2只左耳和9只右耳中有2只右耳发现有酵母菌。在第0天，没有犬的任何一只耳朵同时有细菌和酵母菌。到第14天，10只左耳中只有1只左耳发现了细菌，右耳都没有，但是10只右耳中有1只右耳再次发现了细菌和酵母菌。在第14天，任何耳朵都没有发现酵母菌。
A summary of cytology findings is presented in Table 3. At enrollment, bacteria alone were found in 7/10 left ears and 7/9 right ears, while yeast was found in 2/10 left ears and 2/9 of right ears. No dog had both bacteria and yeast in either ear on Day 0. By Day 14, bacteria alone were found in 1/10 left ears and none of the right ears, while bacteria and yeast were again found in 1/10 right ears. Yeast alone was not found in any ears on Day 14.
安全性
Safety
本研究无副反应报道。在研究过后的第26天，有一只犬出现了一些软便症状，但因为是发生在停止用药后的12天，所以认为不是研究中用药的副反应。
No adverse events were reported during this study. Some loose stools were noted in one dog at study exit on Day 26, but as this was 12 days after the end of dosing, it was not considered an adverse event to medications used in the study.
讨论
Discussion
本研究结果表明，使用奥拉替尼联合外用抗感染耳药，对控制过敏性皮肤病患犬的外耳炎有效。在本研究中，感染最严重的耳道的OTIS评分结果平均在第7天和第14天分别降低61.7%和81.7%。其中一半患犬在第14天的OTIS评分是0，证实外耳炎的临床症状达到完全康复。有两只犬在第7天出现好转，但是在第14天出现临床症状加重。第14天与第0天相比，两者都有一定程度的改善。
The results of this study showed that administration of oclacitinib with a topical anti-infective was effective for the management of otitis externa in dogs with allergic skin disease. In the present study, the OTIS scores showed mean percent reduction in the most severely affected ear of 61.7% on Day 7 and 81.7% on Day 14. Half of the dogs achieved OTIS scores of 0 on Day 14, confirming complete recovery from clinical signs of otitis externa. Two dogs showed improvement on Day 7, but then a worsening of clinical signs on Day 14. Both had modest improvement on Day 14 compared to Day 0.
除了调查人员的OTIS评分，研究中主人每天对每只耳朵也完成了VAS评估。虽然VAS分数的提高比例与OTIS分数的提高比例相当，但是单个动物的改善并不总是与分数相关。在第14天时，OTIS评分表现出轻微改善的两只犬在VAS评分上分别减少了75%和80%，而其他表现有改善的犬在OTIS评分并没有比VAS评分有改善。与OTIS评分相比，主人的VAS是一个单一的主观评估，将动物的所有临床症状进行全面评分。因此，这两个分数之间并没有完全的相关性就不足为奇了。
In addition to the Investigator OTIS scores, the owners also completed VAS assessment for each ear on each day of the study. Although the percentage improvements in the VAS scores were comparable to percent improvements in the OTIS scores, improvements for individual animals did not always correlate between the scales. The two dogs that showed modest improvement on the OTIS scale had 75 and 80% reduction in VAS scores on Day 14, while other dogs that showed improvement in OTIS scores did not show improvement in VAS scores. In contrast to OTIS score, the owner VAS was a single subjective assessment that included all of the animal’s clinical signs in one global score. Thus it is not surprising that there was not perfect correlation between the 2 scores.
从历史观点来看，管理外耳炎是通过耳道清洁和外用抗感染产品（抗生素和抗真菌）以及NSAIDs。更严重的病例则全身性使用糖皮质激素和抗生素。奥拉替尼可能成为治疗过敏性皮肤病继发外耳炎的临床症状的另一种有效的工具。重点要强调的是，不表示奥拉替尼能用于与原发性过敏性皮肤病无关的犬外耳炎，这些的潜在的原发病因可能是寄生虫感染、异物或内分泌疾病。
Historically, otitis externa has been managed through ear cleaning and application of topical anti-infective products (antibiotics and antifungals) and NSAIDs. Systemic glucocorticoids and antibiotics are administered in more severe cases. Oclacitinib may become an additional effective tool for the management of the clinical signs of otitis externa secondary to allergic skin disease. It is important to emphasize that oclacitinib would not be indicated in dogs with otitis externa not associated with primary allergic disease, where the primary underlying disease may instead be parasitic infestations, foreign bodies, or endocrinopathies.
奥拉替尼被批准用于控制与过敏性皮肤病有关的瘙痒，以及用于控制犬的特应性皮炎。在一项关于奥拉替尼控制与过敏性皮肤病有关的瘙痒和皮肤病变的研究中，显示24小时后瘙痒VAS已经减少了30%，而接受奥拉替尼治疗的犬在24后，瘙痒（VAS下降2cm）成功降低到44%。在目前的研究中，当使用奥拉替尼治疗过敏性皮肤病继发的外耳炎时，奥拉替尼的起效作用很迅速。主人报告第3天的左耳VAS减少了39.5%，右耳减少了42.5%。
Oclacitinib is approved for the control of pruritus associated with allergic dermatitis and for the control of atopic dermatitis in dogs. In a study of oclacitinib for the control of pruritus and skin lesions associated with allergic dermatitis, there was already a 30% reduction in pruritus VAS after 24 h, and successful reduction of pruritus (2 cm decrease in the VAS) was achieved in 44% of oclacitinib-treated dogs after 24 h. The onset of action for oclacitinib was rapid in the present study as well, when oclacitinib was administered for the treatment of otitis externa secondary to allergic skin disease. Owners reported Day 3 VAS reductions of 39.5% in the left ear and 42.5% in the right ear.
在本研究中，主人或调查人员没有副反应的报道，这为奥拉替尼在犬上的安全性提供了支持性证据。
No adverse events were observed by the owners or reported to the investigator in this study, providing supportive evidence of safety of oclacitinib in this population of dogs.
这项研究的规模太小，结论可能受到了限制。虽然登记的病例都被诊断为过敏性皮肤病，但是登记的病例数量少限制了品种多样性和严重程度。在此项研究中，只有一只犬被诊断为食物过敏。这只犬对治疗反应良好，是第14天OTIS评分为0的其中一只犬。在本研究中，食物过敏患犬的比例与之前的发现表现一致，即7%特应性皮炎病例之前被诊断为食物过敏。另一个可能的限制是登记时出现酵母菌感染的病例比例很低。在本研究中，在20%的左耳和22.2%的右耳中发现有酵母菌。相比之下，我们对每只耳朵采样，从73%的双侧外耳炎样本中分离出了马拉色菌。目前尚不清楚这些差异对研究结果的影响如何。
The small size of this study limits the conclusions that may be drawn. While the cases enrolled had all been diagnosed with allergic skin disease, the small number of animals limits the variety and severity of cases that were enrolled. Only one dog had been diagnosed with food allergies before being enrolled in this study. This dog responded well to treatment, and was one of the dogs with an OTIS score of 0 on Day 14. The percentage of dogs with food allergies in the present study was consistent with previous findings that found 7% of the cases with atopy had prediagnosed food allergies. Another possible limitation was the low percentage of cases that had yeast infections at enrollment. In the present study, yeast was observed in 20% of the left ears and 22.2% of the right ears at enrollment. In contrast, Malassezia pachydermatis was isolated from 73% of samples from cases with bilateral otitis externa when each ear was sampled independently. It is not known how these differences may have impacted the outcome of the study.
结论
Conclusions
这项目标单一、病变部位单一、无隐藏的研究结果表明，口服奥拉替尼联合使用患耳外用抗感染耳药，每日两次，连用14天，对过敏性皮肤病患犬的继发性外耳炎的管理有效。依据更多的大型对照、盲法研究能进一步评估奥拉替尼的潜在适应症。
The results of this single-arm single-site unmasked study suggest that oral administration of oclacitinib orally together with a topical anti-infective applied to affected ears twice daily for 14 days is effective for the management of otitis externa secondary to allergic skin disease in dogs. Additional larger controlled, blinded studies are warranted to further evaluate this potential indication for oclacitinib.
表1：每个动物的OTIS评分和平均分，以及OTIS评分的下降比例。
Table 1. Individual and Mean Animal OTIS Scores and Percent Reduction in OTIS Scores.
动物 |
天数 |
0 |
71 |
142 |
分数 |
分数 |
下降比例% |
分数 |
下降比例% |
01-001 |
22 |
8 |
63.6 |
2 |
90.9 |
01-002 |
22 |
15 |
31.8 |
19 |
13.6 |
01-003 |
14 |
2 |
85.7 |
0 |
100 |
01-004 |
19 |
0 |
100 |
0 |
100 |
01-005 |
30 |
19 |
36.7 |
1 |
96.7 |
01-007 |
20 |
16 |
20.0 |
0 |
100 |
01-008 |
16 |
8 |
50.0 |
2 |
87.5 |
01-011 |
23 |
8 |
65.2 |
0 |
100 |
01-012 |
14 |
5 |
64.3 |
10 |
28.6 |
01-013 |
17 |
0 |
100 |
0 |
100 |
平均值 |
19.7 |
8.1 |
61.7 |
3.4 |
81.7 |
1：第7天包括第5、7、8和12天
2：第14天包括第14、15、17和26天
表2：主人VAS评分（cm）总结和VAS评分下降比例平均值。
Table 2. Summary of Owner VAS Scores (cm) and mean percentage reduction of VAS Scores.
耳朵 |
天数 |
动物数量 |
VAS评分平均值 |
VAS下降比例平均值% |
左耳 |
1 |
10 |
7.8 |
|
2 |
10 |
6.4 |
18.6 |
3 |
10 |
4.8 |
39.5 |
4 |
10 |
3.9 |
52 |
5 |
10 |
3.8 |
53.6 |
6 |
10 |
3.6 |
55.6 |
7 |
10 |
3.5 |
55.8 |
8 |
10 |
3.2 |
61.2 |
9 |
10 |
2.9 |
65 |
10 |
10 |
2.2 |
73.3 |
11 |
10 |
2.0 |
74.8 |
12 |
10 |
1.6 |
80 |
13 |
10 |
1.3 |
83.2 |
14 |
9 |
0.4 |
94.7 |
右耳 |
1 |
10 |
5.9 |
|
2 |
10 |
4.8 |
16.5 |
3 |
10 |
3.3 |
42.5 |
4 |
10 |
3.0 |
42.5 |
5 |
10 |
2.9 |
44.4 |
6 |
10 |
3.1 |
34.6 |
7 |
10 |
2.5 |
48.5 |
8 |
10 |
2.5 |
49.1 |
9 |
10 |
2.3 |
48.2 |
10 |
10 |
1.9 |
53.1 |
11 |
10 |
1.5 |
62.4 |
12 |
10 |
1.4 |
67.6 |
13 |
10 |
1.2 |
70.5 |
14 |
9 |
0.3 |
80.6 |
表3：细胞学检查总结
Table 3. Summary of Cytological Findings
耳朵 |
天数 |
微生物 |
细菌 |
酵母菌 |
都有 |
都没有 |
n |
% |
n |
% |
n |
% |
n |
% |
左耳 |
0 |
7 |
70 |
2 |
20 |
0 |
0 |
1 |
10 |
7 |
3 |
30 |
0 |
0 |
0 |
0 |
7 |
70 |
14 |
1 |
10 |
0 |
0 |
0 |
0 |
9 |
90 |
右耳 |
0 |
7 |
77.8 |
2 |
22.2 |
0 |
0 |
0 |
0 |
7 |
1 |
10 |
1 |
10 |
1 |
10 |
7 |
70 |
14 |
0 |
0 |
0 |
0 |
1 |
10 |
9 |
90 |
| 
|Archiver|手机版|小黑屋|宠医帮
( 京ICP备2022012070号-2 ) 
发表于 2023-6-24 17:56:35
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