皮肤癣菌病是一种人畜共患病，由小孢子菌属和毛癣菌属的皮肤癣菌引起，主要通过真菌分泌酶系统、生长机械力等侵入动物机体的皮肤角质层、毛发、甲床角蛋白等浅表角化组织，引起丘疹、鳞屑、脱毛、色素沉着、趾甲外观改变等多种临床症状，严重影响患病动物的生活质量和健康。从1958年首次使用灰黄霉素治疗皮肤癣菌病至今，皮肤癣菌病治疗药物的研究已有近70年的历史，但随着临床抗真菌药物的大量使用和滥用，宠物主人频繁换药和随意停药，皮肤癣菌耐药性逐渐增强，耐药菌株逐渐增加，造成临床治疗难度增大。本研究对新兽药氟康唑搽剂的皮肤安全性、体外敏感性、临床治疗效果、最佳剂量等进行了研究，以期为氟康唑搽剂的临床应用提供理论依据。

1 氟康唑搽剂的皮肤刺激性试验

本试验采用 “药物非临床研究质量管理规范（Good Laboratory Practice, GLP）”规定的皮肤刺激性试验评估氟康唑搽剂局部使用时的皮肤刺激性。以新西兰大白兔为模式动物，根据不同的背部皮肤处理分为皮肤完整组和皮肤破损组，每组4只。采用自体对照法，在新西兰大白兔左侧和右侧背部皮肤分别施用氟康唑搽剂和赋形剂丙二醇（药用级），在固定时间点观察并记录皮肤红斑和水肿评分，计算不同观察时间点的皮肤刺激评分均值，以此评价氟康唑搽剂和丙二醇对破损皮肤和完整皮肤的刺激性程度。结果显示氟康唑搽剂在单次给药和多次给药条件下，完整皮肤组和破损皮肤组均未出现红斑、水肿等炎症反应；丙二醇在单次给药和多次给药条件下，完整皮肤组未出现炎症反应，破损皮肤组仅在第一次观察时，个别受试动物出现轻微水肿反应。结果表明，氟康唑搽剂和丙二醇对动物皮肤无刺激性，在局部使用时具有较强的皮肤安全性。

2 氟康唑搽剂对常见皮肤癣菌的体外敏感性测定

    本试验参考美国临床实验室标准化研究所（CLSI）提出的“产孢丝状真菌抗真菌药敏试验参考方案（M38-A2）”，采用微量液基稀释法研究氟康唑（Flconzole, FLU）对5株兽医临床常见的皮肤癣菌临床分离株，包括犬小孢子菌（Microsporum canis）、石膏样小孢子菌（Microsporum gypseum）和须癣毛癣菌（Trichophyton mentagrophyte）的体外敏感性，探究氟康唑搽剂临床应用的可能性。结果显示FLU对上述皮肤癣菌的GM值分别为5.27、4.75、3.36 μg/mL，MIC值范围分别为2~64 μg/mL、1~8 μg/mL、0.25~16 μg/mL。表明，氟康唑对石膏样小孢子菌、须癣毛癣菌的体外敏感性强于犬小孢子菌，对皮肤癣菌具有良好的体外敏感性。

3 氟康唑搽剂对犬皮肤癣菌病的临床疗效研究

本试验诊断并纳入104只皮肤癣菌病患犬，随机分为受试药物推荐剂量组、受试药物加倍剂量组、受试药物减半剂量组、空白对照组和对照药物组，以氟康唑搽剂为受试药物，复方酮康唑软膏为对照药物，持续治疗28 d，通过治疗总有效率和病原培养结果评估氟康唑搽剂的临床疗效；每7 d观察记录各组临床症状评分下降指数、病原转阴率，统计总有效率；每7 d采集血液样本检测血常规和肝肾功能相关生化指标，监测治疗过程中受试药物对机体炎性细胞、红细胞等指标以及肝肾功能是否产生异常影响。通过统计分析，研究氟康唑搽剂临床治疗的最佳剂量、周期以及对血液指标的影响。结果表明，推荐剂量组、加倍剂量组、减半剂量组和对照药物组总有效率分别为100%、100%、95.46%、90.90%，真菌转阴率分别为100%、95.45%、86.95%、90%。氟康唑搽剂推荐剂量组、加倍剂量组和复方酮康唑软膏药物组疗效优于其他治疗组，并且氟康唑搽剂推荐剂量组和加倍剂量组临床疗效优于对照药物组。推荐剂量组、加倍剂量组、减半剂量组在给药28 d内血常规结果和生化结果均处于正常值范围内，且嗜中性粒细胞数量（Neutrophils，NEU）、淋巴细胞数量（Lymphocyte, LYM）、肌酐含量（Creatinine, CREA）、尿素氮含量（Blood Urea NitrogenBUN）与对照药物组变化趋势相符，说明氟康唑搽剂局部外用对动物血细胞指标以及肝肾功能无显著影响。另外与空白对照组相比，推荐剂量组最早（给药7 d）出现临床症状评分的显著降低（p＜0.05），在给药14 ~21 d时临床症状评分显著低于包括对照药物组在内的其他各组（p＜0.05），各组的临床症状评分下降指数随治疗时间的增长均显著升高（p＜0.05）；氟康唑搽剂推荐剂量组、加倍剂量组和减半剂量组病原孢子数在给药28 d内均显著低于空白对照组（p＜0.05），氟康唑搽剂各组与对照药物组在给药14~21 d内结果无显著差异（p＞0.05），各组病原转阴率随治疗时间的增长均显著升高（p＜0.05）；氟康唑搽剂推荐剂量0.15 mL/cm2，3次·d-1，连用28 d是理想的最佳剂量和治疗周期。综上说明，氟康唑搽剂推荐剂量临床疗效好，安全性高，治愈率高，具有临床推广价值。

Dermatophytoses is a zoonosis, which is caused by dermatophytes of Microsporum and Trichophyton species. The dermatophytes invade into superficial keratinized tissue such as stratum corneum, hair, and nail bed keratin of the animals mainly through fungal secretory enzyme system and growth force, and causes papules, scales, depilation, pigmentation, toenail abnormalities, and other clinical symptoms, which seriously affecting the quality of life and health of animals. Since griseofulvinwas first used in dermatophytoses treatment in 1958, the research on the treatment of dermatophytoses has a history of almost 70 years. Because of antifungal drugs abused by veterinary in clinic and changed frequently by pet owners at will, the dermatophytes resistance to antifungal drugs and the proportion of resistant strains gradually increases, leading to the increase of difficulty of clinical treatment. In this study, the skin safety and sensitivity of a new veterinary drug fluconazole liniment in vitro were studied, and the therapeutic effect, optimal dose, and adverse reactions of fluconazole liniment in the clinical treatment were investigated. The study aimed to provide the theoretical data for the clinical application of fluconazole liniment and new possibilities for dermatophytoses treatment in dogs.

1 Skin irritation test of fluconazole liniment

The study evaluated the skin irritataion of fluconazole liniment for topical treatment using the skin irratation test prescribed by "Good Laboratory Pratice(GLP)". New Zealand White Rabbits, as the model animals, were divided into intact skin group and damaged skin group, 4 rabbits in each group, according to different back skin treatments. Fluconazole liniment and pharmaceutical grade of mono propylene glycol (MPG) were separately applied to the left and right back locally of the same rabbit as autologous control. The skin erythema and edema scores were observed and recorded at observed time points, and the average skin irritation scores at different observation time points were calculated. The irritation degree of fluconazole liniment and MPG on damaged and intact skin was observed and recorded after single and multiple skin irritation test. The results showed that non-inflammation reactions such as erythema and edema were observed in both groups after single or multiple irritation test of fluconazole liniment, and non-inflammation response in both groups was observed under single or multiple doses of MPG, except for the slight edema at the first observation of a few rabbits in damaged skin group. The results indicated that fluconazole liniment and MPG had no irritation to animal skin and had strong skin safety when applied topically.

2 Susceptibility testing of fluconazole liniment to common dermatophytes in vitro

This study referred to "Reference Method for Broth Dilution Antifungal Susceptibilty Testing of Filamentous Fungi; Approved Standard—Second Edition(M38-A2)" proposed by the Clinical and Laboratory Standards Institute(CLSI). Broth microdilution methods was used to study in susceptibility of fluconazole to 5 clinical isolates of dermatophytes common in the veterinary clinic, including Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophyte, and to explore the effects of clinical application of fluconazole liniment. The results showed that the geometric mean MICs of FLU against the above fungi were 5.27, 4.75 and 3.36 μg/mL, and the MIC values were 2-64 μg/mL, 1-8 μg/mL and 0.25-16 μg/mL, respectively. The results indicated that FLU had better sensitivity to Microsporidium gypsum and Trichophyton mentagrophyte than to Microsporidium canis, and had good sensitivity in vitro to dermatophytes.

3 The clinical effect of fluconazole liniment on canine dermatophytosis

A total of 104 dogs diagnosed as dermatophytosis were divided into fluconazole liniment recommended-dose group, double-dose group, half-dose group, compound ketoconazole ointment control group and positivecontrol group at random, fluconazole liniment was used as the test drug and compound ketoconazole ointment as the control drug in this work. The clinical therapeutic trials lasted 28 days, and the clinical efficacy of fluconazole liniment was evaluated through the total effective rate of treating dermatophytosis and fungal negative conversion rate. The symptom score decreased index and fungal negative conversion rate in each group were observed and recorded every 7 days, and the total effective rate was counted according to the results; the blood samples were collected every 7 days to detect blood routine and biochemical indexes related to liver and kidney function, and to monitor whether the drugs had abnormal effects on inflammatory cells and red blood cells and so on, and the function of liver and kidney. Based on the above results, the optimal dose, treatment cycle, and adverse reactions of fluconazole liniment in clinical treatment were investigated. The results showed that the total effective rates of the recommended-dose group, double-dose group, half-dose group, and control group were 100%, 100%, 95.46%, 90.90%, and the fungal negative conversion rates were 100%, 95.45%, 86.95%, 90%, respectively. Recommended dose group, the double-dose group and the control group had better clinical efficacy than the other groups, and recommended dose group, the double-dose group had better clinical efficacy than the control group. The blood routine and biochemical results of fluconazole liniment treatment groups were within the normal range during 28 days of the experiment, and the neutrophils count (NEU), lymphocyte count (LYM), creatinine level (CREA) and urea nitrogen content (BUN) were consistent with the changing trend of the ketoconazole ointment control group, which indicated that fluconazole liniment had no significant effect on blood cells and liver and kidney function. In addition, compared with the positive control group, the clinical symptom score of the recommended-dose group was first to appear significantly decreased at 7 days (p<0.05), and was significantly lower at 14 to 21 days than that of the other groups including the control group (p<0.05). The clinical symptom decreased index in all groups were significantly increased with time past (p<0.05). The pathogenic spore number in the recommended-dose group, double-dose group, and half-dose group was significantly lower than that in the positive control group during 28 days of the experiment (p<0.05), and there was no significant difference between the fluconazole liniment groups and the ketoconazole ointment control group at 14 to 21 days (p>0.05). The negative conversion rate of pathogen in all groups were significantly increased over time (p<0.05). The results indicated that the dose of fluconazole liniment at 0.15 mL/cm2 three times a day for 28 days was the ideal optimal dose and treatment cycle. In conclusion, the recommended-dose of fluconazole liniment had good clinical efficacy and high safety, and had a faster onset, which had the significance of clinical application.

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