兽药中异恶唑啉体外杀虫剂的研究进展

王帆

Current review of isoxazoline ectoparasiticides used in veterinary medicine

兽药中异恶唑啉体外杀虫剂的研究进展

Xueying Zhou1 | Alexandra E. Hohman | Walter H. Hsu

翻译：王帆

Abstract

The isoxazolines are a novel class of ectoparasiticides with potent inhibitory activity on glutamate- and gamma-aminobutyric acid-gated chloride channel located in nervous system of invertebrates. In recent years, studies have been performed to evaluate the efficacy and safety of isoxazolines against various types of ectoparasites, including fleas, ticks, and mites. As more single and combined isoxazoline products have been approved by the United States Food and Drug Administration and European Medicines Agency, a more comprehensive understanding of isoxazolines becomes essential for veterinary clinical practitioners. This article provides a complete review of isoxazolines with respect to pharmacodynamics, pharmacokinetics, ectoparasiticidal efficacy, and safety, which will provide veterinarians information to allow them to make the best choice of ectoparasiticide for their clients’ specific needs.

摘要

异恶唑啉是一类新型的体外杀虫剂，对无脊椎动物神经系统中谷氨酸和-氨基丁酸门控的氯离子通道有较强的抑制作用。近年来，对异恶唑啉治疗各种体表寄生虫(包括跳蚤、蜱虫和螨虫)的有效性和安全性进行了研究。随着越来越多的单一和组合异恶唑啉产品获得美国食品药品监督管理局和欧洲药品管理局的批准，对兽医临床从业人员更全面地了解异恶唑啉成为必要。本文就异恶唑类药物的药效学、药代动力学、体外杀虫效果和安全性等方面进行了全面的综述，为兽医提供信息，使他们能够根据客户的特定需求做出最佳的体外杀虫剂选择。

KEYWORDS afoxolaner, ectoparasiticide, fluralaner, isoxazoline, lotilaner, sarolaner

关键词 阿福拉纳、体外杀虫剂、氟雷拉纳、异噁唑啉、洛替拉纳、沙罗拉纳

 

1  | INTRODUCTION

1介绍

Ectoparasites such as fleas, ticks, and mites are the source of several important systemic and local diseases and conditions, including direct damage to the skin barrier through parasitic feeding, tissue invasion, and hypersensitivity reactions, in addition to their function as vectors and reservoirs for significant pathogenic microorganisms such as Bartonella, Rickettsia, Borrelia, Anaplasma, Ehrlichia, and Babesia .

跳蚤、蜱虫和螨虫等体外寄生虫是几种重要的系统性和局部疾病的病原，包括寄生虫采食、组织入侵和过敏反应对皮肤屏障的直接损害，此外，它们还是巴尔通体、立克次体、疏螺旋体、无形体、埃里希体和巴贝斯虫等重要致病微生物的载体和宿主。

 

Ectoparasites are an important concern for health status of animals, as well as prevention of zoonotic diseases. A wide array of compounds are currently on the market for treatment of ecto-parasites for animals, with various modes of action that target arthropod-specific ligand-gated ion channels and G protein-coupled receptors . Afoxolaner, fluralaner, sarolaner, and lotilaner are members of isoxazolines, a novel class of insecticide/acaricide with potent inhibitory activity on glutamateand gamma-aminobutyric acid (GABA)-gated chloride channels in invertebrates, and generally have a high safety margin in vertebrates. These novel ectoparasiticides are currently marketed as oral canine products with FDA-approved labels against fleas, black-legged ticks, American dog ticks, brown dog ticks, and the lone star ticks. Fluralaner is additionally available in topical spot-on form for both dogs and cats. Beyond their FDA-approved usage against common fleas and ticks, all four marketed isoxazoline products have experimentally and clinically demonstrated efficacy in the treatment of mite infestations.

体外寄生虫是影响动物健康和预防人畜共患病的重要因素。目前市场上有大量用于治疗动物外寄生虫的化合物，它们具有针对节肢动物特异性配体门控离子通道和G蛋白偶联受体的各种作用模式。阿福拉纳、氟雷拉纳、沙罗拉纳和洛替拉纳都属于异恶唑啉类，是一类新型的杀虫/杀螨剂，对无脊椎动物中谷氨酸和γ -氨基丁酸(GABA)门控氯离子通道具有较强的抑制活性，在脊椎动物中普遍具有较高的安全裕度。这些新型的体外杀虫剂目前作为犬类口服产品销售，带有FDA批准的标签，用于对抗跳蚤、黑腿蜱、美国犬蜱、棕色犬蜱和孤星蜱。此外，氟雷拉纳另有犬猫使用的外用滴剂形式。除了FDA批准的用于治疗常见的跳蚤和蜱虫外，所有四种上市的异恶唑啉产品都在实验和临床中证明了对螨虫感染的疗效。

 

2  |  PHARMACODYNAMICS

2.1  |  Mechanism of action

2药效学

2.1作用机理

Gamma-aminobutyric acid is the primary inhibitory neurotransmitter within the central nervous system (CNS) of vertebrates and in both the CNS and peripheral nervous system of invertebrates. GABA receptors are members of the Cys-loop superfamily linked to chloride channels. They have five transmembrane subunits, each consisting of four transmembrane helices. Current research indicates the helical subunits are the target of isoxazolines, though the precise inhibition site has not yet been identified . Variation in arrangement and substitution of these subunits is ultimately responsible for the different pharmacological action of the drug targeting the receptor and the degree of safety in the use of a particular isoxazoline in vertebrates. A study utilizing fly and rat models has demonstrated a significant preference of isoxazolines for invertebrate GABA receptors over vertebrates. The glutamate-gated chloride channel, a ligand-gated ion channel unique to invertebrates and the target of macrocyclic lactones, is also targeted by isoxazolines to a lesser degree. GABA and glutamate exert their actions by stimulating chloride influx on the postsynaptic tissue, causing hyperpolarization, preventing the generation of an action potential. Isoxazolines inhibit this modulatory action by binding to the postsynaptic tissue, preventing chloride influx leading to depolarization/hyperexcitation, paralysis, and death of the parasite.

γ-氨基丁酸是脊椎动物中枢神经系统（CNS）以及无脊椎动物中枢神经系统和外周神经系统中主要的抑制性神经递质。GABA受体是与氯离子通道相连的Cys-loop超家族的成员。它们有五个跨膜亚基，每个亚基由四个跨膜螺旋组成。目前的研究表明，螺旋亚基是异恶唑啉的靶点，但其确切的抑制位点尚未确定。这些亚基排列和取代的差异最终决定了靶向受体药物的不同药理作用，以及在脊椎动物中使用特定异恶唑啉的安全程度。一项利用苍蝇和大鼠模型的研究表明，与脊椎动物相比，无脊椎动物的GABA受体更倾向于使用异恶唑啉。谷氨酸门控的氯离子通道是无脊椎动物特有的配体门控离子通道，也是大环内酯的目标，异恶唑啉也在较小程度上靶向。GABA和谷氨酸通过刺激氯离子流入突触后组织而发挥作用，导致超极化，阻止动作电位的产生。异恶唑啉通过与突触后组织结合来抑制这种调节作用，防止氯离子内流导致去极化/过度兴奋、麻痹和寄生虫的死亡。

 

3  |  APPROVED USAGE OF ISOXAZOLINES

3异噁唑啉批准用量

These isoxazoline ectoparasiticides are currently marketed under the trade names NexGard® (afoxolaner, Boehringer Ingelheim), Bravecto® (fluralaner, Merck), Simparica® (sarolaner, Zoetis), and Credelio® (lotilaner, Elanco), as well as combination drugs NexGard Spectra®(afoxolaner and milbemycin oxime, Boehringer Ingelheim), Bravecto Plus®(fluralaner and moxidectin, Merck), Simparica Trio®(sarolaner, moxidectin, and pyrantel, Zoetis), and Revolution Plus® (selamectin and sarolaner, Zoetis) (Tables 1 and 2). Among the isoxazoline products with single active pharmaceutical ingredient, most products contain drugs formulated as chewable tablets for treatment and prevention of fleas (Ctenocephalides felis) infestations and control of common types of ticks in dogs in various countries, including black-legged ticks (Ixodes scapularis), American dog ticks (Dermacentor variabilis), brown dog ticks (Rhipicephalus sanguineus), and lone star ticks (Amblyomma americanum) in the USA and Canada ; ornate cow tick (D. reticulatus), castor bean tick (I. ricinus), Hedgehog tick (I. hexagonus), and brown dog tick in Member States of European Union (EU) ; Australian paralysis ticks (I. holocyclus), brown dog tick, and Asian longhorned tick (Haemaphysalis longicornia) in Australia; and Asian longhorned tick in New Zealand. Other than common tick species, sarolaner has shown additional efficacy against Gulf Coast ticks (Amblyomma maculatum) in dogs. In addition, most isoxazolines with single active substance are approved by EMA for treatment of demodicosis, scabies, and ear mite infestations (Table 1). Fluralaner differs from the other three isoxazolines with prolonged duration up to 12 weeks, which is three times longer than afoxolaner, sarolaner, and lotilaner . Fluralaner is also available as a topical solution for both dogs and cats; in cats, it is for the treatment and prevention of fleas and control of black-legged ticks. Lotilaner has been approved by EMA as chewable tablets for treatment of fleas and ticks (castor bean tick) in cats. As for other detailed information of approved usage, for example, minimum dose and age of animal, please refer to Tables 1 and 2.

这些异恶唑啉体外杀虫剂目前以商品名NexGard (阿福拉纳，勃林格英格翰)、Bravecto (氟雷拉纳，默克)、Simparica (沙罗拉纳, 硕腾)和Credelio (洛替拉纳, 礼来)以及组合药物NexGard Spectra (阿福拉纳和米尔贝肟，勃林格英格翰)上市。Bravecto Plus(氟雷拉纳和莫西克丁，默克)，Simparica Trio(沙罗兰纳、莫西克丁和噻吩嘧啶，Zoetis)， Revolution Plus(赛拉菌素和沙罗兰纳，硕腾)(表1和2)。在含有单一活性药物成分的异恶唑啉产品中，大多数产品含有可咀嚼的药片，用于治疗和预防蚤(猫栉头蚤)感染和控制不同国家常见的犬类蜱虫，包括美国和加拿大的黑腿蜱虫(肩突硬蜱)、美国犬蜱(变异革蜱)、棕色犬蜱(扇头蜱)、孤星蜱(美洲钝眼蜱);欧盟(EU)成员国的花纹牛蜱(网纹革蜱)、蓖麻蜱(蓖麻硬蜱)、刺猬蜱(刺猬硬蜱)和棕色犬蜱;澳大利亚的澳大利亚麻痹蜱(全环硬蜱)、棕色犬蜱和亚洲长角蜱(长角血蜱);以及新西兰的亚洲长角蜱。除了常见的蜱类，沙罗拉纳对犬的墨西哥湾蜱(斑状钝眼蜱)显示出额外的功效。此外，大多数具有单一活性物质的异恶唑啉被EMA批准用于治疗蜱虫病、疥螨和耳螨感染(表1)。与其他三种异恶唑啉不同的是，氟雷拉纳的持续时间最长可达12周，是阿福拉纳、沙罗拉纳、洛替拉纳的3倍。氟雷拉纳也有犬和猫外用产品;在猫上，它是为了治疗和预防跳蚤和控制黑腿蜱。洛替拉纳已被EMA批准作为咀嚼片治疗猫的跳蚤和蜱虫(蓖麻蜱)。有关获批准使用的其他详细资料，例如最低剂量及动物年龄，请参阅表一及表二。

 

4  |  PHARMACOKINETICS

4药代动力学

Pharmacokinetic parameters of currently available isoxazolines are summarized in Table 3. Oral isoxazolines have varied bioavailability ranging from 8.4% to 100% with an average plasma half-life of ~2 weeks , except for lotilaner that possesses the longest plasma halflife of ~30 days in both dogs and cats . It is interesting to note that, although, lotilaner has the longest plasma half-life among isoxazolines, which leads to a moderate degree of accumulation . Its recommended oral dosing interval is the same as afoxolaner and sarolaner of 4 weeks (Table 1). Studies of a prolonged dosing interval (for instance, 8–12 weeks) of lotilaner are suggested to explore sustained efficacy longer than one month. Feeding of the target animal plays a critical role in the pharmacokinetics of lotilaner, especially bioavailability, which is decreased from 82% to 24% when administered to fasted dogs, and 100% to 8.4% in fasted cats . Thus, it is strongly recommended to provide wet or dry food with lotilaner for an effective treatment and prevention of fleas and control of ticks. On the contrary, the plasma concentration of afoxolaner does not appear to be affected by food with a high bioavailability of 74% . Isoxazolines have a high degree of plasma protein binding (≤99.9%), indicating that the clearance is likely largely hepatic rather than renal. The average volume of distribution (Vss) has been determined to be ~3 L/ kg for afoxolaner , fluralaner , and sarolaner , whereas lotilaner has a higher Vss value of ~6 L/kg, which implies a higher distribution into adipose tissue than other isoxazolines . Besides moderate to high distribution, low clearance rate (0.3% of canine daily hepatic blood flow) of isoxazolines is another factor that contributes to the prolonged plasma half-life of isoxazolines . Overall, isoxazolines are highly lipid-soluble and are readily absorbed, particularly with food, and have a persistent efficacy.

表3总结了现有异恶唑类药物的药代动力学参数。口服异恶唑啉的生物利用度从8.4%到100%不等，血浆的平均半衰期约为2周，但洛替拉纳的血浆半衰期最长，约为30天。值得注意的是，在异恶唑类中，洛替拉纳的等离子体半衰期最长，积累程度中等。其推荐的口服给药间隔与阿福拉纳和沙罗拉纳相同，为4周(表1)。建议进行延长给药间隔(如8 - 12周)的研究，以探索1个月以上的持续疗效。给动物喂食在洛替拉纳的药代动力学中起着关键作用，尤其是生物利用度，当禁食的犬吃药时，生物利用度从82%下降到24%，禁食的猫吃药时，生物利用度从100%下降到8.4%。因此，强烈建议提供湿的或干的食物，以有效地治疗和预防跳蚤和控制蜱虫。相反，阿福拉纳血浆浓度似乎不受食物的影响，其生物利用度高达74%。异恶唑啉与血浆蛋白结合程度高(99.9%)，表明其清除可能主要在肝脏而不是肾脏。结果表明，在脂肪组织中的平均分布体积(Vss)约为3 L/kg，而在脂肪组织中的平均分布体积(Vss)约为6 L/kg。异恶唑啉除中高分布外，其清除率低(占犬日肝血流的0.3%)是其血浆半衰期延长的另一个原因。总的来说，异恶唑啉脂溶性强，极易被吸收，特别是在食物中，而且具有持久的功效。

 

5  |  ECTOPARASITICIDAL EFFECTS

5.1  |  Ticks

5体外驱虫作用

5.1蜱虫

Tick infestations have been implicated in the transmission of rickettsial diseases, babesiosis, theileriosis, anaplasmosis, Lyme disease, and ehrlichiosis, along with a number of bacterial, viral, and other pathogens . Isoxazolines have been approved by the USA and Canada against multiple tick species as indicated above and have been demonstrated to be effective against additional species experimentally (Table 4), a majority of which are also registered as ectoparasiticides for veterinary use in EU, Australia, and New Zealand.

蜱虫感染与立克次体病、巴贝斯虫病、泰勒虫病、无形体病、莱姆病、埃里希体病以及一些细菌、病毒和其他病原体的传播有关。如前所述，异恶唑啉已被美国和加拿大批准用于防治多种蜱虫，并在实验中证明对其他蜱虫也有效(表4)，其中大多数在欧盟、澳大利亚和新西兰也被注册为兽药外寄生虫杀虫剂。

 

Several efficacy studies have been performed with a number of common tick species (Table 5), including Dermacentor variabilis (American dog ticks, all four products), Ixodes scapularis (deer ticks, all four products), Ixodes Ricinus (Castor bean ticks, all four products), Amblyomma americanum (lone star ticks, all four products), Amblyomma maculatum (Gulf Coast ticks, sarolaner), and R. sanguineus (brown dog ticks, all four products). Variations in efficacy exist among the drugs and the different genera of ticks. While the efficacy within the first 24 h is variable after treatment with the US FDA-approved recommended dose, though by 24 h, most isoxazolines have 100% efficacy against common tick species . Despite a 12-week label claim for fluralaner for the action against black-legged ticks, American dog ticks, and brown dog ticks, results of studies suggest the efficacy declines in the last month of the dosing interval ; care should be taken by veterinarians prescribing the off-label use of isoxazolines to ensure proper coverage based on different geographical areas.

已经对一些常见的蜱种进行了几项功效研究(表5)，包括各种革蜱(美国犬蜱，所有四种产品)、肩突硬蜱(鹿蜱，所有四种产品)、蓖麻硬蜱(蓖麻豆蜱，所有四种产品)、美洲钝眼蜱(孤星蜱，所有四种产品)、斑状钝眼蜱(墨西哥湾蜱，沙罗拉纳)和红扇头蜱(棕色犬蜱，四种产品)。不同种类的蜱虫在药效上存在差异。虽然在接受美国食品和药物管理局(FDA)批准的推荐剂量治疗后，最初24小时内的疗效各不相同，但在24小时内，大多数异噁唑啉对常见蜱类的疗效为100%。但氟雷拉纳的标签声明对黑腿蜱、美国犬蜱和棕色犬蜱有12周的作用，但研究结果表明，在给药间隔的最后一个月，其功效下降;兽医在给异恶唑啉时应谨慎使用，以确保不同地理区域的适当覆盖范围。

 

5.2  |  Fleas

5.2跳蚤

Commonly used insecticides for the treatment of flea infestations typically possess either a rapid onset of action and/or remain effective long enough to be used as a monthly preventive. Isoxazolines are effective against fleas in 2–4 h and exhibit a prolonged duration of action with efficacy rates >95% by hour 8 following infestation and >99% throughout the respective dosing intervals. Isoxazolines prevent oviposition  and have larvicidal and adulticidal activity . However, with administration of minimum dose of isoxazolines, the primary effect is exerted by rapid onset of adulticidal activity prior to oviposition, as the study of Williams et al was conducted at subinsecticidal concentrations. Isoxazolines are effective in reducing flea infestations within a home environment, a critical aspect of breaking the parasite life cycle, and reduce skin lesions associated with fleaallergic dermatitis and pruritus. There is evidence that isoxazolines outperform spinosad, an insect nicotinic receptor agonist with significantly higher portion of dogs with ≥90% reduction in fleas. All four isoxazolines are 100% effective against fleas 24 h after treatment. As with ticks, the killing speed of afoxolaner, fluralaner, and sarolaner decreases toward the end of the dosing interval; though within 24 h following flea reinfestation, efficacy of these three isoxazolines is near 100% (Table 6).

用于治疗跳蚤感染的常用杀虫剂通常具有作用迅速和/或有效时间足够长，可用于每月预防。异恶唑啉在2 - 4小时内对跳蚤有效，并表现出较长的作用时间，在感染后8小时内的有效性为95%，在整个给药间隔内的有效性为99%。异恶唑啉可防止产卵，并具有杀幼虫和杀成虫的活性。然而，由于Williams等人的研究是在亚杀虫浓度下进行的，当给予最小剂量的异恶唑啉时，主要作用是在产卵前迅速起杀成虫作用。异恶唑啉能有效减少家庭环境中的跳蚤感染，这是破坏寄生虫生命周期的一个重要方面，并能减少与跳蚤过敏性皮炎和瘙痒症相关的皮肤损伤。有证据表明，异恶唑啉类药物的效果优于多杀菌素，一种昆虫烟碱受体激动剂，对犬跳蚤减少率显著提高到90%以上。所有4种异恶唑啉类药物治疗24小时后对跳蚤均100%有效。与蜱虫一样，在给药间隔结束时，阿福拉纳、氟雷拉纳和沙罗拉纳的杀灭速度逐渐降低;在复染后24 h内，3种异恶唑啉类药物的效果均接近100%(表6)。

 

5.3  |  Mites

5.3螨虫

In our opinion, the most important future application of isoxazoline ectoparasiticides is in the treatment of mite infestations, including demodicosis and scabies. While not currently approved by the USA and Canada for use against mites, isoxazolines demonstrate high efficacy in the treatment of mites while offering greater ease of application, safety margin for the animal treated, and efficacy, and are registered for treatment of mite infestations in EU, Australia, and New Zealand (Table 1).

我们认为，异恶唑啉体外杀虫剂未来最重要的应用是用于治疗螨虫感染，包括蠕形螨病和疥螨。目前虽然在美国和加拿大没批准治疗螨虫使用,但异噁唑啉展示高疗效，而且使用更容易，为动物治疗提供更好的安全性和有效性,并在欧盟、澳大利亚和新西兰注册治疗螨虫感染(表1)。

 

5.3.1  |  Demodex

5.3.1蠕形螨

Demodicosis is a common form of mange disease in canine patients, occasionally affecting cats. Conventional treatments including amitraz and macrocyclic lactones have been shown variable likelihood of clinical resolution, some may require prolonged treatment course with high probability of adverse effects .

蠕形螨病是一种犬常见的螨虫病，偶尔影响猫。传统的治疗包括双甲脒和大环内酯类药物临床缓解可能性多样化，有些可能需要延长疗程，且伴随副反应可能性增高。

 

All four isoxazolines have shown efficacy in the treatment of generalized demodicosis, with marked reduction of mites as early as day 14 with the sarolaner treatment. Afoxolaner, fluralaner, and sarolaner have been evaluated against weekly topical application of 2.5 mg/kg moxidectin plus 10 mg/kg imidacloprid (Advocate®), which demonstrated 99% reduction of Demodex in 4 weeks, compared with 90–98% efficacy with topical Advocate® treatment. Lotilaner treatment also killed mites 99.9% with monthly applications. While none of isoxazolines is currently labeled for use against demodicosis in the USA or Canada, they represent an excellent improvement in the field of veterinary dermatology.

所有四种异恶唑啉类药物在治疗全身性蠕形螨病中均显示出疗效，沙罗拉纳治疗第14天就能显著减少螨虫。阿福拉纳、氟雷拉纳和沙罗拉纳对比每周外用2.5 mg/kg莫昔克丁加10 mg/kg吡虫啉(Advocate®)进行评估，结果显示4周内蠕形螨减少99%，而外用(Advocate®)治疗的效果为90-98%。每月使用洛替拉纳治疗能杀死99.9%的螨虫。虽然在美国或加拿大，目前还没有一种异恶唑啉被标记为用于治疗蠕形螨病，但它们代表了兽医皮肤病学领域的一个极好的进步。

 

5.3.2  |  Sarcoptes/Notoedres

5.3.2疥螨/背肛螨

Sarcoptic mange is caused by Sarcoptes scabiei var. canis in dogs and Notoedres cati in cats. This condition (scabies) is characterized by intense pruritus with or without secondary bacterial infection and pyoderma. Treatment modalities involve topical and oral medications with variable licensing based on individual country. These treatment options include lime–sulfur dips, amitraz dips, and topical dose of macrocyclic lactones. As with the treatment of demodicosis, these treatment modalities can be risky and cumbersome. All isoxazolines except lotilaner have been studied extensively for the treatment of canine sarcoptic mange. Sarolaner has been demonstrated to be extremely effective within 14 days of dose against nymphs, larvae, and adults, with over 99% efficacy compared with the control groups by week 2 and 100% reduction by week 4. In a field study juxtaposing the efficacy of sarolaner and imidacloprid/moxidectin topical treatments (Advocate®), clear rates were 89% and 100% for sarolaner by days 30 and 60, respectively, and 85% and 96% for imidacloprid/moxidectin combination. Topical and oral fluralaner were evaluated with complete resolution of mite counts, and significant improvement in clinical signs was observed with both dose routes. Compared with sarolaner, the data of the fluralaner study suggest a more rapid resolution of canine sarcoptic mange by achieving 100% efficacy in a month, while sarolaner required 2 months to reach clinical cure with a monthly dosing interval. In addition, a study of six racoon dogs revealed 100% negative skin scraping in 7 days following a single oral dose of fluralaner; parasitological and clinical cure maintained up to 21 days. Afoxolaner, given orally on days 0, 14, 28, and 56, appeared to exhibit a slower speed of killing against Sarcoptes scabiei in dogs, as it necessitated one more month than sarolaner to obtain 99% efficacy.

疥螨病是由犬疥螨和猫背肛螨引起的疾病。这种疾病(疥螨)的特征是伴有或不伴有继发性细菌感染和脓皮病的强烈瘙痒。治疗方式包括根据个别国家的不同许可外用和口服药物。这些治疗方案包括石硫合剂浸泡、双甲脒浸泡和外用大环内酯类药物。与蠕形螨病的治疗一样，这些治疗方式可能是危险和繁琐的。除洛替拉纳外，所有的异恶唑啉类药物已被广泛研究用于治疗犬疥螨病。沙罗拉纳已被证明在14天内对若虫、幼虫和成虫非常有效，与对照组相比，到第2周时有效性超过99%，第4周100%清除。在一项对比沙罗拉纳和外用吡虫啉/莫昔克丁(Advocate)疗效的现场研究中，沙罗拉纳30天和60天的清除率分别为89%和100%，吡虫啉/莫昔克丁合剂治疗的清除率分别为85%和96%。外用和口服氟雷拉纳均可完全清除螨虫，两种剂量途径均可显著改善临床症状。与沙罗拉纳相比，氟雷拉纳研究的数据表明，在一个月内犬疥螨病得到快速缓解，有效率达到100%，而沙罗拉纳需要一个月一次，持续2个月的时间达到临床治愈。此外，一项对6只浣熊的研究表明，单次口服氟雷拉纳后7天内皮肤刮片为100%阴性。寄生虫学和临床治疗维持了21天。口服阿福拉纳在第0、14、28和56天对犬的杀灭速度似乎较慢，因为它比沙罗拉纳多需要一个月才能获得99%的有效性。

 

To our best knowledge, no research evaluating isoxazolines against the parasite of feline scabies (Notoedres cati) has been published.

据我们所知，没有发表异恶唑啉治疗猫疥螨(猫背肛螨)的研究。

 

5.3.3  |  Otodectes

5.3.3耳螨

Otodectes cynotis, an obligate parasite of the external ear canal, is a common cause of otitis externa, particularly in kittens, with zoonotic potential. Current treatment methods involve topicals, both on- and off-label, and off-label oral moxidectin (0.2 mg/kg oral, twice a day for 10 days). Oral sarolaner at the recommended dose of 2 mg/kg yields a 98.2% mite reduction by day 28, followed by a 99.5% reduction by day 60 following a second monthly dose. Afoxolaner has similar efficacy with >98% mite reduction by day 28 following a single 2.5 mg/kg oral dose. Fluralaner is 100% effective against O. cynotis in both dogs and cats by day 28 after treatment in dogs; both oral and topical applications are effective.

犬耳螨是一种专性外耳道寄生虫，是外耳炎的常见病因，尤其是在幼猫上，具有人畜共患病的可能性。目前的治疗方法包括外用，包括标签内和标签外的，以及标签外口服莫昔克丁(0.2 mg/kg口服，每天两次，持续10天)。口服沙罗拉纳，推荐剂量为2 mg/kg, 28天可减少98.2%的螨虫，第二个月使用后的60天可减少99.5%。单次口服剂量2.5 mg/kg阿福拉纳28天也有＞98%螨虫的清除率。在犬治疗后的第28天，氟雷拉纳对犬和猫的犬耳螨都是100%有效的;口服和外用均有效。

 

5.3.4  |  Miscellaneous ectoparasites

5.3.4其他皮肤外寄生虫

In addition to common mites affecting cats and dogs, fluralaner was investigated against Psoroptes cuniculi in naturally infested rabbits. P. cuniculi is a common ear mite in rabbits, causing otitis externa. Rabbits were treated with a one-time 25 mg/kg oral dose of fluralaner, significant mite reduction was seen by day 4; by day 8, mites were present in only one of the 30 treated rabbits and a marked reduction in ear exudate was also observed. Fluralaner was evaluated for the efficacy compared with moxidectin/imidacloprid treatment for infestations of Lynxacarus radovskyi, feline fur mites that are common in Malaysia. Both treatments demonstrated significant efficacy in mite reduction by day 14 of the treatment period, with 100% elimination in both groups by day 28. Based on the bias present in group selection and inconsistencies in data presentation, the main implication taken from this study is the potential for additional application of isoxazolines in the treatment of many different ectoparasites . Other ectoparasites that are susceptible to isoxazolines include Dermanyssus gallinae (poultry red mites), Tetranychus urticae Koch (two-spotted spider mites), Phlebotomus perniciosus (sand flies), Triatoma infestans nymphs (kissing bugs), canine myiasis (maggots), and Caparinia tripilis (one of the common mites infesting African pygmy hedgehogs).

除常见的影响猫和犬的螨虫外，还研究调查了氟雷拉纳治疗自然感染兔的兔痒螨。兔痒螨是兔常见的耳螨，可引起外耳炎。患兔口服一次25 mg/kg氟雷拉纳，第4天螨虫数量明显减少;在第8天，30只治疗兔中，只有一只出现螨虫，耳分泌物也明显减少。对比氟雷拉纳与莫西克丁/吡虫啉治疗马来西亚常见的猫毛螨感染的疗效进行了评估。到第14天，两种治疗方法均有显著的螨虫清除效果，到第28天，两种治疗方法的除螨率均为100%。基于群体选择中的偏倚和数据表述的不一致，本研究的主要含义是异恶唑啉在许多不同体外寄生虫治疗中的额外应用潜力。其他易受异恶唑啉影响的体外寄生虫包括鸡皮刺螨(禽红螨)、斑叶螨(二斑蛛螨)、白蛉(沙蝇)、蝽属幼虫感染(猎蝽)、犬蝇蛆病(蛆)、以及三毛螨(非洲侏儒刺猬常见的螨虫之一)。

 

6  |  SAFETY

6安全性

As mentioned earlier, isoxazolines block glutamate-gated chloride channels, which exist in invertebrates, but not vertebrates. In addition, isoxazolines selectively block invertebrate GABA-gated chloride channels. These modes of action of isoxazolines account for their high margin of safety for use in veterinary species. Safety studies have been performed for all four isoxazoline compounds at a minimum of five times the recommended doses with no apparent adverse effects, except neurological effects observed. Prescription of isoxazolines should be determined in combination with patient medical histories on individual basis. A recent survey conducted in the USA revealed high occurrence of neurological adverse effects on dogs using isoxazolines (13.7% seizures, 15.9% ataxia, and 16.7% shaking as overall rates for afoxolaner, fluralaner, and sarolaner). However, this survey might be non-representative and biased due to potential disadvantages of online electronic questionnaire and owner-observed reactions that may or may not be associated with isoxazoline use, caution should be taken when considering this article as a reference for isoxazoline safety. Limited safety studies have shown that isoxazolines are safe in cats and MDR1-/- collies . Safety in puppies or kittens on afoxolaner, fluralaner, and lotilaner was confirmed with oral or topical dose at 1, 3, or 5X the maximum FDA-approved dose, while mild and self-limiting ataxia and tremors with seizures were observed in 8-week-old puppies treated at elevated doses (3X and 5X the maximum FDA-approved dose) (Table 7). Limited theriogenological data revealed that isoxazoline treatments have no notable impact on reproductive status or semen analysis, but may lead to limb deformity, enlarged heart and spleen, and cleft palate of new-born puppies. It is our opinion that veterinarians should be cautious when prescribing isoxazolines in pregnant and lactating bitches until further safety studies have been conducted.

如前所述，异恶唑啉会阻断谷氨酸门控的氯离子通道，这种通道存在于无脊椎动物而非脊椎动物中。此外，异恶唑啉选择性阻断无脊椎动物GABA门控的氯离子通道。异恶唑啉的这些作用模式说明了它们在兽药中使用的高安全边际。对所有四种异恶唑啉化合物进行了至少5倍于推荐剂量的安全性研究，除观察到的神经系统影响外，没有明显的不良反应。异恶唑啉类药物的处方应结合患病动物个体病史确定。美国最近进行的一项调查显示，使用异恶唑啉的犬的神经系统不良反应发生率很高(阿福拉纳、氟雷拉纳和沙罗拉纳的总发生率为癫痫13.7%、共济失调15.9%和震颤16.7%)。然而，由于在线电子问卷的潜在缺点，以及宠主观察到的可能与异恶唑啉使用有关的反应，本调查可能不具有代表性和偏倚性，因此在考虑将本文作为异恶唑啉安全性的参考时应谨慎。有限的安全性研究表明，异恶唑啉对猫和MDR1-/-柯利犬是安全的。在幼犬或幼猫上，证实了口服或外用剂量为FDA批准的最大剂量的1倍、3倍或5倍的阿福拉纳、氟雷拉纳和洛替拉纳都是安全的，而8周龄的幼犬高剂量(3和5倍FDA最大批准剂量)治疗有较轻自限性共济失调和伴癫痫的震动症状(表7)。有限动物生殖学数据显示,异噁唑啉治疗没有显著影响生殖状态或精液分析,但可能导致肢体畸形、新生儿心脏和脾脏肿大、腭裂。我们的意见是，兽医在给怀孕和哺乳期的母犬开异噁唑啉时应该谨慎，直到进一步的安全性研究进行为止。

 

7  |  CONCLUSIONS

7结论

Isoxazolines are a novel class of ectoparasiticide that has unique characteristics of rapid absorption, prolonged duration, and broad spectrum activity against fleas/insects, ticks, and mites. The advent of isoxazolines may replace the conventional treatment of demodicosis and sarcoptic mange, due to their high efficacy with rapid resolution and few adverse effects. However, caution should be taken for animals with seizures or other neurological disorders (cerebellar ataxia, central vestibular signs, etc.) before prescribing an isoxazoline ectoparasiticide, as it might enhance the occurrence of neurological disturbances.

异恶唑啉是一类新型的体外杀虫剂，具有快速吸收、持续时间长、广谱抗跳蚤/昆虫、蜱虫、螨虫等特性。随着异恶唑啉类药物的出现，其疗效高、消退快、不良反应少，有望取代常规治疗蠕形螨病和疥螨病的方法。然而，对于有癫痫或其他神经系统疾病(小脑共济失调、中枢前庭症状等)的动物，在开异恶唑啉体外杀虫剂前应谨慎，因为它可能会增加神经系统障碍的发生。

 

 

Ryohei

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