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CiClosporin and the Cat-Current understanding and review of clinical use
环孢素与猫-临床应用现状及综述
作者：Silvia Colombo and Roberta Sartori
翻译：王帆
Practical relevance: Ciclosporin (CsA) is a systemic immunomodulatory drug widely used to treat immune-mediated diseases in humans and veterinary species. CsA was registered for use in cats in the USA and Europe in 2011, and is indicated for the treatment of chronic allergic dermatitis at a recommended daily dose of 7 mg/kg PO.
Audience: This review will be of interest to all veterinarians working with cats, given the wide range of potential applications of CsA and its safety profile. Although the drug is currently only licensed to treat chronic allergic dermatitis in cats, a small number of reports describe its use in non-dermatological conditions.
Evidence base: This article reviews the mechanism of action, pharmacokinetics, drug interactions, adverse effects and clinical use of CsA, both for the licensed indication and for offlabel use in the feline patient. Information presented has been summarised from the existing literature on CsA, with specific interest in studies carried out in cats. For its licensed indication, chronic allergic dermatitis, evidence provided includes randomised, placebo or prednisolone-controlled studies (EBM grade I) and prospective or retrospective open trials.
临床相关性:环孢素(CsA)是一种全身免疫调节即，广泛用于治疗人类和动物的免疫介导性疾病。CsA于2011年在美国和欧洲注册用于猫，并用于治疗慢性过敏性皮肤病，推荐日剂量为7mg /kg口服。
受众:鉴于CsA的广泛潜在应用及其安全性，这篇综述将引起所有与猫打交道的兽医的兴趣。尽管该药物目前仅被许可用于治疗猫的慢性过敏性皮肤病，但少数报告描述了其在非皮肤病中的使用。
证据基础:本文综述了CsA的作用机制、药代动力学、药物相互作用、不良反应和临床应用，包括批准适应症和超说明书使用。所提供的信息总结自现有的关于CsA的文献，并对在猫中进行的研究特别感兴趣。对于其许可的适应症慢性过敏性皮肤病，提供的证据包括随机、安慰剂或泼尼松龙对照研究(EBM级)和前瞻性或回顾性开放试验。
Discovery and development
发现和开发
Ciclosporin (CsA) is a systemic immunomodulatory drug licensed for use in humans and veterinary species. It was registered for use in the cat in the USA and Europe in 2011, and is indicated for the treatment of chronic allergic dermatitis.
环孢素(CsA)是一种被批准用于人类和动物的全身免疫调节药物。它于2011年在美国和欧洲注册用于猫，并用于治疗慢性过敏性皮肤病。
CsA is a cyclic undecapeptide metabolite of the fungus Tolypocladium inflatum Gams and its molecular weight is 1203 Daltons.It was discovered in 1971, during a search for new antibiotics produced by fungi. CsA and other metabolites were initially screened for antifungal activity, but their efficacy was poor.Its immunosuppressive, non-cytotoxic activity was discovered and reported in 1976. The first human trial started at the end of the same year.In the USA, it was approved in 1983 for the prevention of graft rejection following transplantation in human patients, and in 1984 synthetic CsA was produced.
CsA是膨大弯颈霉（Tolypocladium inflatum）的环状非肽代谢物，分子量为1203道尔顿。1971年，人们在寻找由真菌产生的新型抗生素时发现了它。初步筛选了CsA等代谢物的抗真菌活性，但效果较差。其免疫抑制、非细胞毒活性于1976年被发现并报道。同年年底，第一次人体试验开始。在美国，它于1983年被批准用于预防人类患者移植后的移植排斥反应，并于1984年生产了合成CsA。
CsA is fat soluble, extremely hydrophobic, and is poorly absorbed after oral administration. It has been produced in different formulations over time, with the aim of improving its absorption and bioavailability. The first commercially available CsA formulation, only registered for humans, was a solution containing ethanol and corn oil as excipients (Sandimmune; Novartis Pharma). The CsA formulation currently used in humans, dogs and cats is a microemulsion, which enhances oral absorption of the drug.
CsA是脂溶性的，极疏水，口服后吸收不良。随着时间的推移，它以不同的配方生产，目的是提高其吸收和生物利用度。第一个商业上可用的CsA配方，仅注册用于人类，是一种含有乙醇和玉米油作为辅料的溶液(山地明;诺华制药公司)。目前用于人类、犬和猫的CsA配方是一种微乳液，可以增强药物的口服吸收。
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Drug nomenclature Ciclosporin (International Nonproprietary Name [INN] and British Approved name [BAN]) is also called cyclosporine (United States Adopted Name [USAN]), cyclosporin (former BAN) or ciclosporin A.
药物命名法环孢素(国际非专利名称[INN]和英国批准名称[BAN])也被称为环孢素(美国采用名称[USAN])、环孢素(原BAN)或环孢素A。 |
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The oral solution used in the studies described in this review, and the first that was marketed, is a microemulsion containing 100 mg CsA/100 ml (Atoplus per gatti; Elanco Italia Spa) in two size bottles: 5 ml and 17 ml. The excipients are: all-rac-tocopherol (E-307), ethanol anhydrous (E-1510), propylene glycol (E-1520), corn oil-mono-di-triglycerides and macrogolglycerol hydroxystearate.
本综述中描述的研究中使用的口服溶液，也是第一个上市的，是一种微乳液，含有100毫克CsA/100毫升，两种大小的瓶子:5毫升和17毫升。辅料有:全rac -生育酚(E-307)、无水乙醇(E-1510)、丙二醇(E-1520)，玉米油-单二甘油三酯和大甘油羟基硬脂酸酯。 |
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CsA is a metabolite of the fungus Tolypocladium inflatum, discovered during a search for new antibiotics produced by fungi.
CsA是膨大弯颈霉真菌的代谢物，是在寻找真菌产生的新抗生素时发现的。 |
In most studies published before 2011, microemulsified CsA in soft gelatin capsules, registered for the treatment of atopic dermatitis in dogs, was used in feline patients at a daily dose of one 25 mg capsule/cat. In older studies investigating the use of CsA in feline renal transplant recipients, variable dosages were used, according to the different formulations available at the time. Dosages will be specified in this review, unless microemulsified CsA as the oral solution registered for cats was used at the recommended dosage of 7 mg/kg Po q24h.
在2011年之前发表的大多数研究中，用于治疗犬的特应性皮炎的软明胶胶囊中的微乳化CsA被用于患猫，每日剂量为1粒25毫克胶囊/猫。在较早的研究中，调查了在猫肾移植受者中使用CsA的情况，根据当时可用的不同配方，使用了不同的剂量。剂量将在本综述中指定，除非是微乳化CsA作为注册的猫口服液以推荐剂量7mg /kg Po q24h使用。
Mechanism of action
作用机制
CsA is a systemic drug that exerts its effects mainly on the cell-mediated immune system, while humoral immunity is less affected.Its mechanism of action is depicted in Figure 1.CsA suppresses the production of interleukin (IL)-2 and the expression of the IL-2 receptor on T lymphocytes, resulting in inhibition of T cell proliferation and activation. It also inhibits the production of IL-4, IL-5, IL-6, IL-8, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). This leads to a number of different anti-inflammatory effects, including reductions in mast cell degradation, keratinocyte proliferation and cytokine production, as well as decreased tumouricidal and superoxide activity by macrophages. other effects include reduced expression of intercellular adhesion molecule 1 and leukoctye trafficking in endothelial cells, and inhibition of antigenpresenting cell function (Figure 2).
CsA是一种全身性药物，主要作用于细胞免疫系统，对体液免疫的影响较小。其作用机制如图1所示。CsA可抑制T淋巴细胞上白细胞介素(IL)-2的产生和IL-2受体的表达，从而抑制T细胞的增殖和活化。它还能抑制IL-4、IL-5、IL-6、IL-8、IL-13、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、肿瘤坏死因子α (TNF-α)和干扰素γ (IFN-γ)的产生。这导致了许多不同的抗炎作用，包括减少肥大细胞脱颗粒、角质形成细胞增殖和细胞因子产生的减少，以及巨噬细胞杀肿瘤和超氧化物活性的降低。其他作用包括减少内皮细胞中细胞间粘附分子1的表达和白细胞运输，抑制抗原呈递细胞功能(图2)。
Very few studies have been published specifically addressing the effects of CsA in feline species. In the cat, CsA has been shown to suppress in vitro lymphoblast transformation after stimulation with the mitogens concanavalin A and pokeweed within 7 days of administration, with return to a normal response within 7 days after withdrawal.Large individual variations in CsA serum trough levels were observed in both studies.In feline peripheral blood mononuclear cells (PBMCs), CsA suppresses the expression of mRNAs for IL-2, IL-4, IL-10, GM-CSF, IFN-γ and TNF-α, and the number of IL-2 secreting lymphocytes, in a dose-dependent manner.In feline intestinal mucosal biopsies, CsA is able to reduce neutrophil infiltration.
很少有研究专门针对CsA对猫科动物的影响发表。在猫中，CsA已被证明在给药7天内抑制丝裂原伴刀豆球蛋白A和美洲商陆刺激后的体外淋巴细胞转化，并在停药后7天内恢复正常反应。两项研究均观察到CsA血清谷水平存在较大个体差异。在猫外周血单核细胞(PBMC)中，CsA抑制IL-2、IL-4、IL-10、GM-CSF、IFN-γ和TNF-α mRNA的表达以及IL-2分泌淋巴细胞的数量，且呈剂量依赖性。在猫肠粘膜活检中，CsA能够减少中性粒细胞的浸润。
Figure 1 Mechanism of action of CsA. CsA enters the cytoplasm of T cells and binds to the receptor cyclophilin.The drug–receptor complex secondarily binds to calcineurin, inhibiting its action. In the absence of CsA, calcineurin binds to nuclear factor of activated T cells (NF-AT), which in turn enters the nucleus and binds to activator protein 1 (AP-1), a transcription factor. This complex induces the transcription of cytokine genes by the T cell. IL = interleukin; IFN-γ = interferon gamma; TNF-α = tumour necrosis factor alpha; GM-CSF = granulocyte–macrophage colony-stimulating factor
图1 CsA的作用机理。CsA进入T细胞的细胞质并与受体亲环蛋白结合。药物受体复合体继发与钙调磷酸酶结合，抑制其作用。在缺乏CsA的情况下，钙调磷酸酶与活化T细胞的核因子(NF-AT)结合，NF-AT进入细胞核并与转录因子激活蛋白1 (AP-1)结合。该复合物诱导T细胞转录细胞因子基因。IL =白细胞介素;IFN-γ =干扰素γ;TNF-α =肿瘤坏死因子-α;GM-CSF =粒细胞-巨噬细胞集落刺激因子
Figure 2 Cellular targets of CsA. IL = interleukin; GM-CSF = granulocyte–macrophage colony-stimulating factor; TNF-α = tumour necrosis factor alpha; IFN-γ = interferon gamma
图2 CsA的细胞靶点。IL =白细胞介素;GM-CSF =粒细胞-巨噬细胞集落刺激因子;TNF-α =肿瘤坏死因子-α;IFN-γ =干扰素-γ
Pharmacokinetics
药代动力学
After oral administration, microemulsified CsA is absorbed across the intestine by passive diffusion. Absorption is limited by P-glycoproteins in the enterocytes, acting as efflux pumps.After absorption, CsA is widely distributed and stored in the skin and adipose tissue, being a very lipophilic molecule.In humans and dogs, it has been shown that CsA concentrations are higher in the skin than in whole blood or plasma.CsA is metabolised mainly in the liver by enzymes of the cytochrome P450 complex, with minimal metabolism in the kidney and intestine. It is excreted in the bile, with limited excretion in the urine.The pharmacokinetics of microemulsified CsA were studied in six healthy cats after intravenous and oral administration. Bioavailability was 29% after 7 days and 25% after 14 days of oral administration at 3 mg/kg q12h.At the same dosage, peak concentration was reached in 1–2 h and elimination half-life was 8.19 h. Trough plasma levels were extremely variable among the tested cats.
口服后，微乳化CsA通过肠道被动扩散被吸收。吸收受到肠细胞p糖蛋白的限制，p糖蛋白起外排泵的作用。CsA被吸收后广泛分布并储存于皮肤和脂肪组织中，是一种亲脂性很强的分子。研究表明，在人类和犬身上，皮肤中的CsA浓度高于全血或血浆。CsA主要在肝脏中通过细胞色素P450复合物的酶代谢，在肾脏和肠道中代谢最少。它在胆汁中排泄，在尿液中排泄有限。研究了微乳化CsA在6只健康猫体内经静脉和口服给药后的药代动力学。7天后的生物利用度为29%，14天后的生物利用度为25%，口服剂量为3mg /kg，每12小时一次。在相同剂量下，1-2小时内达到峰值浓度，消除半衰期为8.19小时。试验猫的血药谷水平变化很大。
In an attempt to overcome problems with oral administration and absorption, topical ocular administration of an oral solution (Sandimmune) and of CsA in olive oil was studied in cats. Both forms were shown to establish whole blood levels of CsA capable of suppressing in vitro lymphocyte stimulation; and, despite noticing great variability in peak concentrations with both formulations, the authors suggested that topical ocular administration of CsA may be an alternative route when oral administration is not tolerated by the cat.
为了克服口服给药和吸收的问题，在猫身上研究了口服溶液(山地明)和橄榄油中的CsA的局部眼部给药。这两种形式都被证明建立了能够抑制体外淋巴细胞刺激的CsA全血水平;而且，尽管注意到两种剂型的峰值浓度存在很大差异，但作者建议，当猫不能耐受口服给药时，局部眼给药CsA可能是一种替代途径。
Transdermal CsA is poorly absorbed in cats and therapeutic concentrations are not reached with this route of administration.In 2016, an open trial published as an abstract reported successful use of CsA administered subcutaneously at 2.5–5 mg/kg every 24–48 h in 6/11 cats with non-flea, non-food-induced hypersensitivity dermatitis. Two of the cats showed topical injection site reactions.
经皮给药CsA在猫体内吸收不良，这种给药途径无法达到治疗浓度。2016年，一项作为摘要发表的公开试验报告称，6/11只患有非跳蚤、非食物性过敏性皮肤病的猫成功地以每24-48小时2.5-5 mg/kg的剂量皮下注射CsA。其中两只猫出现局部注射部位反应。
CsA is a very lipophilic molecule: concentrations are higher in the skin than in whole blood or plasma.
CsA是一种非常亲脂的分子:其在皮肤中的浓度高于全血或血浆中的浓度。
Therapeutic monitoring
治疗监测
Due to the extreme variability in absorption and metabolism, monitoring the concentrations of CsA in the blood has been recommended. Knowing the blood concentration may help clinicians adjust the dose, in order to maintain ‘effective’ concentrations. Therapeutic monitoring may also be useful to identify cats at a higher risk of adverse effects or opportunistic infections.Monitoring is also suggested in patients treated concurrently with imidazoles (see section on drug interactions). CsA concentration should be evaluated in whole blood rather than plasma, because the drug concentrates within blood cells.Ideally, testing should be carried out after 2 weeks of treatment and, where available, high performance liquid chromatography is a better method than immunoassay for evaluating CsA whole blood concentrations.
由于吸收和代谢的极端可变性，建议监测血液中CsA的浓度。了解血药浓度可以帮助临床医生调整剂量，以维持“有效”浓度。治疗监测也可用于识别不良反应或条件致病性感染风险较高的猫。同时使用咪唑治疗的患者也应进行监测(见药物相互作用一节)。CsA浓度应在全血而不是血浆中评估，因为药物在血细胞中浓缩。理想情况下，检测应在治疗2周后进行，在可行的情况下，高效液相色谱法是评估CsA全血浓度的更好方法。
In older studies using CsA twice daily in feline transplant patients, the recommendation was to adjust the dose in order to maintain the 12 h trough blood levels at 300–500 ng/ml.Trough level is defined as the lowest concentration reached by a drug before the next dose is administered, so if CsA is administered once daily, the blood sample should be taken 24 h after the dose. Since trough plasma levels vary widely between tested cats, it has been suggested that blood levels of CsA 2 h after administration (peak concentration) may be more useful for monitoring both therapeutic drug levels and toxicity; however, therapeutic peak concentrations have not been established.
在较早的研究中，对猫移植患者每天使用两次CsA，建议调整剂量，以维持12小时血药谷水平在300-500 ng/ml。谷水平被定义为药物在下一次给药前达到的最低浓度，因此如果CsA每天给药一次，则应在给药后24小时采血。由于受试猫的血浆谷水平差异很大，因此有人认为，给药后2小时血液中CsA的水平(峰值浓度)可能对监测治疗药物水平和毒性更有用;然而，治疗峰值浓度尚未确定。
Unfortunately, the correlation between clinical efficacy of CsA and trough blood levels is usually poor.Because CsA concentrates in the skin, reaching higher levels compared with blood, the current opinion is that when treating skin diseases with CsA, monitoring trough CsA levels is not particularly useful for evaluating the drug’s effectiveness and such monitoring is not considered mandatory, unless adverse effects are observed.
不幸的是，CsA的临床疗效与血液水平之间的相关性通常很差。由于CsA集中在皮肤中，与血液相比达到更高的水平，目前的观点是，当用CsA治疗皮肤病时，通过CsA水平监测对评估药物的有效性并不是特别有用，除非观察到不良反应，否则这种监测不被认为是强制性的。
An alternative, although not commercially available, method for assessing the effectiveness of CsA involves pharmacodynamic assays, which evaluate the effect of a drug on its target cells. In human medicine, a large number of immunological markers of the immunosuppressive activity of CsA have been studied and validated for pharmacodynamic monitoring.In veterinary medicine, a few studies have investigated the expression of specific cytokines by either PBMCs or lesional skin of dogs treated with CsA, revealing decreased expression of IL-2, IL-4 and IFN-γ. The reduced expression of these biomarkers was very marked with high doses of CsA and still present at the recommended dosage for dogs (5 mg/kg Po q24h), showing that CsA may have immunosuppressive effects even at dosages considered to be low. No studies on pharmacodynamic assays of CsA in the cat have been published yet. However, it is likely that the immunosuppressive effects may be similar to those observed in humans and dogs.
另一种评估CsA有效性的方法，虽然不是市售的，包括药效学分析，评估药物对其靶细胞的作用。在人类医学中，大量CsA免疫抑制活性的免疫学标记物已被研究和验证，用于药效学监测。在兽医学中，一些研究调查了特定细胞因子在PMBC或经CsA处理的犬的病变皮肤中的表达，发现IL-2、IL-4和IFN-γ的表达降低。这些生物标志物的表达减少在高剂量CsA下非常明显，并且在犬的推荐剂量(5mg /kg Po q24h)下仍然存在，这表明即使在被认为是低剂量的CsA也可能具有免疫抑制作用。CsA在猫体内的药效学研究尚未发表。然而，免疫抑制作用可能与在人类和犬身上观察到的相似。
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Current opinion is that when treating skin diseases, monitoring trough CsA levels is not particularly useful for evaluating the drug’s effectiveness.
目前的观点是，在治疗皮肤病时，通过CsA水平监测对评估药物的有效性并不是特别有用。 |
Drug interactions
药物的相互作用
CsA is metabolised by the cytochrome P450 enzymatic system and any drug able to induce or inhibit these enzymes may respectively increase or decrease CsA metabolism, thus decreasing or increasing CsA blood concentration. CsA is also both a substrate for and an inhibitor of P-glycoprotein, which is an efflux pump able to protect the blood–brain barrier from adverse effects of potentially neurotoxic drugs. CsA shows interactions with many drugs: in humans, 853 drugs are reported.The most commonly reported interactions of CsA with other drugs in cats and humans are summarised in Table 1.
CsA通过细胞色素P450酶系统代谢，任何能够诱导或抑制这些酶的药物都可以分别增加或减少CsA的代谢，从而降低或增加CsA血药浓度。CsA也是p -糖蛋白的底物和抑制剂，p -糖蛋白是一种外排泵，能够保护血脑屏障免受潜在神经毒性药物的不良影响。CsA显示出与许多药物的相互作用:在人类中，据报道有853种药物。表1总结了在猫和人类中最常见的CsA与其他药物的相互作用。
Table1: Drugs most commonly reported as interacting with CsA in cats and humans
表1 在猫和人身上，最常报道的药物与CsA相互作用
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药物 |
相互作用 |
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猫中报道 |
克拉霉素
伊曲康唑
酮康唑 |
Inhibition of P450/CYP3A4 enzymes: decreased CsA metabolism, increased blood CsA concentration
抑制P450/CYP3A4酶:降低CsA代谢，增加血CsA浓度 |
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人医报道 |
克拉霉素
红霉素
酮康唑
伊曲康唑
氟康唑
咪康唑
地尔硫卓
戊脉安
尼卡地平
甲泼尼龙
葡萄柚汁 |
Inhibition of P450/CYP3A4 enzymes: decreased CsA metabolism, increased blood CsA concentration
抑制P450/CYP3A4酶:降低CsA代谢，增加血CsA浓度 |
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萘夫西林
利福平
苯巴比妥
苯妥英
卡马西平 |
Upregulation of P450/CYP3A4 enzymes: increased CsA metabolism, decreased blood CsA concentration
P450/CYP3A4酶上调:CsA代谢增加，血中CsA浓度降低 |
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非甾体抗炎药
氨基糖苷类抗生素
依那普利
卡托普利
两性霉素B
美法仑 |
肾毒性/肾衰 |
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头孢菌素
氯霉素
诺氟沙星
磺胺嘧啶
甲氧苄氨嘧啶/磺胺二甲嘧啶
糖皮质激素
圣约翰草
别嘌呤醇
地高辛 |
其他相互作用机制未知 |
Very few studies have been performed to specifically address this issue in feline species.CsA has been shown to interact with both ketoconazole and itraconazole; administration of ketoconazole or itraconazole at 10 mg/kg Po q24h approximately doubles the CsA blood concentration, allowing for a significant reduction of the CsA dose and of the cost of treatment.The interaction with clarithromycin was studied recently. Administration of this antibiotic significantly increased the oral bioavailability of CsA, reducing the CsA dose required to maintain therapeutic levels by 65%.Robson anecdotally reported that concurrent administration with metoclopramide reduced CsA concentrations in 3/8 cats. Co-administration of CsA with macrocyclic lactones does not seem to be associated with neurological adverse effects in cats.
很少有研究专门针对猫科动物的这个问题。CsA已被证明与酮康唑和伊曲康唑相互作用;酮康唑或伊曲康唑以10mg /kg Po q24h给药约使CsA血药浓度增加一倍，从而显著降低CsA剂量和治疗费用。最近对其与克拉霉素的相互作用进行了研究。使用这种抗生素显著增加了CsA的口服生物利用度，使维持治疗水平所需的CsA剂量减少了65%。Robson报道说，与甲氧氯普胺同时服用可以降低3/8只猫的CsA浓度。在猫中，CsA与大环内酯共同给药似乎与神经系统不良反应无关。
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Contraindications
禁忌症
CsA is contraindicated in feline immunodeficiency virus (FIV)- and/or feline leukaemia virus (FeLV)positive cats and if there is a past history of malignant neoplasia. It is also not recommended in diabetic cats. It has not been tested in cats less than 6 months of age and 2.3 kg in weight, or in breeding, pregnant or lactating animals.
猫免疫缺陷病毒(FIV)和/或猫白血病病毒(FeLV)阳性的患猫和既往有恶性肿瘤病史的猫禁用CsA。糖尿病猫也不建议服用。尚未在6个月以下、体重2.3公斤的猫、繁殖动物、怀孕动物或哺乳期动物身上进行试验。 |
Adverse effects
副作用
When using CsA at the recommended daily dose (7 mg/kg Po or, before 2011, 25 mg/cat), the most commonly reported adverse effects have been gastrointestinal (GI).In a study specifically addressing adverse effects in cats treated with CsA, vomiting occurred in 12% of cats and soft stools or diarrhoea in 16% of cats.GI adverse effects are often temporary and many disappear within the first few weeks of treatment. Anecdotally, it has been suggested that metoclopramide 0.3–0.4 mg/kg given orally 20–30 mins before CsA administration, or maropitant 1 mg/kg Po q24h, or freezing the capsule may be used to prevent GI upset.However, metoclopramide in cats may reduce CsA concentration.
当以推荐日剂量(7mg /kg Po或2011年之前的25mg /猫)使用CsA时，最常见的不良反应是胃肠道(GI)。在一项专门针对接受CsA治疗的猫的不良反应的研究中，12%的猫出现呕吐，16%的猫出现软便或腹泻。胃肠道不良反应通常是暂时的，许多在治疗的最初几周内就消失了。有趣的是，有人建议在CsA给药前20-30分钟口服甲氧氯普胺0.3-0.4 mg/kg，或马洛匹坦1 mg/kg Po q24小时，或冷冻胶囊可用于预防胃肠道不适。然而，甲氧氯普胺在猫体内可能会降低CsA浓度。
Anorexia has been reported in 2% of cats in one study and in 10% of cats in another study.Anorexia may be a serious problem in cats, as it can eventually lead to hepatic lipidosis.Weight loss has been described in 5–16% of cats.Some studies reported weight loss at the beginning of CsA therapy, with return to normal weight over the following months after CsA dose reduction.
在一项研究中，2%的猫有厌食症，在另一项研究中，10%的猫有厌食症。厌食症对猫来说可能是一个严重的问题，因为它最终会导致肝脏脂质沉积症。5-16%的猫体重减轻。一些研究报告在CsA治疗开始时体重减轻，在CsA剂量减少后的几个月内体重恢复正常。
Gingival hyperplasia, possibly due to the stimulating effect of CsA on fibroblast proliferation consequent to increased transforming growth factor beta production, has been reported rarely in cats.Recently, systemic CsA has been reported to be a significant risk factor for the development of acute bullous keratopathy in cats.
牙龈增生，可能是由于CsA对成纤维细胞增殖的刺激作用，导致转化生长因子β的产生增加，在猫中很少报道。最近，系统性CsA被报道为猫急性大疱性角膜病变的一个重要危险因素。
other reported adverse effects are polyphagia, polydipsia, hyperactivity, hypertrichosis, weight gain, dental tartar and gingivitis, otitis, inflammatory bowel disease, urinary tract infection, cataract, hyperthyroidism and transient inappropriate urination.However, most of these adverse effects are rare and not likely to be directly caused by CsA.
其他报告的不良反应包括多食、多饮、多毛、体重增加、牙结石和牙龈炎、耳炎、炎性肠病、尿路感染、白内障、甲状腺功能亢进和短暂性排尿不当。然而，大多数不良反应是罕见的，不太可能是由CsA直接引起的。
In experimental studies using CsA at higher doses (up to five times the normal dose), peripheral lymphadenopathy was reported, and death occurred in one cat with a very high trough CsA concentration and bone marrow hypocellularity.In three cats undergoing renal transplantation and given CsA at 5 mg/kg Po q12h, together with prednisone at 0.25 mg/kg Po q12h, haemolytic uraemic syndrome has been described.CsA was deemed responsible for inducing this syndrome in two of these cases.
在使用较高剂量(高达正常剂量的5倍)的CsA的实验研究中，有报告称外周淋巴结肿大，并且在CsA浓度非常高的谷值时，有一只猫死亡和骨髓细胞减少。在3只接受肾移植的猫中，给予CsA 5mg /kg Po q12h，同时给予泼尼松0.25 mg/kg Po q12h，出现了溶血尿毒综合征。在这些病例中，CsA被认为是诱发该综合征的原因。
Haematological concentrations
血液学浓度
In most studies, cats receiving systemic CsA have undergone haematology and biochemistry testing before, during and after the study, in order to identify significant alterations.Relative leukopenia, lymphopenia, neutropenia and eosinopenia, although with values still within normal reference intervals, have all been observed.Biochemistry showed mild increases of total bilirubin, glucose and blood urea nitrogen (BUN) and mild reductions of alanine aminotransferase activity, alkaline phosphatase activity and albumin, but values were also within normal reference intervals.
在大多数研究中，接受全身CsA的猫在研究之前、期间和之后都进行了血液学和生物化学测试，以确定显著的变化。相对白细胞减少、淋巴细胞减少、中性粒细胞减少和嗜酸性粒细胞减少，虽然其值仍在正常参考区间内，但都已观察到。生化指标显示总胆红素、血糖、尿素氮(BUN)轻度升高，谷丙转氨酶活性、碱性磷酸酶活性和白蛋白轻度降低，但均在正常参考区间内。
In experimental studies using CsA at higher doses (up to five times the normal dose), aplastic anaemia, lymphopenia, prolonged activated partial thromboplastin time, reduced total proteins and increased cholesterol, creatinine and BUN were also occasionally reported.
在使用高剂量CsA(高达正常剂量的五倍)的实验研究中，也偶尔报道再生障碍性贫血、淋巴细胞减少、活化部分凝血活酶时间延长、总蛋白减少和胆固醇、肌酐和BUN升高。
Opportunistic infections
条件致病性感染
CsA is an immunosuppressive drug, and opportunistic infections may develop in treated patients. The most commonly reported infection in cats is toxoplasmosis (see box).
CsA是一种免疫抑制药物，治疗后患者可能发生条件致病性感染。猫中最常报告的感染是弓形虫病(见框)。
Feline herpesvirus infection (FHV-1) reactivation has been reported in cats experimentally infected and treated with CsA, methylprednisolone acetate or placebo. In most of the cats showing clinical signs of FHV-1 infection, these were mild and self-limiting; however, one cat with a very high CsA blood concentration developed severe clinical manifestations.Conversely, CsA may have antiviral properties: it has been shown to suppress in vitro FIV production and apoptosis in infected cells, as well as feline infectious peritonitis (FIP) coronavirus replication.
据报道，猫疱疹病毒感染(FHV-1)在实验感染和用CsA、醋酸甲泼尼龙或安慰剂治疗的猫中再次激活。在大多数表现出FHV-1感染临床症状的猫中，这些症状是轻微的和自限性的;然而，一只CsA血药浓度非常高的猫出现了严重的临床表现。相反，CsA可能具有抗病毒特性:它已被证明可以抑制体外感染细胞中FIV的产生和凋亡，以及猫传染性腹膜炎(FIP)冠状病毒的复制。
Urinary tract infections (UTIs) were investigated in 33 cats treated with either CsA or glucocorticoids for more than 3 months and no association between any therapy and UTI could be demonstrated.
对33只接受CsA或糖皮质激素治疗超过3个月的猫进行了尿路感染(UTI)调查，没有发现任何治疗与UTI之间的关联。
Many other infectious diseases in cats receiving CsA have been reported. However, these occurred as single cases and the role of CsA could not be proven with certainty. Moreover, these diseases occurred in cats treated with different dosages of CsA. Reported diseases include Mycobacterium avium complex infection, severe pneumonia caused by Salmonella species,nasal nodular cryptococcosis, dermatophytosis, actinobacillosis, pyelonephritis, retroperitoneal abscess and septicaemia, upper respiratory tract infection, oral abscess, chronic stomatitis, FeLV infection, FIP, fungal pinna dermatitis, septic peritonitis and cholangiohepatitis
在接受CsA治疗的猫中有许多其他传染病的报道。然而，这些都是个案，因此不能肯定地证明CsA的作用。此外，这些疾病发生在不同剂量的CsA治疗的猫。报告的疾病包括鸟分枝杆菌复合体感染、沙门氏菌引起的严重肺炎、鼻结节性隐球菌病、皮肤癣菌病、放线菌病、肾盂肾炎、腹膜后脓肿和败血症、上呼吸道感染、口腔脓肿、慢性口炎、FeLV感染、FIP、真菌性耳廓皮肤病、脓毒性腹膜炎和胆管肝炎
CsA and toxoplamosis
CsA和弓形虫病
Fatal, acute-onset toxoplasmosis was initially reported in three cats undergoing renal transplantation and receiving CsA therapy, followed by reports of three more cats treated with CsA at different dosages and for different diseases.It was unclear whether these cats acquired toxoplasmosis during CsA therapy or the infection reactivated due to the immunosuppressive treatment. As a result, serology for toxoplasmosis before starting immunosuppressive therapy was recommended.
最初在三只接受肾移植和CsA治疗的猫中报告了致命的急性弓形虫病，随后又报告了另外三只接受不同剂量和不同疾病的CsA治疗的猫。目前尚不清楚这些猫是在CsA治疗期间获得弓形虫病，还是由于免疫抑制治疗而重新激活感染。因此，建议在开始免疫抑制治疗前进行弓形虫病血清学检查。
Interestingly, two older papers showed that CsA has antimicrobial properties, particularly anti-Toxoplasma species activity in vitro, and a CsA derivative called SDZ 215-918 successfully inhibited in vitro Toxoplasma gondii replication and invasion.
有趣的是，两篇较早的论文表明，CsA具有抗菌特性，特别是体外抗弓形虫的活性，CsA衍生物SDZ 215-918成功地抑制了弓形虫的体外复制和入侵。
In 2015, Lappin et al conducted a study to evaluate whether CsA at the recommended dose can reactivate T gondii infection in chronically infected cats or aggravate the disease in acutely infected cats. Cats were divided into three groups: group 1 cats received a placebo for 126 days, group 2 cats received a placebo for 84 days followed by CsA for 42 days and group 3 cats were given CsA for 126 days. After successful experimental infection with T gondii, performed on day 42, all cats developed mild and self-limiting GI signs. However, more cats in group 3 also had histological signs of central nervous system and pulmonary involvement and one cat with a very high CsA blood concentration died of systemic toxoplasmosis. Group 2 cats (treated with CsA starting 42 days after infection) did not show reactivation of toxoplasmosis or oocyst shedding. The study confirmed that the real danger is a Toxoplasma species-naive cat acquiring toxoplasmosis during treatment, and that cats with positive IgG titres (chronic infection) appear not to be at risk.Serological testing for toxoplasmosis before starting CsA treatment is not essential but it is currently recommended that cats should be kept indoors, and the feeding of raw meat avoided, to prevent Toxoplasma species infection during treatment. Therapeutic drug monitoring may be useful to identify cats at higher risk of opportunistic infections.
2015年，Lappin等人进行了一项研究，评估了推荐剂量的CsA是否会重新激活慢性感染患猫的弓形虫感染，或加重急性感染猫的弓形虫感染。猫被分为三组:第一组猫服用安慰剂126天，第二组猫服用安慰剂84天，随后服用CsA 42天，第三组猫服用CsA 126天。在第42天成功感染弓形虫实验后，所有猫均出现轻度和自限性GI症状。然而，第三组中更多的猫也有中枢神经系统和肺部患病的组织学症状，一只CsA血药浓度非常高的猫死于系统性弓形虫病。第2组猫(在感染后42天开始接受CsA治疗)没有出现弓形虫病的再激活或卵囊脱落。该研究证实，真正的危险是未接触弓形虫物种的猫在治疗期间感染弓形虫病，而IgG抗体阳性(慢性感染)的猫似乎没有危险。在开始CsA治疗之前对弓形虫病进行血清学检测并不必要，但目前建议应将猫饲养在室内，避免饲喂生肉，以防止治疗期间感染弓形虫。治疗药物监测可能有助于识别条件致病性感染风险较高的猫。
Serology testing for toxoplasmosis is not essential, but might be helpful as seronegative cats may require more careful management to prevent infection during treatment.
弓形虫病的血清学检测不是必需的，但可能会有所帮助，因为血清阴性的猫可能需要更仔细的管理，以防止治疗期间感染。
Malignant neoplasia
恶性肿瘤
The development of neoplasia has been reported in cats treated with CsA. The first report described a cat, immunosuppressed with CsA at 7.5 mg/kg q12h and prednisolone at an initial dosage of 2 mg/kg q24h, which developed FeLV-associated lymphosarcoma 6 months after transplantation surgery.Two retrospective studies on feline transplant patients, treated with combinations of CsA and prednisolone at various dosages, were subsequently published: the first study reported malignant neoplasia in 9/95 (9.5%) cats, while the second reported malignant neoplasia in 11/45 (24%) patients.Types of malignant tumours included GI or multicentric lymphoma, bronchogenic adenocarcinoma, hepatic adenocarcinoma, gastric or intestinal adenocarcinoma, tonsillar or pharyngeal squamous cell carcinoma, pharyngeal plasmacytoma, transitional cell carcinoma and unspecified malignant round-cell neoplasia.The authors observed that transplanted cats had more than six times higher odds of developing malignant neoplasia compared with control cats, but the specific role of CsA remains undetermined.Several human studies have also confirmed an increased incidence of post-transplant malignant neoplasia; however, no increased risk could be demonstrated when patients were immunosuppressed with CsA compared with azathioprine.
在接受CsA治疗的猫中有肿瘤发生的报道。第一份报告描述了一只猫，在移植手术后6个月，用7.5 mg/kg CsA和初始剂量2 mg/kg泼尼松龙(每12小时1次)进行免疫抑制，发生了FeLV相关淋巴肉瘤。随后发表了两项关于猫移植患者的回顾性研究，这些患者使用不同剂量的CsA和泼尼松龙进行联合治疗:第一项研究报告了9/95(9.5%)的猫发生了恶性肿瘤，而第二项研究报告了11/45(24%)的患者发生了恶性肿瘤。恶性肿瘤类型包括胃肠道或多中心淋巴瘤、支气管腺癌、肝腺癌、胃或肠腺癌、扁桃体或咽部鳞状细胞癌、咽部浆细胞瘤、移行细胞癌和未特指恶性圆形细胞瘤。作者观察到，与对照猫相比，移植猫发生恶性肿瘤的几率高出6倍以上，但CsA的具体作用仍未确定。几项人体研究也证实移植后恶性肿瘤的发病率增加;然而，与硫唑嘌呤相比，当患者接受CsA免疫抑制时，未显示风险增加。
In cats treated with CsA at the recommended dose for allergic or immune-mediated diseases, malignant neoplasia appears to be a rare occurrence.
在接受推荐剂量的CsA治疗过敏症或免疫介导性疾病的猫中，恶性肿瘤似乎很少发生。
Vaccinations
免疫
A single study evaluated the effectiveness of vaccinations in cats treated with CsA.Cats were given CsA at a very high dosage (24 mg/kg Po q24h) for 56 days and compared with placebo-treated cats. All cats had been previously vaccinated against calicivirus (FCV), FHV-1, feline parvovirus (FPV), FeLV and rabies, and were given a booster of the same vaccines 4 weeks after initiation of CsA administration. The booster vaccinations were successful in all treatment and placebo group cats. However, a novel vaccination for FIV given at the same time as the boosters did not induce adequate protection in CsA-treated cats. This suggests that booster vaccinations are effective in cats on CsA therapy, but primary immune responses may be impaired. Vaccination with live vaccines is not recommended during CsA therapy.
一项单独的研究评估了对患有CsA的猫接种疫苗的有效性。猫被给予非常高剂量的CsA (24 mg/kg Po q24h)，持续56天，并与安慰剂治疗的猫进行比较。所有猫之前都接种过杯状病毒(FCV)、FHV-1、猫细小病毒(FPV)、FeLV和狂犬病疫苗，并在开始注射CsA后4周接种了相同疫苗的加强剂。在所有治疗组和安慰剂组的猫中，加强疫苗接种都是成功的。然而，与增强剂同时接种的新型FIV疫苗并没有在接受CsA治疗的猫中引起足够的保护。这表明加强疫苗接种对接受CsA治疗的猫有效，但原发性免疫反应可能受损。在CsA治疗期间不建议接种活疫苗。
Clinical uses
临床应用
CsA is licensed only for the treatment of chronic allergic dermatitis in cats, and all other uses mentioned in this review are offlabel. The recommended dosing for CsA is shown on the left. In some of the studies using CsA off-label, the drug was administered at a different dose and this will be noted where relevant. CsA can be given to cats either mixed with a small amount of food or directly into the mouth.
CsA仅被许可用于治疗猫的慢性过敏性皮肤病，本综述中提到的所有其他用途都是未经核准的。CsA的推荐剂量如图所示。在一些使用标签外CsA的研究中，以不同的剂量给药，这将在相关的地方注明。CsA既可以与少量食物混合，也可以直接喂给猫。
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CsA dosing in cats
猫的CsA剂量
~ 7 mg/kg PO q24h until resolution of clinical signs < Then tapered to q48h or, when possible, to twice weekly administration
~ 7 mg/kg PO，每24小时给药，直到临床症状消退，然后逐渐减少到每48小时给药，或者如果可能，每周给药两次 |
At present, recommended pretreatment examinations include complete blood count, biochemistry panel, urinalysis and serology for FeLV and FIV.Serology testing for toxoplasmosis is not essential, but might be helpful as seronegative cats may require more careful management to prevent infection during treatment. Any complicating infection should be treated before commencing CsA administration.
目前，推荐的治疗前检查包括全血细胞计数、生化检查、尿液分析以及FeLV和FIV的血清学检查。弓形虫病的血清学检测不是必需的，但可能会有所帮助，因为血清阴性的猫可能需要更仔细的管理，以防止治疗期间感染。任何并发症感染应在开始CsA给药前进行治疗。
During CsA treatment, physical examination, body weight check, haematology and biochemistry should be performed every 6 months.
CsA治疗期间，每6个月进行一次体格检查、体重检查、血液学和生化检查。
Chronic allergic dermatitis
慢性过敏性皮肤病
Many studies have reported on the effectiveness of CsA in chronic allergic dermatitis (Figure 3), and these are summarised in Table 2. CsA treatment was also used to validate systems for scoring the severity of lesions in allergic cats.
许多研究报道了CsA治疗慢性过敏性皮肤病的有效性(图3)，表2总结了这些研究结果。CsA治疗也被用于验证过敏猫的病变严重程度评分系统。
Figure 3 Feline atopic syndrome. (a) Generalised self-induced alopecia and (b) 1 month after initiation of CsA therapy
图3猫特应性综合征。(a)全身性自损性脱毛(b)开始CsA治疗后1个月
Pemphigus complex
天疱疮复合体
The first report of the use of CsA in cats for the treatment of pemphigus foliaceus (PF) (one cat) and pemphigus erythematosus (PE) (one cat) at 15 mg/kg Po q24h was published in 1989.The PF cat showed a partial and temporary response, while the PE cat showed complete resolution maintained with continuation of CsA.A retrospective study in 2012 evaluated CsA in 15 cats with PF, both as an adjuvant and sole drug, in comparison with chlorambucil. All the cats treated with CsA at 5 mg/kg Po q24h were eventually maintained on CsA only and glucocorticoids were either not used from the beginning or discontinued.In the chlorambucil group, only 1/6 cats could be weaned off glucocorticoids.CsA in feline PF (Figure 4) appears to be a promising drug; however, a controlled, prospective study should be conducted to confirm its effectiveness.
1989年，首次报道了在猫中使用CsA治疗落叶型天疱疮(PF)(1只猫)和红斑性天疱疮(PE)(1只猫)，剂量为15mg /kg Po q24h。PF猫表现出部分和暂时的反应，而持续CsA后PE猫表现出完全消退。2012年的一项回顾性研究评估了15只患有PF的猫的CsA治疗，作为辅助药物和单独药物，与苯丁酸氮芥进行比较。所有以5mg /kg Po q24h剂量给予CsA治疗的猫最终仅维持CsA，从一开始就不使用糖皮质激素或停止使用。在苯丁酸氮芥组中，只有1/6的猫能够戒掉糖皮质激素。CsA在猫PF中的应用(图4)似乎是一种很有前景的药物;然而，需要一项对照的前瞻性研究来证实其有效性。
Figure 4 Feline pemphigus foliaceus. (a) Multifocal crusting covering small erosions on the pinna.(b) Caseous material in the claw fold
图4猫落叶型天疱疮。(a)耳廓上多灶性结痂，覆盖小糜烂病灶。(b)爪褶中的干酪质物质
Miscellaneous skin diseases
其他皮肤病
Many different feline dermatological immunemediated diseases have been treated with CsA off-label and with various doses and protocols. However, this has been described only in single cases or small groups of patients and the results must be viewed with caution.Diseases successfully treated or controlled with CsA include pseudopelade, feline urticaria pigmentosa (Figure 5), idiopathic facial dermatitis of Persian cats, granulomatous folliculitis and furunculosis, sebaceous adenitis, feline lymphocytic mural folliculitis, exfoliative dermatitis not associated with thymoma, an atypical form of feline eosinophilic dermatosis (Figure 6), possibly of genetic origin, and feline plasma cell pododermatitis.
许多不同的猫皮肤病免疫介导的疾病已经用CsA标签外用药和不同的剂量和方案治疗。然而，这种情况仅在单个病例或一小群患者中描述过，因此必须谨慎看待结果。CsA成功治疗或控制的疾病包括假性斑秃、猫的色素性荨麻疹(图5)、波斯猫的特发性面部皮肤病、肉芽肿性毛囊炎和疖病、皮脂腺炎、猫的淋巴细胞性毛囊壁毛囊炎、非胸腺瘤相关表皮剥脱性皮肤病、猫的一种非典型嗜酸性皮肤病(图6)(可能是遗传原因)和猫的浆细胞足皮炎。
Figure 5 Feline urticaria pigmentosa. Note the linear distribution of the lesions
图5猫色素性荨麻疹。注意病灶的线性分布
Figure 6 Feline pedal eosinophilic dermatosis
图6猫足部嗜酸性皮肤病
Transplants
移植
CsA has been used to prevent organ rejection in feline transplant patients for more than 25 years.In an experimental study using the gracilis musculocutaneous flap as an allograft, six cats were treated with CsA (trough whole blood levels 750 ng/ml for 70 days, then 500 ng/ml for 30 days) in combination with prednisolone at 0.5 mg/kg Po q24h, while six other cats were left untreated. In the treated cats, the flaps survived for more than 100 days while the grafts of the untreated cats were rejected within 2 weeks.
25年来，CsA一直用于预防猫移植患者的器官排斥反应。在一项使用股薄肌皮瓣作为同种异体移植物的实验研究中，6只猫接受CsA(全血水平750 ng/ml，持续70天，然后500 ng/ml，持续30天)联合泼尼松龙0.5 mg/kg Po q24h治疗，而其他6只猫不接受治疗。在接受治疗的猫中，皮瓣存活超过100天，而未接受治疗的猫的移植物在2周内出现排斥反应。
The first large case series of renal transplants was published in 1997.Immunosuppressive treatment protocols in this series were based on administration of either CsA at 7.5 mg/kg Po q12h or microemulsified CsA at 3 mg/kg Po q12h, always in association with prednisolone at 0.125–0.25 mg/kg Po q12h. Seventy-one percent of the cats survived until discharge from the veterinary hospital. Eight cats died within a year of immunosuppression-related causes such as infectious or neoplastic diseases. In a second case series, cats were treated with CsA at doses able to maintain target whole blood trough levels at 300–500 ng/ml and prednisolone at 0.25 mg/kg Po q12h; 77.5% of cats survived until discharge, with 65% of cats alive 6 months postoperatively.
1997年发表了第一个大型肾移植病例系列。本系列的免疫抑制治疗方案基于给药CsA (7.5 mg/kg Po q12h)或微乳化CsA (3 mg/kg Po q12h)，总是联合泼尼松龙(0.125-0.25 mg/kg Po q12h)使用。71%的猫存活到从兽医院出院。8只猫在一年内死于免疫抑制相关的原因，如感染性或肿瘤性疾病。在第二个病例系列中，猫接受CsA治疗，其剂量能够维持目标全血谷水平300-500 ng/ml，泼尼松龙剂量为0.25 mg/kg Po q12h;77.5%的猫存活至出院，65%的猫在术后6个月存活。
Haematological diseases
血液学疾病
Treatment with CsA and prednisolone of severe, non-regenerative anaemia due to pure red blood cell aplasia of autoimmune origin was reported in a young cat in 1998.After this case report, three retrospective studies on pure red blood cell aplasia supported the use of CsA (5–20 mg/kg Po q24h) combined with various immunosuppressive drugs (prednisolone 3–4 mg/kg Po q24h, methylprednisolone 2 mg/kg Po q24h, dexamethasone 0.6–0.8 mg/kg q24h or recombinant human erythropoietin 150 U/kg SC three times weekly) to treat this rare condition. Most cats required long-term immunosuppressive treatment to maintain the disease in remission.
1998年报道了用CsA和泼尼松龙治疗自身免疫性单纯红细胞发育不全引起的严重非再生贫血。在此病例报告之后，三个关于纯红细胞发育不全的回顾性研究支持使用CsA (5-20 mg/kg Po q24h)联合各种免疫抑制药物(泼尼松龙3-4 mg/kg Po q24h、甲基泼尼松龙2 mg/kg Po q24h、地塞米松3.6 - 0.8 mg/kg q24h或重组人促红细胞生成素150 U/kg SC，每周3次)治疗这种罕见的疾病。大多数猫需要长期的免疫抑制治疗来维持疾病的缓解。
Two single case reports described the use of CsA in combination with immunosuppressive drugs at similar dosages to treat idiopathic, possibly immune-mediated, thrombocytopenia and immune-mediated granulocytopenia associated with thymoma.
两个单独的病例报告描述了使用CsA联合免疫抑制药物以相似的剂量治疗特发性，可能是免疫介导的，血小板减少症和免疫介导的粒细胞减少症与胸腺瘤相关。
Feline stomatitis
猫口炎
CsA has been reported to be effective in feline gingivostomatitis.A randomised, double blinded, placebo-controlled clinical trial of CsA in cats with chronic refractory stomatitis confirmed CsA efficacy at 2.5 mg/kg Po q12h, with a mean improvement of 52.7% after 6 weeks in the treated group compared with 12.2% in the placebo group.
据报道，CsA对猫的龈口炎有效。一项随机、双盲、安慰剂对照的慢性难治性口炎患猫CsA临床试验证实，服用2.5 mg/kg Po q12h的CsA有效，治疗组6周后平均改善52.7%，而安慰剂组为12.2%。
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CsA has been used to prevent organ rejection in feline transplant patients for more than 25 years.
25年来，CsA一直用于预防猫移植患者的器官排斥反应。 |
Feline asthma
猫哮喘
Information on the use of CsA to treat feline asthma is scarce and contradictory. In one experimental study, CsA (trough levels between 500 and 850 ng/ml) given to Ascaris suum-experimentally sensitised cats prior to antigen challenge was able to inhibit airway hyper-responsiveness, IL-2 production in PBMCs, increase of eosinophils in bronchoalveolar lavage fluid and airway remodelling.However, a second study showed that CsA administration did not inhibit early phase bronchoconstriction and did not inhibit mast cell degranulation within airway smooth muscle occurring after antigen stimulation in A suum-experimentally sensitised cats.A single case report described the clinical use of CsA at 4 mg/kg Po q24h in a 15-year-old cat suffering from feline asthma and concurrently affected by diabetes mellitus and congestive heart failure.
关于使用CsA治疗猫哮喘的信息是稀缺和矛盾的。在一项实验研究中，抗原攻击前给予蛔虫实验致敏猫CsA(最低水平在500至850 ng/ml之间)能够抑制气道高反应性、PBMC中IL-2的产生、支气管肺泡灌洗液中嗜酸性粒细胞的增加和气道重塑。然而，另一项研究表明，在一种经实验致敏的猫中，CsA给药不抑制早期支气管收缩，也不抑制抗原刺激后气道平滑肌内肥大细胞脱颗粒。一个病例报告描述了在一只患有猫哮喘并同时患有糖尿病和充血性心力衰竭的15岁猫的临床应用4 mg/kg Po q24h的CsA。
Miscellaneous immune-mediated diseases
其他免疫介导性疾病
one case report described treatment with CsA at 25 mg/cat q24h, associated with dexamethasone for the first month only, in an FIVand FeLV-positive cat affected by chronic progressive polyarthritis.only anecdotal reports are currently available on the use of CsA in the treatment of feline inflammatory bowel disease.
一个病例报告描述了在一只患有慢性进行性多发性关节炎的FIV和Felv阳性猫中，25 mg/猫q24h的CsA治疗，仅在第一个月与地塞米松联用。目前关于使用CsA治疗猫炎性肠病的报道只有轶事报道。
Prevention of adverse reactions to drugs
预防药物副反应
The use of CsA to control acute carrier-induced hypersensitivity reactions due to the chemotherapeutic agent docetaxel has been reported in cats with various neoplastic diseases.
使用CsA控制化疗药物多西他赛引起的急性载体诱导的超敏反应已在患有各种肿瘤疾病的猫中报道。
Key point
重点
<CsA is a calcineurin inhibitor and very effective in the treatment of allergic dermatitis in cats. It has also been used to manage a variety of immune-mediated diseases in feline species, often with very promising results, although prospective controlled studies are lacking for most diseases.
< CsA is safe: the most commonly reported adverse effect is GI upset, which is often temporary and self-resolving.Being an immunosuppressive drug, CsA may increase susceptibility to opportunistic infections and neoplasia; however, this appears to be rare when the drug is used at recommended doses.
< Cats should be tested for FIV and FeLV before initiating treatment. Owners should be instructed to keep their cat indoors and not to feed raw meat to prevent toxoplasmosis in seronegative cases.
< Routine booster vaccinations can be given to cats on CsA, and have been shown to induce a protective antibody response.
< CsA absorption is variable and this is reflected in CsA blood concentrations, which do not correlate with the clinical response, at least in dermatological patients.
< CsA blood level determination is not considered mandatory, but it may be useful to identify cats at higher risk of opportunistic infections.
< Caution should be used when the concurrent use of CsA with other drugs is required, due to its numerous pharmacological interactions.
<CsA是一种钙调磷酸酶抑制剂，对猫的过敏性皮肤病治疗非常有效。它也被用于管理各种猫科动物的免疫介导疾病，通常具有非常有希望的结果，但缺乏对大多数疾病的前瞻性对照研究。
< CsA是安全的:最常见的不良反应是胃肠道紊乱，通常是暂时的，可自行消退。作为一种免疫抑制药物，CsA可能增加机会性感染和肿瘤的易感性;然而，当药物以推荐剂量使用时，这种情况似乎很少见。
<猫在开始治疗前应检测FIV和FeLV。应指示宠主将猫饲养在室内，并不要喂食生肉，以防止血清呈阴性的猫感染弓形虫病。
<可以给服用CsA患猫进行常规加强疫苗接种，并已被证明可诱导保护性抗体反应。
< CsA吸收是可变的，这反映在CsA血药浓度上，这与临床反应无关，至少在皮肤病患者中如此。
<血中CsA水平的测定不是强制性的，但它可能有助于识别条件致病性感染风险较高的猫。
<当需要与其他药物同时使用CsA时，应谨慎使用，因为CsA有许多药理相互作用。
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发表于 2024-5-13 22:30:04
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