International Veterinary Epilepsy Task Force consensus proposal: medical treatment of canine epilepsy in Europe

国际兽医癫痫工作组共识建议：欧洲犬癫痫的药物治疗（上）

Sofie F.M. Bhatti1*, Luisa De Risio2 , Karen Muñana3 , Jacques Penderis4 , Veronika M. Stein5 , Andrea Tipold5 , Mette Berendt6 , Robyn G. Farquhar7 , Andrea Fischer8 , Sam Long9 , Wolfgang Löscher10, Paul J.J. Mandigers11, Kaspar Matiasek12, Akos Pakozdy13, Edward E. Patterson14, Simon Platt15, Michael Podell16, Heidrun Potschka17, Clare Rusbridge18,19 and Holger A. Volk20

翻译 @苏苏苏苏乔

审核 @宠物神经科医生高健

Abstract

摘要

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years.Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible.

在欧洲，获得许可的犬用抗癫痫药物(AEDs)的数量在过去数年里有了相当大的增长。但是仍然存在类似的问题，包括：1）什么时候开始治疗，2）最初使用哪种药物最好，3）如果使用初始药物治疗效果不理想，可以建议使用哪种辅助抗癫痫药物,  4）什么时候应考虑改变治疗方法。在本共识建议中，概述了抗癫痫药物治疗的目的，什么时候开始犬癫痫的长期治疗，以及目前有哪些兽医用抗癫痫药物用于犬类。关于药物治疗方案的本共识的建议，1）基于当前已发表的循证文献，2)考虑了欧洲兽药处方级联监管的现行法律框架，3)反映了作者们的经验。本文旨在为犬特发性癫痫的治疗提供一个共识。此外，对于结构性癫痫的管理，除了治疗潜在的原因，如果可能的话，抗癫痫药物是难免需要使用的。

Keywords: Dog, Epileptic seizure, Epilepsy, Treatment

关键字：犬，癫痫性抽搐发作，癫痫，治疗

Background

背景

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature [17], 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible.

在欧洲，获得许可的犬用抗癫痫药物(AEDs)的数量在过去数年里有了相当大的增长。但是仍然存在类似的问题，包括：1）什么时候开始治疗，2）最初使用哪种药物最好，3）如果使用初始药物治疗效果不理想，可以建议使用哪种辅助抗癫痫药物,  4）什么时候应考虑改变治疗方法。在本共识建议中，概述了抗癫痫药物治疗的目的，什么时候开始犬癫痫的长期治疗，以及目前有哪些兽医用抗癫痫药物用于犬类。关于药物治疗方案的本共识的建议，1）基于当前已发表的循证文献，2)考虑了欧洲兽药处方级联监管的现行法律框架，3)反映了作者们的经验。本文旨在为犬特发性癫痫的治疗提供一个共识。此外，对于结构性癫痫的管理，除了治疗潜在的原因，如果可能的话，抗癫痫药物是难免需要使用的。

At present, there is no doubt that the administration of AEDs is the mainstay of therapy. In fact, the term AED is rather inappropriate as the mode of action of most AEDs is to suppress epileptic seizures, not epileptogenesis or the pathophysiological mechanisms of epilepsy. Perhaps, in the future, the term anti-seizure drugs might be more applicable in veterinary neurology, a term that is increasingly used in human epilepsy. Additionally, it is known that epileptic seizure frequency appears to increase over time in a subpopulation of dogs with untreated idiopathic epilepsy, reflecting the need of AED treatment in these patients [63].

目前，毫无疑问，抗癫痫药是主要的治疗手段。事实上，抗癫痫药物（antiepileptic drugs AEDs）这个词并不恰当，因为大多数抗癫痫药物的作用方式是抑制癫痫性抽搐发作，而不是致痫灶或癫痫的病理生理机制。也许，在未来，抗抽搐发作药物（anti-seizure drugs）这个术语可能更适用于兽医神经学，这个术语越来越多地用于人类癫痫。此外，据了解，在未经治疗的特发性癫痫犬亚分类群体中，癫痫性抽搐发作频率似乎随着时间的推移而增加，这反映了这些病患需要抗癫痫药治疗[63]。

In our consensus proposal on classification and terminology we have defined idiopathic epilepsy as a disease in its own right, per se. A genetic origin of idiopathic epilepsy is supported by genetic testing (when available) and a genetic influence is supported by a high breed prevalence (>2 %), genealogical analysis and /or familial accumulation of epileptic individuals. However in the clinical setting idiopathic epilepsy remains most commonly a diagnosis of exclusion following diagnostic investigations for causes of reactive seizures and structural epilepsy.

在关于分类和术语的共识中，我们将特发性癫痫（idiopathic epilepsy）本身定义为一种疾病。特发性癫痫的遗传起源可通过基因检测得到支持(如果有的话)，而基因性影响可通过高品种患病率(> 2%)、族谱分析和/或癫痫性个体的家族积累而得到支持。然而，在临床上，癫痫的原因除了反应性抽搐发作和结构性癫痫，最常见的仍然是特发性癫痫。

Aims of AED treatment

抗癫痫药物治疗的目的

The ideal goal of AED therapy is to balance the ability to eliminate epileptic seizures with the quality of life of the patient. Seizure eradication is often not likely in dogs. More realistic goals are to decrease seizure frequency, duration, severity and the total number of epileptic seizures that occur over a short time span, with no or limited and acceptable AED adverse effects to maximize the dog’s and owner’s quality of life. Clinicians should approach treatment using the following paradigm [23, 76, 91, 92, 120]:

– Decide when to start AED treatment – Choose the most appropriate AED and dosage 

– Know if and when to monitor serum AED concentrations and adjust treatment accordingly 

– Know when to add or change to a different AED 

– Promote pet owner compliance

抗癫痫药物治疗的理想目标是在控制癫痫性抽搐发作和维持病患的生活质量之间取得平衡。在犬，根除抽搐发作（Seizure eradication）通常是不可能的。更现实的目标是减少抽搐发作的频率、持续时间、严重程度和在短时间内发生的癫痫性抽搐发作的总数，没有或很少的以及可接受的抗癫痫药物的相关副作用，以最大限度地提高犬和宠主的生活质量。临床医生应采用以下治疗模式[23,76,91,92,120]:

-决定什么时候开始抗癫痫药物治疗 

-选择最合适的抗癫痫药物及剂量 

-知道是否以及什么时候监测血清抗癫痫药物浓度并相应调整治疗 

-知道什么时候添加或更换另一种的抗癫痫药物 -督促宠物主人遵医嘱

When to recommend maintenance AED treatment?

什么时候建议维持性抗癫痫药物治疗?

Definitive, evidence-based data on when to start AED therapy in dogs based on seizure frequency and type is lacking. As such, extrapolation from human medicine may be possible to provide treatment guidelines. Clinicians should consider the general health of the patient, as well as the owner’s lifestyle, financial limitations, and comfort with the proposed therapeutic regimen. Individualized therapy is paramount for choosing a treatment plan. As a general rule, the authors recommend initiation of longterm treatment in dogs with idiopathic epilepsy when any one of the following criteria is present:

对于各种抽搐发作频率和类型的犬，什么时候开始抗癫痫药物治疗，准确和循证的相关数据并不充分。因此，从人类医学的推断可能能提供一些治疗指南。临床医生应考虑病患的整体健康状况，以及宠主的生活方式、经济限制和对拟议治疗方案的舒适度。个体化治疗对于选择治疗方案至关重要。一般情况下，作者建议患有特发性癫痫的犬出现以下任何一种情况时，应进行长期治疗:

– Interictal period of ≤ 6 months (i.e. 2 or more epileptic seizures within a 6 month period) – Status epilepticus or cluster seizures– The postictal signs are considered especially severe (e.g. aggression, blindness) or last longer than 24 hours– The epileptic seizure frequency and/or duration is increasing and/or seizure severity is deteriorating over 3 interictal periods

-发作间期**≤6个月（**即6个月内癫痫性抽搐发作2次及以上） -癫痫持续状态或丛集性抽搐发作-**发作后期症状被认为特别严重（**例如攻击性、失明）或持续时间超过24小时-癫痫性抽搐发作频率和/或发作时长增加和/或抽搐发作严重程度在3个发作周期内恶化

In humans, the decision regarding when to recommend AED treatment is based on a number of risk factors (e.g. risk of recurrence, seizure type, tolerability, adverse  effects) [42, 115]. In people, clear proof exists that there is no benefit initiating AED treatment after a single unprovoked seizure [42], but there is evidence to support starting treatment after the second seizure [43, 108]. In dogs, long-term seizure management is thought to be most successful when appropriate AED therapy is started early in the course of the disease, especially in dogs with a high seizure density and in dog breeds known to suffer from a severe form of epilepsy [12−14]. A total number of ≥ 10 seizures during the first 6 months of the disease appeared to be correlated with a poor outcome in Australian Shepherds with idiopathic epilepsy [132]. Furthermore, recent evidence exists that seizure density is a crucial risk factor, experiencing cluster seizures, and being male is associated with poor AED response [84].

在人类中，关于什么时候推荐抗癫痫药物治疗的决定是基于许多风险因素来下的（如复发风险、抽搐发作类型、耐受性、不良反应）[42,115]。在人类中，有明确的证据表明，在单次非诱发性抽搐发作后开始抗癫痫药物治疗没有任何益处[42]，但有证据支持在第二次抽搐发作后开始治疗有益[43,108]。在犬类中，如果在发病早期就开始适当的抗癫痫药物治疗，长期的抽搐发作管理被认为是最成功的，特别是对于抽搐发作频率高的犬和已知会有严重癫痫的某些犬的品种[12−14]。发病起初6个月抽搐发作次数≥10次，似乎与澳大利亚牧羊犬特发性癫痫的预后不良存在相关性[132]。此外，最近有证据表明，抽搐发作频率是一个关键的危险因素，经历丛集性抽搐发作，雄性均与抗癫痫药物治疗反应差有关[84]。

A strong correlation exists in epileptic people between a high seizure frequency prior to AED treatment and poor AED response [16, 34, 59]. Historically, this has been attributed to kindling, in which seizure activity leads to intensification of subsequent seizures [117]. However, there is little clinical evidence that kindling plays a role in either dogs [54] or humans [111] with recurrent seizures. In humans, a multifactorial pathogenesis is suggested [14, 52]. Recent epidemiologic data suggest that there are differences in the intrinsic severity of epilepsy among individuals, and these differences influence a patient’s response to medication and long-term outcome. Additionally, evidence for seizure-associated alterations that affect the pharmacodynamics and pharmacokinetics of AEDs have been suggested [99]. Breed-related differences in epilepsy severity have been described in dogs, with a moderate to severe clinical course reported in Australian Shepherds [132], Border Collies [49, 84], Italian Spinoni [24], German Shepherds and Staffordshire Bull Terriers [84], whereas a less severe form of the disease has been described in a different cohort of Collies (mainly rough coated) [77], Labrador Retrievers [7] and Belgian Shepherds [45]. Consequently, genetics may affect the success of treatment and may explain why some breeds are more predisposed to drug resistant epilepsy [3, 77].

癫痫人类病患在抗癫痫药物治疗前抽搐频繁发作与抗癫痫药物反应差之间存在很强的相关性[16,34,59]。在过去，这认为是由于点燃机制（kindling）的原因，抽搐发作活动导致随后的抽搐发作加剧（intensification）[117]。然而，很少有临床证据表明点燃机制在复发性抽搐发作的犬[54]或人[111]中起作用。在人类中，可能存在多因素发病机制[14,52]。最近的流行病学数据表明，个体之间癫痫发作的严重程度存在差异，这些差异影响病患对药物的反应和长期预后。此外，有证据表明抽搐发作相关的改变会影响抗癫痫药物的药效学和药代动力学[99]。犬的癫痫严重程度的品种相关差异已有描述，澳大利亚牧羊犬[132]、边境牧羊犬[49,84]、意大利斯皮诺尼犬[24]、德国牧羊犬和斯塔福德郡牛头梗犬[84]的临床病程为中度至重度，而不同的牧羊犬(主要是粗毛犬)[77]、拉布拉多寻回猎犬[7]和比利时牧羊犬[45]的疾病的严重形式较轻。因此，基因可能会影响治疗的成功可能性，或许可能解释为什么某些品种更容易发生耐药性癫痫（drug resistant epilepsy）[3,77]。

Choice of AED therapy

抗癫痫药物治疗的选择

There are no evidence-based guidelines regarding the choice of AEDs in dogs. When choosing an AED for the management of epilepsy in dogs several factors need to be taken into account (AED-specific factors (e.g. regulatory aspects, safety, tolerability, adverse effects, drug interactions, frequency of administration), dog-related factors (e.g. seizure type, frequency and aetiology, underlying pathologies such as kidney/hepatic/gastrointestinal problems) and owner-related factors (e.g. lifestyle, financial circumstances)) [23]. In the end, however, AED choice is often determined on a case-by-case basis.

目前还没有循证的指南来指导犬如何选择抗癫痫药物。在选择抗癫痫药物治疗犬的癫痫时，需要考虑多个因素(抗癫痫药物特异性因素(如监管方面、安全性、耐受性、不良反应、药物相互作用、给药频率)、与犬相关的因素(如抽搐发作类型、频率和病因、潜在病理如肾/肝/胃肠道问题)以及与宠主相关的因素(如生活方式、经济状况))[23]。然而最终，抗癫痫药物的选择通常视情况而定。

Until recently, primary treatment options for dogs with epilepsy have focused mainly on phenobarbital (PB) and potassium bromide (KBr) due to their long standing history, widespread availability, and low cost. While both AEDs are still widely used in veterinary practice, several newer AEDs approved for use in people are also being used for the management of canine idiopathic epilepsy mainly as add-on treatment. Moreover, since early 2013, imepitoin has been introduced in most European countries for the management of recurrent single generalized epileptic seizures in dogs with idiopathic epilepsy.

直到最近，癫痫犬的主要治疗仍然是使用苯巴比妥（phenobarbital PB）和溴化钾（potassium bromide KBr），它们历史悠久、可用性广而且成本低。这两种抗癫痫药物在兽医临床广泛使用的同时，也有多种获准用于人类的新型抗癫痫药也被用于管理犬的特发性癫痫，主要是作为辅助治疗。此外，自2013年初以来，大多数欧洲国家已引入伊匹妥英（imepitoin），用于治疗特发性癫痫犬的复发性单次全身性癫痫性抽搐发作。

Several AEDs of the older generation approved for humans have been shown to be unsuitable for use in dogs as most have an elimination half-life that is too short to allow convenient dosing by owners, these include phenytoin, carbamazepine, valproic acid, and ethosuximide [119]. Some are even toxic in dogs such as lamotrigine (the metabolite is cardiotoxic) [26, 136] and vigabatrin (associated with neurotoxicity and haemolyticanemia) [113, 131, 138].

一些被批准用于人类的老一代抗癫痫药物已被证明不适合用于犬，因为大多数抗癫痫药物对于犬来说的消除半衰期太短，不能方便地让宠主给药，这些抗癫痫药物包括苯妥英（phenytoin）、卡马西平（carbamazepine）、丙戊酸（valproic acid）和乙琥胺（ethosuximide）[119]。有些甚至对犬有毒，如拉莫三嗪（lamotrigine）（其代谢物具有心脏毒性）[26,136]和氨己烯酸（vigabatrin）（与神经毒性和溶血性贫血有关)[113,131,138]。

Since the 1990s, new AEDs with improved tolerability, fewer side effects and reduced drug interaction potential have been approved for the management of epilepsy in humans. Many of these novel drugs appear to be relatively safe in dogs, these include levetiracetam, zonisamide, felbamate, topiramate, gabapentin, and pregabalin. Pharmacokinetic studies on lacosamide [68] and rufinamide [137] support the potential use of these drugs in dogs, but they have not been evaluated in the clinical setting. Although these newer drugs have gained considerable popularity in the management of canine epilepsy, scientific data on their safety and efficacy are very limited and cost is often prohibitive.

自20世纪90年代以来，耐受性更好、副作用更少、药物相互作用可能性更低的新型抗癫痫药已被批准用于治疗人类癫痫。许多新型药物在犬身上似乎相对安全，包括左乙拉西坦（levetiracetam）、唑尼沙胺（zonisamide）、非尔氨脂（felbamate）、托吡酯（topiramate）、加巴喷丁（gabapentin）和普瑞巴林（pregabalin）。拉科酰胺（lacosamide）[68]和卢非酰胺（rufinamide）[137]的药代动力学研究支持这些药物在犬上的潜在应用，但尚未在临床环境中进行评估。尽管这些新药在治疗犬癫痫方面已经获得了相当大的普及，但关于其安全性和有效性的科学数据非常有限，而且成本往往令人望而却步。

Phenobarbital

苯巴比妥

Efficacy

作用效果

PB has the longest history of chronic use of all AEDs in veterinary medicine. After decades of use, it has been approved in 2009 for the prevention of seizures caused by generalized epilepsy in dogs. PB has a favourable pharmacokinetic profile and is relatively safe [2, 87, 97]. PB seems to be effective in decreasing seizure frequency in approximately 60−93 % of dogs with idiopathic epilepsy when plasma concentrations are maintained within the therapeutic range of 25−35 mg/l [10, 31, 74, 105]. According to Charalambous et al. (2014) [17], there is overall good evidence for recommending the use of PB as a monotherapy AED in dogs with idiopathic epilepsy. Moreover, the superior efficacy of PB was demonstrated in a randomized clinical trial comparing PB to bromide (Br) as first-line AED in dogs, in which 85 % of dogs administered PB became seizure-free for 6 months compared with 52 % of dogs administered Br [10].This study demonstrated a higher efficacy of PB compared to Br as a monotherapy, providing better seizure control and showing fewer side effects.

苯巴比妥是所有抗癫痫药物里长期使用历史最长的兽药。经过几十年的使用，它已于2009年被批准用于预防犬全身性癫痫引起的抽搐发作。苯巴比妥具有良好的药代动力学特征，相对安全[2,87,97]。当血浆浓度维持在25 - 35 mg/l的治疗范围内时，在约60 - 93%的特发性癫痫犬似乎可以有效降低癫痫发作频率[10,31,74,105]。根据Charalambous等人(2014)[17]的研究，总体上有良好的证据表明，建议将苯巴比妥作为特发性癫痫犬的单一治疗的抗癫痫药物。此外，一项比较苯巴比妥与溴制剂(Br)作为犬的一线抗癫痫药物的随机临床试验证明了苯巴比妥的优越疗效，其中85%给予苯巴比妥的犬在6个月内无抽搐发作，而给予Br的犬只有52%[10]。该研究表明，与单一治疗相比，苯巴比妥的疗效更好，可以更好地控制抽搐发作，副作用更少。

Pharmacokinetics

药代动力学

PB is rapidly (within 2h) absorbed after oral administration in dogs, with a reported bioavailability of approximately 90 % [2, 87]. Peak serum concentrations are achieved approximately 4−8h after oral administration in dogs [2, 97]. The initial elimination half-life in normal dogs has been reported to range from 37−73h after multiple oral dosing [96]. Plasma protein binding is approximately 45 % in dogs [36]. PB crosses the placenta and can be teratogenic.

苯巴比妥在犬中口服给药可以快速吸收（2h内），据报道其生物利用度约为90%[2,87]。犬口服给药后约4-8小时血清浓度达到峰值[2,97]。据报道，多次口服给药后，正常犬的初始消除半衰期为37-73小时[96]。犬的血浆蛋白结合率约为45%[36]。苯巴比妥可穿透胎盘屏障，可能会致畸。

PB is metabolized primarily by hepatic microsomal enzymes and approximately 25 % is excreted unchanged in the urine. There is individual variability in PB absorption, excretion and elimination half-life [2, 87, 97]. In dogs, PB is a potent inducer of cytochrome P450 enzyme activity in the liver [48], and this significantly increases hepatic production of reactive oxygen species, thus increasing the risk of hepatic injury [107]. Therefore PB is contraindicated in dogs with hepatic dysfunction. The induction of cytochrome P450 activity in the liver can lead to autoinduction or accelerated clearance of itself over time, also known as metabolic tolerance, as well as endogenous compounds (such as thyroid hormones) [40, 48]. As a result, with chronic PB administration in dogs, its total body clearance increases and elimination half-life decreases progressively which stabilizes between 30−45 days after starting therapy [97]. This can result in reduction of PB serum concentrations and therapeutic failure and therefore, monitoring of serum PB concentrations is very important for dose modulation over time.

苯巴比妥主要通过肝微粒体酶代谢，约25%无变化地随尿液排出。苯巴比妥的吸收、排泄和消除半衰期存在个体差异[2,87,97]。在犬体内，苯巴比妥是肝脏细胞色素P450酶活性的有效诱导剂[48]，这会显著增加肝脏活性氧族的产生，从而增加肝损伤的风险[107]。因此，肝功能不全犬禁忌使用苯巴比妥（contraindicated）。随着时间的推移，肝脏细胞色素P450活性的诱导可导致自身诱导（autoinduction）或加速清除，也称为代谢耐受（metabolic tolerance），以及内源性化合物(如甲状腺激素)[40,48]。因此，犬长期给药后，其全身清除率增加，消除半衰期逐渐减短，并在开始治疗30-45天后稳定[97]。这可能导致血清苯巴比妥浓度降低和治疗失败，因此，监测血清苯巴比妥浓度对于长期剂量调节非常重要。

A parenteral form of PB is available for intramuscular (IM) or intravenous (IV) administration. Different PB formulations are available in different countries, it should be emphasized, however, that IM formulations cannot be used IV and vice versa. Parenteral administration of PB is useful for administering maintenance therapy in hospitalized patients that are unable to take oral medication. The pharmacokinetics of IM PB have not been explored in dogs, however, studies in humans have shown a similar absorption after IM administration compared to oral administration [135]. The elimination half-life in dogs after a single IV dose is approximately 93h [87].

苯巴比妥的一种肠外形式可用于肌内(IM)或静脉内(IV)给药。不同国家可获得不同的苯巴比妥剂型，但应强调的是，肌内注射制剂不能用于静脉注射，反之亦然。对于不能口服药物的住院病患，静脉给予苯巴比妥可用于维持治疗。苯巴比妥肌内注射的药代动力学尚未在犬中进行探索，然而，在人类中的研究表明，与口服给药相比，肌内注射给药后的吸收相似[135]。犬单次静脉注射后的消除半衰期约为93小时[87]。

Pharmacokinetic interactions

药代动力学相互作用

In dogs, chronic PB administration can affect the disposition of other co-administered medications which are metabolized by cytochrome P450 subfamilies and/or bound to plasma proteins [48]. PB can alter the pharmacokinetics and as a consequence may decrease the therapeutic effect of other AEDs (levetiracetam, zonisamide, and benzodiazepines) as well as corticosteroids, cyclosporine, metronidazole, voriconazole, digoxin, digitoxin, phenylbutazone and some anaesthetics (e.g. thiopental) [23, 33,72, 82, 130]. As diazepam is used as first-line medicine for emergency use (e.g. status epilepticus) in practice it should be emphasized to double the IV or rectal dose of diazepam in dogs treated chronically with PB [130]. Concurrent administration of PB and medications that inhibit hepatic microsomal cytochrome P450 enzymes such as cimetidine, omeprazole, lansoprazole, chloramphenicol, trimethoprim, fluoroquinolones, tetracyclines, ketoconazole, fluconazole, itraconazole, fluoxetine, felbamate and topiramate may inhibit PB metabolism, increase serum concentration and can result in toxicity [10].

在犬，长期服用苯巴比妥会影响其他同时服用的药物的作用，这些药物通过细胞色素P450亚族和/或与血浆蛋白[48]结合而代谢。苯巴比妥可改变药代动力学，从而可能降低其他抗癫痫药物（左乙拉西坦 levetiracetam、唑尼沙胺 zonisamide 和苯二氮卓类 benzodiazepines）以及皮质类固醇 corticosteroids、环孢素 cyclosporine、甲硝唑 metronidazole、伏立康唑 voriconazole、地高辛 digoxin、洋地黄毒苷 digitoxin、苯保泰松/布他酮 phenylbutazone和一些麻醉药(如硫喷妥 thiopental)的疗效[23,33,72,82,130]。由于地西泮 diazepam 是急诊（如癫痫持续状态）的一线用药，在实践中应强调，在长期使用苯巴比妥治疗的犬中，静脉或直肠给药剂量应加倍（double）[130]。与西咪替丁 cimetidine、奥美拉唑 omeprazole、兰索拉唑 lansoprazole、氯霉素 chloramphenicol、甲氧苄啶 trimethoprim、氟喹诺酮类 fluoroquinolones、四环素 tetracyclines、酮康唑 ketoconazole、氟康唑 fluconazole、伊曲康唑 itraconazole、氟西汀 fluoxetine、非尔氨酯 felbamate、托吡酯 topiramate 等抑制肝微粒体细胞色素P450酶的药物同时用药时可抑制苯巴比妥代谢，升高血药浓度，并可导致中毒反应[10]。

Common adverse effects

常见的不良反应

Most of the adverse effects due to PB are dose dependent, occur early after treatment initiation or dose increase and generally disappear or decrease in the subsequent weeks due to development of pharmacokinetic and pharmacodynamic tolerance [35, 121] (Table 1). The adverse effects include sedation, ataxia, polyphagia, polydipsia and polyuria. For an in-depth review on the adverse effects of PB, the reader is referred to comprehensive book chapters [23, 32, 91].

苯巴比妥引起的大多数不良反应具有剂量依赖性（dose dependent），发生在治疗开始或增加剂量后的前期，通常在随后几周内由于药代动力学和药效学耐受而消失或减少[35,121] (表1)。不良反应包括镇静、共济失调、食欲亢进、多饮和多尿。对于苯巴比妥的不良影响的深入综述，读者可以参考综合的书籍章节[23,32,91]。

Idiosyncratic adverse effects

特质性不良反应

These effects occur uncommonly in dogs and include hepatotoxicity [13, 22, 39, 75], haematologic abnormalities (anaemia, and/or thrombocytopenia, and/or neutropenia) [51, 56]), superficial necrolytic dermatitis [66], potential risk for pancreatitis [38, 46], dyskinesia [58], anxiety [58], and hypoalbuminaemia [41] (Table 1). Most of these idiosyncratic reactions are potentially reversible with discontinuation of PB. For an in-depth review on the idiosyncratic adverse effects of PB the reader is referred to comprehensive book chapters [23, 32, 91].

这些效应在犬中不常见，包括肝毒性[13,22,39,75]、血液学异常(贫血，和/或血小板减少症，和/或中性粒细胞减少症)[51,56])、浅表坏死性松解性皮炎[66]、胰腺炎的潜在风险[38,46]、运动障碍[58]、焦虑[58]和低白蛋白血症[41] (表 1)。停用苯巴比妥后，大多数这些特殊不良反应可能是可逆的。关于苯巴比妥的特质性不良影响的深入综述，读者可参考一些书籍的综合章节[23,32,91]。

Laboratory changes

实验室检查的变化

Laboratory changes related to chronic PB administration in dogs include elevation in serum liver enzyme activities [39, 41, 75], cholesterol and triglyceride concentrations [41]. Alterations in some endocrine function testing may occur (thyroid and adrenal function, pituitary-adrenal axis) [21, 41, 128]. For an in-depth review on these laboratory changes the reader is referred to comprehensive book chapters [23, 32, 91].

与犬的长期苯巴比妥给药相关的实验室检查变化包括血清肝酶活性升高[39,41,75]、胆固醇和甘油三酯浓度[41]升高。一些内分泌功能检测可能发生改变（甲状腺和肾上腺功能，垂体-肾上腺轴）[21,41,128]。关于这些实验室变化的深入综述，读者可以参考一些综合的书籍章节[23,32,91]。

Table 1 Most common reported adverse effects seen in dogs treated with PB, imepitoin and KBr (rarely reported and/or idiosyncratic adverse effects are indicated in grey）

表1 在接受苯巴比妥、伊匹妥因 imepitoin 和KBr治疗的犬中最常见报告的不良反应（很少报告和/或特殊不良反应用灰色表示）

Dose and monitoring (Fig. 1)

剂量与监测（图1）

The recommended oral starting dose of PB in dogs is 2.5−3 mg/kg BID. Subsequently, the oral dosage is tailored to the individual patient based on seizure control, adverse effects and serum concentration monitoring.

推荐苯巴比妥的初始剂量从2.5-3mg/kg开始，每天两次口服。随后，根据抽搐发作控制情况、不良反应和血药浓度监测，为患病动物个体化调整口服剂量。

Because of considerable variability in the pharmacokinetics of PB among individuals, the serum concentration should be measured 14 days after starting therapy (baseline concentration for future adjustments) or after a change in dose. To evaluate the effect of metabolic tolerance, a second PB serum concentration can be measured 6 weeks after initiation of therapy. Recommendations on optimal timing of blood collection for serum PB concentration monitoring in dogs vary among studies [23]. Generally, serum concentrations can be checked at any time in the dosing cycle as the change in PB concentrations through a daily dosing interval is not therapeutically relevant once steady-state has been achieved [62, 70]. However, in dogs receiving a dose of 5 mg/kg BID or higher, trough concentrations were significantly lower than non-trough concentrations and serum PB concentration monitoring at the same time post-drug dosing was recommended, in order to allow accurate comparison of results in these dogs [70]. Another study recommended performing serum PB concentration monitoring on a trough sample as a significant difference between peak and trough PB concentration was identified in individual dogs [10]. The therapeutic range of PB in serum is 15 mg/l to 40 mg/l in dogs. However, it is the authors’ opinion that in the majority of dogs a serum PB concentration between 25−30 mg/l is required for optimal seizure control. Serum concentrations of more than 35 mg/l are associated with an increased risk of hepatotoxicity  and should be avoided [22, 75]. In case of inadequate seizure control, serum PB concentrations must be used to guide increases in drug dose. Dose adjustments can be calculated according to the following formula (Formula A):

由于苯巴比妥的药代动力学在个体间存在较大差异性，因此应在治疗开始14日后（便于用作未来调整的基线浓度）或在剂量改变后测定血清浓度。为了评估代谢耐受性，可以在治疗开始后6周测量第二次苯巴比妥血清浓度。不同研究对犬血清苯巴比妥浓度监测的最佳采血时间提出了不同的建议[23]。通常情况下，血清浓度可在给药周期的任何时间进行检查，因为一旦达到稳态，每日给药间隔导致的苯巴比妥浓度变化就不再具有治疗相关性[62,70]。然而，在接受5 mg/kg BID或更高剂量的犬中，谷值浓度显著低于非谷值浓度，建议在给药后同时监测血清苯巴比妥浓度，以便对这些犬的结果进行准确的比较[70]。另一项研究建议对谷值样本进行血清苯巴比妥浓度监测，因为在单个犬[10]中发现峰值和谷值浓度之间有显著差异。苯巴比妥在犬的治疗作用范围为15~40 mg/L。然而，作者认为，对于大多数犬来说，为了达到最佳的抽搐发作控制效果，血清苯巴比妥浓度一般需要在25~30 mg/L之间。血清浓度超过35 mg/L就会增加肝毒性的风险，应避免超过这个值[22,75]。在抽搐发作控制不佳的情况下，必须建议测量血清苯巴比妥浓度来指导增加药物剂量。剂量调整可按下式（公式A）计算:

New PB total daily dosage in mg =（desired serum PB concentration/actual serum PB concentration )

× actual PB total daily dosage in mg

新的苯巴比妥日总剂量（mg）=（血清苯巴比妥的理想浓度 / 血清苯巴比妥的实际浓度）× 苯巴比妥的实际日总剂量（mg）

A dog with adequate seizure control, but serum drug concentrations below the reported therapeutic range, does not require alteration of the drug dose, as this serum concentration may be sufficient for that individual. Generally, the desired serum AED concentration for individual patients should be the lowest possible concentration associated with >50 % reduction in seizure frequency or seizure-freedom and absence of intolerable adverse effects [23].

对于抽搐发作得到充分控制的，但血清药物浓度低于已报道的治疗范围的犬，不需要调整药物剂量，因为该血清浓度可能对该个体是足够的。一般来说，对于患病动物本身，理想的血清抗癫痫药物浓度应该是与抽搐发作频率减少>50%或无发作和无不可耐受的不良反应的相关的最低可能的浓度。

In animals with cluster seizures, status epilepticus or high seizure frequency, PB can be administered at a loading dose of 15−20 mg/kg IV, IM or PO divided in multiple doses of 3−5 mg/kg over 24−48h to obtain a therapeutic brain concentration quickly and then sustain it [10]. Serum PB concentrations can be measured 1−3 days after loading. Some authors load as soon as possible (over 40 to 60 min) and start with a loading dose of 10 to 12 mg/kg IV followed by two further boluses of 4 to 6 mg/kg 20 min apart.

在有丛集性抽搐发作、癫痫持续状态或高发作频率的动物中，苯巴比妥可在24 ~ 48小时内以15 ~ 20 mg/kg体重的负荷剂量静脉注射、肌肉注射或口服，但是需要分多次(3 ~ 5 mg/kg)给药，以迅速获得治疗性的脑内浓度，然后再持续维持[10]。这种情况下可在给药后1 - 3天后测定血清苯巴比妥浓度。一些作者会尽快负荷给药（40 ~ 60分钟)，并以10 ~ 12 mg/kg体重的负荷剂量静脉给药，之后每间隔20分钟再次推注4 ~ 6 mg/kg体重的剂量。

Complete blood cell count, biochemical profile (including cholesterol and triglycerides), and bile acid stimulation test should be performed before starting PB treatment and periodically at 3 months and then every 6 months during treatment. In case of adequate seizure control, serum PB concentrations should be monitored every 6 months. If the dog is in remission or has no seizures, a periodical control every 12 months is advised.

苯巴比妥治疗前，应进行全血细胞计数、生化指标（包括胆固醇和甘油三酯）和胆汁酸刺激试验，治疗后3个月后检查一次，治疗期间每6个月检查一次。在抽搐发作得到充分控制的情况下，应每6个月监测一次血清苯巴比妥浓度。如果犬得到缓解或没有抽搐发作，建议定期控制每12个月检查一次。

Fig. 1 PB treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise to start with PB (and add KBr if inadequate seizure control after optimal use of PB (Fig. 3)): in dogs with idiopathic epilepsy experiencing recurrent single generalised epileptic seizures; in dogs with idiopathic epilepsy experiencing cluster seizures or status epilepticus; in dogs with other epilepsy types. *Criteria for (in)adequate seizure control with regard to efficacy and tolerability (see Consensus proposal: Outcome of therapeutic interventions in canine and feline epilepsy [94]).

图1 其他方面均健康的犬的抽搐发作管理过程中的苯巴比妥治疗流程图。作者建议使用苯巴比妥开始(在优先选用苯巴比妥时，但使用后抽搐发作控制不充分，则加用溴化钾(图3))：在患特发性癫痫的犬中，经历反复单次全身性抽搐发作；特发性癫痫犬发生丛集性抽搐发作或癫痫持续状态；患有其他类型癫痫的犬。*关于疗效和耐受性方面充分控制抽搐发作的标准（见共识建议：犬猫癫痫治疗干预的结果[94]）。

1. Treatment efficacious:

   a: Achievement of complete treatment success (i.e. seizure freedom or extension of the interseizure interval to three times the longest pretreatment interseizure interval and for a minimum of three months (ideally > 1 year)

   b: Achievement of partial treatment success (i.e. a reduction in seizure frequency including information on seizure incidence (usually at least 50 % or more reduction defines a drug responder), a reduction in seizure severity, or a reduction in frequency of seizure clusters and/or status epilepticus).

2. Treatment not tolerated i.e. appearance of severe adverse effects necessitating discontinuation of the AED

1 . 治疗有效性：

a：治疗完全成功（即，完全无抽搐发作，或三次抽搐发作的时间间隔至少3个月（理想情况下应>1年无发作）

b：治疗部分成功（即，抽搐发作的次数减少，包括抽搐发作概率（因药物作用减少了至少50%的情况出现)，抽搐发作的严重程度减轻，或抽搐发作丛集的频率下降和/或抽搐持续状态减轻。

2.治疗不耐受：即出现严重副作用，需停止使用抗癫痫药物

To be continued ······