国际兽医癫痫工作组共识建议：欧洲犬癫痫的药物治疗

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 By @苏苏苏苏乔

校准 By @宠物神经科医生高健

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，而给予溴制剂的犬只有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]。

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，开始治疗后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。

Fig1

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