國際獸醫(yī)癲癇工作組共識建議：歐洲犬癲癇的藥物治療

Sofie F.M. Bhatti1*, Luisa De Risio2 , Karen Mu?ana3 , Jacques Penderis4 , Veronika M. Stein5 , Andrea Tipold5 , Mette Berendt6 , Robyn G. Farquhar7 , Andrea Fischer8 , Sam Long9 , Wolfgang L?scher10, Paul J.J. Mandigers11, Kaspar Matiasek12, Akos Pakozdy13, Edward E. Patterson14, Simon Platt15, Michael Podell16, Heidrun Potschka17, Clare Rusbridge18,19 and Holger A. Volk20?

翻譯 By?@蘇蘇蘇蘇喬

校準?By @寵物神經(jīng)科醫(yī)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.

苯巴比妥是所有抗癲癇藥物里長期使用歷史最長的獸藥。經(jīng)過幾十年的使用，它已于2009年被批準用于預(yù)防犬全身性癲癇引起的抽搐發(fā)作。苯巴比妥具有良好的藥代動力學(xué)特征，相對安全[2,87,97]。當(dāng)血漿濃度維持在25 - 35 mg/l的治療范圍內(nèi)時，在約60 - 93%的特發(fā)性癲癇犬似乎可以有效降低癲癇發(fā)作頻率[10,31,74,105]。根據(jù)Charalambous等人(2014)[17]的研究，總體上有良好的證據(jù)表明，建議將苯巴比妥作為特發(fā)性癲癇犬的單一治療的抗癲癇藥物。此外，一項比較苯巴比妥與溴制劑(Br)作為犬的一線抗癲癇藥物的隨機臨床試驗證明了苯巴比妥的優(yōu)越療效，其中85%給予苯巴比妥的犬在6個月內(nèi)無抽搐發(fā)作，而給予溴制劑的犬只有52%[10]。該研究表明，與單一治療相比，苯巴比妥的療效更好，可以更好地控制抽搐發(fā)作，副作用更少。

Pharmacokinetics

藥代動力學(xué)

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給藥可以快速吸收（2h內(nèi)），據(jù)報道其生物利用度約為90%[2,87]。犬口服給藥后約4-8小時血清濃度達到峰值[2,97]。據(jù)報道，多次口服給藥后，正常犬的初始消除半衰期為37-73小時[96]。犬的血漿蛋白結(jié)合率約為45%[36]。苯巴比妥可穿透胎盤屏障，可能會致畸。

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.

苯巴比妥主要通過肝微粒體酶代謝，約25%無變化地隨尿液排出。苯巴比妥的吸收、排泄和消除半衰期存在個體差異[2,87,97]。在犬體內(nèi)，苯巴比妥是肝臟細胞色素P450酶活性的有效誘導(dǎo)劑[48]，這會顯著增加肝臟活性氧族的產(chǎn)生，從而增加肝損傷的風(fēng)險[107]。因此，肝功能不全犬禁忌使用苯巴比妥（contraindicated）。隨著時間的推移，肝臟細胞色素P450活性的誘導(dǎo)可導(dǎo)致自身誘導(dǎo)（autoinduction）或加速清除，也稱為代謝耐受（metabolic tolerance），以及內(nèi)源性化合物(如甲狀腺激素)[40,48]。因此，犬長期給藥后，其全身清除率增加，消除半衰期逐漸減短，并在開始治療30-45天后穩(wěn)定[97]。這可能導(dǎo)致血清苯巴比妥濃度降低和治療失敗，因此，監(jiān)測血清苯巴比妥濃度對于長期劑量調(diào)節(jié)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].

苯巴比妥的一種腸外形式可用于肌內(nèi)(IM)或靜脈內(nèi)(IV)給藥。不同國家可獲得不同的苯巴比妥劑型，但應(yīng)強調(diào)的是，肌內(nèi)注射制劑不能用于靜脈注射，反之亦然。對于不能口服藥物的住院病患，靜脈給予苯巴比妥可用于維持治療。苯巴比妥肌內(nèi)注射的藥代動力學(xué)尚未在犬中進行探索，然而，在人類中的研究表明，與口服給藥相比，肌內(nèi)注射給藥后的吸收相似[135]。犬單次靜脈注射后的消除半衰期約為93小時[87]。

Pharmacokinetic interactions

藥代動力學(xué)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，長期服用苯巴比妥會影響其他同時服用的藥物的作用，這些藥物通過細胞色素P450亞族和/或與血漿蛋白[48]結(jié)合而代謝。苯巴比妥可改變藥代動力學(xué)，從而可能降低其他抗癲癇藥物（左乙拉西坦 levetiracetam、唑尼沙胺 zonisamide 和苯二氮卓類 benzodiazepines）以及皮質(zhì)類固醇 corticosteroids、環(huán)孢素 cyclosporine、甲硝唑 metronidazole、伏立康唑 voriconazole、地高辛 digoxin、洋地黃毒苷 digitoxin、苯保泰松/布他酮 phenylbutazone和一些麻醉藥(如硫噴妥 thiopental)的療效[23,33,72,82,130]。由于地西泮 diazepam 是急診（如癲癇持續(xù)狀態(tài)）的一線用藥，在實踐中應(yīng)強調(diào)，在長期使用苯巴比妥治療的犬中，靜脈或直腸給藥劑量應(yīng)加倍（double）[130]。與西咪替丁 cimetidine、奧美拉唑 omeprazole、蘭索拉唑 lansoprazole、氯霉素 chloramphenicol、甲氧芐啶 trimethoprim、氟喹諾酮類 fluoroquinolones、四環(huán)素 tetracyclines、酮康唑 ketoconazole、氟康唑 fluconazole、伊曲康唑 itraconazole、氟西汀 fluoxetine、非爾氨酯 felbamate、托吡酯 topiramate 等抑制肝微粒體細胞色素P450酶的藥物同時用藥時可抑制苯巴比妥代謝，升高血藥濃度，并可導(dǎo)致中毒反應(yīng)[10]。

Common adverse effects

常見的不良反應(yīng)

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數(shù)不良反應(yīng)具有劑量依賴性（dose dependent），發(fā)生在治療開始或增加劑量后的前期，通常在隨后幾周內(nèi)由于藥代動力學(xué)和藥效學(xué)耐受而消失或減少[35,121] (表1)。不良反應(yīng)包括鎮(zhèn)靜、共濟失調(diào)、食欲亢進、多飲和多尿。對于苯巴比妥的不良影響的深入綜述，讀者可以參考綜合的書籍章節(jié)[23,32,91]。

Idiosyncratic adverse effects

特質(zhì)性不良反應(yīng)

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].

這些效應(yīng)在犬中不常見，包括肝毒性[13,22,39,75]、血液學(xué)異常(貧血，和/或血小板減少癥，和/或中性粒細胞減少癥)[51,56])、淺表壞死性松解性皮炎[66]、胰腺炎的潛在風(fēng)險[38,46]、運動障礙[58]、焦慮[58]和低白蛋白血癥[41] (表 1)。停用苯巴比妥后，大多數(shù)這些特殊不良反應(yīng)可能是可逆的。關(guān)于苯巴比妥的特質(zhì)性不良影響的深入綜述，讀者可參考一些書籍的綜合章節(jié)[23,32,91]。

Laboratory changes

實驗室檢查的變化

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].

與犬的長期苯巴比妥給藥相關(guān)的實驗室檢查變化包括血清肝酶活性升高[39,41,75]、膽固醇和甘油三酯濃度[41]升高。一些內(nèi)分泌功能檢測可能發(fā)生改變（甲狀腺和腎上腺功能，垂體-腎上腺軸）[21,41,128]。關(guān)于這些實驗室變化的深入綜述，讀者可以參考一些綜合的書籍章節(jié)[23,32,91]。

Dose and monitoring (Fig. 1)

劑量與監(jiān)測（圖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.

推薦苯巴比妥的初始劑量從2.5-3mg/kg開始，每天兩次口服。隨后，根據(jù)抽搐發(fā)作控制情況、不良反應(yīng)和血藥濃度監(jiān)測，為患病動物個體化調(diào)整口服劑量。

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):

由于苯巴比妥的藥代動力學(xué)在個體間存在較大差異性，因此應(yīng)在治療開始14日后（便于用作未來調(diào)整的基線濃度）或在劑量改變后測定血清濃度。為了評估代謝耐受性，可以在治療開始后6周測量第二次苯巴比妥血清濃度。不同研究對犬血清苯巴比妥濃度監(jiān)測的最佳采血時間提出了不同的建議[23]。通常情況下，血清濃度可在給藥周期的任何時間進行檢查，因為一旦達到穩(wěn)態(tài)，每日給藥間隔導(dǎo)致的苯巴比妥濃度變化就不再具有治療相關(guān)性[62,70]。然而，在接受5 mg/kg BID或更高劑量的犬中，谷值濃度顯著低于非谷值濃度，建議在給藥后同時監(jiān)測血清苯巴比妥濃度，以便對這些犬的結(jié)果進行準確的比較[70]。另一項研究建議對谷值樣本進行血清苯巴比妥濃度監(jiān)測，因為在單個犬[10]中發(fā)現(xiàn)峰值和谷值濃度之間有顯著差異。苯巴比妥在犬的治療作用范圍為15~40 mg/L。然而，作者認為，對于大多數(shù)犬來說，為了達到最佳的抽搐發(fā)作控制效果，血清苯巴比妥濃度一般需要在25~30 mg/L之間。血清濃度超過35 mg/L就會增加肝毒性的風(fēng)險，應(yīng)避免超過這個值[22,75]。在抽搐發(fā)作控制不佳的情況下，必須建議測量血清苯巴比妥濃度來指導(dǎo)增加藥物劑量。劑量調(diào)整可按下式（公式A）計算:

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

× actual PB total daily dosage in mg

新的苯巴比妥日總劑量（mg）=（血清苯巴比妥的理想濃度 / 血清苯巴比妥的實際濃度）× 苯巴比妥的實際日總劑量（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].

對于抽搐發(fā)作得到充分控制的，但血清藥物濃度低于已報道的治療范圍的犬，不需要調(diào)整藥物劑量，因為該血清濃度可能對該個體是足夠的。一般來說，對于患病動物本身，理想的血清抗癲癇藥物濃度應(yīng)該是與抽搐發(fā)作頻率減少>50%或無發(fā)作和無不可耐受的不良反應(yīng)的相關(guān)的最低可能的濃度。

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.

在有叢集性抽搐發(fā)作、癲癇持續(xù)狀態(tài)或高發(fā)作頻率的動物中，苯巴比妥可在24 ~ 48小時內(nèi)以15 ~ 20 mg/kg體重的負荷劑量靜脈注射、肌肉注射或口服，但是需要分多次(3 ~ 5 mg/kg)給藥，以迅速獲得治療性的腦內(nèi)濃度，然后再持續(xù)維持[10]。這種情況下可在給藥后1 - 3天后測定血清苯巴比妥濃度。一些作者會盡快負荷給藥（40 ~ 60分鐘)，并以10 ~ 12 mg/kg體重的負荷劑量靜脈給藥，之后每間隔20分鐘再次推注4 ~ 6 mg/kg體重的劑量。

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.

苯巴比妥治療前，應(yīng)進行全血細胞計數(shù)、生化指標（包括膽固醇和甘油三酯）和膽汁酸刺激試驗，開始治療后3個月后檢查一次，治療期間每6個月檢查一次。在抽搐發(fā)作得到充分控制的情況下，應(yīng)每6個月監(jiān)測一次血清苯巴比妥濃度。如果犬得到緩解或沒有抽搐發(fā)作，建議定期控制每12個月檢查一次。

Fig1

圖1 其他方面均健康的犬的抽搐發(fā)作管理過程中的苯巴比妥治療流程圖。作者建議使用苯巴比妥開始(在優(yōu)先選用苯巴比妥時，但使用后抽搐發(fā)作控制不充分，則加用溴化鉀(圖3))：在患特發(fā)性癲癇的犬中，經(jīng)歷反復(fù)單次全身性抽搐發(fā)作；特發(fā)性癲癇犬發(fā)生叢集性抽搐發(fā)作或癲癇持續(xù)狀態(tài)；患有其他類型癲癇的犬。*關(guān)于療效和耐受性方面充分控制抽搐發(fā)作的標準（見共識建議：犬貓癲癇治療干預(yù)的結(jié)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 . 治療有效性：

a：治療完全成功（即，完全無抽搐發(fā)作，或三次抽搐發(fā)作的時間間隔至少3個月（理想情況下應(yīng)>1年無發(fā)作）

b：治療部分成功（即，抽搐發(fā)作的次數(shù)減少，包括抽搐發(fā)作概率（因藥物作用減少了至少50%的情況出現(xiàn))，抽搐發(fā)作的嚴重程度減輕，或抽搐發(fā)作叢集的頻率下降和/或抽搐持續(xù)狀態(tài)減輕。

2.治療不耐受：即出現(xiàn)嚴重副作用，需停止使用抗癲癇藥物