國(guó)際獸醫(yī)癲癇工作組共識(shí)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

校正 By @寵物神經(jīng)科醫(yī)生高健??

左乙拉西坦

So far, three studies evaluated the efficacy of levetiracetam as an adjunct to other AEDs [79, 114, 127]. In all these studies, the majority of the dogs were treated successfully by oral levetiracetam as adjunct AED. The use of oral levetiracetam was evaluated in an open-label study and a response rate of 57 % was reported in dogs with drug resistant epilepsy [127]. In a recent randomized placebo-controlled study by Mu?ana et al. (2012) [79], the use of levetiracetam was evaluated in dogs with drug resistant epilepsy. A significant decrease in seizure frequency was reported compared with baseline, however, no difference was detected in seizure frequency when levetiractam was compared with placebo. However, the divergence in group size and the small sample size (due to the high dropout rate) may have contributed to this result. Nevertheless, a trend towards a decrease in seizure frequency and increase in responder rate during levetiracetam administration compared to placebo warrants further evaluation in a larger scale study. According to the study of Charalambous et al., (2014) [17], there is a fair evidence for recommending the use of levetiracetam as an adjunct AED. Recently, a retrospective study provided further evidence that administering levetiracetam as an adjunct AED is well tolerated, and suppresses epileptic seizures significantly in dogs with idiopathic epilepsy [83]. The authors also confirmed that if seizure frequency increases, an extra AED may be beneficial and they added the possibility of administering levetiracetam as pulse treatment for cluster seizures。

到目前為止，有3項(xiàng)研究評(píng)估了左乙拉西坦（levetiracetam）作為其他抗癲癇藥物的輔助用藥的療效[79,114,127]。在所有這些研究中，大多數(shù)犬通過(guò)口服左乙拉西坦作為輔助抗癲癇物而治療成功。一項(xiàng)開(kāi)放性研究對(duì)口服左乙拉西坦的使用進(jìn)行了評(píng)估，據(jù)報(bào)道，對(duì)耐藥癲癇犬的有效率為57%[127]。最近，Mu?ana等人（2012年）[79]進(jìn)行了一項(xiàng)隨機(jī)安慰劑對(duì)照研究，評(píng)估了左乙拉西坦在耐藥癲癇犬中的應(yīng)用。據(jù)報(bào)道，與基線相比，抽搐發(fā)作頻率顯著降低。但與安慰劑相比，左乙拉西坦組抽搐發(fā)作頻率方面沒(méi)有發(fā)現(xiàn)差異。然而，群體規(guī)模的差異和小樣本量（由于高棄除率 dropout rate）可能是導(dǎo)致這一結(jié)果的原因。然而，與安慰劑相比，左乙拉西坦治療期間抽搐發(fā)作頻率降低和應(yīng)答率增加的趨勢(shì)值得在更大規(guī)模的研究中進(jìn)一步評(píng)估。Charalambous等（2014年）[17]的研究表明，有充分的證據(jù)推薦使用左乙拉西坦作為輔助性抗癲癇藥物（adjunct AED）。最近，一項(xiàng)回顧性研究提供了進(jìn)一步的證據(jù)，表明左乙拉西坦作為輔助性抗癲癇藥物具有良好的耐受性，可以顯著抑制特發(fā)性癲癇犬的癲癇性抽搐發(fā)作[83]。作者還證實(shí)，如果抽搐發(fā)作頻率升高，增加額外的抗抽搐藥物可能是有益的，這增加了使用左乙拉西坦作為叢集性抽搐發(fā)作脈沖治療的可能性。

Levetiracetam possesses a favourable pharmacokinetic profile in dogs with respect to its use as an add-on AED. It has rapid and complete absorption after oral administration, minimal protein binding, minimal hepatic metabolism and is excreted mainly unchanged via the kidneys. In humans and dogs, renal clearance of levetiracetam is progressively reduced in patients with increasing severity of renal dysfunction [85], thus, dosage reduction should be considered in patients with impaired renal function. As levetiracetam has minimal hepatic metabolism [85], this drug represents a useful therapeutic option in animals with known or suspected hepatic dysfunction. However, its short elimination half-life of 3?6 h necessitates frequent administration. The recommended oral maintenance dose of levetiracetam in dogs is 20 mg/kg TID-QID.

左乙拉西坦在犬身上具有良好的藥代動(dòng)力學(xué)特征，可以作為結(jié)合性抗癲癇藥物（add-on AED）?？诜笪昭杆偻耆鞍踪|(zhì)結(jié)合少，肝臟代謝少，主要經(jīng)腎臟排出。在人和犬中，隨著腎功能不全程度的加重，左乙拉西坦的腎臟清除率逐漸降低[85]，因此，對(duì)于腎功能受損的病患，應(yīng)考慮減少劑量。由于左乙拉西坦的肝臟代謝很少[85]，該藥物對(duì)于已知或疑似肝功能障礙的動(dòng)物是一種有用的治療選擇。然而，它的消除半衰期很短，只有3 ~ 6小時(shí)，因此需要頻繁給藥。犬的左乙拉西坦的推薦口服維持劑量為20 mg/kg TID-QID。

The same dose can be administered parenterally in dogs (SC, IM, IV) when oral administration is not possible [86].In a previous study [127] it was shown that some dogs develop a tolerance to levetiracetam when used chronically. This phenomenon, the ‘honeymoon effect’, has been documented for other AEDs, e.g. zonisamide and levetiracetam in dogs with epilepsy [127, 129]. Therefore, the introduction of the pulse treatment protocol (an initial dose of 60 mg/kg orally or parenterally after a seizure occurs or preictal signs are recognized by the owner, followed by 20 ?mg/kg TID until seizures do not occur for 48h) was developed, in order to start treatment only in case of cluster seizures when therapeutic levetiracetam concentrations need to be reached rapidly. The results in the recent study by Packer et al., 2015 [83] supports this clinical approach. Pulse treatment was, however, associated with more side effects compared to maintenance levetiracetam therapy [83]. Levetiracetam is well tolerated and generally safe in dogs. Except for mild sedation, ataxia, decreased appetite and vomiting adverse effects are very rarely described in dogs [79, 127] (Table 2). Levetiracetam has also a different mode of action compared to other AEDs and therefore may be advantageous when polytherapy is instituted. It selectively binds to a presynaptic protein (SVA2), whereby it seems to modulate the release of neurotransmitters [86]. As, in dogs there is no information available regarding a therapeutic range [79], the human target range of 12?46 μg/l can be used as guidance regarding effective concentrations.

在不能口服給藥的情況下，犬可通過(guò)腸外途徑（SC、IM、IV）以相同劑量給藥[86]。先前的一項(xiàng)研究[127]表明，一些犬長(zhǎng)期使用左乙拉西坦會(huì)產(chǎn)生耐受性。這種被稱為“蜜月效應(yīng)（honeymoon effect）”的現(xiàn)象在其他抗癲癇藥中也有記載，例如對(duì)癲癇犬使用唑尼沙胺和左乙拉西坦時(shí)[127,129]。因此，引入脈沖治療方案（寵主發(fā)現(xiàn)抽搐發(fā)作或發(fā)作前癥狀后，初始劑量為 60 mg/kg 口服或經(jīng)非腸道途徑給藥，隨后劑量為20mg /kg TID，直到48小時(shí)內(nèi)不再發(fā)生抽搐發(fā)作），以便在叢集性抽搐發(fā)作時(shí)快速達(dá)到左乙拉西坦的治療性血清濃度。Packer等人2015年的最新研究結(jié)果[83]支持了這種臨床方法。然而，與維持性左乙拉西坦治療相比，脈沖治療的副作用更多[83]。左乙拉西坦在犬的耐受性良好，通常是安全的。除了輕微的鎮(zhèn)靜作用外，犬很少出現(xiàn)運(yùn)動(dòng)失調(diào)、食欲下降和嘔吐等不良反應(yīng)[79, 127] (表2）。與其他抗癲癇藥相比，左乙拉西坦的作用方式也不同，因此在進(jìn)行多藥聯(lián)合治療時(shí)可能是有利的。它選擇性地與突觸前膜蛋白（SVA2）結(jié)合，從而調(diào)節(jié)神經(jīng)遞質(zhì)的釋放[86]。由于沒(méi)有關(guān)于犬的治療性血藥濃度范圍的信息[79]，人類 12-46 μg/L 的靶范圍可以作為犬有效血藥濃度的一個(gè)指導(dǎo)。

Studies in humans have shown that concomitant administration of AEDs that induce cytochrome P450 metabolism such as PB, can alter the disposition of levetiracetam [19]. Recently, it has been demonstrated that PB administration significantly alters the pharmacokinetics of levetiracetam in normal dogs [73]. Thus, levetiracetam oral dose may need to be increased or dosing time interval may need to be shortened when concurrently administered with PB [73]. Also in dogs with epilepsy, concurrent administration of PB alone or in combination with KBr increases levetiracetam clearance compared to concurrent administration of KBr alone [78]. Thus, dosage increases might be indicated when utilizing levetiracetam as add-on treatment with PB in dogs [78], preferably guided by levetiracetam serum concentration measurement.

人類研究表明，同時(shí)服用含有誘導(dǎo)細(xì)胞色素P450代謝（如苯巴比妥）的抗癲癇藥可改變左乙拉西坦的代謝[19]。最近有研究表明，苯巴比妥給藥可顯著改變左乙拉西坦在正常犬體內(nèi)的藥代動(dòng)力學(xué)[73]。因此，與苯巴比妥同時(shí)給藥時(shí)，左乙拉西坦口服劑量可能需要增加或縮短給藥時(shí)間間隔[73]。同樣在癲癇犬中，與單獨(dú)溴化鉀給藥相比，同時(shí)給藥苯巴比妥或溴化鉀聯(lián)合給藥可加快左乙拉西坦的清除率[78]。因此，將左乙拉西坦作為犬抗癲癇藥附加治療時(shí)，可能需要增加劑量[78]，最好以左乙拉西坦血清濃度測(cè)量為指導(dǎo)。

Table 2 Most common reported adverse effects seen in dogs treated with levetiracetam, zonisamide, felbamate, topiramate, gabapentin, and pregabalin (rarely reported and/or idiosyncratic adverse effects are indicated in grey

表2 左乙拉西坦、唑尼沙胺、非爾氨脂、托吡酯、加巴噴丁和普瑞巴林治療犬最常見(jiàn)的不良反應(yīng)報(bào)告(灰色表示罕見(jiàn)報(bào)告和/或特殊不良反應(yīng))