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

校正?By @寵物神經(jīng)科醫(yī)生高健?

Imepitoin?伊匹妥因

Efficacy?作用效果

Imepitoin was initially developed as a new AED for humans, but, the more favourable pharmacokinetic profile of imepitoin in dogs versus humans led to the decision to develop imepitoin for the treatment of canine idiopathic epilepsy [102]. Based on randomized controlled trials that demonstrated antiepileptic efficacy, high tolerability and safety in epileptic dogs, the drug was approved in 2013 for this indication in Europe [64, 98, 122]. It has been recommended to use imepitoin in dogs with idiopathic epilepsy experiencing recurrent single generalized epileptic seizures, however, its efficacy has not yet been demonstrated in dogs with cluster seizures or status epilepticus [30]. In a recent randomized controlled study [122], the efficacy of imepitoin was compared with PB in 226 client-owned dogs. The administration of imepitoin twice daily in incremental doses of 10, 20 or 30 mg/kg demonstrated that the majority of dogs with idiopathic epilepsy were managed successfully with imepitoin without significant difference to the efficacy of PB. The frequency of adverse events (e.g. sedation, polydipsia, polyphagia) was significantly higher in the PB group [122]. In a study by Rieck et al. (2006) [98], dogs with chronic epilepsy not responding to PB or primidone received imepitoin (in its initial formulation) or KBr as adjunct AED and the seizure frequency improved to a similar degree in both groups. According to Charalambous et al. (2014) [17], there is good evidence for recommending the use of imepitoin as monotherapy in dogs with recurrent single generalized epileptic seizures, but insufficient evidence for use as adjunct AED. At present, scientific data and evidence-based guidelines on which AED can best be combined with imepitoin are lacking, and further research is needed. Nevertheless, at this moment, the authors recommend the use of PB as adjunct AED in dogs receiving the maximum dose of imepitoin and experiencing poor seizure control. According to the authors, in case of combined therapy with imepitoin and PB, it is advised to slowly wean off imepitoin over several months if seizure control appears successful on PB and/or to reduce the dose of imepitoin if adverse effects (e.g. sedation) occur (Fig. 2).

伊匹妥因 Imepitoin 最初是人類的一種新型抗癲癇藥物，但是，與人類相比，伊匹妥因在犬體內(nèi)的藥代動力學(xué)特征更可觀，因此開始嘗試用于治療犬特發(fā)性癲癇[102]?；陔S機對照試驗，該藥物在癲癇犬中具有抗癲癇療效、高耐受性和安全性，于2013年在歐洲獲批準用于此適應(yīng)癥[64,98,122]。已有研究建議對復(fù)發(fā)性單次全身性癲癇性抽搐發(fā)作的特發(fā)性癲癇犬使用伊匹妥因，但其對叢集性抽搐發(fā)作或癲癇持續(xù)狀態(tài)犬的療效尚未得到證實[30]。在最近的一項隨機對照研究[122]中，對226例客戶擁有的犬進行了伊匹妥因與苯巴比妥的療效比較。每日兩次以10、20或30 mg/kg的增量劑量給藥，結(jié)果表明，大多數(shù)特發(fā)性癲癇犬均能成功地使用伊匹妥因治療，對苯巴比妥的療效無顯著影響。不良反應(yīng)（如鎮(zhèn)靜、多飲、食欲亢進）的發(fā)生頻率在苯巴比妥（PB）組明顯更高[122]。在Rieck等人(2006年)[98]的研究中，對苯巴比妥或撲米酮(primidone)無反應(yīng)的慢性癲癇犬接受伊匹妥因(初始制劑)或溴化鉀作為輔助抗癲癇藥物，兩組抽出發(fā)作頻率均有相似程度的改善。根據(jù) Charalambous等人(2014年)[17]的研究，有充分的證據(jù)建議對復(fù)發(fā)性單次全身性癲癇性抽搐發(fā)作的犬使用伊匹妥因作為單藥治療，但沒有足夠的證據(jù)支持將其作為輔助性抗癲癇藥物。目前，抗癲癇藥物與伊匹妥因聯(lián)合應(yīng)用的最佳方法缺乏科學(xué)數(shù)據(jù)和循證指南，有待進一步研究。然而，目前，作者建議在接受最大劑量伊匹妥因且抽搐發(fā)作控制不佳的犬中使用苯巴比妥（PB）作為輔助抗癲癇藥物。根據(jù)作者的說法，在伊匹妥因和苯巴比妥（PB）聯(lián)合治療的情況下，如果苯巴比妥（PB）治療成功地控制了抽搐發(fā)作，建議在幾個月內(nèi)慢慢減量停用伊匹妥因，如果出現(xiàn)不良反應(yīng)(如鎮(zhèn)靜)，建議減少伊匹妥因的劑量(圖2)。

Pharmacokinetics

藥代動力學(xué)

Following oral administration of imepitoin at a dose of 30 mg/kg in healthy Beagle dogs, high plasma levels were observed within 30 min, but maximal plasma levels were only reached after 2?3h following a prolonged absorption time [101]. The elimination half-life was found to be short; approximately 1.5 to 2h. However, in another study in Beagle dogs, a longer half-life (~6 h) was found after higher doses of imepitoin, and accumulation of plasma levels was seen during chronic BID treatment [64]. Also, it has to be considered that Beagle dogs eliminate AEDs more rapidly than other dog strains [122]. Despite the short half-life in healthy Beagle dogs, this pharmacokinetic profile is reported as adequate to maintain therapeutically active concentrations with twice daily dosing in dogs [64, 122]. Imepitoin is extensively metabolized in the liver prior to elimination. In dogs, imepitoin is mainly excreted via the faecal route rather than the urinary route. Neither reduced kidney function nor impaired liver function is likely to greatly influence the pharmacokinetics of imepitoin [122].

健康的比格犬口服30mg/kg劑量的伊匹妥因后，在30分鐘內(nèi)觀察到高血藥濃度，但在延遲吸收時間2-3h后才達到最高血漿水平[101]。而且消除半衰期很短；約1.5到2小時。然而，在另一項對比格犬的研究中，更高劑量的伊匹妥因的半衰期更長(~6小時)，并且在長期每日兩次（BID）治療期間可觀察到血藥濃度的積累[64]。此外，必須考慮到比格犬比其他犬種能更快地消除抗癲癇藥物[122]。盡管在健康的比格犬中半衰期較短，但據(jù)報道，這種藥代動力學(xué)特征足以在犬中維持每日兩次的有效治療濃度[64,122]。在消除之前，伊匹妥因在肝臟中被廣泛代謝。在犬體內(nèi)伊匹妥因主要通過糞便而不是尿液排出體外。無論是腎功能降低還是肝功能受損都不太可能對伊匹妥因的藥代動力學(xué)產(chǎn)生很大影響[122]。

Pharmacokinetic interactions and adverse reactions

藥代動力學(xué)相互作用和副作用

There is no information on pharmacokinetic interactions between imepitoin and other medications. Although, imepitoin is a low affinity partial agonist for the benzodiazepine binding site of the GABAA receptor it has not prevented the pharmacological activity of full benzodiazepine agonists such as diazepam in the clinical setting (e.g. in dogs with status epilepticus) [122]. Consequently, because the affinity of diazepam for the GABAA receptor is much higher than imepitoin, care should be taken in the emergency setting [122]. Therefore, dogs with idiopathic epilepsy treated with imepitoin and presented in status epilepticus might require, in addition to diazepam, an additional AED parenterally (e.g. PB, levetiracetam).

目前還沒有關(guān)于伊匹妥因和其他藥物之間的藥代動力學(xué)相互作用的信息。盡管依匹妥因是GABAA受體苯二氮卓結(jié)合位點的低親和力部分激動劑，但在臨床環(huán)境中，它并沒有阻止全苯二氮卓激動劑(如地西泮)的藥理活性(例如，在癲癇持續(xù)狀態(tài)的犬中)[122]。因此，由于地西泮對GABAA受體的親和力遠高于伊匹妥因，因此在緊急情況下應(yīng)注意使用[122]。因此，接受伊匹妥因治療并呈現(xiàn)癲癇持續(xù)狀態(tài)的特發(fā)性癲癇犬，除了地西泮外，可能還需要額外的抗癲癇藥物（如苯巴比妥、左乙拉西坦levetiracetam）。

Mild and most commonly transient adverse reactions (Table 1) have been reported in dogs administered 10?30 mg/kg BID of imepitoin in its initial formulation; polyphagia at the beginning of the treatment, hyperactivity, polyuria, polydipsia, somnolence, hypersalivation, emesis, ataxia, lethargy, diarrhoea, prolapsed nictitating membranes, decreased vision and sensitivity to sound [64, 98].

據(jù)報道，在初始劑量給予10 - 30 mg/kg BID的伊匹妥因的犬中，出現(xiàn)了輕微和最常見的暫時性不良反應(yīng)（表1）；治療初期多食、過度活躍、多尿、多飲、冷漠、過度流涎、嘔吐、共濟失調(diào)、嗜睡、腹瀉、第三眼瞼脫出、視力下降和對聲音的敏感[64,98]

As part of the development of imepitoin for the treatment of canine epilepsy, a target animal safety study in dogs was conducted [96]. Under laboratory conditions, healthy Beagle dogs were exposed to high doses (up to 150 mg/kg q12h) of imepitoin for 6 months. Clinical signs of toxicity were mild and infrequent and they were mostly CNS (depression, transient ataxia) or gastrointestinal system (vomiting, body weight loss, salivation) related. These clinical signs were not life-threatening and generally resolved within 24h if symptomatic treatment was given. These data indicate that imepitoin is a safe AED and is well tolerated up to high doses in dogs treated twice daily [96]. However, the safety of imepitoin has not been evaluated in dogs weighing less than 5 kg or in dogs with safety concerns such as renal, liver cardiac, gastrointestinal or other disease. No idiosyncratic reactions have been demonstrated so far. The routinely measured liver enzymes’ activity do not appear to be induced by imepitoin [96]. Compared with the traditional benzodiazepines, such as diazepam, which acts as full agonists at the benzodiazepine site of the GABAA receptor, partial agonists such as imepitoin show less sedative adverse effects and are not associated with tolerance and dependence during long-term administration in animal models [122]. Also in epileptic dogs, tolerance did not develop and no withdrawal signs were observed after treatment discontinuation [64].

作為研究伊匹妥因治療犬癲癇的發(fā)展一部分，在犬中進行了靶向動物安全性研究[96]。在實驗室條件下，健康的比格犬暴露于高劑量（高達150mg /kg q12h）的伊匹妥因6個月。臨床癥狀輕微且少見，主要與中樞神經(jīng)系統(tǒng)（沉郁、一過性共濟失調(diào)）或胃腸道系統(tǒng)（嘔吐、體重減輕、流涎）有關(guān)。這些臨床癥狀不危及生命，如果給予對癥治療，一般在24小時內(nèi)消失。這些數(shù)據(jù)表明，伊匹妥因是一種安全的抗癲癇藥，對于每天給藥兩次的犬來說，即使是大劑量，也具有良好的耐受性[96]。然而，尚未對于體重小于5公斤，或有腎臟、肝臟、心臟、胃腸道或其他疾病等安全問題的犬進行伊匹妥因的安全性評估。目前還沒有發(fā)現(xiàn)有特質(zhì)性反應(yīng)（idiosyncratic reactions）。常規(guī)測量的肝酶活性似乎并不是由伊匹妥因?qū)е碌腫96]。與傳統(tǒng)的苯二氮卓類藥物，如地西泮，在GABAA受體的苯二氮卓位點的完全激動劑相比，部分激動劑如伊匹妥因，在動物模型中表現(xiàn)出更小的鎮(zhèn)靜副作用，并且在長期給藥過程中不存在耐受性和依賴性[122]。同樣在癲癇犬中，停藥后未產(chǎn)生耐受性，也未觀察到戒斷癥狀[64]。

Dose and monitoring (Fig. 2)

劑量與監(jiān)測（圖2）

The oral dose range of imepitoin is 10?30 mg/kg BID. The recommended oral starting dose of imepitoin is 10?20 mg/kg BID. If seizure control is not satisfactory after at least 1 week of treatment at this dose and the medication is well tolerated, the dose can be increased up to a maximum of 30 mg/kg BID. Reference range of plasma or serum imepitoin concentrations is unknown and there are no therapeutic monitoring recommendations for imepitoin from the manufacturer. Pharmacokinetic studies in dogs suggest variability in plasma imepitoin concentrations among individuals and sampling times. However, no correlation between plasma imepitoin concentration and seizure frequency reduction was identified [64] therefore and because of its wide therapeutic index, serum imepitoin monitoring is not needed. The authors recommend a complete blood cell count and biochemical profile before starting imepitoin treatment and periodically every 6 months during treatment. If the dog is in remission or has no seizures, a periodical control every 12 months is advised.

伊匹妥因的口服劑量范圍為10 ~ 30 mg/kg BID?？诜疗ネ滓虻耐扑]起始劑量為10 ~ 20mg /kg BID。如果此劑量用藥至少1周后抽搐發(fā)作控制不充分，且藥物耐受性良好，則可將劑量增加至最高30 mg/kg BID。血漿或血清伊匹妥因濃度的參考范圍尚不清楚，廠商也沒有對伊匹妥因的治療監(jiān)測建議。犬的藥代動力學(xué)研究表明，個體之間和采樣時間之間的伊匹妥因血漿濃度存在可變差異。然而，沒有發(fā)現(xiàn)伊匹妥因血漿濃度與抽搐發(fā)作頻率減少之間的相關(guān)性[64]，因此，由于其寬泛的有效治療指數(shù)，依匹妥因血清監(jiān)測是不必要的。作者建議在開始使用依妥匹因治療前進行全血細胞計數(shù)和生化檢查，并在治療期間每6個月定期檢查一次。如果犬的癥狀緩解或沒有抽搐發(fā)作，建議每12個月檢查一次。

Fig. 2 Imepitoin treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise to start with imepitoin in dogs with idiopathic epilepsy experiencing recurrent single generalised epileptic seizures. *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]).

圖2 其他方面均健康犬的抽搐發(fā)作管理決策過程中使用伊匹妥因治療的流程圖。作者建議對患有特發(fā)性癲癇、全身性抽搐反復(fù)發(fā)作的犬開始使用伊匹妥因。*充分控制抽搐發(fā)作的有效性和耐受性標準(見共識提案：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. # Currently there are no data available on which AED should be added to imepitoin in case of inadequate seizure control. At this moment, the authors recommend the use of PB as adjunct AED in dogs receiving the maximum dose of imepitoin and experiencing poor seizure control

1 .治療有效性:

a：治療完全成功(三次發(fā)作間隔至少3個月(理想情況>1年)

b：治療成功一部分(即減少抽搐發(fā)作的次數(shù),包括抽搐發(fā)作的概率（因藥物作用減少了至少50%的情況出現(xiàn)),降低抽搐發(fā)作的嚴重程度,或減少抽搐發(fā)作的頻率和/或抽搐狀態(tài)。

2.治療不耐受：即出現(xiàn)嚴重副作用，需停止使用抗癲癇藥，#目前沒有數(shù)據(jù)表明，在抽搐發(fā)作控制不充分的情況下應(yīng)該增加抗癲癇藥和伊匹妥因聯(lián)用。目前，作者建議在接受最大劑量伊匹妥因且抽搐發(fā)作控制不佳的犬中使用苯巴比妥作為輔助抗癲癇藥