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

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（上）

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 @蘇蘇蘇蘇喬

審核 @寵物神經(jīng)科醫(yī)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.

在歐洲，獲得許可的犬用抗癲癇藥物(AEDs)的數(shù)量在過去數(shù)年里有了相當(dāng)大的增長(zhǎng)。但是仍然存在類似的問題，包括：1）什么時(shí)候開始治療，2）最初使用哪種藥物最好，3）如果使用初始藥物治療效果不理想，可以建議使用哪種輔助抗癲癇藥物, ?4）什么時(shí)候應(yīng)考慮改變治療方法。在本共識(shí)建議中，概述了抗癲癇藥物治療的目的，什么時(shí)候開始犬癲癇的長(zhǎng)期治療，以及目前有哪些獸醫(yī)用抗癲癇藥物用于犬類。關(guān)于藥物治療方案的本共識(shí)的建議，1）基于當(dāng)前已發(fā)表的循證文獻(xiàn)，2)考慮了歐洲獸藥處方級(jí)聯(lián)監(jiān)管的現(xiàn)行法律框架，3)反映了作者們的經(jīng)驗(yàn)。本文旨在為犬特發(fā)性癲癇的治療提供一個(gè)共識(shí)。此外，對(duì)于結(jié)構(gòu)性癲癇的管理，除了治療潛在的原因，如果可能的話，抗癲癇藥物是難免需要使用的。

Keywords: Dog, Epileptic seizure, Epilepsy, Treatment

關(guān)鍵字：犬，癲癇性抽搐發(fā)作，癲癇，治療

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.

在歐洲，獲得許可的犬用抗癲癇藥物(AEDs)的數(shù)量在過去數(shù)年里有了相當(dāng)大的增長(zhǎng)。但是仍然存在類似的問題，包括：1）什么時(shí)候開始治療，2）最初使用哪種藥物最好，3）如果使用初始藥物治療效果不理想，可以建議使用哪種輔助抗癲癇藥物, ?4）什么時(shí)候應(yīng)考慮改變治療方法。在本共識(shí)建議中，概述了抗癲癇藥物治療的目的，什么時(shí)候開始犬癲癇的長(zhǎng)期治療，以及目前有哪些獸醫(yī)用抗癲癇藥物用于犬類。關(guān)于藥物治療方案的本共識(shí)的建議，1）基于當(dāng)前已發(fā)表的循證文獻(xiàn)，2)考慮了歐洲獸藥處方級(jí)聯(lián)監(jiān)管的現(xiàn)行法律框架，3)反映了作者們的經(jīng)驗(yàn)。本文旨在為犬特發(fā)性癲癇的治療提供一個(gè)共識(shí)。此外，對(duì)于結(jié)構(gòu)性癲癇的管理，除了治療潛在的原因，如果可能的話，抗癲癇藥物是難免需要使用的。

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，毫無疑問，抗癲癇藥是主要的治療手段。事實(shí)上，抗癲癇藥物（antiepileptic drugs AEDs）這個(gè)詞并不恰當(dāng)，因?yàn)榇蠖鄶?shù)抗癲癇藥物的作用方式是抑制癲癇性抽搐發(fā)作，而不是致癇灶或癲癇的病理生理機(jī)制。也許，在未來，抗抽搐發(fā)作藥物（anti-seizure drugs）這個(gè)術(shù)語可能更適用于獸醫(yī)神經(jīng)學(xué)，這個(gè)術(shù)語越來越多地用于人類癲癇。此外，據(jù)了解，在未經(jīng)治療的特發(fā)性癲癇犬亞分類群體中，癲癇性抽搐發(fā)作頻率似乎隨著時(shí)間的推移而增加，這反映了這些病患需要抗癲癇藥治療[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.

在關(guān)于分類和術(shù)語的共識(shí)中，我們將特發(fā)性癲癇（idiopathic epilepsy）本身定義為一種疾病。特發(fā)性癲癇的遺傳起源可通過基因檢測(cè)得到支持(如果有的話)，而基因性影響可通過高品種患病率(> 2%)、族譜分析和/或癲癇性個(gè)體的家族積累而得到支持。然而，在臨床上，癲癇的原因除了反應(yīng)性抽搐發(fā)作和結(jié)構(gòu)性癲癇，最常見的仍然是特發(fā)性癲癇。

Aims of AED treatment

抗癲癇藥物治療的目的

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

抗癲癇藥物治療的理想目標(biāo)是在控制癲癇性抽搐發(fā)作和維持病患的生活質(zhì)量之間取得平衡。在犬，根除抽搐發(fā)作（Seizure eradication）通常是不可能的。更現(xiàn)實(shí)的目標(biāo)是減少抽搐發(fā)作的頻率、持續(xù)時(shí)間、嚴(yán)重程度和在短時(shí)間內(nèi)發(fā)生的癲癇性抽搐發(fā)作的總數(shù)，沒有或很少的以及可接受的抗癲癇藥物的相關(guān)副作用，以最大限度地提高犬和寵主的生活質(zhì)量。臨床醫(yī)生應(yīng)采用以下治療模式[23,76,91,92,120]:

-決定什么時(shí)候開始抗癲癇藥物治療?

-選擇最合適的抗癲癇藥物及劑量?

-知道是否以及什么時(shí)候監(jiān)測(cè)血清抗癲癇藥物濃度并相應(yīng)調(diào)整治療?

-知道什么時(shí)候添加或更換另一種的抗癲癇藥物 -督促寵物主人遵醫(yī)囑

When to recommend maintenance AED treatment?

什么時(shí)候建議維持性抗癲癇藥物治療?

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:

對(duì)于各種抽搐發(fā)作頻率和類型的犬，什么時(shí)候開始抗癲癇藥物治療，準(zhǔn)確和循證的相關(guān)數(shù)據(jù)并不充分。因此，從人類醫(yī)學(xué)的推斷可能能提供一些治療指南。臨床醫(yī)生應(yīng)考慮病患的整體健康狀況，以及寵主的生活方式、經(jīng)濟(jì)限制和對(duì)擬議治療方案的舒適度。個(gè)體化治療對(duì)于選擇治療方案至關(guān)重要。一般情況下，作者建議患有特發(fā)性癲癇的犬出現(xiàn)以下任何一種情況時(shí)，應(yīng)進(jìn)行長(zhǎng)期治療:

– 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

-發(fā)作間期**≤6個(gè)月（**即6個(gè)月內(nèi)癲癇性抽搐發(fā)作2次及以上） -癲癇持續(xù)狀態(tài)或叢集性抽搐發(fā)作-**發(fā)作后期癥狀被認(rèn)為特別嚴(yán)重（**例如攻擊性、失明）或持續(xù)時(shí)間超過24小時(shí)-癲癇性抽搐發(fā)作頻率和/或發(fā)作時(shí)長(zhǎng)增加和/或抽搐發(fā)作嚴(yán)重程度在3個(gè)發(fā)作周期內(nèi)惡化

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].

在人類中，關(guān)于什么時(shí)候推薦抗癲癇藥物治療的決定是基于許多風(fēng)險(xiǎn)因素來下的（如復(fù)發(fā)風(fēng)險(xiǎn)、抽搐發(fā)作類型、耐受性、不良反應(yīng)）[42,115]。在人類中，有明確的證據(jù)表明，在單次非誘發(fā)性抽搐發(fā)作后開始抗癲癇藥物治療沒有任何益處[42]，但有證據(jù)支持在第二次抽搐發(fā)作后開始治療有益[43,108]。在犬類中，如果在發(fā)病早期就開始適當(dāng)?shù)目拱d癇藥物治療，長(zhǎng)期的抽搐發(fā)作管理被認(rèn)為是最成功的，特別是對(duì)于抽搐發(fā)作頻率高的犬和已知會(huì)有嚴(yán)重癲癇的某些犬的品種[12?14]。發(fā)病起初6個(gè)月抽搐發(fā)作次數(shù)≥10次，似乎與澳大利亞牧羊犬特發(fā)性癲癇的預(yù)后不良存在相關(guān)性[132]。此外，最近有證據(jù)表明，抽搐發(fā)作頻率是一個(gè)關(guān)鍵的危險(xiǎn)因素，經(jīng)歷叢集性抽搐發(fā)作，雄性均與抗癲癇藥物治療反應(yīng)差有關(guān)[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].

癲癇人類病患在抗癲癇藥物治療前抽搐頻繁發(fā)作與抗癲癇藥物反應(yīng)差之間存在很強(qiáng)的相關(guān)性[16,34,59]。在過去，這認(rèn)為是由于點(diǎn)燃機(jī)制（kindling）的原因，抽搐發(fā)作活動(dòng)導(dǎo)致隨后的抽搐發(fā)作加?。╥ntensification）[117]。然而，很少有臨床證據(jù)表明點(diǎn)燃機(jī)制在復(fù)發(fā)性抽搐發(fā)作的犬[54]或人[111]中起作用。在人類中，可能存在多因素發(fā)病機(jī)制[14,52]。最近的流行病學(xué)數(shù)據(jù)表明，個(gè)體之間癲癇發(fā)作的嚴(yán)重程度存在差異，這些差異影響病患對(duì)藥物的反應(yīng)和長(zhǎng)期預(yù)后。此外，有證據(jù)表明抽搐發(fā)作相關(guān)的改變會(huì)影響抗癲癇藥物的藥效學(xué)和藥代動(dòng)力學(xué)[99]。犬的癲癇嚴(yán)重程度的品種相關(guān)差異已有描述，澳大利亞牧羊犬[132]、邊境牧羊犬[49,84]、意大利斯皮諾尼犬[24]、德國(guó)牧羊犬和斯塔福德郡牛頭梗犬[84]的臨床病程為中度至重度，而不同的牧羊犬(主要是粗毛犬)[77]、拉布拉多尋回獵犬[7]和比利時(shí)牧羊犬[45]的疾病的嚴(yán)重形式較輕。因此，基因可能會(huì)影響治療的成功可能性，或許可能解釋為什么某些品種更容易發(fā)生耐藥性癲癇（drug resistant epilepsy）[3,77]。

Choice of AED therapy

抗癲癇藥物治療的選擇

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.

目前還沒有循證的指南來指導(dǎo)犬如何選擇抗癲癇藥物。在選擇抗癲癇藥物治療犬的癲癇時(shí)，需要考慮多個(gè)因素(抗癲癇藥物特異性因素(如監(jiān)管方面、安全性、耐受性、不良反應(yīng)、藥物相互作用、給藥頻率)、與犬相關(guān)的因素(如抽搐發(fā)作類型、頻率和病因、潛在病理如腎/肝/胃腸道問題)以及與寵主相關(guān)的因素(如生活方式、經(jīng)濟(jì)狀況))[23]。然而最終，抗癲癇藥物的選擇通常視情況而定。

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，癲癇犬的主要治療仍然是使用苯巴比妥（phenobarbital PB）和溴化鉀（potassium bromide KBr），它們歷史悠久、可用性廣而且成本低。這兩種抗癲癇藥物在獸醫(yī)臨床廣泛使用的同時(shí)，也有多種獲準(zhǔn)用于人類的新型抗癲癇藥也被用于管理犬的特發(fā)性癲癇，主要是作為輔助治療。此外，自2013年初以來，大多數(shù)歐洲國(guó)家已引入伊匹妥英（imepitoin），用于治療特發(fā)性癲癇犬的復(fù)發(fā)性單次全身性癲癇性抽搐發(fā)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].

一些被批準(zhǔn)用于人類的老一代抗癲癇藥物已被證明不適合用于犬，因?yàn)榇蠖鄶?shù)抗癲癇藥物對(duì)于犬來說的消除半衰期太短，不能方便地讓寵主給藥，這些抗癲癇藥物包括苯妥英（phenytoin）、卡馬西平（carbamazepine）、丙戊酸（valproic acid）和乙琥胺（ethosuximide）[119]。有些甚至對(duì)犬有毒，如拉莫三嗪（lamotrigine）（其代謝物具有心臟毒性）[26,136]和氨己烯酸（vigabatrin）（與神經(jīng)毒性和溶血性貧血有關(guān))[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世紀(jì)90年代以來，耐受性更好、副作用更少、藥物相互作用可能性更低的新型抗癲癇藥已被批準(zhǔn)用于治療人類癲癇。許多新型藥物在犬身上似乎相對(duì)安全，包括左乙拉西坦（levetiracetam）、唑尼沙胺（zonisamide）、非爾氨脂（felbamate）、托吡酯（topiramate）、加巴噴?。╣abapentin）和普瑞巴林（pregabalin）。拉科酰胺（lacosamide）[68]和盧非酰胺（rufinamide）[137]的藥代動(dòng)力學(xué)研究支持這些藥物在犬上的潛在應(yīng)用，但尚未在臨床環(huán)境中進(jìn)行評(píng)估。盡管這些新藥在治療犬癲癇方面已經(jīng)獲得了相當(dāng)大的普及，但關(guān)于其安全性和有效性的科學(xué)數(shù)據(jù)非常有限，而且成本往往令人望而卻步。

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.

苯巴比妥是所有抗癲癇藥物里長(zhǎng)期使用歷史最長(zhǎng)的獸藥。經(jīng)過幾十年的使用，它已于2009年被批準(zhǔn)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(dòng)力學(xué)特征，相對(duì)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(shí)，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(xiàng)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(jī)臨床試驗(yàn)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(gè)月內(nèi)無抽搐發(fā)作，而給予Br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(dòng)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(bào)道其生物利用度約為90%[2,87]。犬口服給藥后約4-8小時(shí)血清濃度達(dá)到峰值[2,97]。據(jù)報(bào)道，多次口服給藥后，正常犬的初始消除半衰期為37-73小時(shí)[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(huì)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(gè)體差異[2,87,97]。在犬體內(nèi)，苯巴比妥是肝臟細(xì)胞色素P450酶活性的有效誘導(dǎo)劑[48]，這會(huì)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(xiǎn)[107]。因此，肝功能不全犬禁忌使用苯巴比妥（contraindicated）。隨著時(shí)間的推移，肝臟細(xì)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(zhǎng)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(cè)血清苯巴比妥濃度對(duì)于長(zhǎng)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(guó)家可獲得不同的苯巴比妥劑型，但應(yīng)強(qiáng)調(diào)的是，肌內(nèi)注射制劑不能用于靜脈注射，反之亦然。對(duì)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(dòng)力學(xué)尚未在犬中進(jìn)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(shí)[87]。

Pharmacokinetic interactions

藥代動(dòng)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(zhǎng)期服用苯巴比妥會(huì)影響其他同時(shí)服用的藥物的作用，這些藥物通過細(xì)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(dòng)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(shí)踐中應(yīng)強(qiáng)調(diào)，在長(zhǎng)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(xì)胞色素P450酶的藥物同時(shí)用藥時(shí)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(dòng)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(jì)失調(diào)、食欲亢進(jìn)、多飲和多尿。對(duì)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(xì)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(xiǎn)[38,46]、運(yùn)動(dòng)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(shí)驗(yàn)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(zhǎng)期苯巴比妥給藥相關(guān)的實(shí)驗(yàn)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(cè)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(shí)驗(yàn)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]。

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治療的犬中最常見報(bào)告的不良反應(yīng)（很少報(bào)告和/或特殊不良反應(yīng)用灰色表示）

Dose and monitoring (Fig. 1)

劑量與監(jiān)測(cè)（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(cè)，為患病動(dòng)物個(gè)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(dòng)力學(xué)在個(gè)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(cè)定血清濃度。為了評(píng)估代謝耐受性，可以在治療開始后6周測(cè)量第二次苯巴比妥血清濃度。不同研究對(duì)犬血清苯巴比妥濃度監(jiān)測(cè)的最佳采血時(shí)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(shí)間進(jìn)行檢查，因?yàn)橐坏┻_(dá)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(shí)監(jiān)測(cè)血清苯巴比妥濃度，以便對(duì)這些犬的結(jié)果進(jìn)行準(zhǔn)確的比較[70]。另一項(xiàng)研究建議對(duì)谷值樣本進(jìn)行血清苯巴比妥濃度監(jiān)測(cè)，因?yàn)樵趩蝹€(gè)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(rèn)為，對(duì)于大多數(shù)犬來說，為了達(dá)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(huì)增加肝毒性的風(fēng)險(xiǎn)，應(yīng)避免超過這個(gè)值[22,75]。在抽搐發(fā)作控制不佳的情況下，必須建議測(cè)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(jì)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(shí)際濃度）× 苯巴比妥的實(shí)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(duì)于抽搐發(fā)作得到充分控制的，但血清藥物濃度低于已報(bào)道的治療范圍的犬，不需要調(diào)整藥物劑量，因?yàn)樵撗鍧舛瓤赡軐?duì)該個(gè)體是足夠的。一般來說，對(duì)于患病動(dòng)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(dòng)物中，苯巴比妥可在24 ~ 48小時(shí)內(nèi)以15 ~ 20 mg/kg體重的負(fù)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(cè)定血清苯巴比妥濃度。一些作者會(huì)盡快負(fù)荷給藥（40 ~ 60分鐘)，并以10 ~ 12 mg/kg體重的負(fù)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(jìn)行全血細(xì)胞計(jì)數(shù)、生化指標(biāo)（包括膽固醇和甘油三酯）和膽汁酸刺激試驗(yàn)，治療后3個(gè)月后檢查一次，治療期間每6個(gè)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(gè)月監(jiān)測(cè)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(gè)月檢查一次。

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]).

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(shí)，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(biāo)準(zhǔn)（見共識(shí)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(shí)間間隔至少3個(gè)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(yán)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(yán)重副作用，需停止使用抗癲癇藥物

To be continued ······