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?

Bromide?溴

Efficacy?作用效果

Br is usually administered as the potassium salt (KBr).The sodium salt form (NaBr) contains more Br per gram of compound, therefore, the dose should be approximately 15 % less than that calculated for KBr [124]. In most EU countries, KBr is approved only for add-on treatment in dogs with epilepsy drug-resistant to firstline AED therapy. PB and KBr have a synergistic effect and add-on treatment with KBr in epileptic dogs improves seizure control in dogs that are poorly controlled with PB alone [46, 93, 126]. A recent study showed that KBr was less efficacious and tolerable than PB as firstline drug [10]. According to Charalambous et al. (2014) [17] there is fair level of evidence for recommending the use of KBr as a monotherapy, but less as adjunct AED.

溴通常作為鉀鹽（KBr）使用。鈉鹽形式（NaBr）每克化合物含有更多的溴，因此，劑量應(yīng)比溴化鉀計算出的劑量少約15%[124]。在大多數(shù)歐盟國家，溴化鉀僅獲批準(zhǔn)用作一線抗癲癇藥物治療產(chǎn)生耐藥性的癲癇犬的附加治療。苯巴比妥和溴化鉀具有協(xié)同效應(yīng)（synergistic effect），在癲癇犬中加用溴化鉀治療可以改善單獨使用苯巴比妥控制不佳的犬的抽搐發(fā)作[46,93,126]。最近的一項研究表明，溴化鉀作為一線藥物的療效和耐受性不如苯巴比妥 [10]。Charalambous等人(2014年)[17]認(rèn)為，推薦使用溴化鉀單一用藥治療的證據(jù)相當(dāng)多，但作為輔助抗癲癇藥物的證據(jù)較少。

Pharmacokinetics

藥代動力學(xué)

The bioavailability of Br after oral administration in normal dogs is approximately 46 %. The elimination half-life is long and ranges from 25?46 days in dogs, consequently, it can take several months (approximately 3 months) before steady-state concentrations after treatment initiation at maintenance dose are reached [46, 67, 90, 125]. KBr is unbound to plasma proteins and can diffuse freely across cellular membranes. KBr is not metabolised in the liver and is therefore a good alternative in dogs with hepatic dysfunction. KBr is excreted unchanged in the urine and undergoes tubular reabsorption in competition with chloride. Therefore, dietary factors affecting chloride levels can alter serum KBr concentrations [123]. High (low) dietary chloride concentrations increase (decrease) the excretion of KBr and shorten (prolong) its half-life. Dogs administered KBr should be maintained on a constant diet (and chloride intake) to prevent fluctuations in serum KBr concentrations, which could result in therapeutic failure or toxicity. If dietary changes are necessary they should be made gradually (over at least 5 days) and serum concentrations of KBr should be monitored following dietary changes, especially if the dog becomes sedated or has unexpected seizures. On biochemistry profiles serum chloride concentrations are often falsely elevated (“pseudohyperchloraemia”) because the assays cannot distinguish between chloride and Br ions [123].

正常犬口服給藥后溴化物的生物利用度約為46%。在犬體內(nèi)，清除半衰期很長，范圍為25-46天，因此，在以維持劑量開始治療后，可能需要幾個月(約3個月)才能達到穩(wěn)態(tài)濃度[46,67,90,125]。溴化鉀不與血漿蛋白結(jié)合，可以自由地穿過細胞膜擴散。溴化鉀不會在肝臟中代謝，因此對于肝功能障礙的犬來說是一個很好的選擇。溴化鉀以不變的形式隨尿液排出，與氯化物競爭，經(jīng)腎小管重吸收。因此，影響氯化物水平的飲食因素可以改變血清溴化鉀濃度[123]。飲食中氯濃度的高（低）會增加（減少）溴化鉀的排泄并縮短（延長）其半衰期。給予溴化鉀的犬應(yīng)該保持固定的飲食（和氯化物攝入量），以防止血清溴化鉀濃度的波動，這可能導(dǎo)致治療失敗或中毒。如果有必要改變飲食，應(yīng)逐漸（至少5天）進行，并在改變飲食后監(jiān)測血清溴化鉀濃度，特別是當(dāng)犬出現(xiàn)鎮(zhèn)靜或意外抽搐發(fā)作時。在生化結(jié)果上，血清氯離子濃度經(jīng)常被誤認(rèn)為升高（“假性高氯血癥”)，因為常規(guī)檢查無法分辨氯離子和溴離子[123]。

Pharmacokinetic interactions and adverse effects

藥代動力學(xué)和副作用

Pharmacokinetic interactions of KBr are limited as KBr is not metabolized or protein-bound. The main interactions are associated with alterations in the renal excretion of KBr. As already mentioned, the rate of elimination of KBr varies proportionally and inversely to chloride intake. Loop diuretics such as furosemide may enhance KBr elimination by blocking KBr reabsorption through renal tubular chloride channels. KBr should be avoided in dogs with renal dysfunction to prevent toxicity secondary to reduced renal elimination [80].

溴化鉀的藥代動力學(xué)相互作用是有限的，因為溴化鉀不代謝或蛋白質(zhì)結(jié)合。主要的相互作用與腎排泄溴化鉀的改變有關(guān)。如前所述，溴化鉀的代謝與氯化物的攝入量成正比，與消除率成反比。循環(huán)利尿劑如速尿可通過阻斷溴化鉀經(jīng)由腎小管氯離子通道的重吸收來加快溴化鉀的消除。腎功能不全犬應(yīng)避免使用溴化鉀，以避免腎臟清除減少引起的中毒[80]。

Common, dose-dependent adverse effects of KBr in dogs include sedation, ataxia and pelvic limb weakness, polydipsia/polyuria, and polyphagia with weight gain [4, 25, 46, 124] (Table 1). These effects occur in the initial weeks of treatment and may be magnified by concurrent PB administration. These adverse effects subside (partly or completely), once KBr steady-state concentrations are reached [125]. Gastrointestinal irritation and clinical signs can be prevented or minimized by administering Br with food and dividing the daily dose into 2 or more doses [4]. Uncommon idiosyncratic reactions of KBr in dogs include personality changes (aggressive behaviour, irritability, hyperactivity), persistent cough, increased risk of pancreatitis and megaoesofagus [4, 46, 67, 106] (Table 1). KBr may cause skin problems (bromoderma) in humans [106], but no reports exist currently in dogs. For an indepth review on the adverse effects of Br the reader is referred to comprehensive book chapters [23, 32, 91].

溴化鉀對犬常見的劑量依賴性不良反應(yīng)包括鎮(zhèn)靜、共濟失調(diào)和后肢無力、多飲/多尿和食欲亢進伴體重增加[4, 25, 46, 124] (表 1)。這些反應(yīng)發(fā)生在治療的最初幾周，并可能因同時苯巴比妥的給藥而反應(yīng)增大。一旦達到溴化鉀的穩(wěn)態(tài)濃度，這些不良反應(yīng)就會（部分或完全）消退[125]。與食物一起給藥并將每日劑量分成2次或更多次服用，可避免或減少胃腸道刺激和臨床癥狀[4]。溴化鉀在犬中不常見的特殊反應(yīng)包括性格改變(攻擊行為、易怒、多動)、持續(xù)咳嗽、胰腺炎和巨食道的風(fēng)險增加 [4, 46, 67, 106] (表 1)。溴化鉀可能在人類中引起皮膚問題(溴疹)[106]，但目前還沒有關(guān)于犬類的報道。要深入了解溴的副作用，讀者可以參考書籍的綜合章節(jié)[23,32,91]。

Dose and monitoring (Fig. 3)

劑量與監(jiān)測（圖 3）

The recommended oral starting dose of KBr is 15 mg/kg BID when used as an add-on drug. An oral dose of 20 mg/kg BID is advised when used as a monotherapy. Because of the long elimination half-life, KBr can be administered once daily (preferably in the evening), however, twice daily dosing as well as administration with food can help to prevent gastrointestinal mucosa irritation [123]. Twice daily dosing is also recommended if excessive sedation is present. Therapeutic ranges have been reported as approximately 1000 mg/l to 2000 mg/l when administered in conjunction with PB and 2000mg/l to 3000mg/l when administered alone [126]. Br has a long half-life, consequently, reaching a steady-state serum concentration may require several months (approximately 3 months). Due to this long half-life, timing of blood sample collection relative to oral administration is not critical [123].

當(dāng)作為輔助藥物使用時，溴化鉀的推薦口服起始劑量為15 mg/kg BID。單藥治療時，建議20mg/kg BID 口服。由于清除半衰期長，溴化鉀可以每天給藥一次（最好在晚上），然而，每天兩次給藥以及與食物一起給藥可以幫助防止胃腸道粘膜刺激[123]。如果出現(xiàn)過度鎮(zhèn)靜，也建議每天服用兩次。據(jù)報道，與苯巴比妥聯(lián)合使用時，治療性血藥濃度范圍約為1000 mg/L至2000mg/L，單藥治療使用時約為2000 mg/L至3000 mg/L[126]。溴有很長的半衰期，因此，達到穩(wěn)定的血清濃度可能需要幾個月（大約3個月）。由于半衰期很長，口服給藥后的采血時機無關(guān)緊要[123]。

Baseline complete blood cell count, biochemical profile (including cholesterol and triglycerides) should be performed before starting KBr treatment and periodically every 6 months during treatment. Serum KBr concentrations should be monitored 3 months after treatment initiation (or dose change). In the long term, in dogs with adequate seizure control, serum KBr 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.

應(yīng)在開始溴化鉀治療前進行基線全血細胞計數(shù)、生化檢查（包括膽固醇和甘油三酯），并在治療期間每6個月檢查一次。應(yīng)在治療開始（或劑量改變）的3個月后監(jiān)測血清溴化鉀濃度。從長期來看，對于抽搐控制良好的犬，應(yīng)每6個月監(jiān)測一次血清溴化鉀濃度。如果犬的情況得到緩解或沒有抽搐發(fā)作，建議每12個月檢測一次。

A loading dose may be recommended to achieve steady state therapeutic concentrations more rapidly (e.g. in dogs with frequent or severe seizures, or when PB must be rapidly discontinued because of life-threatening adverse effects). Different protocols have been reported. Oral loading can be performed by administering KBr at a dose of 625 mg/kg given over 48h and divided into eight or more doses. A more gradual loading can be accomplished giving 125 mg/kg/day divided in three to four daily administrations for 5 consecutive days. Daily phone contact with the owners is advised. Loading can be associated with adverse effects (e.g. nausea, vomiting, diarrhoea, sedation, ataxia and pelvic limb weakness, polydipsia, polyuria and polyphagia) and the dog should be hospitalized if loading takes place over 48h (7,85). It is advised to stop loading when serious adverse effects occur. Consider that dogs in which KBr is used as adjunct AED to PB may be more prone to adverse effects. In these cases, a PB dose decrease of 25 % may be needed. Serum KBr levels should be monitored 1 month after loading.

為了更快地達到穩(wěn)定的治療性血藥濃度，可能會推薦使用負荷劑量（例如，頻繁或嚴(yán)重抽搐發(fā)作的犬，或者由于苯巴比妥的危及生命的不良反應(yīng)必須迅速停藥時）。多篇文獻報道了各種方案。溴化鉀以 625 mg/kg，48小時內(nèi)，分為8次或8次以上口服。一個更漸進的負荷劑量可以以 125 mg/kg/天，分三到四次，連續(xù)5天給藥。建議每天與主人電話聯(lián)系。負荷劑量可能會出現(xiàn)相關(guān)不良反應(yīng)（如惡心、嘔吐、腹瀉、鎮(zhèn)靜、共濟失調(diào)和后肢無力、多飲、多尿和食欲亢進），如果負荷劑量超過48小時，犬應(yīng)該住院觀察（7,85）。出現(xiàn)嚴(yán)重不良反應(yīng)時，建議停止給藥?？紤]到使用溴化鉀作為以苯巴比妥治療的犬的輔助抗癲癇藥物時，可能更容易出現(xiàn)不良反應(yīng)。在這種情況下，可能需要減少25%的苯巴比妥劑量。用藥后1個月監(jiān)測血清溴化鉀水平。

Dose increases can be calculated according to the following formula Formula B: For concomitant PB and KBr treatment, the new maintenance dose can be calculated as follows: （2000 mg/l ‐ actual serum KBr steady‐state concentration ）×0.02 = mg/kg/day added to existing dose Formula C: In case of monotherapy KBr, the new maintenance dose can be calculated as follows: (2500 mg/l ? actual serum KBr steady?state concentration) ×0.02 =mg/kg/day added to existing dose

劑量增加可按下式計算

公式B: 對于同時使用苯巴比妥和溴化鉀治療的，新的維持劑量可計算如下: （2000 mg/L - 實際血清溴化鉀穩(wěn)態(tài)濃度）×0.02 = 在現(xiàn)有劑量基礎(chǔ)上添加的mg/kg/天

公式C: 在溴化鉀單藥治療的病例，新的維持劑量可以計算如下: （2500 mg/L - 實際血清溴化鉀穩(wěn)態(tài)濃度）×0.02 = 在現(xiàn)有劑量基礎(chǔ)上添加的mg/kg/天

Only PB and imepitoin are approved as first-line treatment of canine epilepsy in the EU. In most EU countries, KBr is only approved as add-on treatment in dogs resistant to first-line treatments. None of the drugs discussed in the following section are approved for treatment of dogs with epilepsy, thus, according to EU drug laws, these drugs can only be used as adjunctive treatment if monotherapy or polytherapy with the approved treatments have failed. Furthermore, except for levetiracetam, none of the AEDs discussed in the following section have been evaluated in randomized controlled trials in epileptic dogs, so that the evidence for their efficacy is very limited [17].

在歐盟，只有苯巴比妥和伊匹妥因獲批作為犬癲癇的一線治療藥物。在大多數(shù)歐盟國家，溴化鉀只被批準(zhǔn)作為對一線用藥有耐藥性的犬的輔助治療。下一節(jié)中討論的藥物都沒有獲批用于治療犬的癲癇，因此，根據(jù)歐盟藥物法案，如果合法的單一療法或多藥療法都失敗了，這些藥物只能作為輔助治療。此外，除左乙拉西坦外，下一節(jié)討論的抗癲癇藥物均未在癲癇犬的隨機對照試驗中進行評估，因此其相關(guān)療效的證據(jù)非常有限[17]。