200835509 九、發明說明： 【發明所屬之技術領域】 [001]本發明關於治療急性缺血性中風人類患者的方法。 這些方法包括投與人類患者依諾肝素鈉（本文中有時稱為 5 「依諾肝素」）。本發明也關於預防或治療急性缺血性中風人 類患者之血栓形成的方法，例如血栓形成發作或靜脈血栓形 成。 【先前技術】 10 [002] 依諾肝素鈉可從賽諾菲一安萬特購得，商標名稱為200835509 IX. Description of the invention: [Technical field to which the invention pertains] [001] The present invention relates to a method for treating a human patient suffering from acute ischemic stroke. These methods include administration of enoxaparin sodium in human patients (sometimes referred to herein as 5 "enoxaparin"). The invention also relates to methods of preventing or treating thrombosis in a human condition of an acute ischemic stroke, such as a thrombotic episode or a venous thrombosis. [Prior Art] 10 [002] Enoxaparin sodium can be purchased from Sanofi-Aventis under the trade name
Lovenox⑧（在其他一些國家為Clexane®)。已知的依諾肝 素鈉劑量療程包括下表所示方案： 劑量療程 適應症 標準療程 嚴重的腎損傷 腹部手術前之預防 40mg皮下，每曰 一次 30 mg皮下，每 日一次 膝關節置換手術前之預 防 30 mg皮下，每12 小時一次 30 mg皮下，每 日一次 髖關節置換手術前之預 防 30 mg皮下，每12 小時一次，或40 mg皮下，每曰一次 30 mg皮下，每 日一次 200835509 患者内科疾病之預防 40 mg皮下’每曰 一次 30 mg皮下，每 日一次 併發或未併發肺栓塞的 急性深靜脈血栓形成 (pVT)住院治療 1 mg/kg皮下’每 12小時一次（與可 邁丁 (warfarin)—起 注射） 1 mg/kg皮下，每 日一次 未併發肺栓塞的急性 DVT門診治療 1.5 mg/kg皮下，每 曰一次（與可邁丁 一起注射） 1 mg/kg皮下，每 日一次 不穩定性絞痛和非Q波 心肌梗塞的局部缺血性 併發症之預防 1 mg/kg皮下，每 12小時一次（與阿 司匹靈一起注射） 1 mg/kg皮下，每 日一次 老年患者··對於75歲或75歲以上老年患者的急性心肌梗 基的/口療’從母12小時一次〇·75 mg/kg皮下注射的劑量開 始0 【發明内容】 [〇〇3]本發明提供了一種治療65歲或65歲以上急性缺血 性中風或平均Nm中風指數為1〇或1〇以上的人類患者的 方法’包括在一個治療用藥期内投與該患者至少一劑4〇 mg 依諾肝素鈉。還提供了 一種在65歲或65歲以上急性缺血 性中風或平均NIH中風指數為1〇或10以上的人類患者中 200835509 預防或治療血栓形成如血栓形成發作的方法，其藉由以依 諾肝素治療該患者。 [004 ]本文所用的術語「依諾肝素鈉」是指經美國食品和 醫藥管理署(FDA)或美國國外任何監管機構所批准的名為 5 Lovenox㊣（依諾肝素鈉注射劑）、Clexane®或Klexane®的 低为子里肝素(LMWH)，以及經美國FDA或美國國外任何 監管機構，基於將Lovenox®(依諾肝素鈉注射劑）、clexane® 或Klexane®列為藥物的申請書，所批准的任何lMWH。依 諾肝素納可從赛諾菲-安萬特購得，在美國以依諾肝素納 10 ’主射劑的形式銷售，商標名稱為Lovenox⑧（在某些其他國 家為Clexane®)。通常，依諾肝素鈉是從豬腸粘液提取的肝 素苄酯經鹼性降解而獲得的。其結構特徵為在分子鏈非還 原端具有一個2-0-磺基_4_烯吡喃糖醛酸基，在還原端具有 一個2-N，6-0-二磺基葡糖胺。平均分子量約為45〇〇道爾 15 頓。其分子量分佈如下： <2000道爾頓 < 20% 2000 to 8000 道爾頓 > 68% >8000道爾頓 < 18% =〇5]依諾肝素納注射劑是一種含有依諾肝素納的無菌水 20 〉谷液。依諾肝素鈉注射劑可從賽諾菲一安萬特購得，其形 式為100 mg/ml預灌裝注射器（3〇 mg/〇 3 預灌裝注射 器、40 mg/0.4 mL預灌裝注射器、6〇 mg/〇 6 mL預灌裝注 射器、80 mg/0.8 mL預灌裝注射器，以及1〇〇 〇 mL預 200835509 5 10 15 灌裝注射器）、帶刻度預灌裝注射器、多劑量小瓶（300 mg/3.0 mL多劑量小瓶），以及安咅瓦瓶（30 mg/CL3 mL)。濃 度為100 mg/mL的依謹肝素鈉注射劑按每0.1 mL注射用水 計含有10 mg依諾肝素鈉（抗Xa因數活性約為1〇〇〇 ιυ [灸 照W.H.O·第一國際低分子量肝素參照標準])。賽諾菲〜安 萬特也有形式為150 mg/ml帶刻度預灌裝注射器（9〇 mg/0.6 mL預灌裝注射器、120 mg/0.8 mL預灌裝注射p， 以及150 mg/1.0 mL預灌裝注射器）的依諾肝素納注射劑。 濃度為150 mg/mL的依諾肝素鈉注射劑按每〇1 mL注射用 水計含有15 mg依諾肝素鈉（抗Xa因數活性約為15〇〇出 [參照W.H.O·第一國際低分子量肝素參照標準])。 [006]依諾肝素納注射劑預灌裝注射器和帶刻度預灌裝注 射器不含保存劑，且僅作為單劑量注射劑使用。另還^備 含有15 mg/1.0 mL苄醇保存劑的多劑量小瓶。誃、、主 PH值為5.5至7.5。依諾肝素納注射劑 :液; 徵用於動脈注射。 狄笾斫才曰 [007] 本文所用的術語「依諾肝素鈉每日一 Α π 立 例如，每24 ±4小時投與一次。 次投與」意為， [_]術語「預防」無論是動詞、動名詞 給最終可能會顯示但尚未顯示出某種 =疋才曰 種症狀（例如血栓形成）的個人實施^4狀況之至少- =該個人出現某種疾病或狀況:症狀=:定= 卞低可表現為，例如，患者身上某種疾病·況二至少— 20 200835509 種症狀的延遲發作。 [009] 本文所用的術語「治療」無論是動詞、動名詞還是 名詞均是指給已經顯示出某種疾病或狀況之至少一種症狀 (例如血栓形成），或先前曾顯示過某種疾病或狀況之至少 5 —種症狀的個人實施治療。 [010] 「體重」是指在依諾肝素納給藥之前經實際稱重確 定或估計的患者重量。如果患者的體重是在第一劑依諾肝 素鈉給藥之前估計的，則患者的體重可在隨後任何一劑依 諾肝素給藥之前經實際稱重而嫁定’而且其後給患者的依 10 諾肝素給藥劑量應予相應地調整。 [011] “Kg”是指以千克計的患者體重。 [012] 本文所用的術語「中風」是指因腦内或腦周圍的乃 部缺血或出血而引起的病灶或全面的神經缺陷的新發作， 並持續24小時以上。顱内出血可藉由相應的腦部造影來冷 15 斷，包括，例如，顯示急性出血血塊存在的CT或mri。缺 血或輕微梗塞可藉由相應的造影來診斷，例如，藉由顯示 下列一種或多種現象存在的造影：低密度、水腫、中線偏 移或腦室消失而無出血的跡象。缺血性梗塞的出血性轉化 可藉由顯示缺血性梗塞及局部性瘀血或流入壞死組織的出 20 血現象的相應造影來診斷。 [013] 本文所用的術語「急性缺血性中風」是指血拾形成 或栓塞而引起的中風。 200835509 [014]本文所用的術語「NIH中風評估表」是指美國國家 衛生研究院中風評估表（NIHSS)，用於衡量中風時神經機 能障礙的嚴重程度。該中風指數通常是在MRI或CT掃描 後1小時内測量的。指數大於25表示非常嚴重的神經損 傷’介於15和25之間的指數表示嚴重損傷，而介於5和 15之間的指數表示輕微至中度的嚴重損傷，小於5則表示 輕微損傷。 [二15]本文所用的術語「治療用藥期」係指在連續基礎上 10 15 諾肝餘第—劑起至投與依浙素崎後—劑止的 嬙^門例如，如果約每24小時服用一劑依諾肝素鈉， 六、匕劑’那麼該治療用藥期就是約9天（或大約216小 打），即弟1劑和第9劑之間的時間。 65 ^ 65 法’其包括在-個治療用藥二2類患者的方 依諾肝錢。還提供了—種在=歲^者至少—劑細g 性中風或平均Nm中^數^ 1Q1歲以上急性缺血 中，預防或治療血栓形成如血^ 以上的人類患者 以依諾肝私療該患者。^柄作的枝，其藉由 脈血栓形成之預 技形成之預防包括靜 括血拾形成發作的治療;=二栓形成的治療包 在某些貝知例中，血检形成的治 '10- 20 200835509 療包括靜脈血栓形成的治療。 [018] 依諾肝素鈉投與方式的例子為注射及皮下注射。 [019] 在某些實施例中，該治療用藥期為，例如，至少6 天、7天、8天、9天、1〇天、11天、12天、13天、14天， 5 或15天。在某些實施例中，該治療用藥期約為10天。 [020] 在該治療用藥期内依諾肝素鈉投與的劑量為，例 如，至少 20 mg、20 mg 至 60 mg、22 mg 至 58 mg、25 mg 至 55 mg、27 mg 至 52 mg、30 mg 至 50 mg、32 mg 至 47 mg、 35 mg 至 45 mg、37 mg 至 43 mg、大約 40 mg，或 40 mg。 i〇 在某些實施例中，依諾肝素鈉的投與量為大約40 mg (或 40 mg)。通常，依諾肝素納每日投與一次。 [021] 在某些實施例中，該治療用藥期是於中風症狀發作 48小時之内起始。在某些實施例中，患者在依諾肝素鈉給 藥之前先接受CT或MRI掃描，以確定診斷，例如急性局 15 部缺血性中風的診斷。 [022] 在某些貫施例中，患者因單腿或雙腿的運動能力受 損若無協助則不能行走。在某些實施例中，上述運動能力 受損在依諾肝素鈉給藥之前已持續至少24小時。 [023] 接受依諾肝素鈉治療的患者通常將是65歲或65歲 2〇 以上。在某些實施例中，該患者的年齡為，例如，至少7〇 歲、至少75歲、至少80歲、至少85歲，或至少9〇歲。 [024] 在某些實施例中，患者顯示的NIH中風指數為，例 200835509 ，至乂 10、至少11、至少12、至少13、至少14，或至 少15 °在某些實施例中，該NIH中風指數在大約5和15 之間。在某些實施例巾，該疆中風指數約為η。 =25]纟某些實施例中，在治療期間投與的依諾肝素納 1 ’、與ACT調節的刪躲相比，足以降低有症狀或無 症狀的冰靜脈血拾形成（DVT)、有症狀肺栓塞（㈤，或 2性PE的主要終點。赠主要可藉由靜脈造影術確定； 二#脈1^衫術不可行時則藉由超聲波檢查法確定。托可藉 VQ掃描、στ掃描，或&管造影術確診。 =]在某些實施例巾，依綺素的投與顯著地降低了主 f療效終點的發生率，例如，降低了至少3G%、至少35%， 3至夕4G/。。在某些貫施例中，相對風險的下降約為44%。 Π在某些實施例中’投與患者至少—種額外的治療 15 月° k類「共;（或「結合治療」）可包括以下實例： 療程中以連續方式投與每種_，以產生結合 有盈效果；和/或 劑 每: 依諾 =]目此’本文方法並不限於投與之順序；依 可在其二㈣給藥之前、同時或之後給藥。此外 藥亭獨.又與’也可與其他治療結合投與’例如 -12. 20 200835509 [029] 在某些實施例中，上述至少一種額外的治療劑是選 自血栓溶解劑、纖維蛋白溶解劑、神經保護劑，以及抗血 小板劑。在某些實施例中，上述至少一種額外的治療劑是 一種血栓溶解劑，選自阿替普酶（alteplase)、阿尼普酶 5 (anistreplase)、瑞替普酶(reteplase)、尿激酶(urokinase)，以 及鏈激酶(streptokinase)。在某些實施例中，上述至少一種 額外的治療劑是一種神經保護劑，選自半胱天冬酶(caspase) 抑制劑、谷氨酸拮抗劑、鈣拮抗劑、鴉片製劑(opiate)拮抗 劑、GAB A-A激動劑、詞啟動蛋白酶(calpain)抑制劑、Nmd A 10 x體拮抗劑、钾離子通道調節劑、PDH激酶抑制劑，以及 抗氧劑。在某些貫施例中，上述至少一種額外的治療劑是 一種抗血小板劑，選自阿司匹靈^叩出幻、氯吡格雷 (clopidogrel)、噻氯匹定(ticlopidine)、阿昔單抗(abdximab)、 表非替得（eptifibatide)、替羅非班(tir〇fiban)以及雙嘧達莫 15 (dipyridamole) 〇 、 [030] 在某些實施例中’上述至少―種額外的治療劑是一 種GP nb/ma抑制劑。在某些實施例中，Gp Ilb/ma抑制劑 包括阿昔單抗（abdximab，以ReaPn)®商標名_隹），妹 羅非班（tirofiban，以Aggrastat®商標名稱銷售），以及^ 2。 非替得（eptifibatide，以Integreli,商標名稱鎖售）々 些貫施例巾至少-種額相治療劑是組織纖溶酶原啟動 劑。在某些實施例中，至少__外的治療劑是雙 例如緩釋型雙嘧達莫。 -13- 200835509 =1]在某些實_中’錢形成之預防包括血栓形 5 10 [32]在k供依諾肝素納劑量療程方面，依諾肝素鈉於遍 的劑量療程是以喊的適應症為基礎。對應於每種^應 症’本文提供了—些方法，包括為患者預防和/或治療急= 缺血性中風的方法。 “ [〇33]對於有關領域一般技術人員顯而易見的是，對本文 所述的方法和應用所作的其他適宜的修改和改進也是適宜 的且是可行的，並不背離本發明之範圍或其任何實施例, 現已詳細地敘述了本發明，通過參考本發明的以下實例， 將月b更β疋地理解本發明；這些實例僅僅是出於說明的目 的而包括在此，並非是意圖限制本發明。 【實施方式】 實例1 ·急性缺血性中風後以低分子量依諾肝素預防靜脈灰 栓栓塞症(PREVAIL)研究 [034] 一些經CT掃描確診及因腿部運動能力受損若無協 助則不能行走的急性缺血性中風患者，登記參加一項前瞻 性、公開標簽、平行分組、多中心研究。這些患者隨機分 組於出現中風症狀48小時内接受依諾肝素40 mg皮下注 射，每天一次’或接受普通型肝素（UFH) 5000 IU皮下注 射，每12小時一次，共10土4天。主要療效終點為治療期 -14- 200835509 間有症狀或無症狀的深靜脈血栓形成（DVT 塞⑽’或致命性則結合。DVT主 確定3靜脈造騎科行日，關料聲波檢 PE藉由VQ掃描、CT掃描，或血管造影術確定。主 終點包括具有臨床意義的顱内出血和顱外大出血。 王 [035]將來自15國的1762名急性缺血性中風患者隨機分 組。各組之間的基線特徵相似。平均年齡為66 〇± 12 9歲， 平均NIH中風指數為η·3。在功效群内（依諾肝素， UFH’n-669)’依諾肝素和UFH的平均預防期均為ι〇·5天。 與UFH相比，依諾肝素將主要療效終點的發生率從181〇/。 (121/669)顯著地降為1〇2%(68/666)，相當於44%的相對風 險下降（ρ=0·_卜按照NIH中風指數的劃分而調整）。具 有S品床思義的顧内出企和顧外大出血之綜合發生率較低且 15 各組之間相似（1.3%依諾肝素相對於0.7% UFH， ρ=Ι0.2275 ) ° [〇36]尤其是，該PREVAIL研究的結果表明，在預防急性 缺血性中風患者的土栓栓塞症(VTE)方面，每天一次注射40 mg依諾肝素比每12小時一次注射ufh明顯地更為有效， 而安全性則相當。 實例2:中風患者的治療 [〇37]確認一位患有急性缺血性中風之患者。該患者66 歲’其NIH中風指數經測定為113。給該患者皮下注射投 -15- 200835509 與40 mg依諾肝素，每天一次共10天。在這ι〇天治療期 内’該患者並未出現任何有症狀或無症狀的深靜脈灰栓形 成（DVT)、有症狀的肺栓塞（pE)，或致命性pE。在這1〇 天治療期内，患者也沒有出現具有臨床意義的顱内出血或 顧外大出J&L。 [〇38』U些實㈣&触綺素_投與加 但並非意2將本發明局限於所述的特定形式， 文意圖涵蓋本發明之精神及如下申浐 ，本 V能包括的各種替代、修改和相當的形式/界疋範圍 【圖式簡單說明】 無 【主要元件符號說明】 無 -16·Lovenox8 (Clexane® in some other countries). The known enoxaparin sodium dosing regimen includes the regimen shown in the following table: Dose course of treatment, standard course of treatment, severe kidney injury, prevention of abdominal surgery before surgery, 40 mg subcutaneous, 30 mg per skin, once daily, knee replacement before surgery Prevention of 30 mg subcutaneous, once every 12 hours 30 mg subcutaneous, once daily hip replacement surgery prevention 30 mg subcutaneous, once every 12 hours, or 40 mg subcutaneous, once every 30 mg subcutaneous, once a day 200835509 patient internal medicine Prevention of disease 40 mg subcutaneously every 30 mg subcutaneously, once daily with or without pulmonary embolism, acute deep vein thrombosis (pVT) hospitalized 1 mg/kg subcutaneously every 12 hours (with Kemaiding ( Warfarin) - 1 mg/kg subcutaneous, once daily without pulmonary embolism, acute DVT outpatient treatment 1.5 mg/kg subcutaneous, once per injection (injected with Kemaiding) 1 mg/kg subcutaneous, once daily Prevention of ischemic complications of unstable colic and non-Q-wave myocardial infarction 1 mg/kg subcutaneously every 12 hours (injected with aspirin) 1 mg/ Kg subcutaneous, once a day elderly patients · For acute myocardial infarction / oral therapy for elderly patients aged 75 or older 'from the mother 12 hours a dose of 75 mg / kg subcutaneous injection starting 0 [Summary] [〇〇3] The present invention provides a method of treating a human patient having an acute ischemic stroke of 65 years or older or an average Nm stroke index of 1 〇 or more, including administering the drug during a therapeutic period of time The patient has at least one dose of 4 mg of enoxaparin sodium. Also provided is a method for preventing or treating thrombosis, such as a thrombotic episode, in a human patient aged 65 years or older with an acute ischemic stroke or an average NIH stroke index of 1 〇 or more, by Heparin is used to treat this patient. [004] The term "enoxaparin sodium" as used herein refers to 5 Lovenox (Enoxaparin Sodium Injection), Clexane® approved by the US Food and Drug Administration (FDA) or any regulatory agency outside the United States. Or Klexane®'s low-grade heparin (LMWH), and any application by the US FDA or any regulatory agency in the United States based on the inclusion of Lovenox® (enoxaparin sodium), clexane® or Klexane® as a drug, Approved for any lMWH. Enoxaparinol is available from Sanofi-Aventis and is marketed in the United States as an enoxaparin 10' main shot under the trade name Lovenox8 (Clexane® in some other countries). Usually, enoxaparin sodium is obtained by alkaline degradation of heparin benzyl ester extracted from pig intestinal mucus. It is structurally characterized in that it has a 2-0-sulfo-4-ene-2-pyranuronic acid group at the non-reduced end of the molecular chain and a 2-N,6-0-disulfosylglucosamine at the reducing end. The average molecular weight is about 45 Torr and 15 tons. Its molecular weight distribution is as follows: <2000 Dalton<20% 2000 to 8000 Dalton> 68% >8000 Dalton<18% =〇5]Enoxaparin injection is an enoxaparin containing enoxaparin Nasal sterile water 20 〉 trough. Enoxaparin Sodium Injection is available from Sanofi-Aventis in the form of a 100 mg/ml prefilled syringe (3〇mg/〇3 prefilled syringe, 40 mg/0.4 mL prefilled syringe, 6〇mg/〇6 mL prefilled syringe, 80 mg/0.8 mL prefilled syringe, and 1〇〇〇mL pre-200835509 5 10 15 filling syringe), pre-filled syringe with scale, multi-dose vial (300 Mg/3.0 mL multi-dose vials), and ampoules (30 mg/CL3 mL). Imazon sodium injection at a concentration of 100 mg/mL contains 10 mg of enoxaparin sodium per 0.1 mL of water for injection (anti-Xa factor activity is about 1 〇〇〇ιυ [Moxibusium WHO·First International Low Molecular Weight Heparin Reference standard]). Sanofi ~ Aventis also has a 150 mg/ml pre-filled syringe with a pre-filled syringe (9 〇 mg/0.6 mL prefilled syringe, 120 mg/0.8 mL prefilled injection p, and 150 mg/1.0 mL pre-filled) Filling the syringe) of enoxaparin injection. Enoxaparin sodium injection at a concentration of 150 mg/mL contains 15 mg of enoxaparin sodium per 1 mL of water for injection (anti-Xa factor activity is about 15 [ [refer to WHO·First International Low Molecular Weight Heparin Reference Standard) ]). [006] Enoxaparin injection prefilled syringes and graduated prefilled syringes do not contain preservatives and are used only as single dose injections. A multi-dose vial containing 15 mg/1.0 mL of benzyl alcohol preservative was also prepared.誃,, the main PH value is 5.5 to 7.5. Enoxaparin injection: fluid; enrolled for arterial injection.狄笾斫才曰 [007] The term "enoxaparin sodium is used once a day, for example, every 24 ± 4 hours. Sub-investment" means that [_] the term "prevention" is either Verbs and gerunds are given to individuals who may eventually display but have not shown a certain type of symptoms (such as thrombosis) to perform at least - the individual has a certain disease or condition: Symptom =: set = Depreciation can be manifested, for example, as a delayed onset of a disease in a patient. [009] The term "treatment" as used herein, whether verb, gerund or noun, refers to at least one symptom (eg, thrombosis) that has been shown to have a disease or condition, or has previously shown a disease or condition. At least 5 individuals with symptoms are treated. [010] "Body weight" means the weight of a patient determined or estimated by actual weighing prior to enoxaparin administration. If the patient's body weight is estimated prior to the first dose of enoxaparin sodium, the patient's body weight can be grafted by actual weighing before any subsequent dose of enoxaparin is administered and the patient's weight is subsequently administered. 10 The dose of norepine should be adjusted accordingly. [011] “Kg” means the patient's weight in kilograms. [012] The term "stroke" as used herein refers to a new episode of a lesion or a comprehensive neurological deficit caused by ischemia or hemorrhage in or around the brain and lasts for more than 24 hours. Intracranial hemorrhage can be chilled by corresponding brain imaging, including, for example, CT or mri showing the presence of an acute hemorrhagic clot. Hemorrhage or mild infarction can be diagnosed by corresponding angiography, for example, by imaging that exhibits one or more of the following phenomena: low density, edema, midline shift, or ventricular disappearance without signs of bleeding. Hemorrhagic transformation of ischemic infarction can be diagnosed by corresponding angiography showing ischemic infarction and localized blood stasis or influx of necrotic tissue. [013] The term "acute ischemic stroke" as used herein refers to a stroke caused by blood formation or embolism. 200835509 [014] The term "NIH Stroke Assessment Form" as used herein refers to the National Institutes of Health Stroke Assessment (NIHSS), which measures the severity of neurological dysfunction during stroke. This stroke index is usually measured within 1 hour after an MRI or CT scan. An index greater than 25 indicates a very severe neurological injury. An index between 15 and 25 indicates severe damage, while an index between 5 and 15 indicates a mild to moderate severe injury, and a score less than 5 indicates a minor injury. [II15] The term "therapeutic period" as used herein refers to a sputum that is administered on a continuous basis from 10 15 Novo-Dr. - for example, if it is about every 24 hours. Take a dose of enoxaparin sodium, hexamidine, and then the treatment period is about 9 days (or about 216 small dozens), which is the time between the first dose and the ninth dose. 65 ^ 65 The law is included in the treatment of two or two types of patients with the disease. Also provided in the case of = age-old ^ at least - agent fine g-type stroke or average Nm ^ ^ 1Q1 years old or older acute ischemia, prevention or treatment of thrombosis such as blood ^ above human patients with enoch liver treatment The patient. The handle of the stem, the prevention of the formation of the vein thrombosis, including the treatment of the formation of seizures; the treatment of the formation of the second plug, in some cases, the treatment of blood formation - 20 200835509 Treatment includes treatment for venous thrombosis. [018] Examples of the mode of administration of enoxaparin sodium are injection and subcutaneous injection. [019] In certain embodiments, the therapeutic period of administration is, for example, at least 6 days, 7 days, 8 days, 9 days, 1 day, 11 days, 12 days, 13 days, 14 days, 5 or 15 day. In certain embodiments, the therapeutic period is about 10 days. [020] The dose of enoxaparin sodium administered during the therapeutic period is, for example, at least 20 mg, 20 mg to 60 mg, 22 mg to 58 mg, 25 mg to 55 mg, 27 mg to 52 mg, 30 Mg to 50 mg, 32 mg to 47 mg, 35 mg to 45 mg, 37 mg to 43 mg, approximately 40 mg, or 40 mg. I〇 In certain embodiments, the enoxaparin sodium is administered in an amount of about 40 mg (or 40 mg). Usually, enoxaparin is administered once a day. [021] In certain embodiments, the therapeutic period of administration begins within 48 hours of the onset of stroke symptoms. In certain embodiments, the patient undergoes a CT or MRI scan prior to administration of enoxaparin sodium to determine a diagnosis, such as the diagnosis of an acute 15 ischemic stroke. [022] In some embodiments, the patient is unable to walk because of the ability to exercise on one or both legs without assistance. In certain embodiments, the above-described impaired exercise capacity has been continued for at least 24 hours prior to administration of enoxaparin sodium. [023] Patients receiving enoxaparin sodium will usually be 65 years of age or older and 2 years of age or older. In certain embodiments, the patient is of, for example, at least 7 years old, at least 75 years old, at least 80 years old, at least 85 years old, or at least 9 years old. [024] In certain embodiments, the patient exhibits an NIH stroke index of, for example, 200835509, to 10, at least 11, at least 12, at least 13, at least 14, or at least 15 °. In certain embodiments, the NIH The stroke index is between about 5 and 15. In certain embodiments, the stroke index is about η. =25] In some embodiments, enoxaparin 1 ' administered during treatment is sufficient to reduce symptomatic or asymptomatic venous blood formation (DVT), as compared to ACT-regulated evasion. Symptoms of pulmonary embolism ((5), or the primary end point of 2 sex PE. The main can be determined by venography; 2# pulse 1^ shirt is not feasible, it is determined by ultrasonic examination. Toke can use VQ scan, στ scan , or & tube angiography confirmed. =] In some embodiments, the administration of vasopressin significantly reduced the incidence of primary f efficacy endpoints, for example, by at least 3G%, at least 35%, 3 to夕4G/. In some embodiments, the relative risk is reduced by approximately 44%. 某些 In some embodiments, 'at least one additional type of treatment is administered to the patient. Combination therapy" can include the following examples: Each of the _ is administered in a continuous manner during the course of treatment to produce a combined pleasing effect; and/or agent per: Enox =] </ RTI> The method herein is not limited to the order of administration; It can be administered before, at the same time as, or after the administration of the second (four). Binding administration 'eg -12. 20 200835509 [029] In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of a thrombolytic agent, a fibrinolytic agent, a neuroprotective agent, and an anti-platelet agent. In some embodiments, the at least one additional therapeutic agent is a thrombolytic agent selected from the group consisting of alteplase, anistreplase, reteplase, and urokinase. And streptokinase. In certain embodiments, the at least one additional therapeutic agent is a neuroprotective agent selected from the group consisting of a caspase inhibitor, a glutamate antagonist, and a calcium antagonist , opiate antagonists, GAB AA agonists, calpain inhibitors, Nmd A 10 x body antagonists, potassium channel modulators, PDH kinase inhibitors, and antioxidants. In one embodiment, the at least one additional therapeutic agent is an anti-platelet agent selected from the group consisting of aspirin, clopidogrel, ticlopidine, abciximab (abdximab) ) (eptifibatide), tirofiban, and dipyridamole 〇, [030] In certain embodiments, at least one of the additional therapeutic agents described above is a GP nb/ma inhibition In certain embodiments, the Gp Ilb/ma inhibitor comprises abciximab (abdximab (ReaPn)® under the trade name _隹), tirofiban (sold under the trade name Aggrastat®), and ^ 2. Non-received (eptifibatide, sold under the trade name Integreli). At least one of the front-phase therapeutic agents is a tissue plasminogen activator. In certain embodiments, at least the therapeutic agent is a double, such as a sustained release dipyridamole. -13- 200835509 =1] In some cases, the prevention of money formation includes thrombus formation 5 10 [32] In the dose regimen of enoxaparinol for k, the dose of enoxaparin sodium is shouted Based on indications. Corresponding to each of the conditions, the present invention provides methods for preventing and/or treating acute/ischemic stroke for a patient. It is apparent to those skilled in the relevant art that other suitable modifications and improvements to the methods and applications described herein are also suitable and feasible without departing from the scope of the invention or any implementation thereof. Having now described the invention in detail, the invention is to be understood by reference to the following examples of the invention, which are included for the purpose of illustration only, and are not intended to limit the invention. [Examples] Example 1 · Prevention of venous ash embolism with low molecular weight enoxaparin after acute ischemic stroke (PREVAIL) [034] Some confirmed by CT scan and impaired leg movement ability without assistance Patients with acute ischemic stroke who are unable to walk are enrolled in a prospective, open-label, parallel-group, multicenter study. These patients were randomized to receive enoxaparin 40 mg subcutaneously within 48 hours of stroke symptoms, once daily. Or receive normal heparin (UFH) 5000 IU subcutaneous injection, every 12 hours, a total of 10 soil 4 days. The main efficacy endpoint is the treatment period-14- 20083 5509 Symptomatic or asymptomatic deep venous thrombosis (DVT plug (10)' or fatal combination. DVT is mainly determined by 3 venous gynecology, and the acoustic echo is detected by VQ scan, CT scan, or angiography. The primary endpoint included clinically significant intracranial hemorrhage and extracranial hemorrhage. Wang [035] randomized 1762 patients with acute ischemic stroke from 15 countries. Baseline characteristics were similar between groups. The mean age was 66. 〇 ± 12 years old, the average NIH stroke index is η·3. Within the efficacy group (enoxaparin, UFH'n-669), the average prophylaxis period of enoxaparin and UFH is ι〇·5 days. In contrast, enoxaparin significantly reduced the incidence of primary efficacy endpoints from 181〇/(121/669) to 1.2% (68/666), which is equivalent to a 44% relative risk reduction (ρ=0· _Bu is adjusted according to the division of the NIH Stroke Index.) The overall incidence of Gushen and Guwai bleeding with S-study is lower and 15 is similar between groups (1.3% enoxaparin vs. 0.7%) UFH, ρ=Ι0.2275 ) ° [〇36] In particular, the results of the PREVAIL study indicate that prevention of acute deficiency In the case of thrombosis embolism (VTE) in patients with stroke, a daily injection of 40 mg of enoxaparin is significantly more effective than an injection of ufh every 12 hours, and safety is comparable. Example 2: Treatment of stroke patients [〇37 Confirm a patient with an acute ischemic stroke. The patient was 66 years old and his NIH stroke index was determined to be 113. The patient was injected subcutaneously with -15-200835509 and 40 mg enoxaparin once daily for 10 days. During this treatment period, the patient did not develop any symptomatic or asymptomatic deep venous thrombosis (DVT), symptomatic pulmonary embolism (pE), or fatal pE. During the 1 day treatment period, the patient did not have clinically significant intracranial hemorrhage or J&L. [ 〇 38 』 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ , modification and equivalent form/boundary range [Simple description of the diagram] No [Main component symbol description] None-16·