TWI306120B - Method of identifying hungtington's disease patients who will respond to epa treatment and related use of epa - Google Patents
Method of identifying hungtington's disease patients who will respond to epa treatment and related use of epa Download PDFInfo
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Description
1306120 玖、發明說明: 【發明所屬之技術領域】 本發明係有關亨丁頓舞蹈症。 【先前技術】 予丁頓舞蹈症(HD)為一種在人類4號染色體上由蛋白質 亨丁亭之基因突變所致之致命遺傳疾$。以任何合適醫藥 形式之脂肪酸,二十碳五烯酸(EPA)可用以治療hd(如述於 歐洲專利申請案號1 148873)。 【發明内容】 本發明有關HD之治療及基於以下之發現,即EpA之治療 作用特別發生在該等具特殊基因形SHD之病患。 本發明提供-種鑑定具肋之病患或在發展HD危險下之個 體,或特別彳能對以任何合適形式之EpA治療有反應者之方 法及包括之步驟為進行試驗,以測定亨丁亭基因中CAG重 複序列之數目及較該等具45個或更少重複序列之個體。 若個體具少於36個重複序列時,意示為正常個體。在較 佳之試驗中,選定之個體為該等具44個或更少,或36至44 個CAG重複序列者。 試驗可在取自個體僅供分析目的及不還給個體之樣品上 進行。診斷步驟將在體外分析。 本發明再提供一種治療HD之方法,及一種預防在發展1?〇 危險下之個體中發展症狀之方法,包括之步驟為測定個體 f因中了 丁苧之CAG重複序列數目,及其為45個或更少 才杈予任何生物有效形式之EPA至個體。在較佳之試驗
O:\89\89537.DOC 1306120 中I疋投予EPA之個體為該等具44個或更少,或36至44 個CAG重複序列者。 用於本發明方法之EPA較佳為乙基_EpA。 46個或更多之CAG重複序列數目在投予安慰劑或EpA之
全部處理組間不顯示任何差異。相反及未預期地,罹患HD 而具45個或更少之CAG重複序列數目之病患在投予EpA上 顯示很大的益處。 雖然全部HD病患在才目同基因中具有基因異常性,但並非 全部病患具有相同的異常性。亨丁亭之正常基因含有cag 重複序列之基因’其基因自身編碼聚麩胺酸序列。甚至在 正常個體中’聚麩胺酸序列為可變的長度,但只要其含有 >、於3 6個CAG重複序列及因此聚越胺酸序列中少於3 6個麩 胺酸,則個體將正常。然而,當序列含有36個或更多個CAg 重複序列及其後麩胺酸序列時,將發展HD。具HD‘病患會 有著自36至多於1〇〇個cag重複序列。 HD常以動作障礙開始,特別為影響臉部、頭和頸部及四 肢。此些進展及常伴隨著精神異常性及認知損傷,而導致 癡呆。異常性最初由亨丁亭傷害至紋狀體之神經元所致, 但其後會涉及更廣之腦部區域。最後,病患變成臥床不起 及70全不忐照顧自己。其常在疾病開始後丨〇至25年内死亡。 CAG重複序列之數目對疾病開始之年齡有著很強的影 響。具僅超過35個數目之病患不會生病直至其5〇或6〇多歲 或甚至更老。具超過60個重複序列之病患會在青少年或甚 至童年時生病。然而’多數病患傾向在3〇至5〇歲間生病。
O:\89\89537.DOC 1306120 EPA可為乙基-EPA之形式、鋰EPA、單-或雙-或三酸甘油 酯EPA或EPA之任何酯或鹽,或游離酸形式之epa ^ EPA亦 可為2-取代衍生物或其他衍生物之形式,其減緩其氧化速 率,此外並不改變其在精神或腦障礙上之生物作用至任何 貫質程度(N. Willumsen等人,Biochimica Biophysica Acta, 1998, 1369: 193-203)。 EPA可與主要作用在神經傳遞素代謝或受器上之藥物組 合。與EPA製備物共同投予之合適藥物為克洛沙平 (clozapine)及典型和非典型神經安定劑類中之任一,包括氯 丙麻井(chlorpromazine)鹵佩里醇(haloperidol)、里斯佩里g同 (ristperidone) > 歐藍沙平(olanzapine)、色提吲哚 (sertindole)、記普拉西酮(ziprasid〇ne)、佐提平(z〇tepine) 或阿米硫皮里德(amisulpiride)。用以減輕一些亨丁頓舞蹈 症狀之標準抗精神分裂藥物、抗抑鬱劑、鎮定劑及抗癲癇 藥物可與EPA調配物一起投藥。 取自EP申請案號1148873作為治療亨丁頓舞蹈症之實 例,96%純乙基-EPA之隨機試驗在亨丁頓舞蹈症最後階段 之7位嚴重失能病患中進行。全部需要24小時看顧,有著嚴 重動作障礙,暴躁且部分痴呆。其在雙盲試驗基礎下隨機 接受2克/天之乙基-EPA或2克/天之安慰劑共6個月。6個月期 間4位病患顯示進展性退化,而3位病患逆轉疾病之進程及 顯示具降低異常動作,降低情緒易變性和暴躁之改進及改 進記憶與認知功能。當密碼解開日夺’發現惡化之4位病患服 用安慰劑,而改進之全部3位病患皆服用乙基_EpA。在2位
O:\89\89537.DOC 1306120 服用乙基-EPA和2位安慰劑之4位病患中,腦部退化在研究 開始與結束時由磁共振造影(順)評估。_允許精確評估 侧腦室大小,即腦半球内之液體填充空間。當亨丁頓舞蹈 症進展時,側腦室擴大,指示著腦組織之損失。在服用安 慰劑之2位病患中’在6個月内側腦室如預期地擴大。在服 用:基舰之2位病患中,疆顯示側腦室大小之降低,指 示著腦組織損失之確實逆轉。 在由異常蛋白質蓄積所致之先前;^可治療,疾病末期之病 患中此些戲劇性結果展現在神經退化障礙中之乙基 值。 本發明在較可能對如此治療有反應之病患中由分析亨 丁亭基因而提供顯著進展。本發明提供以下優點,即可能 地,鑑定在發展疾病危險下之病患及投予EpA至病患以防止 或延緩疾病症狀之發展。 90%和較佳95%或甚至更純形式之EpA調配物可經熟諳 技藝者所知之傳送系統全部口服投藥,包括軟和硬明膠膠 囊;粉末、錠劑或膠囊形式之微膠囊;固體化合物鋰_EpA 之錠劑;或以適當天然或合成乳化劑,包括磷脂質或半乳 糖脂製成之乳化液。化合物亦可以腸外,直接或調配於不 同油或於乳化液或分散液投藥,使用靜脈内、腹膜内、肌 肉内或皮下途徑。使用貼片技術之局部投藥或陰道或直腸 形式之投藥亦在本發明範圍内。 當與用以緩和亨丁頓舞蹈症狀之藥物組合時,EPa化合 物和其他藥物可分開投藥’各以其自己之調配物。其可分
O:\89\89537.DOC •10- 1306120 開包裝或以相同之總包裝呈現。或者,使用熟諳技藝者已 知之技術’ EPA和其他藥物可一起調配,使得克至1〇克/ 天及較佳地0·5克至5克/天之EPA每曰劑量與其他藥物之正 常每日劑量一起提供。 當單獨投藥時,有用之ΕΡΑ每曰劑量可在〇.〇5克至5〇克/ 天,較佳地0.1克至10克/天及極佳地〇·5克至5克/天之範圍 【實施方式】 實例調配物 在以下之各實施例中,產品至少9〇%及較佳地95%或更 純。此很重要於其他脂肪酸將與ΕΡΑ競爭結合部位及降低其 效力。特別地,脂肪酸如DHA、ΑΑ、DPA-n-3分別將以少 於5 °/。及較佳少於3 %之濃度存在《如此競爭化合物之總聚集 物必須少於10%及較佳少於5%。此純度之程度亦有用於降 低每天必須消費之物質量’其為幫助精神病患順從性之重 要因子,而缺少順從性為其一個嚴重的問題。 1·由硬或軟明膠製成之膠囊,其含有250毫克、5〇〇毫克 或1〇〇〇毫克之乙基-EPA、三酸甘油酯EPA或其他合適形式 之 EPA。 2.含有250毫克、500毫克或1〇〇〇毫克鋰_EPA之錠劑,或 含有相似量之硬明膠膠囊。 3 乳化液、溶液或分散液,其中鋰-EPA、乙基-EPA、三 酸甘油酯EPA或其他合適形式之EPA,以美味液體形式製借 供口服投藥。 4.經調配5克EPA化合物之一至其中之栓劑或陰道藥栓。 O:\89\89537.DOC -11- 1306120 5.含有自10毫克至500毫克/毫升EPA化合物之一之靜脈 内溶液或乳化液。 6-10.如實例1-5,但使用EPA之2-取代衍生物。 11-20.如1-10,但其中EPA化合物與用以治療亨丁頓舞 蹈症狀之經常劑量任何其他藥物一起調配。 O:\89\89537.DOC -12-
Claims (1)
160號專利申請案 專利範圍替換本(97年8月) 拾、申請專利範圍: if I. 2曰更)正替換頁 ...... …_1 I _ 1. -種鑑定會對任何生物可利用形式之二十碳五烯酸㈣ 製備物冶療有反應之亨丁頓舞蹈症病患、或有發展亨丁 頓舞蹈症風險之個體之之方法,其中該EPA製備物中之所 有脂肪酸之至少90%為EPA形式且少於5%為二十二碳六 稀酸(DHA)形式’ S包括測定亨丁亭(Himtingtin)基因之 G重複序列數目之步驟,及識別具4 5個或更少重複序 列之個體。 士申叫專利範圍第1項之方法’其中該治療包括乙基φ 之投藥。 3 . 一種任何生物可利用形式之EPA製備物之用途,其中該 EPA製備物中全部脂肪酸之至少9〇%為EpA形式且少於 5%為二十二碳六烯酸(DHA)形式,其係用於製備用以 治療亨丁亭基因中具45或更少之CAG重複序列數目之亨 丁頓舞蹈症病患的藥劑。 4. 一種任何生物可利用形式之EPA製備物之用途,其中該 EPA製備物中全部脂肪酸之至少9〇%為EpA形式且少於 5%為二十二碳六烯酸(DHA)形式,其係用於製備用以 預防亨丁亭基因中具45或更少之CAG重複序列數目之有 發展予丁頓舞蹈症風險之病患的症狀發展的藥劑。 5. 如申請專利範圍第3或4項之用途,其中該EpA係乙基 形式。 6· 一種包含任何生物可利用形式之EPA製備物之醫藥組合 物’其中該EPA製備物中全部脂肪酸之至少9〇%為epa形 O:\89\89537.970826.DOC #』2辦(更)正替換ΐ 式且少於5%為二十二碳六烯酸(DHA)形式,其係用於 治療亨丁亭基因中具45或更少之CAG重複序列數目之亨 丁頓舞蹈症病患。 • 一種包含任何生物可利用形式之EPA製備物之醫藥組合 物’其中該EPA製備物中全部脂肪酸之至少90%為EPA形 式且少於5%為二十二碳六烯酸(DHA)形式,其係用於 預防予丁亭基因中具45或更少之CAG重複序列數目之有 發展亨丁頓舞蹈症風險之病患的症狀發展。
8.如申凊專利範圍第6或7項之醫藥組合物,其中該EPA係乙 基-EPA形式。
O:\89\89537.970826DOC
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GBGB0228079.0A GB0228079D0 (en) | 2002-12-02 | 2002-12-02 | Huntington's Disease |
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TW200418993A TW200418993A (en) | 2004-10-01 |
TWI306120B true TWI306120B (en) | 2009-02-11 |
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TW092133160A TWI306120B (en) | 2002-12-02 | 2003-11-26 | Method of identifying hungtington's disease patients who will respond to epa treatment and related use of epa |
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US (2) | US20070148643A1 (zh) |
EP (1) | EP1567667B1 (zh) |
JP (1) | JP2006507833A (zh) |
KR (1) | KR20050086895A (zh) |
CN (1) | CN1717497A (zh) |
AT (1) | ATE411399T1 (zh) |
AU (1) | AU2003285519A1 (zh) |
BR (1) | BR0316969A (zh) |
CA (1) | CA2506727A1 (zh) |
CY (1) | CY1108730T1 (zh) |
DE (1) | DE60324180D1 (zh) |
DK (1) | DK1567667T3 (zh) |
ES (1) | ES2315543T3 (zh) |
GB (1) | GB0228079D0 (zh) |
HK (1) | HK1081598A1 (zh) |
HR (1) | HRP20050493A2 (zh) |
IS (1) | IS7842A (zh) |
MX (1) | MXPA05005908A (zh) |
MY (1) | MY138759A (zh) |
NO (1) | NO20052955L (zh) |
NZ (1) | NZ539989A (zh) |
PL (1) | PL376101A1 (zh) |
PT (1) | PT1567667E (zh) |
RU (1) | RU2332209C2 (zh) |
SI (1) | SI1567667T1 (zh) |
TW (1) | TWI306120B (zh) |
UA (1) | UA86582C2 (zh) |
WO (1) | WO2004050913A1 (zh) |
ZA (1) | ZA200504003B (zh) |
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US20130131170A1 (en) | 2011-11-07 | 2013-05-23 | Amarin Pharmaceuticals Ireland Limited | Methods of treating hypertriglyceridemia |
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CN104203289B (zh) | 2012-01-27 | 2020-11-03 | 比奥马林技术公司 | 用于治疗杜兴型肌营养不良症和贝克型肌营养不良症的具有改善特性的rna调节性寡核苷酸 |
RS61557B1 (sr) | 2012-06-29 | 2021-04-29 | Amarin Pharmaceuticals Ie Ltd | Postupci za smanjenje rizika od kardiovaskularnog događaja kod pacijenta na terapiji statinom primenom etil estra eikozapentaenske kiseline |
WO2014074552A2 (en) | 2012-11-06 | 2014-05-15 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides without raising ldl-c levels in a subject on concomitant statin therapy |
US20140187633A1 (en) | 2012-12-31 | 2014-07-03 | Amarin Pharmaceuticals Ireland Limited | Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis |
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US9662307B2 (en) | 2013-02-19 | 2017-05-30 | The Regents Of The University Of Colorado | Compositions comprising eicosapentaenoic acid and a hydroxyl compound and methods of use thereof |
US9283201B2 (en) | 2013-03-14 | 2016-03-15 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for treating or preventing obesity in a subject in need thereof |
US20140271841A1 (en) | 2013-03-15 | 2014-09-18 | Amarin Pharmaceuticals Ireland Limited | Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin |
US10966968B2 (en) | 2013-06-06 | 2021-04-06 | Amarin Pharmaceuticals Ireland Limited | Co-administration of rosiglitazone and eicosapentaenoic acid or a derivative thereof |
US20150065572A1 (en) | 2013-09-04 | 2015-03-05 | Amarin Pharmaceuticals Ireland Limited | Methods of treating or preventing prostate cancer |
US9585859B2 (en) | 2013-10-10 | 2017-03-07 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy |
US10561631B2 (en) | 2014-06-11 | 2020-02-18 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing RLP-C |
US10172818B2 (en) | 2014-06-16 | 2019-01-08 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids |
US10406130B2 (en) | 2016-03-15 | 2019-09-10 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids |
US10966951B2 (en) | 2017-05-19 | 2021-04-06 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides in a subject having reduced kidney function |
US11058661B2 (en) | 2018-03-02 | 2021-07-13 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L |
WO2020068163A1 (en) | 2018-09-24 | 2020-04-02 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing the risk of cardiovascular events in a subject |
KR20240012390A (ko) | 2021-04-21 | 2024-01-29 | 애머린 파마슈티칼스 아일랜드 리미티드 | 심부전의 위험을 감소시키는 방법 |
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CA2116280A1 (en) * | 1993-03-05 | 1994-09-06 | Marcy E. Macdonald | Huntingtin dna, protein and uses thereof |
CA2216057A1 (en) * | 1997-09-19 | 1999-03-19 | Ridha Joober | Polymorphic cag repeat-containing gene, diagnosis of psychiatric diseases and therapeutic uses thereof |
GB9901809D0 (en) * | 1999-01-27 | 1999-03-17 | Scarista Limited | Highly purified ethgyl epa and other epa derivatives for psychiatric and neurological disorderes |
WO2001024781A2 (en) * | 1999-10-07 | 2001-04-12 | Novaneuron Inc. | Gene necessary for striatal function, uses thereof, and compounds for modulating same |
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2002
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2003
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- 2003-11-26 MX MXPA05005908A patent/MXPA05005908A/es active IP Right Grant
- 2003-11-26 SI SI200331472T patent/SI1567667T1/sl unknown
- 2003-11-26 US US10/536,927 patent/US20070148643A1/en not_active Abandoned
- 2003-11-26 TW TW092133160A patent/TWI306120B/zh active
- 2003-11-26 DK DK03778516T patent/DK1567667T3/da active
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Also Published As
Publication number | Publication date |
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GB0228079D0 (en) | 2003-01-08 |
PT1567667E (pt) | 2008-11-04 |
AU2003285519A1 (en) | 2004-06-23 |
US20070148643A1 (en) | 2007-06-28 |
NZ539989A (en) | 2006-11-30 |
MY138759A (en) | 2009-07-31 |
DK1567667T3 (da) | 2009-01-12 |
WO2004050913A1 (en) | 2004-06-17 |
SI1567667T1 (sl) | 2009-04-30 |
ATE411399T1 (de) | 2008-10-15 |
CN1717497A (zh) | 2006-01-04 |
MXPA05005908A (es) | 2005-12-12 |
CA2506727A1 (en) | 2004-06-17 |
EP1567667B1 (en) | 2008-10-15 |
HK1081598A1 (en) | 2006-05-19 |
DE60324180D1 (de) | 2008-11-27 |
TW200418993A (en) | 2004-10-01 |
PL376101A1 (en) | 2005-12-12 |
ZA200504003B (en) | 2007-01-31 |
JP2006507833A (ja) | 2006-03-09 |
HRP20050493A2 (en) | 2005-10-31 |
NO20052955L (no) | 2005-06-16 |
BR0316969A (pt) | 2005-10-25 |
US20090270504A1 (en) | 2009-10-29 |
CY1108730T1 (el) | 2014-04-09 |
UA86582C2 (ru) | 2009-05-12 |
RU2005115536A (ru) | 2006-01-27 |
IS7842A (is) | 2005-05-12 |
EP1567667A1 (en) | 2005-08-31 |
RU2332209C2 (ru) | 2008-08-27 |
KR20050086895A (ko) | 2005-08-30 |
ES2315543T3 (es) | 2009-04-01 |
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