TW199096B - - Google Patents
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- TW199096B TW199096B TW081103420A TW81103420A TW199096B TW 199096 B TW199096 B TW 199096B TW 081103420 A TW081103420 A TW 081103420A TW 81103420 A TW81103420 A TW 81103420A TW 199096 B TW199096 B TW 199096B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pyrrole Compounds (AREA)
- Steroid Compounds (AREA)
- Materials For Medical Uses (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
199096 Λ 6 Π 6 五、發明説明（1) 發明之領域 本發明係關於一種癡呆改菩劑，其包含由下式u)表示 之Ν-(2,6 -二甲基苯基）-2-(2 -氣- l- tft咯烷基）乙醛胺（以 下稱為化合物A ):
ch3 (請先閲ift背vfij之注意事項一^填寫本頁) 經濟部屮央櫺準局员工消仲合作杜印製 或其鹽作為有效成份。 發明之背景 在曰本、美國及歐洲各已開發國家中，患有癡呆症之病 患人數隨著老化人口之突然增加已迅速增加。因為對此疾 病尚未有有效的治療方法，對此等病患之對待及照顧成為 嚴重的社會問題。在此情況下，許多藥物已被檢驗以開發 麇呆症之有效治療法。然而，迄今為止仍未發現在臨床上 可用之藥物。 另方面，已知化合物A在延長血氣濃度降低者之存活時 間以及由於腦病引起之記億衰退方面為有效，如』卩-8_62-5 4 0 4 (此處所用之"J P - B ” 一詞意指”已審査日本專利申請案 ”）所示（相對應於美國專利4341790號）。但是，從未報導 有化合物A可臨床使用於改善癡呆症狀。 發明之概述 本發明人等已發現化合物A被患有發呆症如阿耳滋海黙 裝- 訂- 本紙張尺度边用中明明家樣準(CNS)甲4規格(210X297公*) 3 81. 4. 10,000張（H) 199096 Λ 6 Π 6 經濟部中央標準局Μ工消奸合作社印製 五、發明説明（2) 氏（Alzheimer)型麇呆症或腦血管病變型癡呆症之病患服 用時在改善此等類型疾病之症狀上具優異效果，而其效果 從未被習知治療學預期過，本發明因此得以完成。 本發明係關於一種裔呆改善劑，其包含化合物A或其鹽 作為有效成份。 發明之細節說明 本發明有關之疑呆症主要被分成阿耳滋海黙氏型癡呆症 及腦血管病變型癡呆症。阿耳滋海黙氏型癡呆症可被分成 老年性疑呆症及阿耳滋海黙氏型疾病。一般預期化合物A 對此等疾病可發揮優異效果。 化合物A可以每成人60〜900呢/day之劑量（在口服情況下 )被口服或非經腸的投藥（例如，靜脈注射）。含有化合物A 之製劑之例包括錠劑、膠囊、九劑、乳液、懸浮液、稀薄 液劑及注射劑。此等製劑可藉已知藥學技術使用一般添加 劑（例如，《充劑、黏合劑（羥丙基纖維素等）、成份（乳糖 、玉米澱粉等），而被配製成。 化合物A具有高度安全性。當口服至雄鼠及雌鼠時，其 顯示急性毒性（LD50)分別為2005mg/kg及1940mg/kg。因此 ,臨床上己證實化合物A安全性高。 化合物A在改善精神官能之減退如定向力缺失（地方、時 間），其為寂呆症之主要症狀，以及一般副症狀如減少的 自發性、感情的障礙、人際交往障礙、反常行為、日常生 活及動機活動方面之障礙方面有極高功效。因此，化合物 A為極優異的癡呆改善劑。 (請先閲讀背而之注意事項再填窍本頁) 本紙張尺度遑用中8國家標準(CNS)<r4規格(210x297公龙） 4 81. 4. 10,000» (H) 199096 Λ 6 Π 6 經濟部屮央榣準局员工消费合作社印製 五、發明説明（3) 以下藉下列實施例藉一步詳述本發明，但本發明並不受 此等實施例所限制。 實施例1 將300mg/day之化合物Α口服至5位病患（不包括基於 Hachinski腦-絶血的計分之腦血管病變型癡呆症）8〜12週 ，該等病患在CT (電腦的局部）(射線檢法）或MRI (磁共振照像 )中顯示腦萎縮或腦室擴大，因此基於dsm-iii-r(美國精 神病變學會製訂之精神病診斷用手冊）說明之臨床症狀被 診斷為阿耳滋海黙氏型之癡呆症。在投藥前及投藥4週、8 週及12週後，此等病患之疑呆症狀況偽藉評估疑呆症之典 型方法臨床評估，即，藉敏捷度分級（以下簡稱為fast)識 力官能之評估標準（改良的GBS)、細撤精神狀態之檢定（以 下簡稱為MMS)、海茲加華（Hasegawa)之簡化凝呆症標度 (以下簡稱為HDS)及克賴頓（Crichton)之行為評估標準來 分類麇呆症狀之嚴重度。基於如此所得之數據，評估各病 例之最終整髏改善率（以下簡稱為FGIR ‘）及總體安全率（以 下簡稱為0SR)。 表1顯示FGIR及0SR之結果，而表2顯示各症狀改善或惡 化之病患數目。表3及4各顯示一 FGIR改善之病患。 (請先閲-ift背而之注意事項#填寫本頁) 裝· 訂· 線· 本紙张尺度遑用中國國家榣毕(CHS) 規格（210X297公龙） 5 81. 4. 10,000ft (H) 199096- 五、發明説明（4) Λ 6 η 6 表 1 評估 病例數目 • I. II III IV V VI FGIR 5 2 2 1 OSR 5 5 [FGIR] 工：明顯改善 工工：改善 工稍微改善 IV:.未改變 V:稍微加重病情 VI:加重病情 [OSR] 工：無安全問題 11:可忽略的安全問題存在 III:安全問題存在 IV:顯著的安全問題存在 _2_ 改善或惡化的項目（症狀） 病例數目 改善 惡化 (請先閲讀背而之注意事項#填寫本頁) 裝. 訂- 線. 經濟部中央標準局貝工消ft·*合作社印製 礙 障 礙退 之 性障減 動 發礙的之 活 自障往能為活 的的交官行生 少情際神常常 減感人精反日 5 5 5 5 5 5 2 2 2 2 1 1 0 10 0 11 本紙》尺度逍用中Η Η家楳準(CNS)T4規格（210x297公;《：) 6 81. 4.〗0,000張（Η) 199086 Λ 6 I? 6 五、發明説明（5 ) 处谇-/80 300 mg/12 菌 阵淫/将隳 湮 _/取 ΓΙΒ5 β. i¾顆搿 / _ _ 澍 gflasVCT/MRI 笫採阵》&X2并/ 篋栊憨：聶玴， 鏟邮箱)+:-*闲 0 (請先閲讀背面之注意事項再填寫本頁) -•tx - :成S鄉/ ln>a攤漥 »/銪 經濟部中央標準局员工消费合作社印製
5A/{lr/lOJ 燁»蹄/篚-樓& 3 ι-ι-φ/MMS/ ¾铤曾«菰渖 FGIR/OSR »咖/ 铕艰w>通豳 本紙張尺度逍用中Η B家標準(CNS)甲4規格（210x297公龙)7 199086 Λ 6 Π 6 五、發明説明（6 ) 冷 a s* «o S cn cn a 先前 •11 13.( 蝣荖钿 冶a# 顆锻祀 S SR i^· 1¾竽 ssg?5 3画贫 χ 4, " ㈣·. 33 ·* 萍3 ’’ n>®- Nm 锻® 埋理 峰 Η* H-* rfs- mm ® jVJ- 激11$ 薙遂 sa U1 趣 笤艰 H? 商 丄丄 H- l·-* 03 LH Ln Ul 链 J-* Η-* κ* cn to 00 m. »lt5a (請先閲讀背而之注意事項#塡寫本頁) αι @9
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諛逋遒NhMii#钿,«§ S (請先閲讀背而之注意事項再填窍本頁) 蒲 β 菇5S裔狨錁萏3, ffi 辞涞裁M-Mia堋漥en 陆_$1薛封»钿 通甩薄；f^潘 (蔽憨 _ΜΤ 当过+iiK MM-S· "¾啩 _ 菰SSS?··) l-taop 裝· 訂< 3 (a 線· 本紙張尺度逍用中國a家標毕(CNS)肀4規格（210X297公釐） 9 81. Ί.〗0,000張(H) 199096 Λ 6 Β 6 五、發明説明（8) A k /73 300 mg/9 菡 ST 咎辞疳遐 / 山-fir 窓啪豁：畏埘， 菹邮菊沖“-fl-葙
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0_一_ 疼寐葙/篋-擦 &3 It^/MMS/B I S>:逋誃锄、¾斑哲*藏葙 阵渔/l-tfrmflaIBailas笨锻荊味激福lis/CT/MKIln>laE 漤 t_ FGIR/OSR ...... · .................裝.....?τ. ·:線 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度边用中Β國家標準（CNS)甲4規格(210X297公龙） 199086 Λ (5 Ι{6 五、發明説明（9) M· a >f? μ S3 無 s s* , g cn cn aasstf ° ,陳.. 丄丄郎ar 二二*"瞄裔 ί~π 飽阵滿
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IV IV Ί0-2 园 瑯· m 線_ 經濟部屮央楛準局A工消设合作社印製 私紙張尺度逍用中88家棋準(〇奶）肀4規格(210父297公龙）12^ (冷3,趄 (5 S5&
mmi± 'm} 辞 (M· SP 81. 6. 10,000張（H) 五、發明説明（10) 10 11 1 X 1 X 1 丄 1 X 1 X 2 X 2 11 :wss 6:淬饼鍤 11: W 0!35、^ 7:苻 3: 4: Als^fii Co: ijgii翅疳· 9:菌罱 0 裨¾筠 kMI鉍疵,«c»s 泛0Γ 0 ? 汫3 — 12 一丨g_j夺La/沌碑踎％楚荔 (請先閱讀背面之注意事項再填寫本頁) 裝· 經濟部中央#準局ΕΪ工消費合作社印製
5:-mw;5='is一〇: w ssaM g锻漭连SS:雎枭屮葙宠 缄夺强鈿(財饴鄉到翅浬篇葫) HDSi«MMS Se1l»)€® 苺 00睡 wMsf规 gf£5孕滂。 mitM銮，&蹓阵知却葙阵涅|§»雌 9闼萍涞^ma菡猡。 涞 |*|莒5斜 Λ 茹甭，sH3Mt^>ffs w-etiDf 4 (® ) 線· 本紙張尺度逍用中Η國家榣準（CNS)甲4規格（210X297公龙） 199086 Λ 6 Π 6 經濟部屮央櫺準局貝工消作合作社印製 五、發明説明（11) 如上表淸楚顯示，化合物Α對改善患有阿耳滋海黙氏型 癡呆症之病患之精神症狀（例如，減少的自發性、感情障 礙、人際交往障礙、精神官能之減退、反常行為）方面相 當有效。評估對此等症狀改善的功效，化合物A之全部改 善率為40ίϋ(毎所有5個接受試驗的病例中有2値改善的病例 )。又由表1可知，5個病例中有2個病例之精神症狀未惡化 。另外，從所有接受試驗的病患皆未曾被觀察到副作用。 通常，患有阿耳滋海黙氏型癡呆症之病患之主要待歡點 就在此病之症狀愈來愈惡化，而任何藥物從未顯示對此病 之臨床功效。 因此，此等化合物Α對阿耳滋海黙氏型癡呆症之臨床功 效，即，對症狀之改善功效，對有關症狀惡化之抑制功效 及對有關安全性之功效，從對此病之傳統藥物之臨床功效 從未被預期過。 實施例2 令患有腦血管病變型鉸呆症之1 4 5位病患口服1 5 0〜4 5 0 mg /day化合物A歴時8週，該等病患於CT (電腦局部）{射線檢 法）中顯示梗塞形成或出血的病害，而在疑呆症之簡便診 斷所常用之海Η加華簡化癡呆症標度（H DS)中計分低於22 點。在開始投藥前及4週及8週後各病患之臨床狀況用HDS 來評估，HDS常被用來評估醒腦劑（noofropic agent)之功 效。基於此等數據，測定最終整體改善率（FGIR)及全部安 全率（0SR)。 表1顯示FGIR及0SR之結果，表2顯示各症狀之改善率（ίϋ)。 本紙ft尺度逍用中as家樣毕(CNS) Ή規格（2丨0x297公;¢) 81. 4. 10,000張（H) (請先閲讀背而之注意事項Λ-填寫本頁) 199096 A 6 Η 6 五、發明説明（12) %_1 病例數目' I II III IV V DP FGIR 145 7 37 57 33 5 6 72.7 [改善率 (%)*] OSR 145 -134 8 3 0 0 97.9 [•安全率. (%)**] *: 改善率 =(I + 工工 + ΙΙΓ)/139 X 100 **: 安全率 =(工+工工）/145 ；< 100 " [FGIR] 工：明顯改善 II:中度改善 1工工：略有改善 .IV:未改變. V:病情加重 DP·· 放棄 [OSR] 工：無安全問題 工工:·可忽略的安全問題存在 ΙΙΓ:懷疑有安全性 IV 安全 問題存在S > existed. 表 2 ‘症 狀 病· 案號數 改_率 惡化率 (%) (%) 減 少 的 白 發 性 138 59.4 0·0 感 情 障 礙 135 54.1 1,5 Λ 際 交 往 障 礙 122 38.5 0-8 精 神 官 能 之 下 降 139 46.0 2.2 反 常 行 為 49 49.0 10-2 本紙張尺度边用中a S家櫺箏(CNS) τ 4規格(210X297公;a：) 81. 6. 10,000張（Η) (請先閲讀背而之注意节項再填寫本頁) 14 199086 Λ 6 I? 6 經濟部屮央櫺準局β工消"合作社印级 五、發明説明（13) 由上表可清楚顯示，化合物A在改善患有腦血管癡呆症 之病患之精神症狀（例如，減少的自發性、感情障礙、人 際交往障礙、精神官能之減退、反常行為）方面相當有效 。藉一般評估此等結果所測定之全部改善率為72.7S!,顯 示優異功效。 通常，一般認為藥物治療對腦血管病變型癡呆症之功效 劣於對腦血管失調之後遣症即，前者之前期的功效，然而 ,化合物A達到腦血管鉸呆症之高總體改善率（72.7：«),其 相當於，甚至超過傳統醒腦劑對腦血管失調後遣症之總體 改善率（約70¾)。 另外，曾懷疑是否蕖物治療對精神官能之減退，即，癡 呆症之主要症狀有效。化合物A對此症狀之全部改善率為 46SC,其高於安慰劑（25¾)及其他醒腦劑（約355U)。 另方面，亦可證實，化合物A為高度安全性（0SR=97.9!K )而僅在4個病例（3¾)中看到暫時性副作用。 此等結果顯示化合物A在改善腦血管寂呆症之功效方面 較傳統所用之藥物優異得多。 雖然本發明已參照其特定具體例詳述之，任何熟悉此技 藝之人士當可明白，在不脱離其精神及範圍外，可對其作 各種改變及修正。 (請先閲讀背而之注意事項#填寫本頁) 裝· 訂_ 本紙张尺度边用中S Β家標準(CNS)甲4規格（210X297公釐) 15 81. 4.〗0,000張（H)
Claims (1)
- A7199086 B7 ,7 ? C7 Ό7 傅biiZ 12降正」 ί 六、申請專利範圍 古厚、 本年月日 :、充 呆 疑 型 變 病 管 血 腦(I 及式 呆下 疑由基 氏含烷 黙包咯 海係吡 滋其1- 耳.- 阿物 善合(2 改組 2 於藥)-用醫基 種之苯 一 狀基 1.症甲 之 二 之 示 表 氧 胺0 乙C 包 偽 其 物 合 组 藥 醫 之 退 減 UE ,_3 官 申 O 荇精 份 善 成改 效於 有改 為用 作種 鹽 一 其 2 或 基 苯 基份 甲成 一-效 6’有 2 i -為 N-做 含鹽 氣 其 或 胺0 乙 基 烷 咯 tti 能 官 神 揞 中 其 物 合 組00 之 / g者 21失 第缺 圍力 範向 利定 專種 II一 申為 如退 3減 之 (請先閲讀背面之注意事項再填寫本頁) 6·* .裝'一 ί/ 打' .Μ, ，Λ 經濟部中央標準局®:工消費合作杜印製 本纸張尺茂適用中a因家潆準（CNS)甲丨規格（210 X 297 X π ) 81.9.10,000
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| AU727482B2 (en) | 1996-10-01 | 2000-12-14 | Daiichi Pharmaceutical Co., Ltd. | Mitochondrial membrane stabilizer |
| AU8131198A (en) | 1997-07-15 | 1999-02-10 | Daiichi Pharmaceutical Co., Ltd. | Prophylactic or therapeutic agent for amnesia |
| IT1312107B1 (it) * | 1999-05-14 | 2002-04-04 | Umberto Cornelli | Glicosaminoglicani aventi peso molecolare medio di 2400 d atti altrattamento della demenza senile |
| US20040077709A1 (en) * | 1999-05-31 | 2004-04-22 | Daiichi Pharmaceutical Co., Ltd. | Neuronal death inhibitors |
| CA2374921A1 (en) * | 1999-05-31 | 2000-12-07 | Shigeo Watabe | Neuronal death inhibitors |
| US6376489B1 (en) * | 1999-12-23 | 2002-04-23 | Icos Corporation | Cyclic AMP-specific phosphodiesterase inhibitors |
| GB0004297D0 (en) * | 2000-02-23 | 2000-04-12 | Ucb Sa | 2-oxo-1 pyrrolidine derivatives process for preparing them and their uses |
| US6423739B1 (en) | 2000-02-23 | 2002-07-23 | Daiichi Pharmaceutical Co., Ltd. | Method for aiding cerebral recovery following neurodegeneration |
| US6348489B1 (en) * | 2000-04-11 | 2002-02-19 | Daiichi Pharmaceutical Co., Ltd. | Method of treating traumatic brain injury and other neuronal disorders |
| US7608636B2 (en) * | 2000-12-28 | 2009-10-27 | Hamilton Pharmaceuticals, Inc. | Medicines for treatment and prevention of neurogenic pain |
| ES2311537T3 (es) * | 2001-08-22 | 2009-02-16 | Hamilton Pharmaceuticals, Inc. | Utilizacion de nefiracetam en el tratamiento de la neurodegeneracion postquemica. |
| US20060241144A1 (en) * | 2005-04-20 | 2006-10-26 | Albert Cha | Method for treating apathy syndrome |
| US7972633B2 (en) * | 2007-02-07 | 2011-07-05 | Applied Cognitive Sciences, LLC | Nutritional supplements for healthy memory and mental function |
| RU2327480C1 (ru) * | 2007-05-23 | 2008-06-27 | Виктор Иванович Рощин | Активный ингредиент лекарственного средства, лекарственное средство, фармацевтическая композиция и способ лечения больных с дементным синдромом |
| ES2865504T3 (es) * | 2008-10-16 | 2021-10-15 | Univ Johns Hopkins | Procedimientos y composiciones para la mejora de la función cognitiva |
| EP2533645B1 (en) * | 2010-02-09 | 2016-07-27 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
| EP2919788A4 (en) | 2012-11-14 | 2016-05-25 | Univ Johns Hopkins | METHOD AND COMPOSITIONS FOR TREATING SCHIZOPHRENIA |
| WO2014144801A1 (en) | 2013-03-15 | 2014-09-18 | Agenebio Inc. | Methods and compositions for improving cognitive function |
| EP3827820A1 (en) | 2013-03-15 | 2021-06-02 | The Johns Hopkins University | Brivaracetam for improving cognitive function |
| CN112843005B (zh) | 2015-05-22 | 2023-02-21 | 艾吉因生物股份有限公司 | 左乙拉西坦的延时释放药物组合物 |
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| BE864269A (fr) * | 1977-03-03 | 1978-06-16 | Parke Davis & Co | Nouveaux n-(aminoalkyl substitue)-2-oxo-1-pyrrolidine-acetamides et procedes pour les produire |
| IT1141287B (it) * | 1979-06-13 | 1986-10-01 | Nattermann A & Cie | Ammidi di acidi pirrolidin-(2)-on-(1)-ilalchil-carbossilici,procedimento per la loro preparazione e prodotti medicinali che le contengono |
| US4385053A (en) * | 1981-03-11 | 1983-05-24 | Barry Reisberg | Treatment for human memory impairment associated with aging |
| JPH0699307B2 (ja) * | 1987-08-20 | 1994-12-07 | キッセイ薬品工業株式会社 | 抗痴呆剤 |
| IT1231477B (it) * | 1989-07-12 | 1991-12-07 | Sigma Tau Ind Farmaceuti | (pirrolidin-2-one-1-il) acetammidi quali attivatori dei processi di apprendimento e della memoria e composizioni farmaceutiche comprendenti tali composti |
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| MX9202058A (es) | 1993-03-01 |
| KR100310590B1 (ko) | 2001-12-28 |
| US5886023A (en) | 1999-03-23 |
| IL101738A0 (en) | 1992-12-30 |
| DE69231955T2 (de) | 2002-04-04 |
| CA2067614C (en) | 2002-07-30 |
| SG49650A1 (en) | 1998-06-15 |
| HK1002153A1 (zh) | 1998-07-31 |
| NO921724D0 (no) | 1992-04-30 |
| HU9201477D0 (en) | 1992-07-28 |
| DK0515866T3 (da) | 2001-09-24 |
| ES2160097T3 (es) | 2001-11-01 |
| CS130692A3 (en) | 1992-11-18 |
| NO312813B1 (no) | 2002-07-08 |
| HUT62790A (en) | 1993-06-28 |
| EP0515866A1 (en) | 1992-12-02 |
| AU3774595A (en) | 1996-03-07 |
| PT515866E (pt) | 2001-11-30 |
| KR920021143A (ko) | 1992-12-18 |
| AU1595492A (en) | 1992-11-05 |
| ATE203402T1 (de) | 2001-08-15 |
| CZ281170B6 (cs) | 1996-07-17 |
| IL101738A (en) | 1999-01-26 |
| IE921377A1 (en) | 1992-11-04 |
| HU224689B1 (hu) | 2005-12-28 |
| NO921724L (no) | 1992-11-03 |
| CA2067614A1 (en) | 1992-11-03 |
| RU2070042C1 (ru) | 1996-12-10 |
| SK279285B6 (sk) | 1998-09-09 |
| GR3036970T3 (en) | 2002-01-31 |
| AU697936B2 (en) | 1998-10-22 |
| EP0515866B1 (en) | 2001-07-25 |
| DE69231955D1 (de) | 2001-08-30 |
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