TWI289060B - Pharmaceutical composition for improving the recovery of post-stroke patients - Google Patents
Pharmaceutical composition for improving the recovery of post-stroke patients Download PDFInfo
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- TWI289060B TWI289060B TW090104150A TW90104150A TWI289060B TW I289060 B TWI289060 B TW I289060B TW 090104150 A TW090104150 A TW 090104150A TW 90104150 A TW90104150 A TW 90104150A TW I289060 B TWI289060 B TW I289060B
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Description
1289060 五、發明說明(1) 發明領域 本發明係有關使用環狀7 —胺基丁酸(GABA)衍生物,亦 即N-(2, 6 -二曱基苯基)—2-(2 -氧基-1-吡咯啶基)乙醯胺用 於製備神經變性,特別中風後神經變性治療用藥,俾改善 中風後的日常生活活動(Activities of Daily Living, ADL)或復原,或至少改善中風後病人的復原。 本發明亦係有關包含N-( 2, 6 -二甲基苯基)_2-(2 -氧基 -1 -吼洛啶基)乙醯胺作為活性成分之新穎抗神經變性醫藥 組合物。 發明背景
已知評估中風後病人之肉體缺損,除了作神經學的運動 及感覺檢查外,係根據評估等級例如約翰霍普金斯功能清 單(John Hopkins Functioning inventory,jHFI)或類似 清單定量日常活動(ADL )性能的缺陷,該等級可決定病人 元成正常操作的能力,特別維持坐姿或立姿、走路、洗 手、穿衣、脫衣、用餐、沐浴及使用洗手間。中風後Adl 復原的評估、受損及需求由R0bert G. Rc)binsQri rThe
Clinical Neuropsychiatry」,1 9 98 年,劍橋大學出版 社,143、 222-225 及292-293 頁。 憂營症係與中風相關的主要病症,憂鬱症的嚴重程度與 ADL叉損嚴重程度間有相互關聯。為了改善的受損,也 就是改善由中風中復原之狀況,病人主要係使用抗憂營藥 物治療,根據前述參考文獻,除了抗憂鬱劑治療之外並無 任何有文獻記載的藥理治療可改善中風後肉體或認知上^
90104150.ptd 第5頁 1289060
五、發明說明(2) 復原(Robert G. Robinson 同文,293 頁)。 環狀GABA衍生物,更詳細地說為2-氧基咄咯唆衍生物, 為廣用於改善記憶力及注意力的醫藥組合物,稱作記憶力 增強劑或親智能劑。此類之典型藥物包括2_氧基-丨—\比洛 啶乙醯胺(皮拉西坦(piracetam)),卜(4-曱氧笨甲醯 基)-2 -吼洛啶酮(安尼拉西坦(aniracetam))及4—經—2一氧 基-1-吼咯啶乙醯胺(奥西拉西坦(oxiracetam))。 背景技術說明 -。比略。定乙醯胺 質以及調節代謝 已知(BE 883791 - US 4341790)2-氧基-1 之醯替苯胺類具有中樞血管活性及鎮定性 及抑制血小板凝集之功能。如此該化合物被視為可用於治鲁 療腦缺血或萎縮疾病、腦灌流障礙、腦萎縮危象及腦老化 過程。此等2-氧基-1 -咄咯啶乙醯胺之醯替苯胺類中, 6 -二曱基醯替苯胺亦即n—(2, 6-二甲基苯基)一2-(2 —氧基 -1-吼洛咬基)乙醯胺後文稱作尼費拉西坦係以式(A)表示
ch3 (A)
據報告可延長腦氧濃度下降時的存活時間,以及緩和由於 腦病變造成的記憶力缺失。 該參考文獻徹底揭示(例如參考E· 〇ht〇m〇等人,J·
Clin· Exp· Med·,Suppl·,1 994,Π0/9,777-8 1 6 )尼費 拉西坦可用於改善腦血管病如中風(腦梗塞或腦出血)關聯
90104150.ptd 第6頁
1289060 五、發明說明(3) 的精神障礙,此種活性係由於尼費拉西坦對腦灌流產生有 利作用的結果,如BE 88379 1之提示。 也已知(K· Hirata等人,Brain Topography,1996, 8/3, 2 7 9-284)尼費拉西坦可用作為腦代謝加強劑用於改 善中風病人的心智功能受損,如此證實BE 83379 1之提示 揭示該化合物具有代謝調節性質。但Hirata等人歸結心智 功能試驗的改善並不顯著。 曰 此外,已知(US 588 6 023 )尼費拉西坦可改善因心智功能 下降的導致的腦血管或阿茲海默性痴呆症狀。 匕 雖然此等文獻指示尼費拉西坦對心智功能受損的症狀户 療效果主要係由於其可改善腦灌流,或由於其代謝調節^ 貝。於中風後經常觀察到精神症狀及認知受損,因而對疒 人本人及照顧者皆造成負面影響。 ’ 前述Ohtomo等人之文章中, 亦即中風(腦梗塞或腦出血)後 劑的病人,顯示化合物可改善 生活活動方面兩組間並無顯著 果,尼費拉西坦似乎對中風後 改善上無效。此種適應症的正 中風復原’或至少改善由中風 發明綜述 對兩組病人進行臨床研究, 分別投予尼費拉西坦及安慰 精神症狀,但其結論為曰常 差異。如此,根據此等結 病人的日常生活活動障礙上 面效果應提示藥物可促成由 復原。 病後早期或至多於 則可觀察到曰常生 出乎意外地發現若尼費拉西坦係於發 中風後的首六個月以内投予中風病人, 活活動障礙上有顯著改善。
1289060 五、發明說明(4) 特別,發現尼費拉西坦可誘使中風後病人之復原改善 ’但規定尼費拉西坦須於中風後早期投藥,至多係在中風 後的首六個月以内投予。 此外,出乎意外地發現尼費拉西坦具有顯著的注意力改 善活性,可再生受損的神經元,因而可對抗神經變性;尼 費拉西坦用於中風(腦梗塞或腦出血)導致的神經變性特別 有效。 壁Ug之詳細說明 如此,本發明之目的係提供使用尼費拉西坦製備神經變 性治療用藥。
尼費拉西坦作用於神經變性因而可由中風後復原或改善 由中風復原的機轉未知,原因在於尼費拉西坦並不具有已 决可預測具有此種作用的生化活性,例如5 jj T1 - A受體之促 效作用或AMPA敏感性麵胺酸鹽受體的正面調節作用(AMpa 表示α -胺基-3 -羥-5-甲基-4-異嘌唑丙酸)。 ^尼費拉西坦之神經增強性質,特別說是抗神經變性性質 係基於日常生活活動顯著改善的臨床證據,且經由生物化 學及動物試驗證實。 如此、,本發明之另一目的係提供使用尼費拉西坦製造中
風,改善病人日常生活活動(ADL)之藥物。治療包含對病· 人投予有效量之尼費拉西坦,投藥係始於中風後的首六個 月0 為了,示最佳活性,尼費拉西坦係於中風後早期投藥或 儘速投藥,較佳係於三個月内、更佳於一個月内投藥。
90104150.ptd 第8頁 1289060 五、發明說明(5) 尼費拉西坦係以多種 予中風後病人改盖ADL +式技本來達成預定效果,例如投 改善復原狀況。;人物开或。用於中風後病人的復原或至少 藥,醫藥妞合物包:華理::f藥或呈醫藥組合物形式投 分,以及醫藥可接二有效1之尼費拉西坦作為活性成 口服。尼費拉西)齊1投予接受治療的病λ ’較佳為 方之有效量劑量可有變化,且為依據醫師處 合物之例係於寬二人之投藥模式決定經口投予化 2。毫克/公斤、,?及二改為 人體重。尼鲁^ 為笔克/公斤至15毫克/公斤病 有約50毫克$西坦於口服醫藥組合物之單位劑量例如含 =1至t;::1 藥2°。°毫克’通常10一^ 所九中6丘貝。化合物經口投予中風後六個月 以内之位中風後病人,同時有2 7位病人接受安慰劑。兩 組病人至少追蹤8周時間,於第4周結束時以及於第8周 束時追蹤測量日常生活活動的症狀分數。#受尼費拉西: 處理病士顯示中等或顯著改善,而使用安慰劑處理組病人 並未顯不改善。5 9位病人中,於中風後頭三個月内1 9位接 受尼費拉西垣及1 〇位接受安慰劑。約有7 〇 %接受尼費拉西 坦治療病人顯示中等或顯著改善,而接受安慰劑處理病人 未顯示改善。差異顯著(ρ=0· 03 5,%2試驗)。因此,與文 獻之推測不同,發現尼費拉西坦於中風後早期投藥時,具 有出乎意外且獨特之性質,也就是具有明顯良好的活性。 1289060
根據此項 觀改善由 症狀例如 受尼費拉 安慰劑處 坦可改善 早期投藥 善由中風 尼費拉 之注意力 原中病人 外的效果 果0 研九結果’中風後早期使用尼費拉西坦治療可客 主几中復原之狀況’如下述事實顯示,除了精神 h、、者I1早礙以及自發性減低之外,尚有高比例的接 西坦治療病人的智能功能障礙獲得重大改善,而 理病人則未見改善。此外,出乎意外地尼費拉西 ^申I學病徵及尿失禁。如此尼費拉西坦於中風後 可作為第一線藥物,而誘使由中風復原或至少改 復原之狀況。
西坦用於此種適應症的作用機轉(非僅限於藥物 增強活性)為未知,但相信此種改善中風後或復 之ADL或至少改善中風後病人復原狀況的出乎意 ’係由於對抗神經變性以及腦部真正修復的結 對大乳胚乩神經元之海馬回及皮質之初次培養進行試管 内生物學研究顯示,尼費拉西坦於〇. ii、1〇及ι〇〇微莫 耳/、升濃度藉由顯著增加神經突的向外生長而對神經元具 有神經增強效果。此項效果類似基本神經母細胞生長因子 (bFGF)產生的效果,bFGF已經提示可於腦部作為神^增強
因子功月 b(R.S· Morrison 等人,proceedingS
National Academy of Sciences, 1986, 83
7537-7541 ;K· Abe 等人,1 990,w,221127),此種效 果出乎意外地於海馬回神經元可增強。此項發現"強 力提示尼費拉西坦可由血腦屏障良好吸收且跨越屏^,因 而可讓哺乳動物受損的腦神經元例如於中風後受損=腦神
五1發明說明(7) ^再生,士°此有利於腦的修插 砷經變性特別中風後神經變,以及可用於對抗哺乳類 用„經由下述效果獲得證實 ,=費拉西坦或載媒劑治療9日仏,患有腦栓塞的大鼠使 卜日寸内,尼費拉西坦對空間學抑、/Q療係始於栓塞後的24 於栓塞後7至9於位置學習水迷^ =及維持皆有效。特別, |及載媒劑治療組動物間有明顯^驗,觀察到尼費拉西坦 (腦拴塞後第17日)仍然維持尼ς。此外,即使於洗除後 可預測具有腦修補的效果,以及、西坦的效果。此種結果 費拉西坦可誘發中風後認知的恢^拾塞誘發中風後投予尼 如此,本發明之第三目的係: 風後病人復原或至少改善復肩狀;;吏,尼費拉西坦製備中 人投予有效量之尼費拉西,:原=:物。治療包含對病 内,較佳三個月内,及更佳一始於中風後六個月 藥組合物含有藥理有效量 f:。特別,藥物包含醫 筚可桩A 费卞丨士 費拉西坦作為活性成分及醫 永1接文性載劑。有效詈夕尼蟲h π L + w 50至1 ?f)n古古„ s里之匕費拉西坦較佳每單位劑量為 至1200¾克,及更佳1〇〇至6〇〇毫克。 物本:Γ:?四目的係提供一種治療神經變性之醫藥組合 ,/、匕έ樂理有效量之尼費拉西坦作為活 可接受性載劑。 诸表 医本發明之第五目的係提供一種於中風後病人改善ADL之 醫藥組合物,其包含藥理有效量之尼費拉西坦作為活性成 分及醫藥可接受性載劑。 本發明之第六目的係提供一種中風後病人復原或至少改
90104150.ptd 第11頁 1289060 五、發明說明(8) 善復原狀況 坦作為活性 如前述, 劑型較佳含 克尼費拉西 本發明之 法,其包含 西坦,更特 拉西坦作為 法’投予尼 較佳接受治 受損的中風 本發明之 方法,其包 始於中風後 本發明之 少改善復原 拉西坦,投 更佳一個月 之醫藥組 成分及醫 該組合物 有每單位 坦 〇 第七目的 對需要該 別一種醫 活性成分 費拉西坦 療的哺乳 後病人。 第八目的 含對該病 六個月内 第九目的 狀況之方 藥係始於 内〇 行 此等方法係經由 投 本發明之第十目的 治療用藥之用途。 通#尼費拉西坦使 合物,其包含藥理右曰 藥可接受性載劑。 > 里之尼費拉西 較佳係呈口服投藥 劑量50- 1 2 0 0毫克,早位劑型’單位 及更佳100-600毫 係提供一種治療哺瑜 孔類之神經變性方 項治療的哺乳類投予古4二 文性方 -,A u a 了有效夏之尼費拉 表組δ物’其包含藥理有效量之尼費 及醫藥可接受性載劑。根據較佳方、 係用於治療因中風造成的神經變性。 類為中風後之人類病人,較佳為ADL 係提供一種改善中風後病人之ADL之 人投予有效量之尼費拉西坦,投藥係 ’較佳二個月内’及更佳一個月内。 係提供一種改善中風後病人復原或至 法,包含對該病人投予有效量之尼費 中風後六個月内,較佳三個月内,及 予前述呈醫藥組合物之尼費拉西坦進 係提供使用尼費拉西坦製備中風早期 用形式之口服醫藥組合物係以製藥業
90104150.ptd 第12頁 1289060 五、發明說明(9) 界眾所周知之方法製備,且通常包含尼費拉西坦作為活性 成分混合或以其它方式組合醫藥可接受性添加劑。用於製 造該等調配劑,活性成分通常係混合例如賦形劑、崩散劑 或崩散製劑、黏結劑、潤滑劑、塗覆劑、著色劑及稀釋 劑。 至於用於製造醫藥組合物之醫藥可接受性添加劑例如賦 形劑如葡萄糖、乳糖、D-甘露糖醇、澱粉及結晶纖維素; 崩散劑或崩散助劑如羧曱基纖維素、澱粉及羧曱基纖維素 約;黏結劑如經丙基纖維素、經丙基曱基纖維素、聚乙浠 基咄咯啶酮及明膠;潤滑劑如硬脂酸鎂及滑石;以及塗覆 劑如羥丙基甲基纖維素、蔗糖、聚乙二醇及氧化鈦皆可使 用。 組合物可呈錠劑、膠囊劑、散劑、纖細粒劑、粒劑、糖 衣錠、溶液劑、糖漿劑或懸浮液劑形式投予中風後病人。 醫藥組合物之實例; 錠劑 尼費拉西坦 100毫克 乳糖 60毫克 玉米澱粉 30毫克 羥丙基纖維素 4. 5毫克 低取代羥丙基纖維素 5毫克 硬脂酸4美 0. 5毫克 20 0毫克 下述實例舉例說明本發明但非限制性。
90104150.ptd 第13頁 1289060
實例1 ϋ拉西坦對患有腦後^之大氛之空間 體重190-220克之雄鼠,每 動脈共注入700微球(直徑48微米)藉此?丨笋二^右共通頸 检塞動物隨機分成2組,每組13頭帶有相^ ==刻检塞。 標示為「對照組」(栓塞加載媒劑),或「'神鉍缺陷, (栓塞加加尼費拉西坦1〇毫克/千克/日)。=冰拉西坦」 1 3頭「正常(仙)」未栓塞動物。尼費拉西并使用一組 藥係始於栓塞的同一日,且持續 —或载媒劑的投 检t大鼠進行水迷宮試驗,水迷宮試㈣Λ塞^第7日, 任知5式驗。決定找到平台的時間(延遲)。从自摩里斯水 ,秒内找到平台,則結束試驗,將 右大 數。研究係分成二階段進行。於第一階 '私為18〇秒之分 大鼠接受空間學習試驗,每 ::第J曰栓塞 即第17日),進行維持試驗,大鼠連續接後受3日4:,(亦 並記憶平台的所在位置。表i顯示匕成驗來學習 達平台的平均延遲時間(以秒表示)。表1顯維Ϊ试 尼費拉西坦及載媒劑(對照)處理的腦部受傷J V :么 第7-9日試驗砗風π处丄 」赠口丨又傷大鼠於栓塞後 統計意義(比較# = ί有顯著差異。此項差異具有 尼費拉西扭*二^組入’=驗之ρ < 0.05) °本表也顯示 Α1 ^ 拉西坦及載婢有效’試驗中觀察到接受尼費 戟螺劑處理的栓塞動物間有顯著差異。
1289060 五、發明說明(11) 延遲時間(秒) 組別 η 空間學習試驗 維持試驗 第7曰 第8日 第9曰 第17日 丨正常(仙) 13 130.9± 16.8 61:2土 1 5.0 22.5± 5.9 Μ·7± 13.1 對照 13 159.7± 11.4 146.0土 13.0 127.5土 17.0 133.4± 15.0 尼費拉西坦 13 147.6± 14.1 83.7± 17.4 93.1± 16.2 72·2± 17.0 表2摘述於前述條件下無法在1 8 0秒以内找到平台的動物 數目0 表2 無法於1 8 0秒以内找到平台的大鼠數目 組別 η 空間學習試驗 維持試驗 第7曰 第8曰 第9日 第17日 正常(仙) 13 5 1 0 1 對照 13 10 7 5 7 尼費拉西坦 13 8 2 2 2 表2顯示接受尼費拉西坦處理動物與對照組間有明顯差 異。
90104150.ptd 第15頁 1289060 圖式簡單說明 90104150.ptd 第16頁
Claims (1)
1289丨 901愈150 年 月 曰 修正 2006 ~ 2 JUN 替換本 六、申請4卜牙1J聋色圍_:........... 1. 一種用於改善中風後病人的復原時 •正 本Ή、η 藥組合物 其係於病人中風發作後1 2個月内投藥,包含以藥理有效量 之尼費拉西坦或其鹽作為活性成分,以及一醫藥可接受性 載劑。 2. 如申請專利範圍第1項之醫藥組合物,其係於病人中 風發作後6個月内投藥。 3. 如申請專利範圍第1項之醫藥組合物,其係於病人中 風發作後3個月内投藥。 4. 如申請專利範圍第1項之醫藥組合物,其係於病人中 風發作後1個月内投藥。 5. 如申請專利範圍第1項之醫藥組合物,其係用於治療 中風後神經變性。 6. 如申請專利範圍第1項之醫藥組合物,其係用於治療 中風後病人之ADL受損。 7. 如申請專利範圍第1至6項中任一項之醫藥組合物,其 係呈經口投藥之單位劑型。 8. 如申請專利範圍第7項之醫藥組合物,其中該單位劑 型含有50至1200毫克尼費拉西坦。 9. 如申請專利範圍第8項之醫藥組合物,其中該單位劑 型含有100至600毫克尼費拉西坦。 1111 (::\總檔\90\9〇104150\90104150(替換)-3.ptc 第 17 頁
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BR (1) | BR0104586A (zh) |
CA (1) | CA2368352C (zh) |
DE (1) | DE60122252T2 (zh) |
DK (1) | DK1171123T3 (zh) |
ES (1) | ES2270981T3 (zh) |
HK (1) | HK1047038A1 (zh) |
ID (1) | ID30377A (zh) |
IL (1) | IL145799A (zh) |
MX (1) | MXPA01010749A (zh) |
NO (1) | NO321911B1 (zh) |
TW (1) | TWI289060B (zh) |
WO (1) | WO2001062246A1 (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040077709A1 (en) * | 1999-05-31 | 2004-04-22 | Daiichi Pharmaceutical Co., Ltd. | Neuronal death inhibitors |
JPWO2002053153A1 (ja) * | 2000-12-28 | 2004-04-30 | 第一製薬株式会社 | 神経因性疼痛治療及び予防薬 |
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 |
ES2664727T3 (es) | 2009-10-22 | 2018-04-23 | University College Dublin National University Of Ireland, Dublin | Terapia causal de enfermedades o estados asociados con desmielinización del SNC o del SNP |
RU2480214C1 (ru) * | 2011-09-22 | 2013-04-27 | Валентина Ивановна Ахапкина | Состав, обладающий модуляторной активностью с соразмерным влиянием, фармацевтическая субстанция (варианты), применение фармацевтической субстанции, фармацевтическая и парафармацевтическая композиция (варианты), способ получения фармацевтических составов |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2469995A (en) * | 1946-07-23 | 1949-05-10 | Schaul Martin Carl | Process for the production of food preparations from potatoes and similar farinaceoustubers |
US3031314A (en) * | 1960-03-16 | 1962-04-24 | Carl E Hendel | Preparation of dehydrated potatoes |
US3260607A (en) * | 1961-02-07 | 1966-07-12 | Canadian Patents Dev | Preparation of dehydrated cooked mashed potato |
US3968265A (en) * | 1973-02-01 | 1976-07-06 | American Potato Company | Freeze-thaw stable, french fry potato product and process for producing the same |
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 |
DE2923975A1 (de) | 1979-06-13 | 1980-12-18 | Nattermann A & Cie | Pyrrolidinone, verfahren zu deren herstellung und diese enthaltende arzneimittel |
DE2924011C2 (de) | 1979-06-13 | 1982-04-08 | A. Nattermann & Cie GmbH, 5000 Köln | Pyrrolidin-(2)-on-(1)-ylessigsäure-2,6,-dimethylanilid, Verfahren zur Herstellung und Arzneimittel, welche diese Verbindung enthalten |
CA2067614C (en) | 1991-05-02 | 2002-07-30 | Eiichi Otomo | Agent for improving dementia |
US5525058A (en) | 1992-03-27 | 1996-06-11 | American Dental Technologies, Inc. | Dental treatment system |
JP3053434B2 (ja) | 1995-07-10 | 2000-06-19 | 株式会社小寺電子製作所 | 加工線材の挿着装置 |
US6107330A (en) | 1995-08-07 | 2000-08-22 | Daiichi Pharmaceutical Co., Ltd. | Inhibitor for narcotic analgesic dependence/resistance acquisition |
JP2002241272A (ja) | 1996-07-18 | 2002-08-28 | Mitsubishi Pharma Corp | 医薬処方組成物 |
ES2185963T3 (es) | 1996-07-30 | 2003-05-01 | Ecolab Gmbh & Co Ohg | Agente filmogeno para la proteccion contra infecciones. |
WO1998014213A1 (fr) | 1996-10-01 | 1998-04-09 | Daiichi Pharmaceutical Co., Ltd. | Stabilisateur de la membrane mitochondriale |
US6211701B1 (en) | 1996-12-16 | 2001-04-03 | Rose Research, Llc | Low power line switching circuit, device and method |
IT1293533B1 (it) | 1997-07-14 | 1999-03-01 | Angeletti P Ist Richerche Bio | Metodo per la selezione di molecole in grado di mimare, inibire o potenziare gli effetti della interazione tra leptina e cellule che |
ATE266401T1 (de) | 1997-07-15 | 2004-05-15 | Daiichi Seiyaku Co | Nefiracetam zur prophylaxe und behandlung von propofol verursachtem gedächtnisschwund |
JPH1180027A (ja) | 1997-09-12 | 1999-03-23 | Dai Ichi Seiyaku Co Ltd | 向知性薬 |
AR020115A1 (es) | 1998-08-06 | 2002-04-10 | Daiichi Seiyaku Co | Agente terapeutico o preventivo para epilepsias rebeldes y uso del compuesto para la produccion de los mismos |
CN1368882A (zh) | 1999-05-31 | 2002-09-11 | 第一制药株式会社 | 神经元死亡抑制剂 |
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2001
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- 2001-02-21 AR ARP010100761A patent/AR030551A1/es unknown
- 2001-02-23 WO PCT/JP2001/001342 patent/WO2001062246A1/en active IP Right Grant
- 2001-02-23 BR BR0104586-5A patent/BR0104586A/pt not_active Application Discontinuation
- 2001-02-23 ID IDW00200102283A patent/ID30377A/id unknown
- 2001-02-23 ES ES01906242T patent/ES2270981T3/es not_active Expired - Lifetime
- 2001-02-23 CA CA002368352A patent/CA2368352C/en not_active Expired - Fee Related
- 2001-02-23 DE DE60122252T patent/DE60122252T2/de not_active Expired - Lifetime
- 2001-02-23 AU AU34145/01A patent/AU784418B2/en not_active Ceased
- 2001-02-23 MX MXPA01010749A patent/MXPA01010749A/es active IP Right Grant
- 2001-02-23 AT AT01906242T patent/ATE336246T1/de not_active IP Right Cessation
- 2001-02-23 JP JP2001561312A patent/JP2003523385A/ja active Pending
- 2001-02-23 IL IL145799A patent/IL145799A/en not_active IP Right Cessation
- 2001-02-23 CN CN01800298A patent/CN1362877A/zh active Pending
- 2001-02-23 TW TW090104150A patent/TWI289060B/zh not_active IP Right Cessation
- 2001-02-23 KR KR1020017013542A patent/KR20010110798A/ko active Search and Examination
- 2001-02-23 DK DK01906242T patent/DK1171123T3/da active
- 2001-02-23 EP EP01906242A patent/EP1171123B1/en not_active Expired - Lifetime
- 2001-07-17 US US09/906,077 patent/US6399650B2/en not_active Expired - Fee Related
- 2001-10-22 NO NO20015162A patent/NO321911B1/no unknown
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2002
- 2002-11-28 HK HK02108589.8A patent/HK1047038A1/zh unknown
Also Published As
Publication number | Publication date |
---|---|
EP1171123A1 (en) | 2002-01-16 |
JP2003523385A (ja) | 2003-08-05 |
KR20010110798A (ko) | 2001-12-13 |
CA2368352C (en) | 2009-11-10 |
AU784418B2 (en) | 2006-03-30 |
IL145799A (en) | 2006-10-31 |
ES2270981T3 (es) | 2007-04-16 |
CN1362877A (zh) | 2002-08-07 |
IL145799A0 (en) | 2002-07-25 |
US6399650B2 (en) | 2002-06-04 |
ID30377A (id) | 2001-11-29 |
WO2001062246A1 (en) | 2001-08-30 |
DK1171123T3 (da) | 2006-12-04 |
DE60122252T2 (de) | 2007-07-05 |
DE60122252D1 (de) | 2006-09-28 |
MXPA01010749A (es) | 2002-08-20 |
AU3414501A (en) | 2001-09-03 |
NO20015162D0 (no) | 2001-10-22 |
CA2368352A1 (en) | 2001-08-30 |
HK1047038A1 (zh) | 2003-02-07 |
EP1171123B1 (en) | 2006-08-16 |
AR030551A1 (es) | 2003-08-27 |
ATE336246T1 (de) | 2006-09-15 |
US20020055534A1 (en) | 2002-05-09 |
US20010051653A1 (en) | 2001-12-13 |
NO321911B1 (no) | 2006-07-17 |
NO20015162L (no) | 2001-12-21 |
US6423739B1 (en) | 2002-07-23 |
BR0104586A (pt) | 2002-01-08 |
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