TWI309162B - Amino acid composition for improving functional disorder of liver - Google Patents
Amino acid composition for improving functional disorder of liver Download PDFInfo
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- TWI309162B TWI309162B TW091104902A TW91104902A TWI309162B TW I309162 B TWI309162 B TW I309162B TW 091104902 A TW091104902 A TW 091104902A TW 91104902 A TW91104902 A TW 91104902A TW I309162 B TWI309162 B TW I309162B
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- amino acid
- liver
- acid composition
- leucine
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Description
1309162 五、發明說明(1 ) 發明背景 (a) 發明範圍 本發明係關於胺基酸組成物或溶解胺基酸組成物之溶液 ,其對於肝功能疾病具有顯著之改善效果,特別是關於將 胺基酸組成物或溶解胺基酸組成物之溶液有效地給予具有 肝功能疾病之病患,且其包含於大黃蜂(屬)幼蟲 分泌之唾液。 (b )相關技術說明 本發明者致力於硏究大黃蜂幼蟲分泌之唾液,藉以確認 其中所含之胺基酸組成物之配方,並硏究組成物之應用。 本發明關於唾液中所含稱爲“ VAAM”之胺基酸組成物, 其呈現出促進動覺功能之作用(日本專利2518692號)。 促進動覺功能之作用包括肌耐力、營養及強化之增加、營 養供應及疲勞之復原。 肝臟爲一大器官,其包含具有儲存如碳水化合物之肝醣 功能的消化器官、產生及分泌膽汁、分解毒性化合物及由 胺基酸合成蛋白質。這些重要的功能均衡的增加肝之負擔 〇 如飮酒、抽煙及熬夜晚睡過度對於肝臟提供了過度負擔 ,因而產生包括癌症及硬化之肝臟功能不全。 傳統上,將合成藥物給予具有上述疾病之病患’即使合 成藥物之功效十分優良,但這些藥物通常還是具有毒性且 對於其他器官有不良影響。因此,藉由使用上述合成藥物 1309162 五、發明說明(4) 之鼠的組別時,急性中毒之死亡率。 第7圖爲顯示當給予各胺基酸組成物於顯現肝功能疾病 之鼠的組別時,降解率之輪廓。 發明之詳細說明 如前所述,藉由複合作用機制,VAAM明確地具有上述促 進動覺功能之作用,並促進脂肪代謝。本發明者對於藉由 VAAM有效作用於改善其他疾病(並不直接關於促進動覺功 能之作用)所具有之促進動覺功能之作用已詳細測試。 當過度運動或過度攝取酒精,則廢物大致上被累積於具 有上述功能之肝臟中,而當功能不完全的被促進時,則肝 功能疾病之爆發就會發生’即使在其發生之後,在無適當 之治療下,功能疾病會惡化而變得不可治癒。 本發明者已發現藉由給予具有不同於已知VAAM之特殊 配方於具有肝功能疾病之病患,或尙未發生肝功能疾病之 一般人,可使肝功能疾病被改善或抑制其發生。 根據本發明之第一胺基酸組成物(之後稱爲“第一特點 ”)包含1 7種胺基酸爲必要組成’且各胺基酸理想地包 括於其個別的混合比例,其爲2至1 5莫耳之酥胺酸、4至 30吴耳之脑I女S&、7至20吴耳之甘胺酸、4至8莫耳之線 胺酸、3至9莫耳之異白胺酸、2至12莫耳之白胺酸、1 至9莫耳之酪胺酸、0.5至5莫耳之苯丙胺酸、5至11莫 耳之離胺酸、0.1至5莫耳之天冬胺酸、〇1至5莫耳之 絲胺酸、〇_1至4莫耳之麩胺酸、〇1至12莫耳之丙胺酸 1309162 五、發明說明(5) 、0·1至5莫耳之甲硫胺酸、0.1至5莫耳之色胺酸、〇.】 至5莫耳之組胺酸及〇.丨至5莫耳之精胺酸。除這些胺基 酸外’亦可包含其他胺基酸、水溶性維他命、如檸檬酸之 酸或少量添加物。 根據本發明之第二胺基酸組成物(之後稱爲“第二特點 ”)包含除色胺酸之外的第一特點之1 6種胺基酸作爲必 要組成’第二特點之不含色胺酸的胺基酸組成物之作用相 似於或略爲低於第一特點,各胺基酸理想的爲左旋胺基酸 〇 第一及第二特點之胺基酸組成物可以粉末形式或溶於水 中之後的液態形式服用,服用的方式包括如口服、直腸投 與、靜脈內注射及靜脈內輸液之一般給予方法。 在口服情況下,除組成物本身之給予外,在組成物混以 醫藥可允許之載體、賦形劑及稀釋劑之後,組成物可以如 粉末、顆粒藥劑、藥九、膠囊及錠劑使用。然而,以組成 物本身口服較佳,因爲吸收固體粉末或藥九需要較長一段 時間。組成物可以適當之添加劑加入溶液中給予,例如包 括氯化鈉之鹽、pH調節劑及螯合劑。在使用注射之情況下 ,組成物可溶於添加適當緩衝液或等張劑之後的已消毒之 蒸餾水中。 服用之時間並不特別限制,組成物可在發生肝功能疾病 之前或之後的任何時間服用。組成物較佳的在發生肝功能 疾病之前,以如健康飮品(如以營養增加及補充爲目的之 1309162 五、發明說明(6) 飲料、粉末飮品、藥物飮品)之溶液形式服用。
因爲毒性低之緣故,本發明胺基酸組成物之給予量可設 定於較大之範圍內,根據使用之方法及目的,每一劑量一 般可給予0 . 5至5克之組成物,較佳的爲每一劑量1至2 克,且每日1至20克,較佳的爲每日4至10克。在溶劑 之情況下,以每一劑量爲含0 . 5至1 0重量%之組成物溶液 10至1 000 ml,較佳的爲含1至4重量%之組成物溶液1〇〇 至400 ml給予或服用。 由以下實例顯示,本發明之胺基酸組成物對於肝功能疾 病呈現顯著之抑制及治療作用。此外,天然來源之胺基酸 組成物爲低毒性,且對於改善肝功能疾病具有非常有效之 作用。
如前所述,本發明之胺基酸組成物可使用於溶液中,尤 其是水性溶液。在此情況下,可藉由實際上溶解第一或第 二特點之組成物或藉由分別溶解個別之胺基酸於水中加以 製備,以完成含胺基酸組成物之溶液。 實例 本發明之胺基酸組成物將藉由實例及比較例測試改善肝 功能疾病加以敘述。然而,這些實例並不限制本發明。 在敘述關於胺基酸組成物之個別實例之前,先敘述實例 及比較例中之GOT、GPT、總肝膽固醇及三酸甘油酯之濃度 測定。 GOT、GPT、總肝膽固醇及三酸甘油酯之濃度測定 1309162 五、發明說明(7) 於本實例中,發生及治癒肝功能疾病係藉由GOT (麩胺 酸-草醋酸轉胺酶)、GPT (麩胺酸-焦葡萄酸轉胺酶)、 總肝膽固醇及三酸甘油酯作爲肝功能疾病指數加以判定。 GOT及GPT包含於轉胺酶中,其爲一種催化介於胺基酸與 ct -酮基酸之間的胺基重排列之酶。於指數中,GOT及GPT 在臨床是重要的,但在r · GPT之情況,在溶液中其活性爲 無法測定之低値。GOT爲一種催化介於天冬胺酸、α -酮基 戊二酸及麩胺酸、酸草醯乙酸之間的胺基重排列之酶, GOT最常存在於心肌、肝臟及腦中,其次爲骨骼肌及腎臟 。而GPT爲一種催化介於丙胺酸、α-酮基戊二酸及麩胺 酸、丙酮酸之間的胺基重排列之酶,GPT存在於肝臟及腎 臟中。心肌梗塞或猛爆性肝炎明顯地增加血淸GOT,急性 肝炎及慢性肝炎明顯地增加GPT,因此GOT及GPT對於這 些疾病爲可能之診斷指數。 膽固醇(中性脂肪)之濃度係與肝臟與腸道中膽固醇之 形成、吸收及分解及血液中脂蛋白之代謝有密切之關係。 血淸中脂肪包括三酸甘油酯、膽固醇、磷脂質、游離脂 肪酸及少量之親脂性物質,如維他命及胡蘿蔔素。血淸中 三酸甘油酯之測量對於動脈硬化、冠狀動脈硬化及糖尿病 之診斷是重要的檢查。 使用臨床診斷套組來進行測量,其可獲自於W a k ο P u r e 化學工業有限公司。 1309162 五、發明說明(10) 式1 • GOT 天冬胺酸 + α-酮基戊二酸 - 麩胺酸+草醯乙酸 0AC 草醯乙酸 -'~*Η . 丙酮酸 ^ POP 丙酮酸 + 磷酸 +〇2.- 乙醯磷酸+ co2 +h2〇2 H3C-C = 〇~ΝΗϊ
9/(__ _NsCH2CHCH2S〇3Na rw 1 CHg 〇H C2Hs ό 胺基安替比林 T〇〇s =〇--
POO
H3C - C = C 一 HaC—M C—O CHs \NT
CsHs CHzCHCHzSOaNa OH OH" + 3H2〇 0. 藍紫色色素 經使用標準液製備已知濃度之標準樣本在預熱及添加基 底緩衝液之後,測量標準樣本之吸光値及利用測量値製備 校正曲線。 [B] GPT之測量 下列試劑使用作爲GPT之測試。 -12- 1309162 五、發明說明(11) 用於GPT之酶 溶解並使用一種具有下列配方於GPT之酶。 丙酮酸氧化酶(POP )(源自小球菌屬) 5.4單位/ m 1 4 -胺基安替比林 2.0 mmo1/升 抗壞血酸氧化酶(源自南瓜子) 0.90 單位/ml 過氧化氫酶(源自母牛肝臟) 用於GPT之基底緩衝液 270單位/ml 20 mM Good ( HEPES 製)緩衝液 pH 7.0 L-天冬胺酸 產色劑 1 . 0單位/ m 1 當溶解時,使用5.9單位/ml之過氧化酶(源自西洋山菜) 用於產色劑之溶解液 20 mM Good ( HEPES 製)緩衝液 pH 7.0 α -酮基麩胺酸 3 6 mmo 1 / 升 N -乙基-(2 -羥-3 -磺酸基丙基)·間甲苯胺鈉(T00S ) 反應終止液 2 _ 2 mmo1 / 升 檸檬酸 表面活性劑 GPT之標準液 丙酮酸鉀 5 0 mmo 1 /升 GPT 相當於1〇〇柯曼(Karraen)單位 之後,將敘述使用這些試劑測量GPT之基準。 -13- 1309162 五、發明說明(14) 藉由測量紅色吸光率以決定樣本中總膽固醇之濃度。
膽固醇酯酶 膽固醇酯 +ϋ2〇—-> 膽固醇十 脂肪酸 膽固醇氧化酶 膽固醇酯 +〇2 —-:——Δ4-膽固烯酮 +ιι2〇2
4·胺基安替比林 紅色奎寧酮系色素 總膽固醇之測量 將0.01 ml樣本溶於異丙醇之後,在充分攪拌下於37 °C 加熱1 0分鐘後加入1 . 5 m1產色劑,藉由使用肓目樣本( 添加蒸餾水於樣本中)作爲參考之光譜儀,測量在505 nm 之樣本吸光値。 經使用標準液製備已知濃度之標準樣本在預熱及添加基 底緩衝液之後,測量標準樣本之吸光値及利用測量値製備 校正曲線。 -16- 1309162 五、發明說明(15) 三酸甘油酯之測量 下列試劑使用作爲三酸甘油酯之測試。 緩衝溶液 50 _三羥甲基胺基甲烷(tris)緩衝溶液 pH 7.5 對氯酹 5.4 mmol/升 產色劑 當溶解時,使用下列試劑。 脂蛋白脂肪酶(源自產色細菌屬) 三磷酸腺苷三氫化二鈉(ATP)(無芽胞桿菌屬) 甘油激酶(源自鏈黴菌屬) 甘油-3-磷酸氧化酶(GP0)(源自產氣球菌屬) 過氧化酶(源自西洋山菜) 4-胺基安替比林 標準液 3 6單位/ m 1 1. 8單位/ m 1 2.2單位/ m 1 4.4單位/ m 1 2 .1單位/ m 1 069mmo1 /升 甘油 31 . 2 mg/dl 三油酯 相當於300 mg/dl 之後’將敘述使用這些試劑測量三酸甘油酯之基準。 測量脂蛋白脂酶(LPL)分解樣本中之三酸甘油酯成甘 油及脂肪酸之反應。在ATP存在下,所生成之甘油經甘油 激酶(GK )之作用轉化成甘油-3 -磷酸,甘油-3 -磷酸經甘 油-3 -磷酸氧化酶(GP0 )之作用被氧化產生過氧化氫,所 生成之過氧化氫經過氧化酶(POD )之作用,而在量及氧 化上濃縮對氯酚及4 -胺基安替比林以生成紅色色素(參考 -17- 1309162 五、發明說明(21) 1組達到約30%。如所述者,對於給予VAAM之屬的毒性小 於其他組之胺基酸組成物。 關於第7圖所示之降解率,給予VAAM組之比率最小’ 且其他組之胺基酸組成物達到VAAM組之2.5至7倍。特 別地,死亡率爲零之V-Tyr組具有接近70%降解率,其爲 胺基酸組成物中之最高者,這些結果顯示VAAM非常優異 的抑制急性酒精中毒。 上述結果廣泛明顯地顯示VAAM較其他胺基酸組成物更 顯著地抑制酒精性肝功能疾病,且所有鼠之功能恢復亦可 達到。將VAAM中色胺酸排除所製備之V-Trp具有改善肝 功能疾病之作用,但其並不如VAAM。然而,在由V-Trp中 移除任一種胺基酸就會減弱改善作用,而僅提供不稱份之 改善作用。 上述的具體表現僅爲例子,本發明並不限於所述之具體 表現’各種修正或改變可被熟悉此項技術之人在不違反本 發明之範圍下輕易的完成。 -23-
Claims (1)
1309162 修正本%月曰 _无 六、申請專利範圍 第9 1 1 04902號「改善肝功能疾病之胺基酸組成物」專利案 (2005年9月28日修正) Λ申請專利範圍: 1 . 一種改善肝酒精性功能疾病之胺基酸組成物,其包含酥 胺酸、脯胺酸、甘胺酸、纈胺酸、異白胺酸 '白胺酸、 酪胺酸、苯丙胺酸、離胺酸、天冬胺酸、絲胺酸、麩胺 酸、丙胺酸、甲硫胺酸、色胺酸、組胺酸及精胺酸,其 中包含之各胺基酸莫耳比率爲2至15莫耳之酥胺酸、4 至30莫耳之脯胺酸、7至20莫耳之甘胺酸、4至8莫 耳之纈胺酸、3至9莫耳之異白胺酸、2至12莫耳之白 胺酸、1至9莫耳之酪胺酸、0.5至5莫耳之苯丙胺酸 、5至Π莫耳之離胺酸、〇.1至5莫耳之天冬胺酸、 0.1至5莫耳之絲胺酸、〇.丨至4莫耳之麩胺酸、〇.1至 1 2莫耳之丙胺酸、〇 . i至5莫耳之甲硫胺酸、〇 . 1至5 莫耳之色胺酸、0.1至5莫耳之組胺酸及0.1至5莫耳 之精胺酸。 2 ·如申請專利範圍第1項之改善肝酒精性功能疾病之胺基 酸組成物,其爲溶液。 3. —種改善肝功能疾病之不含色胺酸之胺基酸組成物,其 包含醉胺酸、脯胺酸、甘胺酸、纈胺酸、異白胺酸、白 胺酸、酪胺酸、苯丙胺酸、離胺酸、天冬胺酸、絲胺酸 、g胺酸、丙胺酸、甲硫胺酸、組胺酸及精胺酸,其中 包含之各胺基酸莫耳比率爲2至15莫耳之酥胺酸、4至 1309162 六、申請專利範圍 30莫耳之脯胺酸、7至2〇莫耳之甘胺酸、4至8莫耳之 纈胺酸、3至9莫耳之異白胺酸、2至12莫耳之白胺酸 、1至9莫耳之酪胺酸、ο.〗至5莫耳之苯丙胺酸、5至 11莫耳之離胺酸、0.1至5莫耳之天冬胺酸' 0.1至5 莫耳之絲胺酸、0.1至4莫耳之麩胺酸、0.1至12莫耳 之丙胺酸、0.1至5莫耳之甲硫胺酸、0.1至5莫耳之 組胺酸及0 . 1至5莫耳之精胺酸。 4 ·如申請專利範圍第3項之改善肝功能疾病之不含色胺酸 之胺基酸組成物,其爲溶液。 5 .如申請專利範圍第1或3項之胺基酸組成物,其中胺 基酸組成物或溶液用以改善酒精性肝功能疾病。
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JP5188181B2 (ja) * | 2005-08-25 | 2013-04-24 | 協和発酵バイオ株式会社 | 血中アルコール濃度上昇抑制用組成物 |
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BRPI1012956A8 (pt) | 2009-06-08 | 2021-11-03 | Ocera Therapeutics Inc | Usos da l-ornitina e de pelo menos um de fenilacetato e fenilbutirato |
KR101213825B1 (ko) * | 2010-07-16 | 2012-12-18 | 서울대학교산학협력단 | 세린을 유효성분으로 함유하는 지방간 질환의 예방 및 치료용 조성물 |
JP6087284B2 (ja) | 2010-10-06 | 2017-03-01 | オセラ セラピューティクス, インコーポレイテッド | L−オルニチンフェニルアセテートを製造するための方法 |
CN107206021B (zh) | 2014-11-24 | 2021-09-03 | Ucl商业有限公司 | 使用降氨疗法治疗与肝星状细胞激活相关的疾病 |
JP2016132622A (ja) * | 2015-01-16 | 2016-07-25 | イーエヌ大塚製薬株式会社 | 敗血症治療又は予防用栄養組成物 |
AU2016308641B2 (en) | 2015-08-18 | 2022-02-03 | Ocera Therapeutics, Inc. | Treatment and prevention of muscle loss using L-ornithine in combination with at least one of phenylacetate and phenylbutyrate |
JOP20190146A1 (ar) | 2016-12-19 | 2019-06-18 | Axcella Health Inc | تركيبات حمض أميني وطرق لمعالجة أمراض الكبد |
AU2018258250A1 (en) * | 2017-04-25 | 2019-12-12 | Almeda Labs Llc | Amino acid formulations for pancreatic viability |
AU2018266357B2 (en) | 2017-05-11 | 2022-12-08 | Ocera Therapeutics, Inc. | Processes of making L-ornithine phenylacetate |
CN111295187A (zh) * | 2017-08-14 | 2020-06-16 | 胺细拉健康公司 | 用于治疗肝脏疾病的氨基酸组合物 |
US11173143B2 (en) | 2017-08-30 | 2021-11-16 | Asahi Group Holdings, Ltd. | Composition for decreasing serum uric acid level |
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US3950529A (en) * | 1975-02-03 | 1976-04-13 | Massachusetts General Hospital | Amino acid formulations for patients with liver disease and method of using same |
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