JP2001514667A

JP2001514667A - Composition for prevention of hepatic steatosis

Info

Publication number: JP2001514667A
Application number: JP53996498A
Authority: JP
Inventors: イシダ，ナオブミ
Original assignee: タム，ユンケー．; ザマン，ヌツハット
Priority date: 1997-03-17
Filing date: 1997-03-17
Publication date: 2001-09-11
Also published as: WO1998041216A1; AU2089297A; HK1027508A1

Abstract

(57)【要約】非経口的栄養素での長期の治療は、脂肪肝としても知られる肝脂肪症を誘導する傾向がある。腸内細菌との胆汁酸の長期の接触により引きおこされる毒性二次胆汁酸の形成量の増加及び腸内腔からのこれらの二次胆汁酸の吸収は、肝臓に毒性効果を与え、結果として肝脂肪症を導く。血清コレステロールを低下させるために便利に用いられる胆汁酸封鎖剤が、非経口的栄養素に関連した肝脂肪症を防止又は緩和することができることが発見された。任意に免疫栄養素、例えばオメガ−３ポリ不飽和脂肪酸、短鎖脂肪酸、グルタミン、アルギニン、酸化防止剤、リボ核酸又はヌクレオチドと組み合わせた、胆汁酸封鎖剤、好ましくはコチスチラミンの経口摂取は肝脂肪症を防止又は緩和することができる。本発明は、直接又は間接的に他の状態、例えば癌化学療法、敗血症、内毒素血症、火傷、傷ついた腸の機能、細菌のトランスロケーション又はAIDSから生じた肝脂肪症の防止又は緩和にも関する。 (57) [Summary] Long-term treatment with parenteral nutrients tends to induce hepatic steatosis, also known as fatty liver. The increased formation of toxic secondary bile acids and the absorption of these secondary bile acids from the intestinal lumen, caused by prolonged contact of bile acids with intestinal bacteria, have toxic effects on the liver and consequently Leads to hepatic steatosis. It has been discovered that bile acid sequestrants that are conveniently used to lower serum cholesterol can prevent or alleviate hepatic steatosis associated with parenteral nutrients. Oral ingestion of a bile acid sequestrant, preferably costyramine, optionally in combination with immunonutrients, such as omega-3 polyunsaturated fatty acids, short chain fatty acids, glutamine, arginine, antioxidants, ribonucleic acids or nucleotides, can reduce hepatic steatosis. Can be prevented or mitigated. The present invention relates to the prevention or alleviation of other conditions, directly or indirectly, such as cancer chemotherapy, sepsis, endotoxemia, burns, injured intestinal function, bacterial translocation or hepatic steatosis resulting from AIDS. Also concerns.

Description

【発明の詳細な説明】肝臓脂肪症の予防のための組成物技術分野本発明は肝臓の治療の分野、そしてより詳しくは肝臓脂肪症の予防又は緩和の目的のための胆汁酸封鎖剤の利用に関する。背景技術非経口栄養法又は完全非経口栄養法(TPN)として知られる内在式カテーテルを介する静脈供給を通じての栄養分の投与は消化過程を迂回し、そして身体により必要とされる栄養分、例えばアミノ酸、糖分、脂肪分、ビタミン及びミネラルを血流に直接搬送する。非経口栄養法は経口経腸供給を寛容できない重症な病個体に栄養分を供給するのに幅広く利用されている。しかしながら、非経口栄養法を通じての消化の迂回は腸内細菌の過剰増殖、腸内腔から身体への細菌の転移、及び内毒血症を招くことがある。非経口栄養法は肝臓脂肪症、ヘパトステアソシス又は脂肪肝として知られる肝臓中での脂肪の浸潤をも招きうる。肝臓障害の指標としての肝不全と非経口栄養法との間には発表済みの関係が存在する(Fisher，Gastroenterol.Clin.N.Am.，18:645-666，1989;Hodes 3，J.Ped iatr.Surg.17:463-468，1982)。肝不全は幼児及び子供の非経口栄養法治療において大きな問題を提示する。肝不全は血清肝性酵素及びビリルビンのレベルの高揚(Grantら、Surg.Gynecol.Obstet.145:573-586，1977)又は肝臓脂肪症の発症（ Keim，JPEN 11:18-22，1987;Keimら、J.Nutr.114:1807-1815，1984）により明白となりうる。患者が腸内絶食に付される長期間の非経口栄養法治療は胃腸運動の低下、胃腸通過時間の短縮及び糞量の減少をもたらす。このような作用は腸内腔からの二次胆汁酸の再吸収の増大、それによる血清中の二次胆汁酸の濃度の増大の原因となりうる（Vileisisら、J.Pediatr.96:893-897，1980）。末梢小腸又は結腸中の一次胆汁酸の細菌性デヒドロキシル化により生成される二次胆汁酸、特にリトコール酸は数多くの動物種において毒性が示されている(Vousefら、Gastroenterolog y 80:233-241，1981)。非経口栄養法治療及び腸内絶食の間、腸は休止し、そして結腸細菌が二次胆汁酸を生成する機会が増大するものと信じられている。付随する腸運動の低下は二次胆汁酸が生成される時間及び腸肝リサイクルを通じて再吸収される時間を延長しうる。かくして、身体における毒性胆汁酸プールは増大しうる(Hofimann，Hep atology 4:4S-14S，1984)。コレスチラミンは胆汁酸と結合できる塩基性陰イオン交換樹脂であり、それ故胆汁酸封鎖剤として知られる。コレスチラミンは胆汁酸の腸肝リサイクルの中断を通じて血液コレステロールを下げるために慣用されている。コレスチラミンを血清脂質調節剤と一緒に含む組成物が、血液コレステロールの低下の目的のために米国特許第4,814,354号に開示されている。血液コレステロールを下げるのに利用するためのコレスチラミン及び非吸収性、非消化性ポリオールポリエステルを含む組成物が米国特許第5,116,610号に開示されている。患者に経口投与すると、コレスチラミンは腸内腔の内容物のアルカリ性pHでプロトン化されたままとなり、それ故胆汁酸の最大の結合が行われる。このように胆汁酸の結合したコレスチラミン樹脂は糞を通じて身体から排泄され、かくして結合胆汁酸の再吸収は阻止又は抑制される。その他の胆汁酸封鎖剤が似たような結果を供しうる（Ast & Fr ishman，J.Clin.Pharmacol．106:99-106，1990）。コレステロールは胆汁酸合成における前駆体分子である。身体から胆汁酸を排除することにより、代替胆汁酸が身体のコレステロールプールから合成され、かくして血液コレステロールは低下する傾向にある。肝臓脂肪症を引き起こすことがあるその他の生理学的条件には、癌の化学療法、内毒血症、敗血症、火傷及び様々な腸障害、細菌転移、AIDS又は幼児の低生誕体重が挙げられる。何種類かの合成樹脂が生物学的流体からタンパク質性物質を除去するうえで有効である(Nolanら、Effect of cholestyramine on endotoxin toxicity and abs orption.Digestive Diseases 17:161-166，1972)。米国特許第3,769,401及び3,0 97,141号は解毒法としての生物学的流体からのタンパク質性物質の除去のための方法を開示する。これらの方法はイオン的に帯電した樹脂であって、タンパク質性物質がそれに返接して置かれたときにそれに対する親和性を有する樹脂を利用する。本発明の目的は非経口栄養法治療に由来しうる肝臓脂肪症を予防又は緩和することにある。発明の開示胆汁酸封鎖剤、例えばコレスチラミンを含む組成物は、非経口栄養法治療と関連する、又はその他の治療もしくは症状に由来する肝臓脂肪症を予防又は緩和できることが発見された。本発明の一の観点に従うと、胆汁酸封鎖剤の利用であって、有効量の封鎖剤が肝臓脂肪症の予防又は緩和のために被検体により摂取されることを特徴とする利用を提供する。本発明の別の観点に従うと、被検体の肝臓脂肪症の予防又は緩和のための組成物の利用であって、当該組成物が経口又は経腸投与のために適合していることを特徴とし、且つ有効量の胆汁酸封鎖剤及び薬理学的に許容される担体を含んで成るものである、利用を提供する。本発明の更なる観点に従うと、肝臓脂肪症の予防又は緩和のための被検体への経口又は経腸投与に適合した組成物であって、有効量の胆汁酸封鎖剤、免疫栄養素及び薬理学的に許容される担体を含んで成ることを特徴とする組成物を提供する。本発明の別の観点に従うと、被検体の肝臓脂肪症を予防又は緩和する方法であって、この被検体により有効量の胆汁酸封鎖剤が摂取されることを特徴とする方法を提供する。本発明の別の観点に従うと、被検体の肝臓損傷を予防又は緩和する方法であって、この被検体により有効量の胆汁酸封鎖剤及び薬理学的に許容される担体を含んで成る組成物が摂取されることを特徴とする方法を提供する。肝臓脂肪症はその他の症状にも由来しうる。従って、本発明は癌の化学療法、内毒血症、敗血症、火傷、細菌転移及びAIDSの如き症状から最終的にもたらされる肝臓脂肪症を予防又は緩和するために利用されうる。本発明はその他の特定の又は未知の要因に基づき損傷した腸機能に由来する肝臓脂肪症の予防又は緩和のためにも利用されうる。本発明は特定の又は未知の要因により惹起された肝臓脂肪症の予防又は緩和のために利用されうる。肝臓脂肪症は更に損われた免疫素に由来する又はそれをもたらしうる。本発明の組成物における免疫栄養素の存在は腸機能を高め、更には細菌転移、内毒血症及び敗血症に対する感受性を下げることを司りうる。胆汁酸封鎖剤、例えばコレスチラミンと組合せると、免疫栄養素は肝臓脂肪症の予防又は緩和を更に助けることができる。図面の簡単な説明本発明に関する図面において、図１は、腸管外経路で栄養を摂取し、そしてコレスチラミン処理されなかったラットの肝臓を示す顕微鏡写真であり；図２は、腸管外経路で栄養を摂取し、そしてコレスチラミン処理されたラットの肝臓を示す顕微鏡写真であり；そして、図３は、齧歯類用飼料を摂取したラットの肝臓を示す顕微鏡写真である。発明の最良の実施態様本発明の好ましい態様では、コレスチラミン及び医薬に適する担体を含んでいる組成物を対象に経口投与する。成体の体重に基づいて約40ｇ／日を超えない範囲で、腸管外栄養供給から生じる肝臓脂肪症を予防又は軽減するために有効なレベルで、コレスチラミンを投与する。好ましいコレスチラミンの範囲は、１〜40 ｇ／日である。本明細書で示した全ての投与量は、約40kg〜150kgの範囲の成人体重に基づく。この範囲外の体重を有する個体に本発明を使用することも考えられ、この場合、当該投与量は通常体重に比例する。例えば、化学療法、AIDS、敗血症、熱傷、及び腸管外栄養供給を必要とする症状は、しばしば重度の体重減少を伴う。場合によっては、１種類以上の免疫栄養素を、コレスチラミンと医薬に適する担体との組成物に添加することができる。本明細書では、免疫栄養素を、免疫機能に有益な効果を有する栄養素として定義し、これには、限定ではないが、アミノ酸、例えばアルギニン及びグルタミン；抗酸化剤、例えばビタミンＡ，Ｃ，Ｅ、及びβ−カロテン；オメガ−３ポリ不飽和脂肪酸、例えばリノレン酸（18：２）、エイコサペンタエン酸（20：5）、及びドコサヘキサエン酸（22：６）；短鎖脂肪酸、例えば酢酸、プロピオン酸及び酪酸；オメガ−３ポリ不飽和脂肪酸及び／又は短鎖脂肪酸を含んでいるトリグリセリド；並びに、リボ核酸又はヌクレオチドが含まれる。遊離型のアルギニンの投与量は、好ましくは約17〜25ｇ／日である。グルタミンの投与量は、好ましくは約60ｇ／日を超えない有効量である。グルタミンの一日投与量は、好ましくは約0.16±0.02ｇ／kg体重である。オメガ−３ポリ不飽和脂肪酸の投与量は、好ましくは約１〜４ｇ／日である。リボ核酸又はヌクレオチドの投与量は、好ましくは約0.75〜３ｇ／日である。２つの有用な胆汁酸吸収剤（sequestrauts）は、コレスチラミン及びコレスチポル(Ast & Frishman，J.Clin.Pharmacol.106:99-106，1990)である。好ましくは、コレスチラミンを胆汁酸吸収剤として用いる。コレスチラミンは、スチレン −ジビニルベンゼンコポリマーに付加された４級アンモニウム基を含んでいる合成強塩基性陰イオン交換樹脂である（Merck Index，9th Edition，1976，p.2194 ）。コレスチポルは、ジエチレントリアミン及び１−クロロ−２，３−エポキシプロパン（場合によっては塩酸塩）からなる塩基性陰イオン交換コポリマーで、アミノ窒素５個毎に約１個がプロトン化されているものであり（Merck Index，9th Edition，1976，p.2436）、これはしばしば粉末のコレスチポル塩酸塩として供給される。この投与量は、好ましくは30ｇ／日を超えない有効な量であり、好ましくは約５〜30ｇ／日の範囲である。本発明では、任意の投与剤形、又は、胆汁酸結合能が阻害されない本樹脂の任意の構造上の修飾を有する剤形として胆汁酸吸収剤を使用することが考えられる。本発明では、任意の医薬に適する投与剤形に一致する種々の投与剤形の本胆汁酸吸収剤を用いることができる。本発明では、本胆汁酸吸収剤又は本発明の組成物を、主として固体、ゲル又は液体の形での経口投与か、あるいは栄養補給用腸チューブを介して摂取することが考えられる。本発明は、好ましくは、肝臓損傷を引き起こす症状を治療する際に適用される。以下の実施例によって本発明を説明する。実施例体重200−230ｇのラットをメトキシフルランで麻酔し、そしてシリコンゴムチューブのカテーテルを右頸静脈に通した。このカテーテルを、皮下を通して、肩甲骨あたりで体外に出し、そこの所で、動物が自由に動ける様に、スイベル上に固定された金属製スプリングコイルに接続した。この手術後、各動物を、12時間周期の明暗を繰り返す部屋内の代謝用ケージに入れた。動物を少くとも２日間手術から回復させた。その間、動物が、自由に標準的な実験ラット用飼料及び水を摂取できる様にした。動物を、以下の３つの処置群のいずれかにランダムに割りあてた：（ａ）PN、栄養分を腸管外注入したもの；（ｂ）PNC、栄養分を腸管外注入し、さらに１日あたり0.34ｇ／kg体重の量のコレスチラミンを経口投与したもの；並びに、（ｃ）CF、生理食塩水を腸管外注入し、そして齧歯類用飼料を自由に摂取できる様にしたもの。全ての動物に、７または14日間、１時間３mlの割合で、計量式注入ポンプで注入を行った。PNC群の動物には、給餌用針を用いて経口で胃管内にコレスチラミンを毎日投与した。PN群及びCF群の動物には、給餌用針を用いて経口で胃管内に相当量の水を毎日投与した。腸管外用の栄養溶液は、デキストロース242ｇ／Ｌ、電解質を有する10％Trava sol^TMブレンドＢ（Baxter Corporation，Canada）の形で供給されるアミノ酸52 ｇ／Ｌ、マルチビタミン溶液２mL／Ｌ及びグルコン酸カルシウム2.25mmol／Ｌを含んでなる。７日間の実験期間の終りには、総血清ビリルビン（mg／dL）は、PNC群の動物に比べてPN群の動物でより高かったが（PN，0.62±0.22対PNC，0.36±0.13，Ｐ＜0.05、平均±SD）、どちらの群も、CF群の動物に比べて有意な差はなかった（ CF，0.53±0.36）。この３つの処置群において、血清アミノ酸レベルは類似していた（表１）。CF 群の動物と比べて、PN群の動物では、セリン、グリシン、スレオニン及びメチオニンのレベルが上がっていた。PNC群の動物と比べて、PN群の動物では、スレオニン及びグリシンのレベルが上がっていた。表１血清アミノ酸濃度（μmol／Ｌ）各値は平均±SD（各群ｎ＝６）である； ¹Ｐ＜0.05，CF群に対する有意差；²Ｐ＜0.05，CF及びPNC群に対する有意差； ³Ｐ＜0.05，PNC群に対する有意差最終体重に対する肝臓重量の百分率は、CF群動物と比べて、PN群及びPNC群の動物では低かった（PN，3.34±0.33；PNC，3.41±0.29；CF，3.86±0.30；Ｐ＜0 .05、平均±SD）。14日間処置した後に、肝臓脂肪症の評価を組織学的に決定した。CF群及びPNC群の両動物では、肝臓脂肪症は見られなかったが、PN群の動物ではこれが認められた。図１は、腸管外で栄養を摂取した動物群（PN）のラット肝臓の代表的な顕微鏡写真である。この肝細胞中には、大及び小脂肪滴（「Ｆ」で印す）の両方の形が明白に認められる。図２は、腸管外で栄養を摂取し、さらにコレスチラミンを摂取した動物群(PNC )のラット肝臓の代表的な顕微鏡写真である。図１とは異なり、正常な細胞構造が明白であり、そして肝臓脂肪症の兆候はない。図３は、齧歯類用飼料を摂取した動物群（CF）のラット肝臓の顕微鏡写真であり、図２と同様な正常な細胞構造が見られる。図１〜３は、Ｈ＆Ｅで染色した組織切片を880倍に拡大した像として得た。組織学的証拠は、図１に見られるように、非経口的栄養治療が肝脂肪症に関連すること、及び図２に示されるようにコレスチラミン治療が肝異常を逆転させることを示す。この結果は、毒性二次胆汁酸の吸収におけるコレスチラミンの効果と一致する。なぜならこの胆汁酸は、肝機能不全の発達にかなり寄与性からである。この例は、コレスチラミンの経口投与が非経口的栄養摂取により誘導される肝脂肪症を防ぐことを示す。工業利用性本発明は、非経口的栄養摂取、癌化学療法、内毒血症、敗血症、やけど及び腸の機能を傷つけ得る他の病状、細菌の移動及びAIDSのような病状に通常、関速する肝脂肪症の防止又は軽減を許容する。任意に免疫栄養法と組み合わせた胆汁酸封鎖剤の使用は、肝脂肪を減少又は最少化し、個体の全体の健康を増進させる。Description: FIELD OF THE INVENTION The present invention relates to the field of liver therapy and more particularly to the use of bile acid sequestrants for the purpose of preventing or alleviating hepatic steatosis. About. Background of the Invention The administration of nutrients via intravenous supply via an indwelling catheter known as parenteral nutrition or total parenteral nutrition (TPN) bypasses the digestive process and requires nutrients such as amino acids, sugars required by the body. Transports fats, vitamins and minerals directly into the bloodstream. Parenteral nutrition is widely used to provide nutrition to severely ill individuals who cannot tolerate oral enteral feeding. However, bypassing digestion through parenteral nutrition can lead to overgrowth of intestinal bacteria, transfer of bacteria from the intestinal lumen to the body, and endotoxemia. Parenteral nutrition can also lead to fatty infiltration in the liver, known as hepatic steatosis, hepatostearosis or fatty liver. There is a published relationship between liver failure and parenteral nutrition as an indicator of liver damage (Fisher, Gastroenterol. Clin. N. Am., 18: 645-666, 1989; Hodes 3, J. et al. Pediatr. Surg. 17: 463-468, 1982). Liver failure presents a major problem in parenteral nutrition treatment of infants and children. Hepatic failure can be elevated serum hepatic enzymes and bilirubin levels (Grant et al., Surg. Gynecol. Obstet. 145: 573-586, 1977) or develop hepatic steatosis (Keim, JPEN 11: 18-22, 1987; Keim) J. Nutr. 114: 1807-1815, 1984). Prolonged parenteral nutrition therapy in which patients are subjected to intestinal fasting results in reduced gastrointestinal motility, reduced gastrointestinal transit time, and reduced fecal volume. Such effects can cause increased reabsorption of secondary bile acids from the intestinal lumen, thereby increasing the concentration of secondary bile acids in serum (Vileisis et al., J. Pediatr. 96: 893-897). , 1980). Secondary bile acids produced by bacterial dehydroxylation of primary bile acids in the peripheral small intestine or colon, especially lithocholic acid, have been shown to be toxic in a number of animal species (Vousef et al., Gastroenterolog y 80: 233-241). , 1981). It is believed that during parenteral nutrition therapy and intestinal fasting, the gut is quiescent and the chances for colon bacteria to produce secondary bile acids are increased. The concomitant decrease in bowel motility can extend the time that secondary bile acids are generated and reabsorbed through enterohepatic recycle. Thus, the pool of toxic bile acids in the body can be increased (Hofimann, Hepatology 4: 4S-14S, 1984). Cholestyramine is a basic anion exchange resin that can bind bile acids and is therefore known as a bile acid sequestrant. Cholestyramine is commonly used to lower blood cholesterol through interruption of enterohepatic recycling of bile acids. A composition comprising cholestyramine together with a serum lipid modulator is disclosed in US Pat. No. 4,814,354 for the purpose of lowering blood cholesterol. A composition comprising cholestyramine and a non-absorbable, non-digestible polyol polyester for use in lowering blood cholesterol is disclosed in US Pat. No. 5,116,610. When administered orally to patients, cholestyramine remains protonated at the alkaline pH of the contents of the intestinal lumen, thus maximizing bile acid binding. The cholestyramine resin to which bile acid is bound in this way is excreted from the body through feces, and thus reabsorption of bound bile acid is prevented or suppressed. Other bile acid sequestrants may provide similar results (Ast & Frenchman, J. Clin. Pharmacol. 106: 99-106, 1990). Cholesterol is a precursor molecule in bile acid synthesis. By eliminating bile acids from the body, alternative bile acids are synthesized from the body's cholesterol pool, thus tending to lower blood cholesterol. Other physiological conditions that can cause hepatic steatosis include cancer chemotherapy, endotoxemia, sepsis, burns and various bowel disorders, bacterial metastases, AIDS or low birth weight of infants. Several synthetic resins are effective in removing proteinaceous materials from biological fluids (Nolan et al., Effect of cholestyramine on endotoxin toxicity and abs orption. Digestive Diseases 17: 161-166, 1972). U.S. Pat. Nos. 3,769,401 and 3,097,141 disclose methods for the removal of proteinaceous material from biological fluids as a detoxification method. These methods utilize an ionically charged resin that has an affinity for the proteinaceous material when placed back on it. It is an object of the present invention to prevent or alleviate hepatic steatosis, which may result from parenteral nutrition therapy. DISCLOSURE OF THE INVENTION It has been discovered that compositions comprising a bile acid sequestrant, such as cholestyramine, can prevent or alleviate hepatic steatosis associated with parenteral nutrition therapy or derived from other treatments or conditions. In accordance with one aspect of the present invention, there is provided a use of a bile acid sequestrant, wherein an effective amount of the sequestrant is taken by a subject for the prevention or alleviation of hepatic steatosis. . According to another aspect of the present invention, there is provided use of a composition for preventing or alleviating hepatic steatosis in a subject, characterized in that the composition is adapted for oral or enteral administration. And an effective amount of a bile acid sequestering agent and a pharmacologically acceptable carrier. According to a further aspect of the present invention, there is provided a composition adapted for oral or enteral administration to a subject for prevention or alleviation of hepatic steatosis, comprising an effective amount of a bile acid sequestering agent, immunonutrient and pharmacology. A composition comprising a chemically acceptable carrier. In accordance with another aspect of the present invention, there is provided a method of preventing or alleviating hepatic steatosis in a subject, the method comprising ingesting an effective amount of a bile acid sequestering agent by the subject. According to another aspect of the present invention, there is provided a method of preventing or mitigating liver damage to a subject, the composition comprising an effective amount of a bile acid sequestering agent and a pharmacologically acceptable carrier according to the subject. Is ingested. Liver steatosis can also result from other symptoms. Thus, the present invention can be used to prevent or alleviate liver steatosis ultimately resulting from symptoms such as cancer chemotherapy, endotoxemia, sepsis, burns, bacterial metastasis and AIDS. The present invention may also be used for the prevention or alleviation of hepatic steatosis resulting from impaired intestinal function based on other specific or unknown factors. The present invention can be used for the prevention or alleviation of hepatic steatosis caused by specific or unknown factors. Liver steatosis can also result from or result from impaired immunogens. The presence of immunonutrients in the compositions of the present invention may enhance intestinal function and further reduce susceptibility to bacterial transfer, endotoxemia and sepsis. When combined with bile acid sequestrants, such as cholestyramine, immunonutrients can further help prevent or alleviate hepatic steatosis. BRIEF DESCRIPTION OF THE DRAWINGS In the drawings relating to the present invention: FIG. 1 is a micrograph showing the liver of a rat that has taken nutrients by the parenteral route and has not been treated with cholestyramine; FIG. 4 is a photomicrograph showing the liver of a rat receiving cholesterylamine-treated and cholestyramine; and FIG. 3 is a photomicrograph showing the liver of a rat receiving a rodent diet. BEST MODE FOR CARRYING OUT THE INVENTION In a preferred embodiment of the invention, a composition comprising cholestyramine and a pharmaceutically suitable carrier is administered orally to a subject. Cholestyramine is administered at a level effective to prevent or reduce hepatic steatosis resulting from parenteral nutrition, not to exceed about 40 g / day based on the weight of the adult. A preferred cholestyramine range is 1 to 40 g / day. All dosages given herein are based on adult body weight, which ranges from about 40 kg to 150 kg. It is also conceivable to use the invention on individuals having a weight outside this range, in which case the dosage is usually proportional to body weight. For example, chemotherapy, AIDS, sepsis, burns, and conditions requiring parenteral nutrition are often accompanied by severe weight loss. Optionally, one or more immunonutrients can be added to the composition of cholestyramine and a pharmaceutically suitable carrier. Immunonutrients are defined herein as nutrients that have a beneficial effect on immune function, including but not limited to amino acids, such as arginine and glutamine; antioxidants, such as vitamins A, C, E, And β-carotene; omega-3 polyunsaturated fatty acids such as linolenic acid (18: 2), eicosapentaenoic acid (20: 5), and docosahexaenoic acid (22: 6); short chain fatty acids such as acetic acid, propionic acid and Butyric acid; triglycerides containing omega-3 polyunsaturated fatty acids and / or short chain fatty acids; and ribonucleic acids or nucleotides. The dosage of free arginine is preferably about 17-25 g / day. The dose of glutamine is preferably an effective amount that does not exceed about 60 g / day. The daily dose of glutamine is preferably about 0.16 ± 0.02 g / kg body weight. The dosage of omega-3 polyunsaturated fatty acids is preferably about 1-4 g / day. The dosage of ribonucleic acids or nucleotides is preferably about 0.75-3 g / day. Two useful bile acid sequesters are cholestyramine and cholestipol (Ast & Frishman, J. Clin. Pharmacol. 106: 99-106, 1990). Preferably, cholestyramine is used as a bile acid absorber. Cholestyramine is a synthetic strong basic anion exchange resin containing quaternary ammonium groups added to a styrene-divinylbenzene copolymer (Merck Index, 9th Edition, 1976, p. 2194). Colestipol is a basic anion-exchange copolymer consisting of diethylenetriamine and 1-chloro-2,3-epoxypropane (or hydrochloride in some cases), wherein about one of every five amino nitrogens is protonated. (Merck Index, 9th Edition, 1976, p. 2436), which is often supplied as powdered colestipol hydrochloride. This dosage is preferably an effective amount not exceeding 30 g / day, and preferably ranges from about 5 to 30 g / day. In the present invention, it is conceivable to use a bile acid absorber as an arbitrary dosage form or a dosage form having any structural modification of the present resin in which bile acid binding ability is not inhibited. In the present invention, various dosage forms of the present bile acid absorber can be used that match the dosage form suitable for any pharmaceutical. In the present invention, it is conceivable that the bile acid absorber or the composition of the present invention is administered orally mainly in the form of a solid, gel or liquid, or ingested via a feeding gut tube. The present invention is preferably applied in treating conditions that cause liver damage. The following examples illustrate the invention. Example Rats weighing 200-230 g were anesthetized with methoxyflurane and a silicone rubber tube catheter was passed through the right jugular vein. The catheter was passed subcutaneously and out of the body about the scapula where it was connected to a metal spring coil fixed on a swivel so that the animal could move freely. After this operation, each animal was placed in a metabolic cage in a room with a 12-hour light / dark cycle. Animals were allowed to recover from surgery for at least two days. During that time, animals had free access to standard laboratory rat chow and water. Animals were randomly assigned to any of the following three treatment groups: (a) PN, parenterally injected nutrients; (b) PNC, parenterally injected nutrients, plus 0.34 g per day Cholestyramine orally in an amount of / kg body weight; and (c) a parenteral injection of CF, saline, and free access to rodent diet. All animals were infused with a metered infusion pump at a rate of 3 ml / hour for 7 or 14 days. Animals in the PNC group were dosed daily with cholestyramine orally in the stomach tube using a feeding needle. Animals in the PN group and the CF group received a daily oral dose of a significant amount of water in the stomach tube using a feeding needle. The parenteral nutrient solution comprises dextrose 242 g / L, amino acids 52 g / L supplied in the form of 10% Travasol ^™ blend B with electrolytes (Baxter Corporation, Canada), multi-vitamin solution 2 mL / L and calcium gluconate 2.25 mmol / L. At the end of the 7-day experimental period, total serum bilirubin (mg / dL) was higher in animals in the PN group compared to animals in the PNC group (PN, 0.62 ± 0.22 vs. PNC, 0.36 ± 0.13, P <0.05, mean ± SD), neither group was significantly different from the CF group animals (CF, 0.53 ± 0.36). Serum amino acid levels were similar in the three treatment groups (Table 1). Serine, glycine, threonine, and methionine levels were higher in animals in the PN group than in animals in the CF group. Threonine and glycine levels were higher in animals in the PN group than in animals in the PNC group. Table 1 Serum amino acid concentration (μmol / L) Each value is mean ± SD (n = 6 for each group); ¹ P <0.05, significant difference for CF group; ² P <0.05, significant difference for CF and PNC groups; ³ P <0.05, significant difference for PNC group The percentage of liver weight to final body weight was lower in animals in the PN and PNC groups compared to animals in the CF group (PN, 3.34 ± 0.33; PNC, 3.41 ± 0.29; CF, 3.86 ± 0.30; P <0.05). , Mean ± SD). After 14 days of treatment, the assessment of hepatic steatosis was determined histologically. Liver steatosis was not observed in both animals in the CF and PNC groups, but was observed in animals in the PN group. FIG. 1 is a representative micrograph of a rat liver of a group of animals (PN) that have taken parenteral nutrition. Both large and small lipid droplets (marked with "F") are clearly visible in the hepatocytes. FIG. 2 is a representative photomicrograph of the liver of a rat from a group of animals (PNC) that have taken nutrients outside the intestine and have also taken cholestyramine. Unlike FIG. 1, normal cell structure is evident and there are no signs of liver steatosis. FIG. 3 is a micrograph of a rat liver of a group of animals (CF) that has received a rodent feed, and shows the same normal cell structure as in FIG. Figs. 1 to 3 show tissue sections stained with H & E as images magnified 880 times. Histological evidence indicates that parenteral nutrition therapy is associated with hepatic steatosis, as seen in FIG. 1, and that cholestyramine treatment reverses liver abnormalities, as shown in FIG. This result is consistent with the effect of cholestyramine on absorption of toxic secondary bile acids. This is because bile acids contribute significantly to the development of liver dysfunction. This example shows that oral administration of cholestyramine prevents hepatic steatosis induced by parenteral nutrition. INDUSTRIAL APPLICABILITY The present invention is generally associated with parenteral nutrition, cancer chemotherapy, endotoxemia, sepsis, burns and other conditions that can impair intestinal function, bacterial migration and conditions such as AIDS. To prevent or reduce hepatic steatosis. The use of bile acid sequestrants, optionally in combination with immunonutrition, reduces or minimizes hepatic fat and enhances the overall health of the individual.

【手続補正書】特許法第１８４条の８第１項【提出日】平成１０年１０月７日（１９９８．１０．７）【補正内容】請求の範囲 26．内毒素血症の軽減又は根絶のための胆汁酸封鎖剤の使用であって、有効量の前記封鎖剤を目的とする被検体に摂取させることを特徴とする使用。 27．前記内毒素血症が、非経口栄養法、癌療法、敗血症、熱傷又はAIDSによる栄養不良の結果としておこることを特徴とする請求項26に記載の使用。[Procedure of Amendment] Article 184-8, Paragraph 1 of the Patent Act [Submission date] October 7, 1998 (1998.10.7) [Correction contents] The scope of the claims 26. Use of a bile acid sequestrant to reduce or eradicate endotoxemia, comprising an effective amount Use of the above-mentioned blocking agent in a subject to be ingested. 27. The endotoxemia is due to parenteral nutrition, cancer therapy, sepsis, burns or AIDS 27. The use according to claim 26, which occurs as a result of malnutrition.

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Claims

[Claims] 1. Intake the subject with an effective amount of a bile acid sequestrant to prevent or alleviate hepatic steatosis Use of a bile acid sequestering agent, characterized in that the agent is used. 2. The use according to claim 1, wherein the sequestering agent is cholestyramine. for. 3. Use of a composition for preventing or alleviating hepatic steatosis in a subject, The composition is suitable for oral or enteral administration and is effective as a bile acid sequestering agent and as a medicament Use characterized by including an acceptable carrier. 4. The use according to claim 3, wherein the sequestering agent is cholestyramine. for. 5. Said hepatic steatosis, parenteral nutrition, cancer chemotherapy, endotoxemia, sepsis, Selected from groups including burns, injured intestinal function, bacterial translocation and AIDS 5. Use according to claim 1, 2, 3 or 4 characterized by the result of the state selected. for. 6. The hepatic steatosis is the result of parenteral nutrition. Use as described in. 7. Suitable for oral or enteral administration to subjects to prevent or alleviate hepatic steatosis A composition comprising an effective amount of a bile acid sequestrant, an immunonutrient, and a pharmaceutically acceptable And a carrier to be used. 8. The combination of claim 7, wherein the sequestering agent is cholestyramine. Adult. 9. Cholestyramine is included in the composition so that the intake does not exceed 40 g per day 9. The composition according to claim 8, which is included. Ten. The immunonutrient is an amino acid, an antioxidant, an omega-3 polyunsaturated fatty acid; , Short-chain fatty acids, and their triglyceride-containing groups The composition according to claim 7, 8 or 9, wherein the composition is selected from the group consisting of: 11． The immunonutrient is a ribonucleic acid or a nucleotide. Item 10. The composition according to Item 7, 8, or 9. 12． The immunonutrient is arginine, glutamine, vitamin A, vitamin C, Vitamin E, β-carotene, linolenic acid, eicosapentaenoic acid, docosahexa Characterized by being selected from the group comprising enic acids and their triglycerides A composition according to claim 10. 13. The immunonutrient is arginine and is provided at a level of about 17-25 g per day. 13. The composition according to claim 12, wherein the composition is prepared. 14. The immunonutrient is glutamine, and the intake does not exceed about 60 g per day 13. The composition according to claim 12, wherein the composition is provided in an amount. 15． The immunonutrient is an omega-3 polyunsaturated fatty acid, and is about 1 to 4 per day. 13. The composition according to claim 12, provided at a level of g. 16． Said hepatic steatosis, parenteral nutrition, cancer chemotherapy, endotoxemia, sepsis, Selected from groups including burns, injured intestinal function, bacterial translocation and AIDS 7. The result of the selected state, wherein the result is a selected state. Use of the composition according to 15. 17． 17. The method of claim 16, wherein the hepatic steatosis is the result of parenteral nutrition. Use as described in. 18． Administering an effective amount of the composition of claim 7, 8, 9, 12, 13, 14, or 15. A method for preventing or alleviating hepatic steatosis in a subject. 19. Said hepatic steatosis, parenteral nutrition, cancer chemotherapy, endotoxemia, sepsis, Burned and injured bowel function, bacterial translocation Claims that are the result of a condition selected from the group comprising the option and the AIDS. 18. The method according to 18. 20. A method of preventing or alleviating hepatic steatosis in a subject, the method comprising: A method comprising causing a test sample to take a sap acid sequestering agent. twenty one. The method according to claim 20, wherein the sequestering agent is cholestyramine. Law. twenty two. A method of preventing or alleviating hepatic steatosis in a subject, the method comprising an effective amount of bile Ingesting a composition containing an acid sequestering agent and a pharmaceutically acceptable carrier into a subject A method characterized by the following. twenty three. The use according to claim 22, wherein the sequestering agent is cholestyramine. for. twenty four. Said hepatic steatosis, parenteral nutrition, cancer chemotherapy, endotoxemia, sepsis, Selected from groups including burns, injured intestinal function, bacterial translocation and AIDS 24. The method according to claim 20, 21, 22, or 23, wherein the result is a selected state. Law. twenty five. The method of claim 19, wherein the hepatic steatosis is the result of parenteral nutrition. Or the method of 24.