JP5177785B2 - Drugs for perioperative patients - Google Patents
Drugs for perioperative patients Download PDFInfo
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- JP5177785B2 JP5177785B2 JP2005319615A JP2005319615A JP5177785B2 JP 5177785 B2 JP5177785 B2 JP 5177785B2 JP 2005319615 A JP2005319615 A JP 2005319615A JP 2005319615 A JP2005319615 A JP 2005319615A JP 5177785 B2 JP5177785 B2 JP 5177785B2
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- body temperature
- administration
- inhibitor
- perioperative
- isoleucine
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Description
本発明は、例えば、医薬品又は食品の形態にある周術期患者用薬剤、及び手術時の全身麻酔による体温低下を抑制する体温低下抑制剤に関する。 The present invention relates to a drug for perioperative patients in the form of pharmaceuticals or foods, and a body temperature decrease inhibitor that suppresses body temperature decrease due to general anesthesia during surgery.
外科手術時等の患者においては、全身麻酔により体温調節機構が抑制されるため、周囲の環境温度の影響を受けやすい状態となり患者の体温（核心温）の低下が起こる。この体温低下により悪寒・不快感、シバリング、頻脈・虚血性心電図変化、覚醒遅延、創部感染、創傷治癒遅延、免疫力低下、血液凝固障害等の合併症が発症している。また、外科手術では術中一時的に局所の血流を遮断し、再び血流を開通させる操作を行うため、これによる虚血再灌流障害が生じ、筋タンパク崩壊が生じる。
このような体温低下、体温低下に伴う合併症及び手術操作に起因する組織障害を防止するため、外科手術時にアルミニウム保温材、循環式加温マット、加温輸液、温風式加温等による保温対策が知られている。
しかしながら、従来の循環式加温マットは患者の体位によっては保温部位が局部的になり保温効果が十分でなかった。また、温風式加温は有効な手段であったが患者を被うウォーミングカバー等の消耗品が必要であることからコストの面で問題となっている。体温低下が体温中枢の閾値を越えて低下した場合、従来の保温対策を行っても体温回復には長時間を必要とする。また、高用量の総合型のアミノ酸輸液製剤（総アミノ酸濃度１０Ｗ／Ｖ％以上）が体温低下抑制に有効であるとの報告（非特許文献１〜３）があるが、本発明の有効成分の開示はなく、また本発明と同じ総アミノ酸濃度のアミノ酸製剤は開示されていない。
In patients at the time of surgery or the like, since the body temperature regulation mechanism is suppressed by general anesthesia, the body temperature (core heart temperature) of the patient is lowered because the body temperature is easily affected by the surrounding environmental temperature. This decrease in body temperature causes complications such as chills / discomfort, shivering, tachycardia / ischemic electrocardiogram changes, delayed arousal, wound infection, delayed wound healing, decreased immunity, and blood coagulation disorder. In addition, in the surgical operation, an operation for temporarily blocking the local blood flow and reopening the blood flow is performed during the operation, thereby causing ischemia-reperfusion injury and muscle protein collapse.
In order to prevent such a decrease in body temperature, complications associated with a decrease in body temperature, and tissue damage due to surgical operation, heat insulation by an aluminum heat insulating material, a circulation warming mat, warming infusion, warm air warming, etc. during surgery Countermeasures are known.
However, according to the conventional circulation warming mat, depending on the posture of the patient, the heat retaining portion is localized and the heat retaining effect is not sufficient. Although warm air heating is an effective means, it requires a consumable item such as a warming cover to cover the patient, which is problematic in terms of cost. If the decrease in body temperature exceeds the threshold of the body temperature center, it takes a long time to recover the body temperature even if conventional measures for keeping warm are performed. In addition, there is a report (Non-patent Documents 1 to 3) that a high-dose total type amino acid infusion preparation (total amino acid concentration of 10 W / V% or more) is effective in suppressing body temperature decrease. There is no disclosure, and no amino acid preparation having the same total amino acid concentration as the present invention is disclosed.
本発明は、又、周術期合併症を予防および／あるいは改善する周術期患者用薬剤を提供することを目的とする。
本発明は、又、全身麻酔等による体温低下を抑制し、体温低下に伴う合併症や手術操作に起因する組織障害を予防および／または改善する体温低下抑制剤を提供することを目的とする。
本発明は、又、医薬品又は飲食品の形態にある体温低下抑制剤を提供することを目的とする。
Another object of the present invention is to provide a drug for perioperative patients that prevents and / or ameliorates perioperative complications.
Another object of the present invention is to provide a body temperature lowering inhibitor that suppresses a decrease in body temperature due to general anesthesia or the like, and prevents and / or ameliorates a tissue disorder caused by a complication associated with a decrease in body temperature or a surgical operation.
Another object of the present invention is to provide a body temperature decrease inhibitor in the form of a pharmaceutical product or food or drink.
本発明者らは、上記目的を達成するため様々な種類のアミノ酸及び/又はアミノスルホン酸について鋭意研究した結果、ある種のアミノ酸又はアミノスルホン酸が単独で、又複数種組合せて周術期合併症を予防および／あるいは改善できること、又体温低下抑制作用を有することを見出し、本発明を完成するに至った。
すなわち、本発明は、バリン、アスパラギン酸、システイン、グリシン、アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン及びタウリンからなる群から選択される少なくとも１種又は少なくとも２種を組み合わせてなる混合物又はこれらのペプチド結合体を有効成分として含有することを特徴とする周術期患者用薬剤を提供する。
本発明は、又、アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン及びタウリンからなる群から選択される少なくとも１種又は少なくとも２種又はこれらのペプチド結合体を有効成分として含有することを特徴とする体温低下抑制剤を提供する。
As a result of intensive studies on various types of amino acids and / or aminosulfonic acids to achieve the above object, the present inventors have found that a certain type of amino acid or aminosulfonic acid is used alone or in combination of a plurality of types, and is a perioperative merger. The present inventors have found that the disease can be prevented and / or improved, and have an effect of suppressing the decrease in body temperature, and the present invention has been completed.
That is, the present invention is at least selected from the group consisting of valine, aspartic acid, cysteine, glycine, alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine and taurine. There is provided a drug for perioperative patients, comprising one or a mixture of at least two or a peptide conjugate thereof as an active ingredient.
The present invention also includes at least one or at least two selected from the group consisting of alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine and taurine, or these There is provided a body temperature decrease inhibitor comprising a peptide conjugate as an active ingredient.
本発明により、タンパク合成促進、免疫賦活による創傷治癒促進、外科的糖尿病抑制、再還流障害抑制作用、特にタンパク合成を促進させて筋タンパクの崩壊を抑制する作用を有する周術期患者用薬剤を提供される。又、全身麻酔等による体温低下を抑制し、体温低下に伴う合併症を予防および／または改善する体温低下抑制剤が提供される。本発明の体温低下抑制剤を用いると、体温（核心温）の低下抑制をこれまでの周術期に投与されていた細胞外液組成の輸液に添加した製剤とすることで、従来の体温低下抑制方法に比較し、簡便に安価で行うことが出来る。また、従来の方法と組み合わせることによりさらに有効に体温低下の抑制を達成できる。 According to the present invention, there is provided a drug for perioperative patients having an activity of promoting protein synthesis, promoting wound healing by immunostimulation, suppressing surgical diabetes, inhibiting reperfusion injury, and in particular, promoting protein synthesis and suppressing muscle protein breakdown. Provided. Also provided is a body temperature lowering inhibitor that suppresses body temperature decrease due to general anesthesia or the like and prevents and / or ameliorates complications associated with body temperature decrease. When the body temperature lowering inhibitor of the present invention is used, a conventional body temperature lowering can be achieved by adding a body temperature (nuclear core temperature) lowering suppression to an infusion of an extracellular fluid composition that has been administered in the previous perioperative period. Compared with the suppression method, it can be carried out simply and inexpensively. Further, by combining with the conventional method, it is possible to more effectively suppress the decrease in body temperature.
本発明の周術期患者用薬剤は、バリン、アスパラギン酸、システイン、グリシン、アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン及びタウリンからなる群から選択される少なくとも１種又は少なくとも２種を有効成分として含有することを特徴とする。中でもアラニン、プロリン、セリンがより好ましい。これらは、それぞれ単独で含有しても良いし、それぞれを任意に組み合わせて含有しても良い。それぞれのアミノ酸は、市販品、合成品、その他製法に関係なく使用できる。Ｄ体、Ｌ体、ＤＬ体の何れでも使用可能であるが、Ｌ体であることが好ましい。各アミノ酸は必ずしも遊離アミノ酸として使用される必要はなく、医薬品又は飲食品で許容される塩の形態でもよく、例えば無機酸塩、有機酸塩、生体内で加水分解可能なエステル体、Ｎ−アシル誘導体などの形態で使用してもよい。また、同種あるいは異種のアミノ酸及び/又はアミノスルホン酸をペプチド結合させたペプチド類の形態で使用してもよい。ここで、ペプチド結合体としては、上記２つのアミノ酸（特にＬ体のアミノ酸）のペプチド結合体であるのが好ましい。具体的には、Ｌ−アラニンとＬ−グルタミンとのペプチド結合体であるＬ−アラニル−Ｌ−グルタミンが好ましいものとしてあげられる。これは、Ｌ−アラニンのカルボキシル基にＬ−グルタミンのアミノ基がペプチド結合したものである。さらに、Ｌ−グリシル−Ｌ−グルタミンも好ましいペプチド結合体としてあげることができる。これらのアミノ酸のペプチド結合体は、合成あるいは醗酵法等により得ることができる。
又、本発明の周術期患者用薬剤は、イソロイシン、ロイシン及びバリンを有効成分として含有するのが好ましい。
これらの周術期患者用薬剤は、輸液製剤の形態であるのが好ましく、更に電解質を含有するのが好ましい。又、飲食品の形態であるのも好ましい。
The drug for perioperative patients of the present invention is a group consisting of valine, aspartic acid, cysteine, glycine, alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine and taurine It contains at least one or at least two selected from the above as an active ingredient. Of these, alanine, proline, and serine are more preferable. These may be contained alone or in any combination. Each amino acid can be used regardless of a commercial product, a synthetic product, or other production methods. Any of D-form, L-form and DL-form can be used, but L-form is preferred. Each amino acid does not necessarily need to be used as a free amino acid, and may be in the form of a salt that is acceptable for pharmaceuticals or foods and drinks, for example, an inorganic acid salt, an organic acid salt, a hydrolyzable ester, N-acyl You may use with forms, such as a derivative. Alternatively, the same or different amino acids and / or aminosulfonic acids may be used in the form of peptides having a peptide bond. Here, the peptide conjugate is preferably a peptide conjugate of the above-mentioned two amino acids (particularly L-amino acid). Specifically, L-alanyl-L-glutamine, which is a peptide conjugate of L-alanine and L-glutamine, is preferred. This is a peptide bond of the amino group of L-glutamine to the carboxyl group of L-alanine. Furthermore, L-glycyl-L-glutamine can also be mentioned as a preferred peptide conjugate. Peptide conjugates of these amino acids can be obtained by synthesis or fermentation methods.
The perioperative patient drug of the present invention preferably contains isoleucine, leucine and valine as active ingredients.
These drugs for perioperative patients are preferably in the form of an infusion preparation, and further preferably contain an electrolyte. Moreover, it is also preferable that it is the form of food-drinks.
本発明の体温低下抑制剤において、有効成分として使用できるアミノ酸及び/又はアミノスルホン酸は、アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン、タウリンであり、中でもアラニン、プロリン、セリンがより好ましい。これらは、それぞれ単独で含有しても良いし、それぞれを任意に組み合わせて含有しても良い。これらは、市販品、合成品、その他製法に関係なく使用できる。
Ｄ体、Ｌ体、ＤＬ体の何れでも使用可能であるが、Ｌ体であることが好ましい。各アミノ酸は必ずしも遊離アミノ酸として使用される必要はなく、医薬品又は飲食品で許容される塩の形態でもよく、例えば無機酸塩、有機酸塩、生体内で加水分解可能なエステル体、Ｎ−アシル誘導体などの形態で使用してもよい。また、同種あるいは異種のアミノ酸をペプチド結合させたペプチド類の形態で使用してもよい。ペプチド結合させたペプチド結合体（ペプチド類）としては、周術期患者用薬剤の項において述べたのと同様のものが好ましいものとしてあげられる。尚、本発明の体温低下抑制剤に用いるアミノ酸としては、上記アミノ酸のみを用いることができるが、バリン、アスパラギン酸、システイン、グリシンの１種以上と併用してもよい。
本発明の覚醒遅延防止剤においても、上記周術期患者用薬剤および体温低下抑制剤と同様に作成することが可能である。
本発明の周術期患者用薬剤、体温低下抑制剤及び覚醒遅延防止剤の投与方法としては、経口投与、静脈内投与などが可能であるが、特にこれらに限定されるものではない。静脈内投与の場合は末梢静脈、中心静脈等から持続投与することが好ましい。
In the body temperature decrease inhibitor of the present invention, amino acids and / or aminosulfonic acids that can be used as active ingredients are alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine, taurine. Among them, alanine, proline, and serine are more preferable. These may be contained alone or in any combination. These can be used regardless of commercial products, synthetic products, and other production methods.
Any of D-form, L-form and DL-form can be used, but L-form is preferred. Each amino acid does not necessarily need to be used as a free amino acid, and may be in the form of a salt that is acceptable for pharmaceuticals or foods and drinks, for example, an inorganic acid salt, an organic acid salt, a hydrolyzable ester, N-acyl You may use with forms, such as a derivative. Further, it may be used in the form of peptides in which the same or different amino acids are peptide-bonded. Preferable peptide conjugates (peptides) that are peptide-bonded are the same as those described in the section on drugs for perioperative patients. In addition, as an amino acid used for the body temperature fall inhibitor of this invention, although only the said amino acid can be used, you may use together with 1 or more types of valine, aspartic acid, cysteine, and glycine.
The anti-wake delay agent of the present invention can be prepared in the same manner as the perioperative patient drug and the body temperature decrease inhibitor.
The administration method of the drug for perioperative patients, the body temperature decrease inhibitor and the arousal delay inhibitor of the present invention can be oral or intravenous, but is not particularly limited thereto. In the case of intravenous administration, continuous administration from peripheral veins, central veins, etc. is preferable.
有効成分とするアラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン、タウリンなどの投与量は投与方法、患者の症状や程度、剤形の種類により適宜選択すれば良いが、経口投与の場合、１投与あたりそれぞれ１０ｍｇ〜１００００ｍｇの範囲で投与すればよい。静脈内投与する場合は経口投与の１／２０〜１／２程度の量を投与すればよい。これらの投与量は必要によっては数回に分割して投与しても良いし、また必要によっては１日数回投与しても良い。一方、静脈内に持続投与する場合には１０ｍｇ〜１０００ｍｇ／ｋｇ／ｈｒの範囲の投与速度で少なくとも２時間程度投与することが好ましい。
本発明の周術期患者用薬剤、体温低下抑制剤及び覚醒遅延防止剤の医薬品の形態、例えば、医薬品製剤は、投与方法によって変更可能であり特に限定されるものではない。例えば、液剤、錠剤、カプセル剤、顆粒剤、細粒剤、粉末剤、散剤等が考えられる。このような剤型を調製するためには医薬上許容しうる液体または固体状の適当な賦形剤、充填剤、増量剤、溶剤、乳化剤、滑沢剤、風味補正剤、香料、染料、緩衝物質等の補助剤を加えて行うのが好ましい。
The doses of active ingredients such as alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine, taurine, etc. depend on the method of administration, patient symptoms and degree, and type of dosage form. What is necessary is just to select suitably, However, In the case of oral administration, what is necessary is just to administer in the range of 10 mg-10000 mg per administration, respectively. In the case of intravenous administration, an amount of about 1/20 to 1/2 of oral administration may be administered. These doses may be divided into several doses as necessary, or may be administered several times a day as necessary. On the other hand, in the case of continuous administration intravenously, it is preferable to administer at least about 2 hours at an administration rate in the range of 10 mg to 1000 mg / kg / hr.
The pharmaceutical forms of the drug for perioperative patients, the body temperature decrease inhibitor and the arousal delay inhibitor of the present invention, for example, the pharmaceutical preparation, can be changed depending on the administration method and are not particularly limited. For example, liquids, tablets, capsules, granules, fine granules, powders, powders, and the like can be considered. In order to prepare such a dosage form, a suitable pharmaceutically acceptable liquid or solid excipient, filler, extender, solvent, emulsifier, lubricant, flavor corrector, flavor, dye, buffer It is preferable to carry out by adding auxiliary substances such as substances.
本発明の周術期患者用薬剤、体温低下抑制剤及び覚醒遅延防止剤は、輸液製剤の態様にあるのが好ましいので、輸液製剤の態様について特に詳細に説明する。輸液製剤においてはアラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン、タウリンなどのうち任意の組合せを含有すればよい。
アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン、タウリンなどの少なくともいずれか一つのアミノ酸を１０％以下、好ましくは０．０１〜９Ｗ／Ｖ％、より好ましくは０．０３〜６Ｗ／Ｖ％、更に好ましくは０．０５〜４Ｗ／Ｖ％、最も好ましくは０．１〜３．３％の濃度範囲に設定すればよい。
また、３種のアミノ酸の組み合わせとしては、イソロイシン、ロイシン、バリンの組み合わせなどがある。イソロイシン、ロイシン、バリンの組み合わせの含有比率（重量比）はイソロイシン：ロイシン：バリン＝2.5〜3：3.5〜5.5：2〜4であることが好ましい。
Since it is preferable that the medicine for perioperative patients, the body temperature decrease inhibitor, and the arousal delay inhibitor of the present invention are in the form of an infusion preparation, the embodiment of the infusion preparation will be described in detail. The infusion preparation may contain any combination of alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine, taurine and the like.
At least one amino acid such as alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine, taurine or the like is 10% or less, preferably 0.01 to 9 W / V%. More preferably, the concentration range may be set to 0.03 to 6 W / V%, more preferably 0.05 to 4 W / V%, and most preferably 0.1 to 3.3%.
Examples of combinations of the three amino acids include combinations of isoleucine, leucine, and valine. The content ratio (weight ratio) of the combination of isoleucine, leucine and valine is preferably isoleucine: leucine: valine = 2.5-3: 3.5-5.5: 2-4.
上記輸液製剤には、輸液成分として通常用いられる電解質、糖、ｐＨ調整剤、微量元素、ビタミン等の成分を必要とされる量を任意に配合しても良い。特に電解質を配合していることが好ましい。ここでいう電解質とは水溶液中でイオンを生じる化合物であり、特にＮａ+、Ｋ+、Ｃｌ-などのイオンを水溶液中で生じさせる無機塩、有機塩などが好ましい。更に具体的には、以下の濃度範囲のイオンを生じさせる電解質を配合していることが好ましい。
Ｎａ+ ２０．０〜１６０．０mEq/L
Ｋ+ ３．０〜４０．０mEq/L
Ｃｌ- １５．０〜１６０mEq/L
このような輸液製剤はｐＨが３．０〜８．５に調製されていることが好ましい。
In the above-mentioned infusion preparation, an amount that requires components such as electrolytes, sugars, pH adjusters, trace elements, vitamins and the like that are usually used as infusion components may be arbitrarily blended. In particular, an electrolyte is preferably blended. The electrolyte here is a compound that generates ions in an aqueous solution, and in particular, inorganic salts, organic salts, and the like that generate ions such as Na + , K + , and Cl − in an aqueous solution are preferable. More specifically, an electrolyte that generates ions in the following concentration range is preferably blended.
Na + 20.0-160.0 mEq / L
K + 3.0-40.0mEq / L
Cl - 15.0-160 mEq / L
Such an infusion preparation is preferably prepared to have a pH of 3.0 to 8.5.
より簡便な輸液製剤としては、使用時に上記アミノ酸を直接既存の輸液製剤に配合してもよく、その際本発明の体温低下抑制剤は、必要とされる量を含有する粉剤、顆粒剤、錠剤、濃厚液剤、あるいはこれらの組合せの形態であっても良い。配合される輸液製剤としては、電解質液が好ましく、中でも周術期に使用されるような等張電解質輸液、低張電解質輸液が好ましく、例えば、生理食塩水、リンゲル液、乳酸リンゲル液、酢酸リンゲル液、開始液、脱水補給液、維持液、術後回復液が好ましい。またそれらに糖を配合した輸液でもよい。手術時に投与する際には、上記輸液製剤を手術２時間前から術中にかけて１０〜４０ｍｌ／ｋｇ／ｈｒの速度で投与するのが好ましい。 As a simpler infusion preparation, the above-mentioned amino acid may be directly blended into an existing infusion preparation at the time of use, and the body temperature decrease inhibitor of the present invention is a powder, granule, tablet containing the required amount. , A concentrated liquid agent, or a combination thereof. As an infusion preparation to be blended, an electrolyte solution is preferable, and isotonic electrolyte infusion and hypotonic electrolyte infusion as used in the perioperative period are preferable, for example, physiological saline, Ringer's solution, lactated Ringer's solution, Ringer's acetate solution, start Liquid, dehydration replenisher, maintenance liquid, and postoperative recovery liquid are preferred. Moreover, the infusion which mix | blended sugar with them may be sufficient. When administered at the time of surgery, the infusion preparation is preferably administered at a rate of 10 to 40 ml / kg / hr from 2 hours before surgery to during surgery.
本発明の周術期患者用薬剤、体温低下抑制剤及び覚醒遅延防止剤の輸液製剤は、容器に充填されることが好ましく、必要に応じて各成分を複数の室に分割して充填しても良い。糖として還元糖を配合した場合アミノ酸と還元糖が経時的にメイラード反応を生じる場合があるため、アミノ酸と糖は隔離収容される方が好ましい。例えば２室を有する輸液容器において、第１室に糖・電解質液を充填し、第２室にアミノ酸液を充填すればよい。２室に区画する方法としては、使用時に外部からの押圧で剥離可能なシール部で区画する方法が好ましい。輸液容器の本体を構成する材料としては、可撓性、透明性に優れ、且低温保存後に落下しても破袋し難い軟質の樹脂材料が好ましい。特に、通常医療用容器に用いられているポリオレフィン類からなるものを好適に挙げることができる。ポリオレフィン類は、例えば、ポリエチレン、ポリプロピレン、ポリ１-ブテン、ポリ４-メチル-１-ペンテン等の重合応体を挙げることができる。容器本体は、前記樹脂をブロー成形、インフレーションあるいはデフレーション成形したものいずれでも使用できる。また、２枚の樹脂シートの周縁部を溶着して形成したものでも良い。既存の輸液製剤に配合する形態の場合には、必要成分のみを必要量、粉剤、顆粒剤、錠剤、濃縮溶液、あるいはこれらの組合せの形態で含有できる容器でよく、バイアル瓶でも良い。この場合既存の輸液製剤とのキット製品としてもよい。 The infusion preparation of the perioperative patient drug, the body temperature lowering inhibitor and the arousal delay inhibitor of the present invention is preferably filled in a container, and each component is divided into a plurality of chambers and filled as necessary. Also good. When reducing sugar is added as sugar, amino acid and reducing sugar may cause Maillard reaction over time. Therefore, it is preferable that amino acid and sugar are stored separately. For example, in an infusion container having two chambers, the first chamber may be filled with a sugar / electrolyte solution, and the second chamber may be filled with an amino acid solution. As a method of partitioning into two chambers, a method of partitioning with a seal part that can be peeled off by external pressure during use is preferable. The material constituting the main body of the infusion container is preferably a soft resin material that is excellent in flexibility and transparency and that does not easily break even if dropped after being stored at low temperature. Particularly preferred are those made of polyolefins usually used in medical containers. Examples of polyolefins include polymerized polymers such as polyethylene, polypropylene, poly-1-butene, and poly-4-methyl-1-pentene. As the container body, any of those obtained by blow molding, inflation or deflation molding of the resin can be used. Moreover, what formed by welding the peripheral part of two resin sheets may be used. In the case of a form to be blended with an existing infusion preparation, it may be a container that can contain only necessary components in the form of a necessary amount, powder, granule, tablet, concentrated solution, or a combination thereof, or a vial. In this case, a kit product with an existing infusion preparation may be used.
また、本発明の周術期患者用薬剤、体温低下抑制剤及び覚醒遅延防止剤は、上記のように医薬品の形態で実施することができるだけでなく、医薬品の実施形態を参考にして飲食品へ含有させることにより飲食品への用途を容易に実施できる。
本発明の周術期患者用薬剤は、タンパク合成促進、免疫賦活による創傷治癒促進、外科的糖尿病抑制、再還流障害抑制作用、特にタンパク合成を促進させて筋タンパクの崩壊を抑制する作用により、外科手術等の周術期患者における合併症及び虚血再灌流障害による筋タンパク崩壊を予防・軽減する周術期患者用薬剤として有用である。また、本発明の体温低下抑制剤は、体温低下を抑制する目的であればどのような症状・病態にも使用することが可能であるが、特に外科手術時の全身麻酔による体温低下によって手術中から手術終了後に発症する合併症（悪寒・不快感、シバリング、頻脈・虚血性心電図変化、覚醒遅延、創部感染、創傷治癒遅延、免疫力低下、血液凝固障害等などの周術期合併症）を予防および／あるいは改善する体温低下抑制剤として有用である。
次に、実施例により本発明を説明する。
In addition, the perioperative drug, body temperature lowering inhibitor and wakefulness delay-preventing agent of the present invention can be implemented in the form of a pharmaceutical product as described above, and to foods and beverages with reference to the pharmaceutical product embodiment. By containing, the use to food and drink can be easily carried out.
The drug for perioperative patients of the present invention is protein synthesis promotion, wound healing promotion by immunostimulation, surgical diabetes suppression, reperfusion injury suppression action, particularly by promoting protein synthesis and suppressing muscle protein breakdown, It is useful as a drug for perioperative patients to prevent and reduce muscle protein breakdown due to complications and ischemia-reperfusion injury in perioperative patients such as surgery. In addition, the body temperature decrease inhibitor of the present invention can be used for any symptom or pathological condition as long as it is intended to suppress body temperature decrease. Complications that occur after surgery (coldness / discomfort, shivering, tachycardia / ischemic electrocardiogram changes, delayed arousal, wound infection, delayed wound healing, decreased immunity, blood coagulation disorder, etc.) It is useful as a body temperature lowering inhibitor that prevents and / or improves
Next, an example explains the present invention.
実施例１
（１）アミノ酸液の調製
各アミノ酸溶液は、表1に示すそれぞれのアミノ酸が1.0W/V%（溶解度が1g/dL未満のものについては0.05または0.5W/V%）となるように注射用蒸留水に溶解して作製した。各アミノ酸溶液は、投与前にろ過滅菌した。
Example 1
(1) Preparation of amino acid solution Each amino acid solution is for injection so that each amino acid shown in Table 1 is 1.0 W / V% (0.05 or 0.5 W / V% for a solubility of less than 1 g / dL). It was prepared by dissolving in distilled water. Each amino acid solution was sterilized by filtration before administration.
表１
（２）ラットにおける体温低下抑制効果測定
評価に用いるラットは予め外頚静脈にカテーテルを挿入し背部にその先端を出しヘパリンでロックした状態で数日間回復させた。挿入カテーテルより生理的食塩液または表１の各アミノ酸液10.5mL/kgを麻酔剤（プロポフォール）の投与前60分より15分間隔で4回投与し、さらに麻酔剤投与開始と同時に42mL/kgで1時間持続投与した。各群の例数は4〜9例とした。麻酔剤の投与は、最初に15mg/kgをbolusにてカテーテルから静脈内投与し、同時に45mg/kg/hrの持続投与を開始した。その1時間後からは投与速度を22.5mg/kg/hrにし、合計３時間の持続投与を行った。体温の測定は、直腸体温計にてアミノ酸液を投与する前に前値を測定し、麻酔剤投与開始から終了後の3時間までは30分間隔で測定した。
(2) Measurement of body temperature decrease inhibitory effect in rats Rats used for evaluation were recovered for several days in a state where a catheter was previously inserted into the external jugular vein, the tip was put out on the back and locked with heparin. From the insertion catheter, physiological saline or 10.5 mL / kg of each amino acid solution in Table 1 was administered four times at 15-minute intervals from 60 minutes before administration of the anesthetic (propofol), and at the same time as the start of anesthetic administration, 42 mL / kg. Administration was continued for 1 hour. The number of cases in each group was 4-9. As for administration of anesthetic, 15 mg / kg was first administered intravenously through a catheter using bolus, and at the same time, continuous administration of 45 mg / kg / hr was started. One hour later, the administration rate was 22.5 mg / kg / hr, and continuous administration was performed for a total of 3 hours. The body temperature was measured before the amino acid solution was administered with a rectal thermometer, and was measured at 30-minute intervals from the start of anesthetic administration to 3 hours after the end.
測定結果は、麻酔液投与3時間後の各々の投与前値に対する変化量（投与前値-投与後値）とし、平均±標準偏差で示した。統計学的な検定は、生理食塩液との2群間比較をstudentｔ-testにて行った。
結果を表2に示す。バリン，アスパラギン酸，システイン，グリシン，アラニン，プロリン，セリン，BCAA（1）及びBCAA（2）の各溶液を投与した場合，生理食塩液を投与した場合と比較して，有意に体温（核心温）低下抑制効果が認められた。また，ロイシン，フェニルアラニン，イソロイシン，スレオニン，ヒスチジン，チロシン，グルタミン酸，グルタミン，オルニチン，アスパラギン，タウリン，Ala-Glnの各溶液を投与した場合においても，生理食塩液を投与した場合と比較して，有意差はないものの体温（核心温）低下を抑制する傾向が認められた。
The measurement results were expressed as the mean ± standard deviation as the amount of change (pre-dose value−post-dose value) with respect to each pre-dose value 3 hours after administration of the anesthetic solution. Statistical test was performed by student-test for comparison between two groups with physiological saline.
The results are shown in Table 2. When valine, aspartic acid, cysteine, glycine, alanine, proline, serine, BCAA (1) and BCAA (2) solutions were administered, body temperature (core heart temperature) was significantly higher than when saline was administered. ) A reduction-suppressing effect was observed. In addition, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine, taurine, and Ala-Gln were also significantly administered compared with physiological saline. Although there was no difference, there was a tendency to suppress the decrease in body temperature (core temperature).
表２
（平均±標準偏差、*: P <0.05, **:P <0.01,単位：℃）
Table 2
（３）イヌにおけるAla-Glnの体温低下抑制効果測定
予め送信器を腹腔内に埋め込んだ雄性ビーグル犬５匹を用いて、実験1日前に飼育室から実験室となる防音室に移動し、ジャケットを装着し馴化を行った。投与経路は静脈内持続注入とし、プロポフォールの投与には、ケージ外に設置したインフュージョンポンプと接続し、前肢橈側皮静脈に留置した留置針を介して静脈内に注入した。また、Ala-Glnの投与には、動物に装着したジャケット中の輸液ポンプを介し前肢橈側皮静脈に留置した留置針より静脈内に持続注入した。実験は2回行い、2回目の実験には1回目と異なる群を割り当てた。1回目と2回目の間は約1週間休薬した。体温は、体温の信号をテレメトリー方式にて受信機(RMC-1，DATA SCIENCES)を介し受信し、テレメトリーシステムのデータ取得・解析システム(Dataquest A.R.T., U-ART1.1S/2.3S)を用いて測定した。測定モニターは、実験前日より開始し、5分間隔10秒間連続して行った。プロポフォール投与前60分から投与開始後240分までの取得データを解析した。プロポフォールの投与について麻酔導入に8〜9 mg/kg、維持に30〜35 mg/kg/hrで2時間行い、回復経過観察時間を2時間とした。Ala-Glnの投与は、用量を800（４%）mg/kg/hrとし、プロポフォール投与1時間前より投与を開始し、持続投与時間を3時間としてAla-Glnの効果を検討した。
(3) Measurement of Ala-Gln body temperature reduction inhibitory effect in dogs Using five male beagle dogs with transmitters embedded in the abdominal cavity in advance, the dog moved from the breeding room to the soundproof room that became the laboratory one day before the experiment. I was accustomed to wearing. The administration route was continuous intravenous infusion, and propofol was administered by infusion into the vein via an indwelling needle placed in the forelimb cephalic vein connected to an infusion pump installed outside the cage. In addition, Ala-Gln was continuously infused into the vein from an indwelling needle placed in the forelimb cephalic vein via an infusion pump in a jacket attached to the animal. The experiment was performed twice, and a different group was assigned to the second experiment. The drug was withdrawn for about a week between the first and second rounds. The body temperature is received through a receiver (RMC-1, DATA SCIENCES) in the telemetry method, and the body temperature is received using the data acquisition / analysis system (Dataquest ART, U-ART1.1S / 2.3S) of the telemetry system. It was measured. Measurement monitoring was started from the day before the experiment, and was continuously performed at intervals of 5 minutes for 10 seconds. Data obtained from 60 minutes before propofol administration to 240 minutes after administration was analyzed. Propofol was administered at 8-9 mg / kg for induction of anesthesia and at 30-35 mg / kg / hr for maintenance for 2 hours, and the recovery follow-up time was 2 hours. Ala-Gln was administered at a dose of 800 (4%) mg / kg / hr, started 1 hour before propofol administration, and the duration of administration was 3 hours to examine the effects of Ala-Gln.
測定結果は、麻酔液投与２時間後の各々の投与前値に対する変化量（投与前値-投与後値）とし、平均±標準偏差で示した。統計学的な検定は、生理食塩液との2群間比較をPairedｔtestにて行った。4％Ala-GlnはSalineに比し麻酔投与中１時間、1.5時間、２時間(表３)及び麻酔終了後0.5時間で体温低下を有意に抑制した。
表３
Table 3
（４）Ala-Glnの覚醒時間に対する効果検討
評価に用いるラットは予め外頚静脈にカテーテルを挿入し背部にその先端を出しヘパリンでロックした状態で数日間回復させた。挿入カテーテルより生理的食塩液または２％Ala-Gln溶液５mL/kgを麻酔剤（プロポフォール）の投与前60分より15分間隔で4回投与し、さらに麻酔剤投与開始と同時に20mL/kgで1時間持続投与した。例数は生理食塩液が８例、Ala-Gln投与群が10例とした。麻酔剤の投与は、最初に15mg/kgをbolusにてカテーテルから静脈内投与し、同時に33.75mg/kg/hrの持続投与を開始し、合計３時間の持続投与を行った。覚醒の確認は、麻酔剤投与終了後の60分及び90分後に行い、四肢で立ち上がった状態を覚醒とした（１回目）。
観察結果を表４に示す。生理食塩液群では90分後で３例のみの覚醒であったのに対し、Ala-Gln投与群では60分後ですでに３例、90分後で7例が覚醒し、生理食塩液群よりAla-Gln群の方が早く覚醒した。
(4) Examination of effect of Ala-Gln on awakening time Rats used for evaluation were recovered for several days in a state where a catheter was previously inserted into the external jugular vein, the tip was put out on the back and locked with heparin. From the insertion catheter, physiological saline or 2% Ala-Gln solution 5mL / kg is administered four times at 15-minute intervals from 60 minutes before administration of the anesthetic (propofol), and at the same time the anesthetic is started, 1 at 20mL / kg. Administration was continued for a period of time. The number of cases was 8 in the physiological saline solution and 10 in the Ala-Gln administration group. The anesthetic was first administered intravenously at 15 mg / kg from the catheter via bolus, and at the same time, the continuous administration of 33.75 mg / kg / hr was started for a total of 3 hours. Confirmation of arousal was performed 60 minutes and 90 minutes after the end of administration of the anesthetic, and the state of standing up on the extremities was regarded as arousal (first time).
The observation results are shown in Table 4. In the physiological saline group, only 3 cases were awakened after 90 minutes, whereas in the Ala-Gln group, 3 cases were already awakened after 60 minutes, and 7 cases were awakened after 90 minutes. The Ala-Gln group woke up earlier.
表４
上記１回目の操作を繰り返した（２回目）。このようにして得られた２回目の観察結果を表５に示す。生理食塩液群では60分後で３例、120分後でも4例のみの覚醒であったのに対し、Ala-Gln投与群では60分後ですでに全例が覚醒し、生理食塩液群よりAla-Gln群の方が早く覚醒した。
表５
The first operation was repeated (second time). Table 5 shows the results of the second observation thus obtained. In the physiological saline group, 3 cases were awakened after 60 minutes and only 4 cases were awakened after 120 minutes, whereas in the Ala-Gln group, all cases were already awakened after 60 minutes. The Ala-Gln group woke up earlier.
Table 5
（５）Ala-Glnの開腹侵襲時の生存率に対する効果検討
評価に用いるラットは予め外頚静脈にカテーテルを挿入し背部にその先端を出しヘパリンでロックした状態で数日間回復させた。挿入カテーテルより生理的食塩液または２％Ala-Gln溶液５mL/kgを麻酔剤（プロポフォール）の投与前60分より15分間隔で4回投与し、さらに麻酔剤投与開始と同時に20mL/kgで5時間持続投与した。例数は生理食塩液、Ala-Gln投与群各々10例とした。麻酔剤の投与は、最初に15mg/kgをbolusにてカテーテルから静脈内投与し、同時に33.75mg/kg/hrの持続投与を開始し、合計5時間の持続投与を行った。 開腹侵襲は最初の麻酔剤bolus投与後、正中線に沿って腹部を約4cm切開し盲腸部を腹腔外に出し15分間空気暴露することにより行い、縫合し閉腹した。生存率の確認は、輸液投与終了後18時間に行った。
生存率の結果を表６に示す。18時間後における生存率は生理食塩液が50％であったの対しAla-Gln投与群では70％となり生存率の改善がみられた。
(5) Examination of the effect of Ala-Gln on the survival rate during laparotomy Invasion of rats used for evaluation was allowed to recover for several days in a state where a catheter was inserted into the external jugular vein, the tip was put out in the back and locked with heparin. From the insertion catheter, physiological saline or 2% Ala-Gln solution 5mL / kg is administered 4 times at 15-minute intervals from 60 minutes before the administration of the anesthetic (propofol). Administration was continued for a period of time. The number of cases was 10 in each of the physiological saline solution and Ala-Gln administration groups. As for administration of anesthetics, 15 mg / kg was first intravenously administered through a catheter using bolus, and at the same time, continuous administration of 33.75 mg / kg / hr was started, for a total of 5 hours. The laparotomy invasion was performed by incising the abdomen about 4 cm along the midline after the administration of the first anesthetic agent bolus, exposing the cecum outside the abdominal cavity and exposing it to air for 15 minutes, and then closing the sutured abdomen. The survival rate was confirmed 18 hours after the end of infusion administration.
The results of the survival rate are shown in Table 6. The survival rate after 18 hours was 50% in the physiological saline solution, and 70% in the Ala-Gln group, indicating an improvement in survival rate.
表６
（６）筋蛋白崩壊(蛋白異化)及び創傷治癒に対する効果検討
評価に用いるラットは予め外頚静脈にカテーテルを挿入し背部にその先端を出しヘパリンでロックした状態で数日間回復させた。創傷治癒の評価は、ラットを用いて約16時間絶食を行い、麻酔下(プロポフォール/45mg/kg/hr、1時間)にて背部を約1.5cm切開しPVA(ポリビニールアルコール)を左右皮下に埋め込み、5日目にPVAを取り出しPVA中に合成されたコラーゲン合成量(Hypとして)を指標として行い、また筋蛋白崩壊の評価は、同一ラットでPVAを埋め込んだ後、更に絶食下で24時間の蓄尿を行い、尿中に排泄された3-MH量(3-メチルヒスチジン)をクレアチニンで除して指標として行った。Ala-Gln及び生理食塩液の投与(1000mg/kg/hr)はPVAを埋め込み前１時間から３時間の投与を行った。
結果を表７に示す。Ala-Glnは3-MHを有意に低下させ、蛋白異化抑制作用を示した。また、Ala-Glnは、Hypを増加させ創傷治癒促進作用を示した。
(6) Examination of effects on muscle protein breakdown (protein catabolism) and wound healing Rats used for evaluation were recovered for several days in a state where a catheter was inserted in the external jugular vein, the tip was put out in the back and locked with heparin. Wound healing was evaluated using rats with fasting for about 16 hours, under anesthesia (propofol / 45 mg / kg / hr, 1 hour) with an incision of about 1.5 cm in the back and PVA (polyvinyl alcohol) subcutaneously on the left and right. Implantation, PVA was taken out on the 5th day, and the amount of collagen synthesis (as Hyp) synthesized in PVA was used as an index, and muscle protein breakdown was evaluated by implanting PVA in the same rat, and further under fasting for 24 hours The amount of 3-MH excreted in urine (3-methylhistidine) was divided by creatinine and used as an index. Ala-Gln and physiological saline (1000 mg / kg / hr) were administered for 1 to 3 hours before implantation of PVA.
The results are shown in Table 7. Ala-Gln significantly reduced 3-MH and showed an inhibitory effect on protein catabolism. Ala-Gln increased Hyp and showed wound healing promotion effect.
表７
次に、本発明の好ましい態様を示す。
1. バリン、アスパラギン酸、システイン、グリシン、アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン、タウリン及びこれらのペプチド結合体からなる群から選択される少なくとも１種を有効成分として含有することを特徴とする周術期患者用薬剤。
2. バリン、アスパラギン酸、システイン、グリシン、アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン及びタウリンからなる群から選択される少なくとも２種を有効成分として含有することを特徴とする周術期患者用薬剤。
3. 少なくともイソロイシンおよびロイシンの何れか１つを有効成分として含有することを特徴とする周術期患者用薬剤。
4. イソロイシン、ロイシン及びバリンを有効成分として含有することを特徴とする周術期患者用薬剤。
5. ペプチド結合体が、請求項１記載の２つの化合物のペプチド結合体である請求項１記載の周術期患者用薬剤。
6. ペプチド結合体が、アラニル−グルタミンである請求項５記載の周術期患者用薬剤。
7. 輸液製剤の形態である請求項１〜６のいずれか１項記載の周術期患者用薬剤。
8. 更に電解質を含有する請求項７記載の周術期患者用薬剤。
9. 飲食品の形態である請求項１〜６のいずれか１項記載の周術期患者用薬剤。
10. アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン、タウリン及びこれらのペプチド結合体からなる群から選択される少なくとも１種を有効成分として含有することを特徴とする体温低下抑制剤。
11. アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン及びタウリンからなる群から選択される少なくとも２種を有効成分として含有することを特徴とする体温低下抑制剤。
12. 少なくともイソロイシンおよびロイシンの何れか１つを有効成分として含有することを特徴とする体温低下抑制剤。
13. イソロイシン、ロイシン及びバリンを有効成分として含有することを特徴とする体温低下抑制剤。
14. ペプチド結合体が、請求項１０記載の２つの化合物のペプチド結合体である請求項１０記載の体温低下抑制剤。
15. ペプチド結合体が、アラニル−グルタミンである請求項１４記載の体温低下抑制剤。
16. 医薬品の形態である請求項９〜１５のいずれか１項記載の体温低下抑制剤。
17. 医薬品が輸液製剤の形態である請求項１６記載の体温低下抑制剤。
18. アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン及びタウリンのいずれかの濃度が０．０１〜１０Ｗ／Ｖ％である請求項１０又は１１記載の体温低下抑制剤。
19. 更に電解質を含有することを特徴とする請求項１０〜１８のいずれか１項記載の体温低下抑制剤。
20. 使用時に輸液製剤に配合することを特徴とする請求項１６〜１９のいずれか１項記載の体温低下抑制剤。
21. 飲食品の形態である請求項１０〜１５のいずれか記載の体温低下抑制剤。
22. 周術期合併症を予防および／あるいは改善する請求項１０〜２１のいずれか１項記載の体温低下抑制剤。
23. バリン、アスパラギン酸、システイン、グリシン、アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン、タウリン及びこれらのペプチド結合体からなる群から選択される少なくとも１種を有効成分として含有することを特徴とする覚醒遅延防止剤。
24. バリン、アスパラギン酸、システイン、グリシン、アラニン、プロリン、セリン、ロイシン、フェニルアラニン、イソロイシン、スレオニン、ヒスチジン、チロシン、グルタミン酸、グルタミン、オルニチン、アスパラギン及びタウリンからなる群から選択される少なくとも２種を有効成分として含有することを特徴とする覚醒遅延防止剤。
25. 少なくともイソロイシンおよびロイシンの何れか１つを有効成分として含有することを特徴とする覚醒遅延防止剤。
26. イソロイシン、ロイシン及びバリンを有効成分として含有することを特徴とする覚醒遅延防止剤。
27. ペプチド結合体が、請求項２３記載の２つの化合物のペプチド結合体である請求項２３記載の覚醒遅延防止剤。
28. ペプチド結合体が、アラニル−グルタミンである請求項２７記載の覚醒遅延防止剤。
29. 医薬品の形態である請求項２３〜２８のいずれか１項記載の覚醒遅延防止剤。
30. 医薬品が輸液製剤の形態である請求項２９記載の覚醒遅延防止剤。
31. 更に電解質を含有する請求項３０記載の覚醒遅延防止剤。
32. 飲食品の形態である請求項２３〜２８のいずれか１項記載の覚醒遅延防止剤。
Table 7
Next, a preferred embodiment of the present invention will be shown.
1. selected from the group consisting of valine, aspartic acid, cysteine, glycine, alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine, taurine and their peptide conjugates A drug for perioperative patients, comprising at least one of these as an active ingredient.
2. Effective at least two selected from the group consisting of valine, aspartic acid, cysteine, glycine, alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine and taurine A drug for perioperative patients characterized by containing as a component.
3. A drug for perioperative patients, comprising at least one of isoleucine and leucine as an active ingredient.
4. A drug for perioperative patients comprising isoleucine, leucine and valine as active ingredients.
5. The drug for perioperative patients according to claim 1, wherein the peptide conjugate is a peptide conjugate of the two compounds according to claim 1.
6. The drug for perioperative patients according to claim 5, wherein the peptide conjugate is alanyl-glutamine.
7. The drug for perioperative patients according to any one of claims 1 to 6, which is in the form of an infusion preparation.
8. The drug for perioperative patients according to claim 7, further comprising an electrolyte.
9. The drug for perioperative patients according to any one of claims 1 to 6, which is in the form of a food or drink.
10. Contains at least one selected from the group consisting of alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine, taurine and their peptide conjugates as an active ingredient A body temperature decrease inhibitor characterized by:
11. It contains at least two kinds selected from the group consisting of alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine and taurine as active ingredients. Body temperature reduction inhibitor.
12. A body temperature lowering inhibitor comprising at least one of isoleucine and leucine as an active ingredient.
13. A body temperature lowering inhibitor comprising isoleucine, leucine and valine as active ingredients.
14. The body temperature lowering inhibitor according to claim 10, wherein the peptide conjugate is a peptide conjugate of the two compounds according to claim 10.
15. The body temperature lowering inhibitor according to claim 14, wherein the peptide conjugate is alanyl-glutamine.
16. The body temperature decrease inhibitor according to any one of claims 9 to 15, which is in the form of a pharmaceutical product.
17. The body temperature decrease inhibitor according to claim 16, wherein the pharmaceutical is in the form of an infusion preparation.
18. The concentration of any one of alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine and taurine is 0.01 to 10 W / V%. The body temperature reduction inhibitor as described.
19. The body temperature lowering inhibitor according to any one of claims 10 to 18, further comprising an electrolyte.
20. The body temperature decrease inhibitor according to any one of claims 16 to 19, which is formulated into an infusion preparation at the time of use.
21. The body temperature decrease inhibitor according to any one of claims 10 to 15, which is in the form of a food or drink.
22. The body temperature lowering inhibitor according to any one of claims 10 to 21, which prevents and / or improves perioperative complications.
23. selected from the group consisting of valine, aspartic acid, cysteine, glycine, alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine, taurine and their peptide conjugates A wakefulness delay-preventing agent, comprising at least one active ingredient as an active ingredient.
24. Effective at least two selected from the group consisting of valine, aspartic acid, cysteine, glycine, alanine, proline, serine, leucine, phenylalanine, isoleucine, threonine, histidine, tyrosine, glutamic acid, glutamine, ornithine, asparagine and taurine A wakefulness delay inhibitor characterized by containing as a component.
25. A wakefulness delay-preventing agent comprising at least one of isoleucine and leucine as an active ingredient.
26. An agent for preventing arousal delay, comprising isoleucine, leucine and valine as active ingredients.
27. The agent for preventing arousal delay according to claim 23, wherein the peptide conjugate is a peptide conjugate of the two compounds according to claim 23.
28. The agent for preventing arousal delay according to claim 27, wherein the peptide conjugate is alanyl-glutamine.
29. The agent for preventing arousal delay according to any one of claims 23 to 28, which is in the form of a pharmaceutical product.
30. The agent for preventing arousal delay according to claim 29, wherein the pharmaceutical is in the form of an infusion preparation.
31. The agent for preventing awakening delay according to claim 30, further comprising an electrolyte.
32. The agent for preventing arousal delay according to any one of claims 23 to 28, which is in the form of a food or drink.
Claims (1)
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| JP2005319615A JP5177785B2 (en) | 2004-11-02 | 2005-11-02 | Drugs for perioperative patients |
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| JP2005219281 | 2005-07-28 | ||
| JP2005319615A JP5177785B2 (en) | 2004-11-02 | 2005-11-02 | Drugs for perioperative patients |
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| JP5177785B2 true JP5177785B2 (en) | 2013-04-10 |
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| TWI445540B (en) * | 2007-04-20 | 2014-07-21 | Ajinomoto Kk | Anti-hypothermia composition |
| JP2011241149A (en) * | 2010-05-14 | 2011-12-01 | Terumo Corp | Digestible oral nutrient |
| JP5997425B2 (en) * | 2011-08-18 | 2016-09-28 | 協和発酵バイオ株式会社 | Ornithine-containing composition |
| JP2014159381A (en) * | 2013-02-19 | 2014-09-04 | Kyowa Hakko Bio Co Ltd | Ornithine-containing composition for improving body composition |
| JOP20190146A1 (en) | 2016-12-19 | 2019-06-18 | Axcella Health Inc | Amino acid compositions and methods for the treatment of liver diseases |
| WO2019036471A1 (en) | 2017-08-14 | 2019-02-21 | Axcella Health Inc. | Amino acid for the treatment of liver disease |
| JP2021527670A (en) | 2018-06-20 | 2021-10-14 | アクセラ・ヘルス・インコーポレイテッドＡｘｃｅｌｌａ Ｈｅａｌｔｈ Ｉｎｃ． | Compositions and methods for the treatment of fat infiltration in muscle |
| CN108721596B (en) * | 2018-06-29 | 2021-09-21 | 复旦大学附属中山医院 | Compound amino acid vitamin injection and application thereof |
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| SE8704217D0 (en) * | 1987-10-29 | 1987-10-29 | Vinnars Erik Ab | AMINO ACID COMPOSITION FOR PARENTERAL NUTRITION |
| JPH02128670A (en) * | 1988-11-08 | 1990-05-17 | Ajinomoto Co Inc | Amino acid-containing food composition |
| JPH03264525A (en) * | 1990-03-14 | 1991-11-25 | Otsuka Pharmaceut Factory Inc | Amino acid infusion solution |
| JPH0710770A (en) * | 1990-03-14 | 1995-01-13 | Otsuka Pharmaceut Factory Inc | Amino acid infusion |
| JPH06227974A (en) * | 1993-01-29 | 1994-08-16 | Kyowa Hakko Kogyo Co Ltd | Nutritive composition |
| AU2004210266B2 (en) * | 2003-02-06 | 2008-09-25 | Otsuka Pharmaceutical Factory, Inc. | Inhibitor for perioperative blood sugar elevation |
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