JP2654518B2 - Hepatocyte proliferation promoter - Google Patents
Hepatocyte proliferation promoterInfo
- Publication number
- JP2654518B2 JP2654518B2 JP2356189A JP2356189A JP2654518B2 JP 2654518 B2 JP2654518 B2 JP 2654518B2 JP 2356189 A JP2356189 A JP 2356189A JP 2356189 A JP2356189 A JP 2356189A JP 2654518 B2 JP2654518 B2 JP 2654518B2
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- present
- liver
- injection
- promoting
- hepatocyte proliferation
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Description
【発明の詳細な説明】 産業上の利用分野 本発明は、肝細胞増殖促進剤、より詳しくはフルクト
ース−1,6−ジホスフェート、フルクトース−2,6−ジホ
スフェート及び之等の薬理的に許容される塩からなる群
から選ばれた少なくとも１種を有効成分として含有する
肝細胞増殖促進剤に関する。Description: FIELD OF THE INVENTION The present invention relates to hepatocyte growth promoters, and more particularly, to pharmacologically acceptable agents such as fructose-1,6-diphosphate, fructose-2,6-diphosphate and the like. The present invention relates to a hepatocyte growth promoter containing at least one selected from the group consisting of salts as active ingredients.
従来技術とその問題点 肝は胆汁の分泌、吸収栄養分の過と解毒、糖分の貯
蔵と血糖の調節等の生体内中間代謝の中心的役割を果す
高度に分化の進んだ腺性器官であると共に、フィブリノ
ーゲン、ヘパリン、貧血阻止物質等の生成器官でもあ
る。該肝はまた他の臓器とは異なって、その一部の切除
等によって残存肝に核***が生じ、盛んな増殖再生の起
こることが知られている。しかして肝障害患者の肝の再
生促進には、一般に例えばHGF（hepatocyte growth fac
tor）、インシュリン、グリカゴン、PGE1等の肝の再生
促進作用を有する薬剤を投与する方法が図られている。
之等の薬剤は切除された肝の再生を促進する効果は奏す
るものの、正常な肝細胞や肝機能の低下した肝細胞の増
殖を促進する効果は実質的に有しておらず、之等に代る
新しい肝細胞増殖促進物質の研究開発が斯界で要望され
ている現状にある。Prior art and its problems The liver is a highly differentiated glandular organ that plays a central role in in vivo metabolism such as secretion of bile, excess and detoxification of absorbed nutrients, storage of sugar and regulation of blood sugar, It is also a production organ of fibrinogen, heparin, anemia inhibitor and the like. It is known that the liver is different from other organs, and nuclear remnants are generated in the remaining liver by excision of a part of the liver, and active proliferation and regeneration occur. Thus, for example, HGF (hepatocyte growth fac
tor), insulin, Gurikagon, a method of administering a drug having a regeneration promoting action of liver, such as PGE 1 is achieved.
Although these drugs have the effect of promoting the regeneration of the resected liver, they do not substantially have the effect of promoting the growth of normal hepatocytes or hepatocytes with impaired liver function. Research and development of alternative new hepatocyte growth promoting substances are now demanded in the art.
問題点を解決するための手段 本発明の目的は、上記斯界の要望に合致する新しい肝
細胞増殖促進活性を有する物質乃至これを含む医薬品を
提供することにある。Means for Solving the Problems It is an object of the present invention to provide a new substance having a hepatocyte growth promoting activity which meets the above-mentioned needs in the art, or a drug containing the same.
本発明者は上記目的より鋭意研究を重ねた結果、従来
より動物細胞の解糖に重要な役割を果し、現在例えば抗
アレルギー剤〔特開昭59−21617号公報〕、火傷患者治
療剤〔特開昭57−139016号公報〕等として実用性が研究
段階にあり、また既に市販されている糖代謝改善剤〔Bi
omedica Foscama社〕、強壮剤等の有効成分化合物であ
るフルクトース−1,6−ジホスフェート（以下「Ｆ−1,6
−DP」という）及びフルクトース−2,6−ジホスフェー
ト（以下「Ｆ−2,6−DP」という）に着目し、之等化合
物について鋭意研究を重ねた。その結果、実に驚くべき
ことに之等化合物を注射剤形態で生体内に投与するとき
には、肝再生を促進するのみならず、正常肝細胞及び肝
機能の低下した肝細胞の増殖をも促進する作用を奏する
ことを見出した。本発明はこの知見に基づいて完成され
たものである。The present inventors have conducted intensive studies for the above purpose, and as a result, have conventionally played an important role in glycolysis of animal cells, and currently have, for example, antiallergic agents (Japanese Patent Application Laid-Open No. 59-21617), agents for treating burn patients [ Japanese Patent Application Laid-Open No. 57-139016] is in the research stage, and already a commercially available sugar metabolism improver [Bi
omedica Foscama], fructose-1,6-diphosphate (hereinafter referred to as "F-1,6
−DP ”) and fructose-2,6-diphosphate (hereinafter referred to as“ F-2,6-DP ”), and conducted intensive research on these compounds. As a result, surprisingly, when these compounds are administered in vivo in the form of an injection, they not only promote liver regeneration, but also promote the proliferation of normal hepatocytes and hepatocytes with reduced liver function. Was found to play. The present invention has been completed based on this finding.
問題点を解決するための手段 即ち、本発明によればＦ−1,6−DP、Ｆ−2,6−DP及び
之等の薬理的に許容される塩からなる群から選ばれた少
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
る肝細胞増殖促進剤が提供される。Means for Solving the Problems According to the present invention, at least one selected from the group consisting of F-1,6-DP, F-2,6-DP and pharmaceutically acceptable salts thereof is provided. There is provided a hepatocyte proliferation promoter comprising a seed as an active ingredient.
本発明の肝細胞増殖促進剤の有効成分であるＦ−1,6
−DP及びＦ−2,6−DPは、いずれも公知化合物である。
また之等の薬理的に許容される塩としては、之等各化合
物にナトリウム、カリウム等のアルカリ金属が１〜３個
結合したモノ、ジ、トリ−アルカリ金属塩等を具体例と
して例示でき、之等の塩は常法に従い調製できる。之等
は本発明肝細胞増殖促進剤の有効成分として１種単独で
用いることもでき、２種以上を組合せて用いることもで
きる。特に本発明では之等化合物及びその塩の内、Ｆ−
1,6−DP及びＦ−2,6−DPのナトリウム塩を用いるのが好
ましい。F-1,6 which is an active ingredient of the hepatocyte growth promoting agent of the present invention.
-DP and F-2,6-DP are both known compounds.
Examples of the pharmacologically acceptable salts thereof include mono-, di-, and tri-alkali metal salts in which each of these compounds has one to three alkali metals such as sodium and potassium bonded thereto. These salts can be prepared according to a conventional method. These can be used alone as an active ingredient of the hepatocyte proliferation promoter of the present invention, or two or more can be used in combination. In particular, in the present invention, among these compounds and salts thereof, F-
It is preferred to use the sodium salts of 1,6-DP and F-2,6-DP.
本発明肝細胞増殖促進剤は、通常一般的な医薬製剤形
態に調製される。該製剤形態としては、経静脈投与に適
した注射剤形態が最も一般的であるが、用時溶解用の粉
末剤等に調製することも可能である。上記注射剤の調製
方法としては、特に限定されず、従来公知の注射剤等と
実質的に同様の方法によることができ、例えば代表的に
は、注射用蒸留水、生理食塩水、リンゲル液等の希釈剤
中に有効成分化合物を混合溶解し、必要に応じて例えば
サリチル酸ナトリウム、酢酸ナトリウム、アンニトール
等の溶解補助剤、クエン酸ナトリウム、リン酸ナトリウ
ム等の緩衝剤、ブドウ糖、ショ糖、塩化ナトリウム等の
等張剤、メチルパラベン、塩化ベンザルコニウム、フェ
ノール等の保存剤、亜硫酸塩、システイン、アスコルビ
ン酸等の安定化剤、塩酸、酢酸、乳酸、リンゴ酸、クエ
ン酸、水酸化ナトリウム等のpH調節剤、ブドウ糖、グル
コン酸カルシウム、塩酸プロカイン等の無痛化剤、その
他の添加剤等を加えて、得られる水溶液を加熱滅菌又は
無菌過等により無菌化する方法により調製できる。The hepatocyte proliferation promoter of the present invention is usually prepared in a general pharmaceutical preparation form. The preparation is most commonly in the form of an injection suitable for intravenous administration, but can also be prepared as a powder for dissolution at the time of use. The method for preparing the injection is not particularly limited, and can be substantially the same as a conventionally known injection. For example, typically, distilled water for injection, physiological saline, Ringer's solution and the like can be used. The active ingredient compound is mixed and dissolved in a diluent, and if necessary, for example, a solubilizing agent such as sodium salicylate, sodium acetate, and mannitol; a buffer such as sodium citrate and sodium phosphate; glucose, sucrose, and sodium chloride Isotonic agents, preservatives such as methylparaben, benzalkonium chloride, and phenol; stabilizers such as sulfite, cysteine, and ascorbic acid; and pH adjustment of hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, and sodium hydroxide. Agents, glucose, calcium gluconate, analgesics such as procaine hydrochloride, and other additives, etc., and heat-sterilize the resulting aqueous solution or It can be prepared by a method of sterilization by bacteria over like.
また、用時溶解粉末剤の調製は、例えば有効成分化合
物の有効量を、注射用蒸留水、生理食塩水、ブドウ糖水
溶液等の希釈剤に溶解した後、必要に応じてカルボキシ
メチルセルロース（CMC）、アルギン酸ナトリウム等の
賦形剤、ベンジルアルコール、塩化ベンザルコニウム、
フェノール等の保存剤、ブドウ糖、グルコン酸カルシウ
ム、塩酸プロカイン等の無痛化剤、更に上記例示の安定
化剤、pH調節剤等を加え、常法に従い、混合物を凍結乾
燥することにより調製できる。かくして調製される用時
溶解粉末剤形態の本発明肝細胞増殖促進剤は、通常の用
時溶解粉末剤と同様にして、これを注射用蒸留水等に溶
解して投与することができる。Preparation of the powder for dissolution at the time of use can be performed, for example, by dissolving an effective amount of the active ingredient compound in a diluent such as distilled water for injection, physiological saline, or aqueous glucose solution, and then, if necessary, carboxymethyl cellulose (CMC). Excipients such as sodium alginate, benzyl alcohol, benzalkonium chloride,
A preservative such as phenol, a soothing agent such as glucose, calcium gluconate, procaine hydrochloride, and the above-mentioned stabilizers and pH regulators can be added, and the mixture can be freeze-dried according to a conventional method. The hepatocyte proliferation promoter of the present invention thus prepared in the form of a powder for use at the time of use can be administered by dissolving it in distilled water for injection or the like in the same manner as a usual powder for use at the time of use.
上記各方法により調製される本発明の肝細胞増殖促進
剤は、通常そのpH（用時溶解粉末剤の場合はこれを注射
用蒸留水等に溶解した後の溶液のpH）が約3.0〜8.0、好
ましくは約5.0〜7.5の範囲にあるのがよく、また製剤中
の有効成分化合物の濃度は通常約５〜20％（w/v％、以
下同じ）、好ましくは約８〜12％であるのが適当であ
る。The hepatocyte proliferation promoter of the present invention prepared by each of the above methods usually has a pH (in the case of a powder to be dissolved before use, the pH of a solution after dissolving the same in distilled water for injection) of about 3.0 to 8.0. , Preferably in the range of about 5.0 to 7.5, and the concentration of the active ingredient compound in the preparation is usually about 5 to 20% (w / v%, the same applies hereinafter), preferably about 8 to 12%. Is appropriate.
かくして得られる本発明製剤の投与量は、一日成人一
人当り有効成分化合物量が約10mg〜15gの範囲、好まし
くは約100mg〜10gの範囲となる量を目安とするのがよ
く、これは該製剤を投与すべき患者の病理状態等、年
齢、体重、併用薬剤の種類及び量等に応じて、適宜増減
させることができる。また本発明薬剤は、肝切除等の手
術を施すべき患者に対してこれを適用する場合は、その
手術前（即ち肝再生前）及び手術後の肝再生時期のいず
れの時期に投与することもでき、いずれの場合も略々同
等に本発明の所期の効果を奏し得る。また本発明薬剤は
肝再生促進効果を有する他の薬剤等と併用することもで
き、かかる併用によって之等薬剤の肝再生促進効果を更
に一層助長する効果もある。The dosage of the preparation of the present invention thus obtained is preferably such that the amount of the active ingredient compound per adult per day is in the range of about 10 mg to 15 g, and preferably in the range of about 100 mg to 10 g. The dose can be appropriately increased or decreased according to the pathological condition of the patient to whom the preparation is to be administered, age, body weight, type and amount of the concomitant drug, and the like. When the agent of the present invention is applied to a patient who is to undergo surgery such as hepatectomy, it may be administered at any time before the surgery (that is, before liver regeneration) and at the time of liver regeneration after surgery. In each case, the desired effects of the present invention can be obtained substantially equally. Further, the agent of the present invention can be used in combination with other agents having a liver regeneration promoting effect, and the combined use also has the effect of further promoting the liver regeneration promoting effect of these agents.
発明の効果 本発明の肝細胞増殖促進剤は、その生体内投与によ
り、肝再生を促進するのみならず、正常肝細胞及び肝機
能の低下した肝細胞の増殖をも促進する作用を奏する。
またこれは肝再生促進効果を有する他の薬剤等との併用
により、之等併用薬剤の効果を助長し得る。Effect of the Invention The hepatocyte proliferation promoting agent of the present invention exerts not only an effect of promoting liver regeneration but also an effect of promoting the proliferation of normal hepatocytes and hepatocytes with reduced liver function, when administered in vivo.
In addition, it can promote the effect of the concomitant drug when used in combination with another drug having a liver regeneration promoting effect.
実施例 以下、本発明を更に詳しく説明するため、本発明肝細
胞増殖促進剤の製剤例を実施例として挙げ、次に本発明
薬剤の有効成分化合物につき行なった薬理試験例を挙げ
る。尚、之等各例において用いたＦ−1,6−DPトリナト
リウム塩及びＦ−2,6−DPは、いずれもシグマ社（Sigma
Chemical Co.）製の試薬である。Examples Hereinafter, in order to explain the present invention in more detail, Formulation Examples of the hepatocyte proliferation promoter of the present invention will be described as Examples, and then pharmacological test examples performed on the active ingredient compounds of the drug of the present invention will be described. The F-1,6-DP trisodium salt and F-2,6-DP used in each of these examples were all manufactured by Sigma.
Chemical Co.).
実施例 １ 注射剤の調製 静脈内投与に適する殺菌した水溶液形態の本発明薬剤
を下記処方に従い調製した。成分 配合量 Ｆ−1,6−DP・3Na 3.25g （Ｆ−1,6−DPとして 2.72g） 塩化ナトリウム 0.27g 注射用蒸留水 適 量 全量 30 ml 即ち、上記注射用蒸留水に、Ｆ−1,6−DP・3Na塩及び
塩化ナトリウムを溶解させた後、無菌過し、50mlのバ
イアル瓶に注入して空間部を窒素置換した後、溶封して
上記組成の注射剤を得た。Example 1 Preparation of Injection A drug of the present invention in the form of a sterilized aqueous solution suitable for intravenous administration was prepared according to the following formulation. Component amount F-1,6-DP.3Na 3.25 g (2.72 g as F-1,6-DP) Sodium chloride 0.27 g Distilled water for injection qs 30 ml. After dissolving the 1,6-DP.3Na salt and sodium chloride, the mixture was aseptically filtered, poured into a 50 ml vial, the space was replaced with nitrogen, and then sealed to obtain an injection having the above composition.
実施例 ２ 用時溶解粉末剤の調製 実施例１と同様の方法により、下記組成の静脈内投与
用注射剤を調製し、これを50mlのバイアル瓶に分注した
後、−40℃で凍結乾燥し、バイアル瓶の空間部を窒素ガ
スで置換し、施栓巻締して上記組成の用時溶解粉末剤を
得た。Example 2 Preparation of powder for dissolution before use In the same manner as in Example 1, an injection for intravenous administration having the following composition was prepared, dispensed into a 50 ml vial, and then lyophilized at -40 ° C. Then, the space in the vial was replaced with nitrogen gas, and the vial was closed and wound to obtain a powder to be used at the time of dissolution having the above composition.
このものは、用時注射用蒸留水50mlに溶解して用いら
れる。成分 配合量 Ｆ−2,6−DP・3Na 53.7g （Ｆ−2,6−DPとして 45.0g） マンニトール 2.0g 生理食塩水 適 量 全量 500 ml 薬理試験例 １ 体重250〜350gのウイスター（Wistar）系雄性ラット
の尾静脈より、Ｆ−1,6−DPトリナトリウム塩を0.8m mo
l/kgとなる量で注射用蒸留水に溶解して投与した（薬剤
投与実験群）。It is used by dissolving it in 50 ml of distilled water for injection before use. Component blending amount F-2,6-DP.3Na 53.7g (45.0g as F-2,6-DP) Mannitol 2.0g physiological saline solution qs 500ml Pharmacological test example 1 Wistar with 250-350g body weight 0.8 mM of F-1,6-DP trisodium salt was injected from the tail vein of a male rat.
l / kg was dissolved in distilled water for injection and administered (drug administration experimental group).
また対照群として生理食塩水の同量を投与した群を設
けた。In addition, a group to which the same amount of physiological saline was administered was provided as a control group.
之等投与後、直ちに各群ラットの左外側葉を基部で切
除し、中間葉を鎌状間膜の部で左外側を切除して、40％
肝切除術を施した。尚、上記肝切除には、平和電子工業
株式会社製マイクロ波凝固装置「マイクロトロンMT−7
P」を用いた。Immediately after this administration, the left lateral lobe of each group of rats was excised at the base, and the middle lobe was excised at the left sickle at the sickle mesenchyme.
Hepatectomy was performed. The hepatectomy was performed using a microwave coagulation device “Microtron MT-7” manufactured by Heiwa Electronics Industry Co., Ltd.
P "was used.
上記肝切除45時間後に肝を摘出し、氷冷ハンクス液に
浸した後、0.5mm巾にスライスして、下記〜のスラ
イス片標本（巾0.5mm、複数個）を作成した。45 hours after the liver resection, the liver was excised, immersed in ice-cold Hanks' solution, and sliced to a width of 0.5 mm to prepare the following sliced specimens (width 0.5 mm, plural pieces).
…壊死又は凝固辺縁部 …上記辺縁部より3mm内部 …上記辺縁部より5mm内部 …右葉 25mlエーレンマイヤーフラスコ中でダグラスら（Doug
las et al.）の方法〔J.Physiol.,248,273−284（197
5）〕に準じて、上記各スライス片標本を3H−チミジン2
0μＣ及び14C−ロイシン10μＣを含むハンクス液5.0ml
に浸し、95％O2＋５％CO2の条件で60秒間前培養し、そ
の後フラスコに栓をし、37℃で３時間振盪培養を続け
た。… Necrotic or coagulated margin… 3 mm inside from the above margin… 5 mm inside from the above margin… Right lobe Douglas et al. In a 25 ml Ehrenmeyer flask (Doug
las et al.) [J. Physiol., 248 , 273-284 (197
5) According to 3), each of the above sliced specimens was subjected to 3 H-thymidine 2
5.0 ml of Hanks solution containing 0 μC and 10 μC of 14 C-leucine
, And pre-cultured for 60 seconds under the conditions of 95% O 2 + 5% CO 2 , and then the flask was stoppered, followed by shaking at 37 ° C. for 3 hours.
肝切除後48時間目における3H−チミジン取込み量（DN
A合成活性、単位:DPM/μgDNA）及び14C−ロイシン取込
み量（蛋白合成活性、単位:DPM/μｇ蛋白）の測定を行
なった。之等はいずれも肝細胞の増殖を反映する指標で
ある。 3 H- thymidine uptake at 48 hours after hepatectomy (DN
A synthesis activity, unit: DPM / μg DNA) and 14 C-leucine uptake (protein synthesis activity, unit: DPM / μg protein) were measured. These are indicators that reflect the proliferation of hepatocytes.
本発明の薬剤投与実験群につき得られた結果を第１表
（１）（DNA合成活性）及び同（２）（蛋白合成活性）
に、生理食塩水投与の対照群につき得られた結果を第２
表（１）（DNA合成活性）及び同（２）（蛋白合成活
性）に示す。Table 1 (1) (DNA synthesis activity) and (2) (protein synthesis activity) obtained from the experimental group administered with the drug of the present invention.
The results obtained for the saline-administered control group were
The results are shown in Tables (1) (DNA synthesis activity) and (2) (protein synthesis activity).
上記第１表と第２表との対比より、本発明肝細胞増殖
促進剤有効成分化合物の利用によれば、肝切除術を施さ
れた肝細胞及び正常肝細胞のいずれも、それらの顕著な
増殖再生が認められることが判る。また切除術の際のマ
イクロ波による熱の影響を受けた肝細胞もまた同様に顕
著な増殖再生が認められることが明らかである。 From the comparison between Table 1 and Table 2, according to the use of the active ingredient compound for promoting hepatocyte proliferation of the present invention, both hepatocytes subjected to hepatectomy and normal hepatocytes have their remarkable effects. It can be seen that proliferation and regeneration are observed. It is also evident that hepatocytes that were affected by the heat of the microwaves during the resection also showed significant proliferation and regeneration.
また、上記においてＦ−1,6−DPトリウム塩に代えて
Ｆ−2,6−DPトリナトリウムを用いた実験群を作成し、
この群について同一試験を行なった結果、第１表（１）
及び同（２）と略々同様の結果が得られた。In the above, an experimental group using F-2,6-DP trisodium in place of the F-1,6-DP thorium salt was created,
As a result of performing the same test on this group, Table 1 (1)
And substantially the same results as in (2) were obtained.
之等のことより、本発明肝細胞増殖促進剤は、優れた
肝臓細胞増殖促進効果を奏することが明らかである。From these results, it is clear that the hepatocyte growth promoting agent of the present invention exhibits an excellent hepatocyte growth promoting effect.
Claims (1)
ルクトース−2,6−ジホスフェート及び之等の薬理的に
許容される塩からなる群から選ばれた少なくとも１種を
有効成分として含有することを特徴とする肝細胞増殖促
進剤。1. An active ingredient comprising at least one selected from the group consisting of fructose-1,6-diphosphate, fructose-2,6-diphosphate and pharmaceutically acceptable salts thereof. A hepatocyte proliferation promoter characterized by the following.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2356189A JP2654518B2 (en) | 1989-01-31 | 1989-01-31 | Hepatocyte proliferation promoter |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2356189A JP2654518B2 (en) | 1989-01-31 | 1989-01-31 | Hepatocyte proliferation promoter |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02202822A JPH02202822A (en) | 1990-08-10 |
| JP2654518B2 true JP2654518B2 (en) | 1997-09-17 |
Family
ID=12113930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2356189A Expired - Fee Related JP2654518B2 (en) | 1989-01-31 | 1989-01-31 | Hepatocyte proliferation promoter |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2654518B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL383868A1 (en) * | 2007-11-25 | 2009-06-08 | Instytut Chemii Bioorganicznej Pan | Crystal-graphical model of binding point and modulator adjusting catalythic activity of phosphofructokinase (PFK), manner of designing, selection and production of PFK modulator, the manner of computer analysis of influences between molecular structure of |
-
1989
- 1989-01-31 JP JP2356189A patent/JP2654518B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02202822A (en) | 1990-08-10 |
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