JPS6054320A - Remedy for renal disease - Google Patents
Remedy for renal diseaseInfo
- Publication number
- JPS6054320A JPS6054320A JP16076083A JP16076083A JPS6054320A JP S6054320 A JPS6054320 A JP S6054320A JP 16076083 A JP16076083 A JP 16076083A JP 16076083 A JP16076083 A JP 16076083A JP S6054320 A JPS6054320 A JP S6054320A
- Authority
- JP
- Japan
- Prior art keywords
- creatine
- renal
- acid
- glycocyamine
- creatinephosphoric
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、クレアチンリン酸及び生体内でクレアチンリ
ン酸に変換される代謝前駆物質の少なくとも1種を有効
成分として含有する腎疾患治療剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for renal disease containing as an active ingredient at least one of creatine phosphate and a metabolic precursor that is converted to creatine phosphate in vivo.
慢性腎不全をはじめとする腎疾患患者の末期には腎機能
低下に基づく高窒素血症、低栄養状態、高リン酸血症、
低カルシウム血症、貧血など多様な尿毒症症状を呈し、
その対策として従来は、食事療法、必須アミノ酸療法な
どが試みられているにすぎず、終局的には透析療法、腎
移植などに頼らざるを得なかった。In the end stages of renal disease patients, including chronic renal failure, azotemia, malnutrition, hyperphosphatemia, and
The patient exhibits various uremic symptoms such as hypocalcemia and anemia,
Until now, attempts have been made to counter this by using diet therapy, essential amino acid therapy, etc., but in the end, patients had no choice but to rely on dialysis therapy, kidney transplantation, etc.
本発明者らは、上述の状況に鑑み鋭意研究した結果、ク
レアチンリン酸及びその代謝前駆物質であるクレアチン
やグリコシアミンに顕著な腎機能保持作用、すなわち実
験的には尿毒症物質の低下作用、尿毒症症状の改善、延
命効果などの作用のあることを見いだし、本発明を完成
するに至った。As a result of intensive research in view of the above-mentioned circumstances, the present inventors have found that creatine phosphate and its metabolic precursors, creatine and glycocyamine, have a remarkable effect on maintaining renal function, that is, an effect on reducing uremic substances, and an effect on uremic toxicity. The present inventors discovered that the present invention has effects such as improving the symptoms of the disease and prolonging life, leading to the completion of the present invention.
本発明の有効成分として用いられる化合物には、前記の
クレアチンリン酸、クレアチン及びグリコシアミンのほ
か、これら化合物のアルカリ金属塩、アルカリ土類金属
塩、鉱酸塩、有機酸塩あるいは製剤学士のプロトラング
など生体内でクレアチンリン酸に変換される物質、すな
わち代謝前駆物質の範躊に入るいずれの化合物も含まれ
る。In addition to the above-mentioned creatine phosphate, creatine, and glycocyamine, the compounds used as the active ingredients of the present invention include alkali metal salts, alkaline earth metal salts, mineral salts, organic acid salts, and formulations of these compounds. Also included are substances that are converted to creatine phosphate in vivo, that is, any compounds that fall into the category of metabolic precursors.
前記の塩類としては、クレアチン又はグリコシアミンと
医薬の塩として繁用されているナトリウム、カリウム、
カルシウム、マグネシウム、塩酸、臭化水素酸、硫酸、
酢酸、蓚酸等との塩あるいはクレアチンリン酸のナトリ
ウム塩などを例示できる。Examples of the above-mentioned salts include sodium, potassium, and creatine or glycocyamine, which are often used as pharmaceutical salts.
Calcium, magnesium, hydrochloric acid, hydrobromic acid, sulfuric acid,
Examples include salts with acetic acid, oxalic acid, etc., and sodium salts of creatine phosphate.
また、前記プロドラッグの代表的な例としては、クレア
チン又はグリコシアミンとアルコール類から常法によっ
て合成されるエステル類、具体的には、クレアチンのメ
チルエステル、エチルエステル、n−プロピルエステル
、nニブチルエステル及びグリコシアミンのエチルエス
テル等の低級アルキルエステルを挙げることができる。Typical examples of the prodrugs include esters synthesized from creatine or glycocyamine and alcohols by conventional methods, specifically creatine methyl ester, ethyl ester, n-propyl ester, n-nibutyl ester. Mention may be made of lower alkyl esters such as esters and ethyl esters of glycocyamines.
本発明の有効成分として上記具体例示の化合物は公知の
化合物であり、例えば、三浦義彰監訳:ハーパー・生化
学、349(+971)、丸善、(東京)に記載されて
いるように、クレアチンリン酸は生体内の高エネルギー
物質として、クレアチン及びグリコシアミンはその前駆
物質として知られている。また、クレアチンの上記低級
アルキルエステルについては、ジャーナル・オブ・バイ
オロジカルeケミストリ、第54巻、671−3(19
22)に、グリコシアミンエチルエステルについては、
カナディアン・ジャーナル・オブ・ケミストリ、第32
巻、1012−16(1954)にそれぞれ合成法が記
載されている。The compounds specifically exemplified above as active ingredients of the present invention are known compounds, such as creatine phosphate, as described in Harper Seikagaku, 349 (+971), Maruzen, (Tokyo), supervised translation by Yoshiaki Miura. Creatine and glycocyamine are known as high-energy substances in living organisms, and creatine and glycocyamine are known as their precursor substances. Further, regarding the above lower alkyl ester of creatine, see Journal of Biological e-Chemistry, Vol. 54, 671-3 (19
22), regarding glycocyamine ethyl ester,
Canadian Journal of Chemistry, No. 32
The synthesis methods are described in Vol., 1012-16 (1954).
しかし、上述のクレアチンリン酸をはじめとする本発明
に係る化合物が、外的に与えられることによって、腎機
能保持作用などの腎疾患病態に著効を示すという示唆な
いし事実は今までに開示されていない。However, no suggestion or fact has been disclosed to date that the compounds according to the present invention, including the above-mentioned creatine phosphate, exhibit significant effects on renal disease pathology, such as renal function preserving effects, when administered externally. Not yet.
以下、本発明に係るクレアチンリン酸及びその代謝前駆
物質の薬理作用について詳述する。Hereinafter, the pharmacological effects of creatine phosphate and its metabolic precursors according to the present invention will be explained in detail.
実験例1
腎疾患モデルでの短期投与効果
体重170〜180yのウィスター系雄ラットを用いベ
ンドパルビタール麻酔下に一方の腎臓の皮質部分を外利
的に削除し、2週間後に他方の腎臓を摘出した。腎摘出
手術後2週間目に血中尿素窒素を測定し、その濃度が6
Qmg/di以上のものを腎疾患病態のモデルとした。Experimental Example 1 Short-term administration effect in renal disease model Using Wistar male rats weighing 170 to 180 years, the cortex of one kidney was excised externally under bendoparbital anesthesia, and the other kidney was removed 2 weeks later. did. Two weeks after nephrectomy, blood urea nitrogen was measured and the concentration was 6.
Qmg/di or higher was used as a model for renal disease pathology.
この腎疾患ラットを4群に分け、(A)グリコシアミン
投4群、(B)クレアチン投jj2群、(C)クレアチ
ンリン酸投与群、(D)対照の無投与群とし、投り、計
は(A)〜(C)群0.2 rnmolθ/ d、ay
とした。投り、方法は各群のラットに完全静脈栄養法を
施行(菊地武夫ら、栄養と食糧、65.42′5、+9
83)L、、最初の6日間は(D)群の被検薬物を含ま
ない輸液を投与し、その後各群の被検薬物を含む輸液に
切り換えて5日間の投与を行なった。各群の投り、カロ
リー量、投与窒素量は同一となるよう@液管理し、血中
尿素窒素、血清クレアチニン濃度13 J:び腎機能の
指標であるクレアチニン・クリアランスの変化を比較し
た。These renal disease rats were divided into 4 groups: (A) 4 groups treated with glycocyamine, (B) 2 groups treated with creatine, (C) a group treated with creatine phosphate, and (D) a control group without treatment. Groups (A) to (C) 0.2 rnmolθ/d, ay
And so. The method was to administer total parenteral nutrition to each group of rats (Takeo Kikuchi et al., Nutrition and Food, 65.42'5, +9
83) L. For the first 6 days, an infusion containing no test drug of group (D) was administered, and then the infusion was switched to an infusion containing the test drug of each group, and administration was carried out for 5 days. Each group was controlled to have the same amount of energy, calories, and nitrogen, and the changes in blood urea nitrogen, serum creatinine concentration, and creatinine clearance, which is an index of renal function, were compared.
その結果、表1に示す通り対照の(T))群に比較して
(A)〜(C) 群の各JIFで血中尿素窒素、血清ク
レアチニン濃度の紙上あるいは維持、およびクレアチニ
ン・クリアランスで示されるように腎機能の悪化を防止
する成績を得た。As a result, as shown in Table 1, blood urea nitrogen, serum creatinine concentration on paper or maintenance, and creatinine clearance were shown in each JIF of groups (A) to (C) compared to the control group (T). The results showed that the drug prevented the deterioration of renal function.
前記と同様の効果は、クレアチンメチルエステルやグリ
コシアミンエチルエステルなど、生体内でクレアチンリ
ン酸の前駆物質に変換されるものにも認められる。Effects similar to those described above are also observed in substances that are converted into precursors of creatine phosphate in vivo, such as creatine methyl ester and glycocyamine ethyl ester.
(余 白)
実験例2
腎疾患モデルでの長期投与効果
実験例1で示された腎機能保持・改善効果をさらに明確
に裏付けるため、グリコシアミンを例に同腎疾患モデル
を用いさらに詳細な検討を長期に渡って実施した。実験
群として(A)群には001%グリコシアミン含有水道
水、(B)群には01%グリコシアミン含有水道水、(
C)群には水道水のそれぞれを市販の固型飼料とともに
8週間にわたり自由摂取させた。この間のラットの生存
率、8週目の血液化学性状、クレアチニン・クリアラン
ス、尿毒症物質であるグアニジノ化合物の動態を検討し
た。(Margin) Experimental Example 2 Effect of long-term administration in a renal disease model In order to further clearly support the renal function preservation and improvement effect shown in Experimental Example 1, a more detailed study was conducted using the same renal disease model using glycocyamine as an example. It was carried out over a long period of time. As experimental groups, group (A) received 001% glycocyamine-containing tap water, group (B) received 01% glycocyamine-containing tap water, (
Group C) was given free access to tap water and commercially available solid feed for 8 weeks. During this period, the survival rate of the rats, blood chemical properties at 8 weeks, creatinine clearance, and the dynamics of guanidino compounds, which are uremic substances, were examined.
その結果、8週目の生存率は(A)群7/15(47%
)、8群+1/+7(65%)、(Cり群6/18(3
5%)とグリコシアミン投与により延命効果を認めた。As a result, the survival rate at 8 weeks was 7/15 (47%) in group (A).
), Group 8 +1/+7 (65%), Group C 6/18 (3
5%) and that glycocyamine administration had a survival effect.
さらに8週目での血液化学性状および腎機能を比較する
と、表2の如く(A)、(B)群で有意な腎疾患病態の
改善効果を認めた。Furthermore, when blood chemical properties and renal function were compared at 8 weeks, significant improvement in renal disease pathology was observed in groups (A) and (B) as shown in Table 2.
すなわち、対照の(C)群に比べ(A)(B)群では面
中尿7−
素窒素、血清クレアチニン濃度を低下させ、腎疾患病態
で乱れたカルシウム、リン酸レベルを正常化し、血清蛋
白質濃度も高値に保つことが判明した。また、腎機能の
指標となるクレアチニン・クリアランスも改善した。That is, compared to the control group (C), groups (A) and (B) lowered surface urine nitrogen and serum creatinine concentrations, normalized calcium and phosphate levels that were disturbed in the pathological state of kidney disease, and decreased serum protein levels. It was also found that the concentration remained high. Creatinine clearance, an indicator of renal function, also improved.
次に尿毒症物質として知られているグアニジノコハク酸
、メチルグアニジンの動態について表6に示した。Next, Table 6 shows the dynamics of guanidinosuccinic acid and methylguanidine, which are known as uremic substances.
血清レベルおJ:び尿中排泄はのいずれもグリコシアミ
ンを投rj、 (、た(A)、 (B)群で低値を示し
、尿毒症物質の産生低ド、ひいては腎疾病の病態改善効
果が認められた。Serum levels and urinary excretion were all low in groups administered with glycocyamine (A) and (B), indicating that the production of uremic substances was reduced and that the condition of kidney disease was improved. was recognized.
(余 白)
実験例ろ
急性毒性
クレアチンリン酸、クレアチン、クレアチンメチルエス
テル塩酸塩、グリコシアミン及びグリコシアミンエチル
エステル塩酸塩の急性毒性試験として、各々10匹のウ
ィスター系ラット(雄)に500mg/しを経口投与し
た。(Margin) Experimental Example Acute Toxicity As an acute toxicity test of creatine phosphate, creatine, creatine methyl ester hydrochloride, glycocyamine, and glycocyamine ethyl ester hydrochloride, 500 mg/ml of each was administered to 10 Wistar rats (male). was administered orally.
その結果、いずれの被検薬においても死亡例並びに何ら
の毒性所見も観察されなかった。As a result, no deaths or any toxic findings were observed for any of the test drugs.
以上の薬理試験の諸結果より明らかなようにクレアチン
リン酸およびその代謝前駆物質であるクレアチン及びグ
リコシアミンは、腎疾患時に投与することによりその病
態増悪を防止あるいは改善し、したがって容易に前記代
謝前駆物に変換されるプロドラッグも含め本発明に係る
化合物は臨床上有用である。As is clear from the results of the above pharmacological tests, creatine phosphate and its metabolic precursors, creatine and glycocyamine, can prevent or ameliorate the aggravation of the disease by administering it during renal disease, and therefore can easily reduce the metabolic precursors. Compounds of the present invention, including prodrugs that are converted to , are clinically useful.
次に、本発明に係るクレアチン及びその代謝前駆物質の
投与方法および投与量について述べる。Next, the administration method and dosage of creatine and its metabolic precursors according to the present invention will be described.
本発明の薬理学的に有効なりレアチンリン酸とその代謝
前駆物質を治療に用いる時の投与方法は、それらの物質
を病態に応じて、単独あるいは組み合せで直接投q、す
ることにより可能であるが、好ましくは、製剤ト許容さ
れる賦形剤を添加、加工した形での投り組成物として投
与することが良い結91を生む。When the pharmacologically effective reatine phosphate and its metabolic precursors of the present invention are used for treatment, it is possible to administer these substances directly or in combination depending on the pathological condition. However, it is preferable to administer the formulation as a cast composition in a processed form with the addition of acceptable excipients, resulting in good results.
投与組成物について更に具体的に述べれば、後記製剤例
に示す様な組成となる。錠剤、顆粒剤、細粒剤、粉末剤
、硬カプセル剤、軟カプセル剤、注射剤、坐剤、口腔剤
、バッカル剤の形となるのが望ましい。しかしながら、
特にこれらの剤形に限る必要はなくて、投q−可能な剤
形であれば何らその反り、後の薬理効果発現を防げるも
のではない。More specifically, the composition for administration will be as shown in the formulation examples below. Preferably, the formulation is in the form of tablets, granules, fine granules, powders, hard capsules, soft capsules, injections, suppositories, buccal preparations, or buccal preparations. however,
There is no particular need to limit the dosage form to these, and as long as it is a dosage form that can be thrown, there is no way to prevent warping or subsequent manifestation of pharmacological effects.
以下に薬理活性物質の1つを含有する例としてグリコシ
アミンを含む製剤例、あるいは薬理活性物質の2〜3つ
を含有する製剤例を示す。Examples of formulations containing glycocyamine or formulations containing two to three pharmacologically active substances are shown below as examples containing one pharmacologically active substance.
製剤例1 カプセル剤 次の処方に従って医薬組成物を製造する。Formulation Example 1 Capsule A pharmaceutical composition is manufactured according to the following recipe.
構成要素 量
グリコシアミン 150rnII
乳酸 75■
デンプン 25mfl
タルク 5mg
ステアリン酸マグネシウム 2mg
これらの成分をふるいに通し、混合し、硬カプセルに入
れる。Components Quantity Glycocyamine 150rnII Lactic Acid 75■ Starch 25mfl Talc 5mg Magnesium Stearate 2mg These ingredients are passed through a sieve, mixed and placed in a hard capsule.
製剤例2 錠 剤 次の処方に従って医薬組成物を製造する。Formulation example 2 tablets A pharmaceutical composition is manufactured according to the following recipe.
構成要素 量 グリコシアミン 100mg クレアチン 50mfl 乳酸 40ff1g デンプン 15+++y カルボキシメチルセルロース 10■ メチルセルロース 8■ タルク l my 製剤例ろ 注射剤 次の処方に従って医薬組成物を製造する。Component amount Glycocyamine 100mg Creatine 50mfl Lactic acid 40ff1g Starch 15+++y Carboxymethylcellulose 10■ Methylcellulose 8■ talc my Example of formulation Injection A pharmaceutical composition is manufactured according to the following recipe.
構成要素 量
クレアチンリン酸 50〜
クレアチン 5omg
グリコシアミン 5omg
塩化ナトリウム 40mg
注射用蒸留水 5me
これらの成分を混合溶IW L、ろ過し、アンプルに注
入し、溶封しi14菌する。Components Quantity Creatine phosphate 50~ Creatine 5omg Glycocyamine 5omg Sodium chloride 40mg Distilled water for injection 5me These components are mixed and dissolved in IWL, filtered, poured into an ampoule, fused and sealed with I14 bacteria.
本発明に係る化合物の成人男子に対する1日没’j 1
7tは、各薬物をlli独で用いる場合には経口で20
0 mgないし4.000 mg、好ましくは500■
ないし1.500 mgである。1 Sunset'j 1 of the compound according to the present invention on adult males
7t is 20 orally when each drug is used alone.
0 mg to 4.000 mg, preferably 500 mg
and 1.500 mg.
特許出願人 森下製薬株式会社Patent applicant: Morishita Pharmaceutical Co., Ltd.
Claims (3)
酸に変換される代謝前駆物質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腎疾患治
療剤。(1) At least one selected from creatine phosphate and metabolic precursors that are converted to creatine phosphate in vivo.
A therapeutic agent for renal diseases characterized by containing seeds as an active ingredient.
物質が、クレアチン、クレアチンの低級アルキルエステ
ル又は薬理学的に許容されるそれらの塩である特許請求
の範囲第1項記載の腎疾患治療剤。(2) The renal disease treatment according to claim 1, wherein the metabolic precursor that is converted to creatine phosphate in vivo is creatine, a lower alkyl ester of creatine, or a pharmacologically acceptable salt thereof. agent.
物質が、グリコシアミン、グリコシアミンの低級アルキ
ルエステル又は薬理学的に許容されるそれらの塩である
特許請求の範囲第1項記載の腎疾患治療剤。(3) Kidney disease according to claim 1, wherein the oxidation precursor that is converted to creatine phosphate in vivo is glycocyamine, a lower alkyl ester of glycocyamine, or a pharmacologically acceptable salt thereof. therapeutic agent.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16076083A JPS6054320A (en) | 1983-08-31 | 1983-08-31 | Remedy for renal disease |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16076083A JPS6054320A (en) | 1983-08-31 | 1983-08-31 | Remedy for renal disease |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS6054320A true JPS6054320A (en) | 1985-03-28 |
Family
ID=15721868
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16076083A Pending JPS6054320A (en) | 1983-08-31 | 1983-08-31 | Remedy for renal disease |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6054320A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19537494A1 (en) * | 1995-09-25 | 1997-03-27 | Desitin Arzneimittel Gmbh | Creatine to protect neural tissue |
EP1142571A1 (en) * | 2000-04-06 | 2001-10-10 | Basf Aktiengesellschaft | Method to produce solid creatine dosage forms and dosage forms thus obtained |
US11512047B2 (en) | 2019-07-12 | 2022-11-29 | Alzchem Trostberg Gmbh | Metastable crystal modification and method for producing the same (I) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6436803A (en) * | 1987-08-01 | 1989-02-07 | Furukawa Electric Co Ltd | Snow melting panel |
-
1983
- 1983-08-31 JP JP16076083A patent/JPS6054320A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6436803A (en) * | 1987-08-01 | 1989-02-07 | Furukawa Electric Co Ltd | Snow melting panel |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19537494A1 (en) * | 1995-09-25 | 1997-03-27 | Desitin Arzneimittel Gmbh | Creatine to protect neural tissue |
EP1142571A1 (en) * | 2000-04-06 | 2001-10-10 | Basf Aktiengesellschaft | Method to produce solid creatine dosage forms and dosage forms thus obtained |
US6689299B2 (en) | 2000-04-06 | 2004-02-10 | Basf Aktiengesellschaft | Process for producing solid creatine dosage forms and dosage forms obtainable thereby |
US11512047B2 (en) | 2019-07-12 | 2022-11-29 | Alzchem Trostberg Gmbh | Metastable crystal modification and method for producing the same (I) |
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