JPS6054320A - Remedy for renal disease - Google Patents

Abstract

PURPOSE:An agent, containing a substance selected from creatinephosphoric acid and metabolic precursors convertible into the creatinephosphoric acid in the living body as an active constituent, and useful for renal diseases such as chronic renal insufficiency. CONSTITUTION:A remedy for renal diseases containing at least one selected from creatinephosphoric acid and metabolic presursors convertible into the creatinephosphoric acid in the living body, e.g. creatine or glycosylamine, as an active constituent. In the end of patients with renal diseases including chronic renal insufficiency, various anemia symptoms such as hyperazetomia, subnutrition, hyperphosphatemia, hypocalcemia or anemia due to renal hypofunction are developed, but the active constituent is capable of reducing or keeping the blood serum creatine concentration and preventing the deterioration of the renal function expressed by creatine clearance.

Description

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.

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.

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.

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.

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.

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.

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).

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.

Hereinafter, the pharmacological effects of creatine phosphate and its metabolic precursors according to the present invention will be explained in detail.

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.

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.

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.

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.

(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.

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.

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.

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.

Next, Table 6 shows the dynamics of guanidinosuccinic acid and methylguanidine, which are known as uremic substances.

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.

(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.

As a result, no deaths or any toxic findings were observed for any of the test drugs.

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.

Next, the administration method and dosage of creatine and its metabolic precursors according to the present invention will be described.

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.

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.

Examples of formulations containing glycocyamine or formulations containing two to three pharmacologically active substances are shown below as examples containing one pharmacologically active substance.

Formulation Example 1 Capsule A pharmaceutical composition is manufactured according to the following recipe.

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.

Formulation example 2 tablets A pharmaceutical composition is manufactured according to the following recipe.

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.

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.

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.

Patent applicant: Morishita Pharmaceutical Co., Ltd.

Claims (3)

[Claims] (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. (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. (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.