JPH0513928B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to an agent for eliminating the side effects of chemotherapeutic agents having a nucleic acid biosynthesis inhibiting effect. PRIOR ART There are chemotherapeutic agents that inhibit nucleic acid biosynthesis to inhibit the growth of viruses or tumor cells and to eliminate them. It also affects nucleic acid biosynthesis, which is related to important life functions, and causes side effects, so if used continuously over a long period of time, normal functions are threatened and the original therapeutic purpose cannot be achieved. Chemotherapy is a desirable therapy if the side effects of chemotherapeutic agents can be completely eliminated. However, since it has not been possible to develop a drug that targets viruses, tumors, etc., we are currently using palliative treatments to treat various side effects, but no satisfactory effects have been obtained. Fundamentally, activating nucleic acid biosynthesis, which is the host's impaired spontaneous healing function, is a therapy to eliminate side effects, but such a drug has not yet been developed. Problems to be Solved by the Invention The present inventor has already discovered that L-carnosine acts as a stimulant for endobud formation (Nagai K., Suda, T. et al; SURGERY
Vol.100, No.5, pp.815-821, 1986) followed by L-
We have identified the immunomodulatory effects (USA 792157) and tissue repair effects of carnosine. It has been proven that the spontaneous self-healing function can be manipulated by L-carnosine. The present inventors have demonstrated that L-carnosine is effective against a decrease in white blood cell count, which is the main side effect of mitomycin C (MMC) and 5-fluoruracil (5-FU), which are said to have strong side effects as representative chemotherapeutic agents. It was found that this drug was effective in eliminating the side effect of leukopenia. Means for Solving the Problems According to the present invention, there is provided an agent for eliminating the side effects of a chemotherapeutic agent having a nucleic acid biosynthesis inhibiting effect, which is characterized by containing L-carnosine or a salt thereof as an active ingredient. L-carnosine is a dipeptide consisting of -alanine and L-histidine that was discovered in Liebig meat extract by Gulewitch et al. in 1900, and is contained in large amounts in mammalian skeletal muscles. Although many studies have been published since its discovery, its physiological significance has not been determined. L-carnosine has a melting point of 250℃ (decomposition), [〓 ₂₀ ] =
+20.0° (H ₂ O), it is a tasteless and odorless white crystalline powder that is easily soluble in water. It is represented by the following structural formula. Its aqueous solution has a pH of 8.0-8.5. L-carnosine is a substance contained mainly in the skeletal muscles of mammals at about 0.1 to 0.3%, and is ingested as food from daily meat and is a source of the essential amino acid L-histidine. It is also biosynthesized from L-histidine and -alanine. After absorption, ingested L-carnosine is broken down into L-histidine and 〓-alanine by carnosinase to become nutrients, and a portion is resynthesized to L-carnosine [as an intermediate in L-carnosine biosynthesis 〓-alanyl- 1-methyl-histidine (Anse-rine)]. As mentioned above, L-carnosine is a highly safe substance that is similar to food, and after absorption, it is broken down by carnosinase present in various organs, so many other drugs are metabolized in the liver, causing a burden on liver function. It is a completely different substance. Next, the acute toxicity of L-carnosine will be described. Toxicity: Various doses of L-carnosine were administered to groups of 10 mice intraperitoneally and orally, and symptoms of acute toxicity were observed 5 hours after administration. LD ₅₀ was calculated by the Vander Waerden method from the number of deaths after 72 hours.
L-carnosine was dissolved in physiological saline so that the amount of the administered solution was 0.1 to 0.3 ml/10 g. L-carnosine toxicity symptoms include 15,000
Approximately 30 minutes after administration of mg/Kg intravaginally (LD ₁₀₀ ), locomotor activity decreased, the patient took a prone position, and breathing rate decreased and became irregular, but no loss of righting reflex or withdrawal reflex was observed. Half of the subjects showed occasional tail-raising reactions or developed clonic convulsions. As his symptoms progressed, he repeatedly rolled over, his reflexes decreased in response to contact stimulation, and he began to induce convulsions, which progressed to tonic convulsions and led to his death. Half of the cases died after 1 hour and 30 minutes, 80% died after 2 hours, and all cases died after 5 hours. After oral administration of 15,000 mg/Kg, there was almost no effect, but death was observed in 1 out of 10 patients 1 hour later. Table 1 LD ₅₀ (90% confidence limit) of L-carnosine Administration method Dose (mg/Kg) Intraperitoneal 9087 (8320-9925) Oral >14930 [Minimum lethal dose] Acute toxicity to DDY male mice (72 time value)
As shown in the table, L-carnosine can be said to be a compound with extremely low toxicity. Furthermore, L-carnosine has already been commercialized as a drug for treating anorexia by Merck of Spain for about 10 years, and is a substance that has already been confirmed to be safe and has no side effects. The synthesis method of L-carnosine is known (Jour
−nal of Riological Chemistry, 1087531935),
Carbobenzoxy-alanine is converted into chloride with phosphorus pentachloride, converted into methyl ester with methanol, converted into azide via hydroazide, L
- coupled with histidine methyl ester,
Finally, L-carnosine can be obtained by removing the carbobenzoxy group by catalytic reduction. The present invention also includes a therapeutic agent consisting of a salt of L-carnosine, and examples of the salt of L-carbonosine include salts based on a carboxylic acid group and acid addition salts based on an amino group and a pharmacologically acceptable acid. There is,
There are also salts based on both carboxylic acid groups and amino groups. Salts based on carboxylic acid groups include sodium,
Salts with metals such as potassium, calcium, magnesium, zinc and aluminum, ammonium salts and substituted ammonium salts, salts with trialkylamines and other amines such as triethylamine; salts based on amino groups include hydrochloric acid, Sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid,
There are salts with inorganic and organic acids such as tartaric acid, citric acid, succinic acid, maleic acid, benzenesulfonic acid, and toluenesulfonic acid, but these themselves are
Free L-carnosine can be prepared by reacting with a stoichiometrically calculated amount of the selected acid or base according to known methods. The side effects of nucleic acid biosynthesis inhibition are wide-ranging, but regarding the side effect of leukopenia, which is a clinically important issue, we will next discuss MMC and 5FU, which are representative drugs with strong non-specific nucleic acid biosynthesis inhibition.
The side effect removing effect of L-carnosine will be explained using an experimental example. Estimated clinical dose: L-carnosine 100mg/based on the results of animal experiments
Kg/day (subcutaneous administration) is the optimum dose for immunomodulatory effects, which yields a value of 5 g/day for an adult weighing 50 kg. The constituent ingredients are 〓-alanine and L-histidine, which are amino acids in the body, and are highly safe and can be used without worrying about side effects. Drugs that require removal of side effects using L-carnosine include drugs that cause side effects by not only attacking targets such as cancer and viruses, but also inhibiting nucleic acid biosynthesis in host organs, and inhibiting the growth of cancer and AIDS viruses. There are chemotherapeutic agents that L-carnosine is used to eliminate side effects caused by the nucleic acid biosynthesis inhibiting effect of these drugs, eliminate host function disorders, and exert the original effects of chemotherapeutic agents. L-carnosine is extremely safe and can be used in combination with anti-AIDS chemotherapeutic agents for a long period of time without worrying about side effects. L-carnosine may be administered in any convenient form for oral or parenteral administration, such as injections, powders, granules, tablets, capsules, enteric coated formulations, troches, etc. Various dosage forms can be mentioned, and these can be used alone or in combination depending on the symptoms. It goes without saying that the dosage varies greatly depending on the route of administration, dosage form, symptoms, etc. Typical dosage forms, dosages, and administration methods of the therapeutic agent of the present invention are illustrated below.

[Table] Note that the usage and dosage described here are merely a guideline, and as mentioned above, L-carnosine is an extremely safe substance, so there is no problem in increasing or decreasing the dosage as appropriate depending on the patient's symptoms. Since L-carnosine is easily soluble in water, for example, 0.3
%, 0.5% or 1.0% isotonic solutions can be made. L-carnosine powder, which is lyophilized and sealed in an ampoule or vial under a stream of inert gas, may be immediately used for injection as a 0.3%, 0.5% or 1.0% isotonic solution immediately before injection. Powders, granules, tablets or capsules for oral administration may contain binders such as syrup acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, excipients such as lactose, corn starch, calcium phosphate, sorbitate or glycine, lubricants such as They are formulated in a manner conventional in the art using magnesium stearate, talc, polyethylene glycol, hydroxypropylmethylcellulose or silica, a disintegrant such as potato starch, or a wetting agent such as sodium lauryl sulfate. The tablets may be coated by methods well known in the art. Formulation Example 1 (Injection) Under aseptic operation, the synthesized L-carnosine was filled into ampoules as a 5% or 1% isotonic solution. Formulation Example 2 (Granules) Granules were manufactured using the synthesized L-carnosine according to the following formulation. L-carnosine 0.2g Lactose 0.34g Corn starch 0.45g Hydroxypropyl methyl cellulose 0.01 granule 1,00g Example In the experiment, 5 to 6 5-week-old DDY mice were used per group. L-carnosine (100 mg/Kg/day, sc) was administered in combination with the antitumor agent MMC (1 mg/Kg/day, ip) or 5-FU (50 mg/Kg/day, ip) for 7 days.
The white blood cell count (WBC) was calculated the next day. Result is
With MMC and 5-FU, the white blood cell count decreased to 20-30%. By using L-carnosine in combination, the white blood cell count recovered to 50-80%. The results are shown in Tables 1 and 2. From this, it was found that -carnosine can restore immune function that has been decreased by anti-tumor drugs.

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Claims (1)

[Claims] 1. An agent for eliminating side effects of a chemotherapeutic agent having a nucleic acid biosynthesis inhibiting effect, characterized by containing L-carnosine or a salt thereof as an active ingredient.