JPS645006B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic agent for hyperlipidemia peroxidation. General conditions for the formation of lipid peroxide in living organisms include the presence of polyunsaturated fatty acids and the presence of active oxygen or free radicals. Active oxygen or free radicals attack the double bonds of polyunsaturated fatty acids, and unlike normal oxidation, which introduces one molecule of oxygen, this method involves introducing two molecules of oxygen into the same part. The formation of lipid peroxides as hydroperoxides is observed using a trowel that changes the cis double bond structure into a conjugated double bond while causing peroxidation. Polyunsaturated fatty acids exist in large amounts in the β-position of phospholipids in living organisms, and phospholipids constitute the matrix of cell membranes throughout the body, so they are present in large amounts in cell membranes. Oxygen also maintains the respiration of living organisms and exists in tissues throughout the body as an electron acceptor for oxidation reactions, and free radicals can also be oxidized by peroxidation. The conditions for lipid production are found throughout the body. In fact, their creation and disappearance are constantly repeated within the body. Of course, not all peroxidation reactions are pathological; physiological functions such as photosynthesis, prostaglandin biosynthesis, and drug detoxification are based on peroxidation reactions. However, when lipid peroxide is formed within cells, it destroys cell membranes, denatures enzyme proteins, and causes acute local tissue damage.When released in large quantities from cells, serum lipid peroxide increases. Serum hyperlipidemia causes damage to various peripheral organs. Like lipofuscin, which chronically accumulates in cells and is associated with cell aging, platelet aggregation and vascular flow occur through the production of prostaglandin in platelets. Suppressing the production of lipid peroxide has great clinical significance because it causes harmful effects such as causing shrinkage. During a clinical trial in which ML-236B was administered to hypercholesterolemic patients and the effect on serum cholesterol was observed, the present inventors discovered that this substance has the effect of lowering serum lipid peroxide. ML-236B is a substance isolated and purified from the metabolites of Penicillium titrinum, a type of blue mold, and is a rate-limiting enzyme for cholesterol biosynthesis, 3-hydroxy-3-, in enzyme systems isolated from laboratory animals and in cultured cell systems. It is known that it inhibits methylglutaryl coenzyme A reductase by competing with it, and exhibits a strong serum cholesterol-lowering effect even at the individual animal level (Japanese Patent Application Laid-open No. 155690/1989, Journal of Antibiotics). Biotakes, Vol. 29, pp. 1346-1348, 1976). ML-236B has the following chemical structure, and two types are known: lactone type and carboxylic acid type. Note that carboxylic acid type ML-236B may be used in the form of sodium salt, and therefore the present invention
ML-236B also includes lactone type, carboxylic acid type, and its sodium salt.

【formula】

[Formula] ML-236B Administration Study Subjects and Methods The subject patients were 16 hyperlipidemic patients (5 males, 11 females) attending the Department of Internal Medicine, Keio University Hospital.
As shown in Table 1, the average age of the target patients was 51 years old (male: 59 years old, female: 48 years old), and the average serum lipid peroxide level was
3.00n mol/ml (3.46n mol/ml for men, 2.79n for women)
mol/ml). The drug used was ML-236B white powder 1,
5, 10, and 20 mg were packed into white capsules and used. The administration method for ML-236B is 1 to 5 mg per day for mild cases, and 5 to 5 mg per day for moderate cases, depending on the severity of hyperlipidemia based on the serum lipid concentration before treatment, after a 2 to 4 week preparation period. In severe cases, administer as little as possible, starting with 10 to 20 mg per day, and after 6 to 8 weeks, increase the dose in small increments if necessary. Due to the dosage, if you are taking 1mg, 5mg, or 10mg a day, in principle, take 2mg or 10mg once a day after breakfast.
For those taking 20mg, 3mg twice a day, twice in the morning and evening, 15
For those taking mg, the dose was given 3 times after each meal. As a general rule, patients taking medication are interviewed about their symptoms and medication status every two weeks, and at the same time, their weight and blood pressure are measured, and a physical examination is performed.
Triglycerides, HDL-cholesterol, free fatty acids, lipid peroxides, serum lipids such as lipoprotein electrophoresis, and other tests included liver function, renal function, blood sugar, and uric acid. Serum lipid peroxides were measured using microfluorescence method [Biochem.Med.]
15, pp. 212-216, 1976]. The effect of ML-236B on serum lipid peroxide 6
Observations were made for ~22 weeks (average 12 weeks), and the average rate of decrease from the previous value was determined for each dose group. Then, for each case, the unit effective dose of ML-236B against serum lipid peroxide was determined using the integral method. As shown in the example in Figure 1, the unit effective dose is calculated by the integral method by using the serum lipid peroxide before treatment as the baseline, and dividing the area enclosed by the line graph drawn by serum lipid peroxide by extending that baseline and treatment. Calculated quadratically. The ML is calculated by dividing the area (n mol/ml x day) by the actual amount of medication taken (mg x day) confirmed by interview, that is, the prescribed dosage minus the remaining drug amount. - Reduction amount of serum lipid peroxide per unit amount of 236B, that is, unit effective amount (n
mol/ml/mg). Although it is not listed in Table 1, Figure 1 shows that ML-236B was administered once to a 58-year-old man.
This is an example when a daily dose of 20 mg is administered. S at the bottom right of the graph is the area surrounded by the baseline and the graph, and MLB is the amount the patient actually took of ML-236B (prescribed amount x number of days - remaining amount). However, D represents the unit effective amount determined by S÷MLB. Test results As shown in Table 1, the serum lipid peroxide concentration of 16 target patients before administration was 3.00±0.74nmol/
It was hot in ml. In Table 1, lipid peroxide indicates the serum lipid peroxide concentration before administration, and ΔLPO/MLB is the ML-236B for serum lipid peroxide determined by the integral method.
Indicates the unit decrease in . These cases were divided into 1 mg, 2 mg, 5 mg, and 10 mg administration groups according to the dose, and cases in which the dose was changed midway through the same case (changes in numerical values such as 1 → 2 in the dose column in Table 1) Table 2 shows the number of cases by dose group and the average value of lipid peroxide when counted in total. As is clear from Table 2, the reduction rate of serum lipid peroxide was 17.9 in the 1 mg to 10 mg dose groups, respectively.
%, 5.4%, 7.5%, and 17.0%, all of which showed the effectiveness of ML-236B. However, no correlation with dosage was observed. No abnormal values were observed in other tests related to peripheral blood, liver function, and kidney function, or in blood sugar, uric acid, etc. during the observation period of 6 to 22 weeks. The acute toxicity of ML-236B when administered intraperitoneally to mice is low with an LD ₅₀ of 400 mg/Kg or more.

【table】

[Table] As mentioned above, ML-236B has the effect of lowering lipid peroxide in the blood, so it can be used as a therapeutic agent for hyperlipidemia peroxidation. ML-236B can be administered orally or parenterally in the form of capsules, tablets, injections, and the like. The dosage varies depending on age, symptoms, body weight, etc., but the usual dosage for adults is approximately 0.1 to 100 mg per day.
~ Administered in 4 divided doses. However, ML-236B
When the dosage of ML-236B was set to 20mg/day, there were cases where serum lipid peroxide did not decrease but increased slightly, so it is preferable to keep the dosage of ML-236B below 20mg/day. Conceivable. ML-236B can be used in any dosage form, such as tablets, capsules, powders, granules, injections, suppositories, suspensions, etc., by known formulation methods. These various preparations can be formulated according to conventional methods using known adjuvants that can be commonly used in the field of pharmaceutical preparation, such as solid or liquid carriers, diluents, buffers, and excipients. Formulation Example 1 (Capsule) ML-236B 10.0mg Lactose 151.2 Corn starch 37.8 Magnesium stearate 1.0 200mg Mix the powder of the above formulation and pass through a 60 mesh sieve, then put 200mg of this powder into a No. 3 gelatin capsule and capsule. It was used as a drug. Formulation example 2 (tablet) ML-236B 5.0mg Lactose 77.4 Corn starch 13.0 Magnesium stearate 0.6 L-HPC (Shin-Etsu Chemical) 24.0 120mg One tablet of the above formulation was prepared using the normal formulation process.
It was made into a 120 mg tablet.

[Brief explanation of drawings]

Figure 1 shows the relationship between the period of ML-236B administration and serum lipid peroxide levels.

Claims (1)

[Claims] 1. A therapeutic agent for hyperlipidemia peroxidation containing ML-236B as an active ingredient.