JPH027293B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic agent for physical dysfunction caused by brain disorders, which contains S-adenosyl-L-methionine as an active ingredient. An object of the present invention is to provide a therapeutic agent for physical dysfunction caused by brain disorders such as cerebrovascular disorders, brain contusions caused by head trauma, or various disorders in the cerebrovascular system. Brain disorders as used in the present invention refer to disorders in the brain caused by internal or external factors.In other words, disorders caused by internal factors include cerebral infarction, cerebral infarction,
It refers to so-called cerebrovascular disorders caused by pathological changes in cerebral blood vessels, such as intracranial hemorrhage, arteriosclerosis, and cerebral venous thrombosis.In terms of disorders caused by external factors, it refers to external forces such as cerebral contusions and intracranial hemorrhage. This refers to damage to the brain or cerebrovascular vessels that occurs during a so-called head injury. These brain disorders cause various physical dysfunctions in the human body, but most commonly, consciousness disorders often appear first, accompanied by impairments in limb movement perception, visual and hearing impairments, and speech and language impairments. Even after disorders appear and the disturbance of consciousness has improved to some extent, many of these disorders often remain as aftereffects. Until now, there have been few drugs suitable for these disorders.
The effects of those currently in use are extremely unsatisfactory. Conventionally, for disorders of consciousness during cerebrovascular disorders,
Drugs called agents for treating disorders of consciousness or metabolic activators such as cytochrome-C, γ-aminobutyric acid, meclofenoxate hydrochloride, cytidine diphosphorylcholine, and baby calf blood extract, and thrombolytic agents such as urokinase. drugs have been administered. However, these drugs have the disadvantage of being difficult to use due to their antigenic properties, such as cytochrome-C and calf blood extract, and they also have their own serious disadvantages as follows. None of these drugs could be administered from the early stages of brain damage except in extremely limited cases, and they were not commonly used. To explain this in more detail, brain cells in areas where blood flow is cut off due to such brain damage quickly die, and since dead brain cells do not recover, the various bodily functions that occur due to this In order to halt the decline in brain function and to recover by compensating for the deteriorated function with remaining brain cells, it is necessary to start treatment as soon as possible after the injury, but none of the medical treatments mentioned above For the following reasons, it has not been possible to administer it early except in extremely limited cases, and it has not been possible to meet the therapeutic needs described above. In other words, most of these drugs are known to have the effect of increasing cerebral blood flow, and for this reason, in the case of a hemorrhagic disorder, which is a typical type of cerebrovascular disorder, it is possible to If these drugs are administered while bleeding continues, it may accelerate the bleeding, so administration within 2 to 4 weeks after the attack, which is the acute stage, is contraindicated. Therefore, it is customary to administer the drug only after the bleeding has subsided and the symptoms are considered to have stabilized.
Naturally, during that time, brain cells were damaged, resulting in impaired consciousness as an aftereffect, and the desired results were not achieved. On the other hand, in the case of infarction, which is a typical type of cerebrovascular disorder, an increase in cerebral blood flow would be desirable, but it is generally not easy to distinguish between infarction and hemorrhage, so it may be a hemorrhagic disorder. It was treated in the same way as a bleeding disorder, taking into account the unknowns. When trying to use urokinase, a thrombolytic agent, for brain disorders such as those mentioned above, urokinase does not have the effect of increasing blood flow, but it dissolves blood clots,
Because it has the effect of increasing bleeding, it cannot be used for bleeding disorders, and it can only be used after a confirmed diagnosis of infarction disorder, so it is also used early after the disorder. The circumstances that make it difficult to use are the same as in the previous case. Furthermore, of course, none of the drugs can be used in patients with both hemorrhagic disorders and infarct disorders. In the treatment of consciousness disorders due to head trauma, exactly the same situation as in the case of hemorrhagic cerebrovascular disorders described above can be seen. On the other hand, cerebral contusion, which is a typical form of head trauma, involves damage to the brain parenchyma, and therefore often causes so-called withdrawal symptoms in which the functions controlled by the injured part are lost. Conventionally, there are almost no medicines that can restore such lost functions, and the previously mentioned cytochrome-C, meclofenoxate hydrochloride, cytidine diphosphorylcholine, etc. are used for after-effects such as headache and dizziness. Furthermore, although cytidine diphosphorylcholine has been used to treat hemiplegia due to stroke, which is one of the after-effects of cerebrovascular disorders, the effect was extremely insufficient. The present inventors have conducted various basic and clinical research in order to develop a therapeutic agent for physical dysfunction caused by brain damage, and as a result, we unexpectedly found that S-adenosyl-L-methionine was effective in recovering from functional impairment caused by brain damage. It has been found that it is highly effective and, surprisingly, can be administered immediately after the injury. The present invention has been made based on this knowledge. The present invention will be explained in detail below. S-adenosyl-L- which is the active ingredient of the present invention
Methionine (hereinafter abbreviated as SAM) is widely distributed in various tissues in the body, and in addition to acting as a methyl group donor in methylation reactions by various transmethylases in the body, it also acts as an aminopropyl group donor. It is a substance known as a physiologically active substance that plays a wide range of important roles, such as acting as a bioactive substance. Attempts to use SAM in medicine are
It has not been done for a long time because it is an unstable compound,
Although many attempts have been made since the establishment of a stable method for producing salt, it is currently only used as an antidepressant, anti-fatty liver agent, and analgesic and anti-inflammatory agent in some countries. However, no research has been published that suggests its application to brain disorders. To explain in more detail the effect of SAM on physical dysfunction caused by brain injury, as shown in Example 5 below, when SAM is administered to patients with impaired consciousness due to cerebrovascular disorder within a few days of the attack, in early cases A marked improvement in consciousness was observed on the 1st to 2nd day of administration, and even in late cases by the 1st week. Furthermore, as shown in Example 6, when SAM was administered to cynomolgus monkeys whose motor function was impaired due to experimental cerebral contusion, which was a surgical injury to the brain, from the second day after the injury, they began to move much more quickly than controls. It was found that the function was restored. SAM shows almost no effect on increasing blood flow or on the blood pseudosolid system, so it can be administered in the case of either infarction or hemorrhagic brain damage. It can be administered even in cases where it is difficult to distinguish between the two, and moreover, it can be administered immediately after the occurrence of a brain injury, so it has a far superior advantage over conventional drug therapy. In order to understand the mechanism of SAM's effect on physical dysfunction caused by brain damage, the present inventors conducted an experiment on the effect of promoting the production of high-energy phosphoric acid in the brain of mice as shown in Reference Example 1 below. We considered that the therapeutic effect on physical dysfunction is related to the effect of promoting high-energy phosphate production in the brain. However, such considerations are not directly related to the gist of the present invention. SAM, the active ingredient used in the present invention, is
Since sulfonium ions are originally present in its structure, it always exists in the form of a salt with an anion. Therefore, SAM as an active ingredient in the therapeutic agent for bodily dysfunction of the present invention is actually used in the form of the above-mentioned salt. Furthermore, since SAM has basic N atoms in its structure, including amino groups, various salts are formed at these parts. Therefore, in the present invention, these SAMs are used in the form of various salts or compositions for forming these salts. Stable salts or compositions of SAM that can be used in the present invention include, for example, salts with sulfuric acid, salts with paratoluenesulfonic acid, salts with sulfuric acid and paratoluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc. Complex salts of one or more organic sulfonic acids such as chondroitin sulfate, various salts such as those mentioned above, cytidine-5'-monosulfate, cytidine-3',5'-disulfate and uridine-
A composition comprising one or more mono- or disulfate esters of nucleosides such as 2'(3'),5'-disulfate, or various salts such as those mentioned above, and glucose sulfate or lactose sulfate. Examples include compositions comprising one or more types of sugar sulfate esters such as esters. In addition, in the usage mode of the SAM salt or composition of the present invention,
Depending on their purpose of action, the necessary inorganic salts, e.g.
It can be used by mixing magnesium sulfate, sodium sulfate, etc. The composition ratio of the components constituting the salt or composition is not specified. One preferred example of these salts or compositions is a complex salt of sulfuric acid and para-toluene sulfonic acid, particularly when the molar ratio of SAM, sulfuric acid and para-toluene sulfonic acid is 1:2. :1. Since SAM is a biological component, its toxicity is low, and in acute toxicity tests using rats, the LD ₅₀ for intraperitoneal administration was 2000 to 2500 mg/Kg {VM
Andreoli et al., Transmethylation and Central Nervous Systems, p. 144 (Springer-Verlag, Berlin, 1978). Also,
As shown in Reference Example 2, when 100 to 900 mg of SAM per day is administered by intravenous drip in 1 to 3 doses to 6 healthy men, no harmful effects are shown. The clinical dosage is usually in the range of 100 to 1500 mg of SAM per day, although it depends on the administration method. Administration methods include intravenous, intramuscular, oral, and intrarectal administration, and in the case of intravenous administration, normal intravenous injection and intravenous drip infusion are possible. Since the patient to whom the therapeutic agent for physical dysfunction due to brain disorder according to the present invention is applied is unconscious, intravenous drip infusion is one of the suitable administration methods. Stable salts or compositions of SAM often exhibit a fairly low pH, so in such cases, the pH should be raised with a physiologically harmless alkali, such as sodium phosphate, and then dissolved in glucose solution, Ringer's solution, etc. It is also possible to dissolve the drug in physiological saline or the like and inject it intravenously. SAM-containing preparations are manufactured by conventional methods using conventional excipients and additives. The injectable preparation may be, for example, an injectable powder preparation. In that case, add one or more suitable water-soluble excipients such as mannitol, sucrose, lactose, maltose, glucose, fructose, etc., dissolve in water, dispense into vials or ampoules, freeze-dry and seal. It can be made into a formulation. Oral preparations include ordinary tablets, capsules, granules, fine granules, and powders, as well as enteric-coated preparations. In the case of enteric-coated preparations, excipients such as mannitol, sucrose, lactose, maltose, starch, and calcium phosphate, lubricants such as magnesium stearate, binders such as carboxymethylcellulose, methylcellulose, gelatin, and gum arabic,
After adding additives such as disintegrants such as carboxymethyl cellulose calcium as necessary to make tablets, granules, fine granules, etc., cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol phthalate, styrene/maleic anhydride are prepared. Coating with one or more enteric bases such as acid copolymer, styrene/maleic acid copolymer, methyl methacrylate/methacrylic acid copolymer, methyl acrylate/methacrylic acid copolymer, etc. Besides, the enteric-coated granules or fine granules prepared here can be filled into capsules to make capsules. In addition, capsules prepared in a conventional manner may be coated with the enteric base to make them enteric-coated, or capsules may be prepared using the enteric base alone or by mixing gelatin with the enteric base. It is also possible to formulate enteric-coated capsules. For suppositories, cacao butter, lipophilic bases such as semi-synthetic bases made by mixing fatty acid triglyceride, fatty acid monoglyceride, and fatty acid diglyceride in various proportions, and hydrophilic bases such as polyethylene glycol and glycerogelatin can be heated. Suppositories can be made by adding the molten product, mixing it uniformly, and molding it into a mold. Pharmaceuticals containing the thus obtained SAM as an active ingredient can be used to treat various brain disorders, including cerebral infarction in which blood vessels are occluded due to various causes, intracranial hemorrhage in which blood vessels rupture due to internal or external factors, and In the event of a brain contusion, etc. in which the brain parenchyma is damaged due to external factors,
By using them immediately after their occurrence, they exhibit superior effects in treating various physical dysfunctions that occur as a result of these brain disorders. The medicine according to the present invention is of course effective not only when the external cause is an accidental trauma but also when the external cause is an artificial cause such as brain surgery. Examples of the present invention are shown below together with reference examples. Example 1 Distilled water for injection was added to 192 g of a complex salt of SAM in which the molar ratio of SAM, sulfuric acid, and para-toluenesulfonic acid was 1:2:1 and 120 g of mannitrate.
The volume should be 1500ml. This was sterile filtered using a 0.22 micron Millipore filter, dispensed into 5 ml vials in 1.5 ml portions, freeze-dried, and immediately sealed to obtain a powder preparation for injection. Example 2 Distilled water for injection was added to 936 g of powder containing 576 g of the same SAM complex salt as in Example 1 and 360 g of mannitrate to make a total volume of 4500 ml. This was sterile filtered using a 0.22 micron Millipore filter, with a volume of 15
The mixture was dispensed into 4.5 ml vials, freeze-dried, and immediately sealed to obtain a powder preparation for injection. Example 3 114 g of mannitrate, 150 g of corn starch, and 10 g of magnesium stearate were added to 576 g of the same SAM complex salt as in Example 1 and mixed uniformly.
Make granules using a conventional method. Separately 108g of hydroxypropyl methylcellulose phthalate, 28g of Cerac
g, 14 g of glycerin fatty acid ester, 462 g of methylene chloride, 922 g of isopropyl alcohol, 462 g of water
After coating the previously obtained granules with this liquid, 500 mg each was filled into capsules to obtain capsules. Example 4 576 g of the same complex salt of SAM as in Example 1 was prepared into a suppository base containing fatty acid triglyceride as the main component.
After adding 1424g and heating it to disperse it evenly, one
2.0 g of suppositories were obtained. Example 5 For stroke patients with impaired consciousness,
From day 2, 600 to 900 mg of a complex salt of SAM in which the molar ratio of SAM, sulfuric acid, and para-toluenesulfonic acid was 1:2:1 was dissolved in a dibasic sodium phosphate solution, and It was diluted with Ringer's solution or glucose solution and administered intravenously. The degree of consciousness disturbance was determined according to the following classification (3-3-9 degree system). ◎Clear consciousness 0 points ◎A state of being awake even without stimulation ●Almost clear consciousness, but not very clear
1 point ●Has orientation 2 points ●Cannot say own name or date of birth 3 points ◎ State of being awake when stimulated - falls asleep when stimulation is stopped - ● Easily opens eyes with normal calls 10 points ● Loud voice or Open the eyes by shaking the body 20 points ●If you repeat the call while applying painful stimulation, the eyes will barely open 30 points ◎A state in which the patient does not wake up even if stimulation is applied ●Makes movements to push away the painful stimulation 100 points ● 200 points if the patient moves his/her limbs slightly or grimaces due to the painful stimulus ●300 points if the patient does not respond to the painful stimulus The results are shown in the table below.

[Table] Example 6 Motor function recovery test for brain-injured monkeys Two male cynomolgus monkeys were made to learn the following four items on their right hand in advance. d is the maximum load weight that the monkey was able to pull.
Each was measured over 5 days before the experiment and the average value was taken. a. Take the bait from the bottom of a box that is 5cm long and 5cm wide and 9cm deep. b Go through a tunnel that is 5 cm in length and width and 10 cm in depth to catch the bait on the other side. c. Take the bait from the bottom of a box measuring 2 cm in length and width and 3 cm in depth. d Pull the loaded board towards you and pick up the bait placed on the board. Next, a hole was made in a part of the monkey's skull, and the part of the cerebral cortex that controls right hand movement was removed by suction.
For monkey No. 2, from the 2nd day after surgery to the 21st day,
A complex salt of SAM with a molar ratio of SAM, sulfuric acid, and paratoluenesulfonic acid of 1:2:1 was intramuscularly administered at 20 mg/Kg as SAM, and the above a, b, c,
Tests were conducted on four items of d. In addition, monkey No. 1 was subjected to a similar test without being administered anything as a control. Three months later, the left hand was taught in the same way as the previous time, and the part that controls left hand movement was removed by suction in the same way. No. 1 was given the drug, and No. 2 was used as a control. The same test was conducted. The results are shown in FIGS. 1 to 4 as changes corresponding to the average value before surgery as 0. The SAM-treated group showed clearly faster recovery of motor function than the control group. Reference example 1 Promoting high-energy phosphate production in mouse brain In male DD mice weighing 25-28g (6 mice per group),
A complex salt of SAM in which the molar ratio of SAM, sulfuric acid, and para-toluene sulfonic acid was 1:2:1 was intravenously administered at a concentration of 100 mg/Kg as SAM, and 30 minutes later, it was subjected to an experiment. Mice were decapitated and frozen in liquid nitrogen 10 or 30 seconds after decapitation, and for the zero-second decapitation group, the whole body was similarly frozen without decapitation.
The brain tissue was extracted and powdered in a frozen state, and the concentrations of creatine phosphate, adenosine triphosphate, glucose, lactic acid, and glycogen in this sample were measured and converted into μmol per gram of brain. In addition, a group treated and measured in the same manner without administering SAM salt was used as a control group. Furthermore, according to the following formula,
The metabolic rate was calculated. metabolic rate (μmol/g/min) =△PhosPhocreation+2△ATP+2△glucose+2.9
Gycogen results are shown in the following table as a ratio to the control group.

[Table] Yes.
Reference Example 2 Administration experiment on healthy people After dissolving the injectable powder preparation containing SAM obtained in Example 1 in a sodium phosphate solution for injection and further mixing it with Ringer's solution, it was administered to healthy men aged 38 to 66 6
It was given as an intravenous drip to people. Examples of administration include one dose of 100mg as SAM,
One patient each received 100 mg twice a day, one patient received 200 mg twice a day, and one patient received 200 mg twice a day on the first day.
Two cases were given 300mg twice a day on the second day, and 200mg three times a day on the first day and 300mg on the second day.
One case was administered 3 mg each day. Physiological tests, subjective symptoms, blood tests, serum biochemical tests, blood gas analysis, and urine tests were conducted before, during, and after administration, but no effects that could be attributed to SAM administration were observed in any of the cases. .

[Brief explanation of drawings]

1 to 4 are for explaining the test results of Example 6 of the present invention. Figure 1 shows the results of the test in section a described in Examples, and Figure 2
also shows the results of section b, FIG. 3 shows the results of section c, and FIG. 4 shows the results of section d. In each of the above figures, the horizontal axis represents the number of days after surgery, and -● − is −Γ− when administered with SAM salt
indicates the case of control, and * indicates that the action was impossible.

Claims (1)

[Claims] 1. A therapeutic agent for physical dysfunction caused by brain disorders, containing S-adenosyl-L-methionine as an active ingredient.