JPH06263636A - Therapeutic agent for cerebral or higher nervous disease - Google Patents

Abstract

PURPOSE:To obtain a therapeutic agent for cerebral or higher nervous diseases containing dantrolene or its pharmacologically permissible salt as an active ingredient. CONSTITUTION:Dantrolene expressed by the formula or its pharmacologically permissible salt has excellent blocking effect on necrosis, disorder and elimination of brain ischemic neurocyte and is very useful to cerebral nerve diseases such as geriatric dementia, Parkinsonian disease and Huntington's chorea and has high safety. This compound can be prepared into various pharmaceutical preparations according to directions and is preferably administered by injection, dropping injection, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical preparation which is very effective as a therapeutic agent for brain or higher nerve diseases.

More specifically, a formula showing a good protective action against acute and delayed neuronal necrosis, damage and loss due to ischemia or hypoxia.

[0003]

[Chemical 2]

Acute or delayed neuronal necrosis, injury or loss due to ischemic state induction or hypoxic insult, which comprises dantrolene or a pharmacologically acceptable salt thereof represented by The present invention relates to a pharmaceutical preparation which is very useful as a therapeutic agent for brain or higher nerve diseases caused by.

Such acute and delayed neuronal necrosis,
As a brain or higher nerve disease caused by disability, dropout,
Examples thereof include neurological diseases such as senile dementia (including Alzheimer's disease), Parkinson's disease, Huntington's disease, neuropathy after cerebral infarction, neuropathy associated with head trauma, or hydrocephalus.

[0006]

2. Description of the Related Art When the cerebral circulation is impaired due to disorders such as cerebral thrombus or cerebral hemorrhage, or the oxygen partial pressure in the blood is lowered due to gas poisoning or drowning, the ischemic state or the partial pressure of blood oxygen is temporarily reduced Is caused, and the supply of oxygen to the brain is suddenly reduced or stopped, resulting in acute damage to nerve cells. In such a case, even if functional recovery is apparently observed in nerve cells due to the resumption of normal blood circulation thereafter, damage progresses again for some reason, and delayed neuronal necrosis or damage occurs. , Dropout develops [Brain Res. 23
9, pp. 57-69, 1982].

[0007] In recent years, with the aging of the population, the problem of medical care for the elderly has been highlighted and emphasized. Against this background, the incidence of senile neurological diseases such as dementia is increasing, which is a kind of social problem. Therefore, researches on therapeutic agents for senile neurological diseases are currently being actively conducted, and among them, various agents for protecting delayed neuronal necrosis caused by cerebral ischemia have also been investigated. However, the nerve cells are increased under the ischemic condition and after the ischemic condition, for example, the extracellular glutamate concentration increases, and N-methyl-D-aspartic acid (NMDA)
The various biochemical reactions mediated by the glutamate-type glutamate receptor or the non-NMDA-type receptor are in a state of being extremely activated, etc. (Neuropsychopharmacology, Vol. 15, No. 1, 45-51, 1993). It is known that the disease and pathophysiology are complicatedly changed. Therefore, the development of a drug that protects against delayed neuronal necrosis is extremely difficult and slow.

[0008] To date, as agents for protecting ischemic delayed neuron death, calcium antagonist, excitatory amino acid antagonist, radical scavenger, messenger regulation of serotonin, adenosine, second messenger regulation, etc. Have been found in [Cerebrovascular and Brain Metabolism Review (Cerebrovascular a
nd Brain Metabolism Rev. )
Volume 2, No. 1; 93, 1990]. However, even these drugs have not yet obtained satisfactory effects. For example, by using calcium antagonists, excitatory amino acid receptor antagonists and the like, various biochemical overreactions caused by high concentrations of intracellular calcium ions by blocking the influx of calcium ions from the outside of cells. The inhibition effect is partial unless the release of calcium ions from intracellular calcium stores can be suppressed even if it is attempted to inhibit. Therefore, there is a great demand for the appearance of a drug having a stronger protective action against delayed neuronal necrosis and a higher safety.

[0009]

DISCLOSURE OF THE INVENTION The object of the present invention is to induce neuronal necrosis, injury, or induction of ischemic state or hypoxic insult,
It is to provide a new type of drug with excellent protection against shedding.

[0010]

Means for Solving the Problems The present inventor has conducted diligent research to find out a compound having an excellent protective action against neuronal necrosis, injury and loss caused by cerebral ischemia, and as a result, a peripheral muscle relaxant was found. , Which is useful for spastic paralysis associated with sequelae of cerebrovascular accidents and malignant hyperthermia during anesthesia, the dantrolene represented by the above formula (I) releases calcium ion from ryanodine-sensitive intracellular calcium ion storage. It was confirmed that they have actions such as suppression, and obtained the surprising finding that they exert an excellent protective effect against cerebral ischemic neuronal necrosis, injury, and dropout, resulting in the present invention. .

The present inventor, in an in vivo experiment using gerbils loaded with transient forebrain ischemia, controls the brain temperature at about 37 ° C. for 1 hour before and after ischemia and restarts blood flow for 30 minutes. Then, a dantrolene solution was injected into both lateral ventricles, and after one week, hippocampal CA1 pyramidal cells were observed histologically. As a result, in most of the CA1 pyramidal cells in the ischemic control group, degenerative loss was observed. On the other hand, for example, in the ischemic group administered with dantrolene 1.6 mM (6 μl), it was confirmed that most of CA1 pyramidal cells, 70 to 90%, were alive. As can be seen from this experiment, dantrolene is a highly useful compound showing a strong neuroprotective effect.

As described above, the dantrolene represented by the above formula (I) has an excellent protective action against cerebral ischemic nerve cell necrosis, injury and loss, and the brain caused by these disorders or It is a compound showing a very useful pharmacological action as a therapeutic agent for higher nervous diseases.

Therefore, by using the dantrolene represented by the above formula (I) as an active ingredient, a pharmaceutical preparation useful as a therapeutic agent for the brain or higher nerve diseases caused by ischemic nerve cell necrosis, injury or loss. Can be manufactured.

The dantrolene represented by the above formula (I), which is the main component of the pharmaceutical composition of the present invention, is a drug which is already widely used clinically as a peripheral muscle relaxant, and particularly serious side effects. Etc. have not been reported, and it is a compound already recognized to be extremely useful as a drug in terms of safety.

As the dosage form of the pharmaceutical preparation of the present invention, various dosage forms generally used can be considered depending on the usage. Various administration methods are possible, but in actual therapy, the drug is usually administered by injection or infusion. An injection is preferable when administering to an urgent disease. In the case of administration by injection, a liquid preparation prepared in advance may be used, or a lyophilized product or a mixture with a suitable pharmaceutical additive may be dissolved in a suitable solvent before use. When the drug is administered by instillation or the like, a liquid form may be mixed with the infusion solution in the same manner, or a solid preparation such as a freeze-dried preparation may be dissolved in the infusion solution before use.

Such a preparation can be prepared by a usual pharmaceutical method. For example, an injection may be prepared by using dantrolene or a pharmacologically acceptable salt thereof in a suitable solvent, a solubilizing agent, an isotonicity agent, a buffering agent, a soothing agent, a thickening agent, etc. according to a method used in pharmacy. It can be produced by appropriately mixing the above-mentioned pharmaceutical additives, sterilizing, sterilizing, etc., and preparing according to a conventional method.

In the pharmaceutical additives used in the above injections, water for injection (distilled water, etc.), corn oil, sesame oil, olive oil, soybean oil, etc. can be mentioned as a solvent, and polyethylene glycol as a solubilizing agent,
Mention may be made of propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate or sodium citrate. Examples of the tonicity agent include D-mannitol, sodium chloride, glycerin and the like, and examples of the buffering agent include acetate salts such as aminoacetic acid, phosphate salts, carbonate salts, citrate salts and the like. it can. Further, soothing agents can include lidocaine hydrochloride, benzyl alcohol, procaine hydrochloride, meprilcaine hydrochloride and the like, and thickeners include egg yolk lecithin, gelatin, gum arabic, tragacanth, methylcellulose, carboxymethylcellulose sodium, chondroitin sulfate, alginic acid. Examples thereof include sodium and polyvinylpyrrolidone.

When the pharmaceutical preparation of the present invention is used for actual treatment, the dose of the active ingredient dantrolene or a pharmaceutically acceptable salt thereof is appropriately determined depending on the patient's age, sex, body weight, degree of disease and the like. Determined, but generally adult 1
It can be administered in the range of 0.001 mg / kg to 7 mg / kg per day. Further, it is effective to administer the drug locally as soon as possible after the ischemic state occurs, and the effect generally decreases if the timing of the drug administration is delayed.

[0019]

EXAMPLES The present invention will be described in more detail by way of test examples and examples.

Test Example Experiment for Confirming Protective Effect Against Delayed Neuronal Necrosis Dantrolene was dissolved in dimethylsulfoxide-phosphate buffer and 3 μl of the prepared dantrolene solution was injected into both lateral ventricles of gerbils. The infusion time was 5 minutes, and the infusion time was 30 minutes before ischemia or 30 minutes after ischemia. The bilateral common carotid arteries were ligated for 3 minutes to maintain the cerebral ischemic state while controlling the brain temperature at 37 ± 0.2 ° C., and then the blood flow was restarted. One week after the blood flow was restarted, a histochemical search of the cerebral hippocampus region was performed according to a conventional method.

As a result, in the control group administered with dimethylsulfoxide, about 90% of hippocampal CA1 pyramidal cells had degenerated dropout, and typical delayed necrosis was observed. In the post-ischemic administration group of dantrolene 1.6 mM, remarkable survival of about 70 to 90% of hippocampal CA1 pyramidal cells was confirmed. With dantrolene 0.4 mM, the degree of survival was slight, showing a dose-dependent neuroprotective effect. On the other hand, the neuronal cell protective effect was not clear in the dantrolene 1.6 mM pre-ischemic administration group.

[0022]

[Figure 1]

Examples Formulation Example 2 g of dantrolene sodium and D-mannitol 300
After dissolving g in distilled water for injection, dust removal and sterilization filtration were performed, and the filtered drug solution was washed, dried, and sterilized, and an appropriate amount was filled into the vial. After freeze-drying, 100 vials were manufactured by completely closing the rubber stopper and sealing with a cap.

The prescription used in the present invention is not limited to the above prescription.

[Brief description of drawings]

FIG. 1 is a graph showing the effect of intracerebroventricular administration of dantrolene on neuronal cell death in the hippocampus region of gerbils obtained by the pharmacological experiment of the test example, and the vertical axis represents 10
Represents the number of surviving CA1 neurons per 0 × 500 μm.

Claims (1)

[Claims] 1. The formula: A therapeutic agent for the brain or higher nerves, which comprises dantrolene represented by or a pharmacologically acceptable salt thereof as an active ingredient.