JPWO2005072721A1 - Pharmaceutical composition for prevention or treatment of nervous system disorders associated with decreased local cerebral blood flow - Google Patents

Abstract

The present invention comprises isoleucine, leucine and valine as active ingredients to prevent or treat neurological disorders associated with decreased local cerebral blood flow by increasing local cerebral blood flow, particularly from latent hepatic encephalopathy to overt encephalopathy. It is a pharmaceutical composition effective in preventing the transition of

Description

  The present invention relates to a pharmaceutical composition for preventing or treating a nervous system disorder associated with a decrease in local cerebral blood flow.

  In recent years, with the progress of an aging society, various cerebrovascular diseases are increasing. In addition, nervous system disorders such as consciousness disorder caused by severe liver diseases such as fulminant hepatitis and cirrhosis are increasing.

  In general, the causative diseases vary, but local cerebral blood flow reduction is classified into thrombotic, embolic, and hemodynamic, and is a pathological condition in which oxygen deficiency, decreased substrate supply, and accumulation of metabolites proceed simultaneously. it is conceivable that. The type and degree of nervous system disorders vary depending on the cause of the disease and the degree of blood flow reduction, but it is important to prevent and treat seriously impaired or relatively mild cases, as it impairs the patient's QOL. It becomes. Furthermore, it is important to prevent the occurrence of a nervous system disorder in advance, and it is also characterized as a disorder that requires immediate effect on the therapeutic effect.

  Relatively mild nervous system disorders include, for example, age-related cognitive or memory decline, cognitive ability and concentration, lack mental clarity and clarity, mental vitality, short-term memory, and learning Patients with problems are also important for treatment.

  One example of a nervous system disorder is hepatic encephalopathy. Hepatic encephalopathy is a neuropsychiatric symptom centered on consciousness disorder caused by severe liver disorders such as fulminant hepatitis and cirrhosis. It has been considered that neuropsychiatric symptoms in hepatic encephalopathy are scarce or not seen at all before the onset of hepatic encephalopathy or the onset of overt encephalopathy. However, in recent years, when neuropsychiatric symptoms are not obvious, such as overt hepatic encephalopathy, and when a sensitive and quantitative neuropsychiatric function test is performed in cirrhosis that is not clinically recognized as hepatic encephalopathy, abnormal neuropsychiatric function The existence of a pathological condition is pointed out, and this is called latent hepatic encephalopathy. There are no standard diagnostic criteria or neuropsychiatric testing methods for diagnosing subclinical hepatic encephalopathy, but comprehensive examination of abnormalities is performed by performing neuropsychiatric function tests (symbol follow-up tests, etc.) and neurological tests (electroencephalograms, etc.) An attempt has been made to make a diagnosis (see Non-Patent Document 1). Although the rate of transition from occult hepatic encephalopathy to overt encephalopathy has not yet been clarified, it has been reported to be about 40% and is expected to be a very high rate of transition. Therefore, it is considered that the usefulness of a medicine having an effect of reducing the transition rate of latent hepatic encephalopathy to overt encephalopathy is high.

  Vasodilators and the like have a certain effect as therapeutic agents for nervous system disorders, but are carefully administered to the aforementioned patients in consideration of side effects. In that case, considerable care is required in selecting the drug corresponding to the patient's underlying disease and determining the dosage and administration period. In addition, the drug may be administered prophylactically, but there are many cases where the administration is interrupted due to the occurrence of side effects.

  A small molecule that prevents neuronal cell death, such as neuroprotective drugs, while reducing local cerebral blood flow, has fewer side effects, and is expected to provide drugs that can be expected to produce rapid therapeutic effects or preventive effects. Treatment methods using many drugs, such as compounds and brain cell metabolism improving agents, have been proposed, but there are no side effects and rapid clinical effects on neurological disorders that occur due to local blood flow reduction in the brain. It has not yet been found.

  As a branched-chain amino acid (BCAA) formulation containing isoleucine, leucine and valine as active ingredients for the purpose of improving hypoalbuminemia in patients with cirrhosis, Ajinomoto Co., Inc.'s Rebact (registered trademark) is used. Yes. Regarding the usefulness of this branched-chain amino acid preparation for cirrhosis, nutritional effects such as improvement of nitrogen balance and hypoalbuminemia and increase in muscle protein have been studied and reported. Regarding effects other than effects, there are the following reports.

  In Patent Document 1, as the life expectancy increases, cerebral damage caused by ischemia or oxygen deprivation increases as a typical example, and cerebral ischemic stroke and senile dementia are typical examples. L-isoleucine has been described as a drug for treating this.

  In Patent Document 1, the time until the respiratory arrest of the mouse ligated with the artery after the intraperitoneal administration of L-leucine is measured, and the time until the respiratory arrest of the mouse is prolonged by the administration of L-leucine. Experimental results are shown. From this result, it is assumed that intraperitoneal administration of L-leucine is effective in prolonging survival time under cerebral ischemia or oxygen deprivation. However, Patent Document 1 does not describe any effect of L-leucine administration on a nervous system disorder associated with a decrease in local cerebral blood flow.

  In Patent Document 2, intellectual function recovery is observed by ingesting branched chain amino acids to senile dementia patients for 3 months, conducting a simple intellectual function test, and continuing to take branched chain amino acids. There is a description that it was considered that there was an effect of improving cell metabolism. However, although it was described that there was an effect in the intellectual function test when the branched-chain amino acid was simply administered, suggesting the usefulness when the dementia of the test patient is due to abnormal brain cell metabolism, It is useful for patients with neurological disorders associated with decline, and is useful for neurological disorders associated with decreased local cerebral blood flow that is based on hepatic encephalopathy due to liver disease other than demented patients, for example Absent.

  Patent Document 3 proposes a therapeutic agent for ischemic encephalopathy using an amino acid selected from isoleucine, leucine, and arginine in combination with glucose. Oral administration of arginine and glucose in combination with mice and arch Experimental data has been described in which nuclei damage is reduced. From this result, typical nutrients such as arginine and glucose can suppress or reduce abnormal increase of glutamic acid in the brain due to cerebral ischemia, and can prevent and treat brain disorders represented by arcuate nucleus disorder. It is described. However, in Patent Document 3, no experiment has been conducted as to whether isoleucine and leucine have the same effect as arginine, and it is effective in improving neurological symptoms by improving, for example, arcuate nucleus disorder in the brain. There is no description, nor is there any experimental data or explanation that suggests improving cerebral ischemia itself, that is, improving the nervous system disorder associated with a decrease in local cerebral blood flow.

  Non-Patent Document 1 describes that there is a symptom diagnosed as latent hepatic encephalopathy as a pre-stage of hepatic overt encephalopathy.

  Furthermore, the present inventors intravenously administer a transfusion agent for treating hepatic encephalopathy (trade name: Morihepamine (registered trademark), manufactured by Ajinomoto Co., Inc.) containing a plurality of amino acids such as branched chain amino acid (BCAA) and arginine to cirrhosis patients. Cerebral blood flow SPECT (single photon emission computed tomography) images are analyzed before and after administration, and it has already been reported that cerebral blood flow increases and local cerebral blood flow disorder improves (non-patent literature) 2).

However, since the cerebral blood flow improvement effect by the infusion solution cannot be denied that it may be affected by changes in the circulatory dynamics associated with the administration of the infusion solution, vasodilation by arginine contained in the infusion solution, etc. It has not been clarified at all whether or not there is an effect of improving local cerebral blood flow disorder and whether or not it is effective in a short time by oral administration.
JP-A-1-180823 (8-3 lines from the lower right column on page 148, 2 lines on the lower right column on page 151) JP-A-2-172915 (page 96, lower left column, lines 7 to 6 from the bottom) Patent Registration No. 2814529 (9th to 4th lines from the bottom of column 6 of page (3)) Kato, Akinori, “Hepatobiliary pancreas”, 47, 1 issue, July 2003, 63-73, July 28, 2003 (Introduction to page 63 1, page 67-71 3 Concept of latent hepatic encephalopathy) Motoo Iwasa, “Liver” Vol. 43 Suppl. (3), November 5, 2002, published by the Japanese Society of Hepatology, Abstracts of the 34th Annual Meeting of the Japanese Society of Hepatology, A271, Liver S6-4

  An object of the present invention is to provide a novel pharmaceutical composition comprising a branched chain amino acid for improving a decrease in local cerebral blood flow and treating or preventing a nervous system disorder.

  The present invention is characterized in that isoleucine, leucine and valine are active ingredients and the mass ratio thereof is from 1: 1.9 to 2.2: 1.1 to 1.3, which is administered orally and enterally. The present invention relates to a pharmaceutical composition for use in the prevention or treatment of neurological disorders associated with decreased local cerebral blood flow.

The dose of the active ingredient in the pharmaceutical composition of the present invention is preferably 1.0 to 50 g. The pharmaceutical composition of the present invention is effective for the prevention and treatment of nervous system disorders of the central nervous system. The pharmaceutical composition of the present invention improves the decrease in cerebral blood flow at one or more of the thalamus, zonal gyrus, and parietal region. The pharmaceutical composition of the present invention is effective for the prevention and treatment of nervous system disorders caused by latent hepatic encephalopathy. A particularly useful use in the pharmaceutical composition of the present invention is prevention of transition from latent hepatic encephalopathy to overt encephalopathy.

  According to the pharmaceutical composition of the present invention, a decrease in local cerebral blood flow can be improved by simple administration such as oral or enteral administration, and the prevention or treatment of a nervous system disorder associated with the decrease in local cerebral blood flow is possible. Become. In particular, it is useful for preventing the transition from latent hepatic encephalopathy to overt encephalopathy.

FIG. 1 is a diagram showing the results of examining changes in cerebral blood flow before and after BCAA granule administration using SPM analysis of SPECT images. FIG. 2 is a diagram showing the results of examining changes in cerebral blood flow before and after administration of corn starch granules using SPM analysis of SPECT images.

The present invention will be specifically described below.
The present inventors examined the influence on local cerebral blood flow by analysis of cerebral blood flow SPECT images when a composition containing a branched chain amino acid as an active ingredient was orally administered. As a result, it has been found that the composition has an effect of improving a local cerebral blood flow disorder observed by analysis of a cerebral blood flow SPECT image, specifically, an effect of increasing cerebral blood flow in the thalamus, zonal gyrus, and parietal region. Thus, it has been found that it is possible to prevent or treat a nervous system disorder associated with a decrease in local cerebral blood flow.

  The present inventors have also found that the pharmaceutical composition of the present invention reduces the rate of transition from latent hepatic encephalopathy to overt hepatic encephalopathy.

Here, the structure of the brain will be described.
The diencephalon can be divided into layers of the upper thalamus, the thalamus, and the hypothalamus that are stacked on top of each other. The thalamus can be further distinguished into a dorsal thalamus and a ventral thalamus.

  The dorsal thalamus is where the sensory and sensory tracts (skin perception, taste, vision, hearing, and vestibular tract) end and communicates with the cerebral cortex. The ventral thalamus is a continuation of the midbrain tegment, and this region is considered the motor region of the diencephalon. Movement disorders and painful seizures are treated by stereotaxic surgery of the thalamus. In addition, by cutting the thalamic cortical tract, which is a specific part of the thalamus, the state of excitement becomes calm, and at the same time, overall indifference and personality flattening are observed. In addition, language problems occur due to thalamic pillow problems. Thus, thalamic disorders affect sensory organs such as movement and vision.

  The zonal gyrus (marginal gyrus) surrounds the corpus callosum, is located at the margin of the corpus callosum, separated from the dentate gyrus by the hippocampal groove on the caudal side, and ends on the endplate paracirculatory and lower beam area on the rostral side Yes. The cingulate cortex affects the hypothalamus and plant nervous system. The limbic system, such as the zonal gyrus, plays an important role in the regulation of basic life processes such as food intake, digestion and reproduction.

  The perceptual path has ended in the parietal (parietal lobe), which is called the somatosensory cortex, and consists of the first, second and third fields. In the second field, the position and movement of the limbs are recorded. When the head is upset, obstacles to symbolic thinking occur. In other words, since the ability to understand letters and numbers is lost, it becomes impossible to read, write, and count, and a three-dimensional spatial concept is changed.

  Therefore, the present invention can prevent and treat various nervous system disorders by improving local cerebral blood flow reduction in the thalamus, zonal gyrus, and parietal region.

  In addition, the preventive or therapeutic agent of the present invention can be preferably used in patients whose nervous system disorder is latent hepatic encephalopathy.

  The pharmaceutical composition for prevention or treatment of the present invention preferably contains isoleucine, leucine and valine as active ingredients and contains a pharmaceutically acceptable pharmaceutical substance.

  Regarding the isomers of leucine, isoleucine and valine used as active ingredients in the present invention, any of L-form, D-form, and DL-form can be used. preferable.

  More preferably, isoleucine / leucine / valine is used in a composition range such that isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1 to 1.3 in the blending ratio (weight ratio) of isoleucine, leucine and valine. .

  When calculating the dose (intake amount) of the active ingredient used in the present invention, as the active ingredient of the drug of the present invention (drug used for the purpose of treatment or prevention of disease abnormality targeted by the present invention) Since the above calculation range is determined, for branched-chain amino acids that are ingested or administered for other purposes, for example, due to the need for normal eating habits, or for the treatment of other diseases, this is calculated as described above. Need not be included.

  For example, it is not necessary to calculate by deducting the amount of isoleucine, leucine and valine per day taken from the normal diet from the daily dose of the active ingredient in the present invention.

  The pharmaceutical composition of the present invention is administered orally. In this case, the dose varies depending on the symptom, age, and administration method of the patient to be administered, but is usually 0.1 to 30.0 g of isoleucine, 0.1 to 30.0 g of leucine, and 0.1 to valine. It is about 30.0 g. In general adults, preferably 0.5 to 10.0 g of isoleucine, 0.5 to 10.0 g of leucine, and 0.5 to 10.0 g of valine, more preferably 1.0 to 5. 0 g, leucine 2.0-8.0 g, and valine 1.0-5.0 g. The dose per administration may be the above-mentioned daily dose, or may be divided into several doses. In the case of oral administration, the dose should be 20 g or less per dose. Is more preferable, and 10 g or less is more preferable.

  The pharmaceutical composition of the present invention can be prepared by a conventional method. Various pharmacologically acceptable substances for preparation (as adjuvants etc.) can also be included. The substance for the preparation can be appropriately selected depending on the dosage form of the preparation. For example, the excipient, the diluent, the additive, the disintegrant, the binder, the coating agent, the lubricant, the lubricant, the lubricant, and the flavoring agent. , Sweeteners, solubilizers and the like. Furthermore, specific examples of the pharmaceutical substance include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, Mention may be made, for example, of sterile water and mono- or polyhydric alcohols such as glycerol.

  As a pharmaceutical substance, it is preferable to contain at least one selected from a flavoring agent, a flavoring agent, an excipient, or a coating agent that does not impair the absorption of the active ingredient in the digestive tract.

  Further, a preparation for preparing an easily absorbable preparation so that an effective amount of an active ingredient for improving a decrease in local cerebral blood flow can be absorbed within 1 hour by the preventive or therapeutic agent of the present invention. Materials for use can be suitably selected.

  In the present invention, it can be used together with other pharmacological components (pharmaceutical active substances), for example, in combination or in combination. In such a case, the active ingredients intended in the present invention, preferably L-isoleucine, L-leucine and Any pharmaceutical composition of the present invention may be used as long as it contains a mixture of L-valine in the aforementioned preferred ratio and exhibits the desired pharmacological activity. In addition, each amino acid used for the active ingredient in this invention can also be used with the form of a salt, respectively about one part or all part.

  The pharmaceutical composition of the present invention is in the form of various pharmaceutical preparations known or developed in the future as described above. As described above, for example, oral administration, intraperitoneal administration, transdermal administration, intravenous administration, inhalation administration, etc. The dosage form can be prepared. In order to prepare the drug of the present invention in the form of these various pharmaceutical preparations, known or future developed methods can be appropriately employed.

  Examples of these various pharmaceutical preparation forms include, for example, suitable solid or liquid preparation forms such as granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops. Agents, injectable solutions, formulations that prolong the release of the active substance, and the like.

  It goes without saying that the drug of the present invention in the preparation form exemplified above should contain an effective amount of the above-mentioned components to exert a medicinal effect.

Although "Ribakuto ^(R) granules" are commercially available as branched chain amino acid formula, the formulation L
-Since it is an orally administrable granule containing isoleucine (952 mg), L-leucine (1904 mg) and L-valine (1144 mg), it is a formulation useful as one form of the pharmaceutical composition of the present invention. is there.

  EXAMPLES The present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples.

Clinical Test Example 1 (Local cerebral blood flow improvement effect)
The effect of the branched chain amino acid preparation of the present invention on local cerebral blood flow was tested.
(Subject and administration)
Against 35 people out of 10 patients diagnosed with cirrhosis, branched chain amino acid preparation containing the active ingredients shown in Table 1 (trade name: Ribakuto ^(R) granules, Ajinomoto Co.) 2 follicles (9.48 g) Was administered orally (BCAA granule administration group), and cerebral blood flow SPECT images before and after administration were analyzed.
BCAA granule administration group: 10 cases (6 males, 4 females, 8 had no history of overt hepatic encephalopathy, 2 had repeated encephalopathy, but had overt encephalopathy at the time of examination There was no.
As a control, corn starch was orally administered in the same amount as the branched chain amino acid preparation (corn starch group), and the same analysis as in the BCAA granule administration group was performed. )
Cornstarch group: 9 (6 males, 3 females, 8 had no history of overt hepatic encephalopathy, 1 had repeated encephalopathy, but no cases with overt encephalopathy at the time of examination )

(Analysis of cerebral blood flow SPECT image)
In each group, patients were rested and supine 26 minutes before taking 1.5 ml of 99mTc-ethyl.
A cysteinate dimer (ECD) was injected, and a baseline SPECT before administration of both agents was photographed using a SPECT apparatus GCA-9300A / DI manufactured by Toshiba. Subsequently, 1.5 minutes of ECD was administered again 60 minutes after administration of both agents, and SPECT was performed.
Statistical analysis of SPECT images was performed using Statistical Parametric Mapping (SPM) software (SPM97). Furthermore, regions of interest were set in the frontal lobe, parietal lobe, temporal lobe, occipital lobe, and cerebellum, and changes in cerebral blood flow before and after administration of both agents were investigated. The results are shown in FIG. 1 and FIG.

As a result of the test, the cerebral blood flow did not change before and after administration in the corn starch group (FIG. 2), but in the BCAA administration group, cerebral blood flow was observed at 3 sites of the zonal gyrus, parietal region, and thalamus in 1 hour after administration. An increase was observed (FIG. 1).
Administration of branched-chain amino acids increased cerebral blood flow in the gyrus, parietal, and thalamus, and local blood flow disturbances were relieved, so branched-chain amino acids directly acted on the central nervous system, causing patients with latent hepatic encephalopathy It proved useful.

Clinical trial example 2 (prophylactic effect of overt encephalopathy in patients with latent hepatic encephalopathy)
The effect of the branched-chain amino acid preparation of the present invention on the rate of transition to occult encephalopathy was investigated.
Of the 35 patients diagnosed with cirrhosis, 10 branched-chain amino acid preparations (trade name: LIVACT® granules ⁾ used in Example 1 for 10 patients who were determined to have latent encephalopathy from neurological function tests 9.48 g (manufactured by Ajinomoto Co., Inc.) was orally administered for 2 to 42 months.
2 out of 10 patients showed a manifestation of hepatic encephalopathy (transition rate 20%).

  There are the following reports on the transition of patients with latent hepatic encephalopathy to overt encephalopathy. Manuel Romero-Gomez, M.M. D. According to et al., Subclinical Hepatic Encephalopathy Predicts the Development of Overt Hepatic Encephalopathy, THE AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol. 96, No. 9, 2001, pp. 2718-2723, out of 34 patients with latent encephalopathy , 16 (47%) are said to have transitioned to overt encephalopathy. Also, Ieneke J. C. Hartmann, M.M. D. et al., The Prognostic Significance of Subclinical Hepatic Encephalopathy, THE AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol.95, No.8, 2000, pp.2029-2034), 10 out of 25 patients with latent encephalopathy (40%) are said to have shifted to overt encephalopathy.

Therefore, when the transition rate in the case of no treatment was set to 40% and the result of this example was compared with 20%, it is considered that the incidence of overt encephalopathy was reduced by administration of the branched chain amino acid granules.
It can be evaluated that the increase in local cerebral blood flow by administration of the branched chain amino acid shown in Example 1 is one improvement factor and prevents the onset of overt encephalopathy.

  According to the pharmaceutical composition of the present invention, a decrease in local cerebral blood flow can be improved by simple administration such as oral or enteral administration, and the prevention or treatment of a nervous system disorder associated with the decrease in local cerebral blood flow is possible. Become. In particular, it is useful for preventing the transition from latent hepatic encephalopathy to overt encephalopathy.

Claims (5)

A local brain comprising isoleucine, leucine and valine as active ingredients and having a mass ratio of 1: 1.9 to 2.2: 1.1 to 1.3 and administered orally or enterally A pharmaceutical composition for use in the prevention or treatment of nervous system disorders associated with decreased blood flow. The pharmaceutical composition according to claim 1, wherein the nervous system disorder associated with a decrease in local cerebral blood flow is a central nervous system disorder. The pharmaceutical composition according to claim 1 or 2, for improving a decrease in cerebral blood flow at one or more of the thalamus, zonal gyrus, and parietal region. The pharmaceutical composition according to any one of claims 1 to 3, wherein the nervous system disorder associated with the decrease in local cerebral blood flow results from latent hepatic encephalopathy. The pharmaceutical composition according to any one of claims 1 to 4, wherein the prevention of a nervous system disorder associated with a decrease in local cerebral blood flow is prevention of transition from latent hepatic encephalopathy to overt encephalopathy. .

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