JP2588191B2 - Therapeutic agent for improving neurological symptoms associated with malignant tumors and severe viral infections - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a therapeutic agent for malignant tumors containing tetrahydrobiopterin and its derivatives as an active ingredient and for abnormal amino acid metabolism associated with severe viral infections.

(Prior art) Among malignant tumors, various neurological symptoms appear with the progression of the tumors, which may hinder the treatment thereof. For example, malignant reticulopathy (malignant his tiocytosis) is a malignant tumor of macrophages, wherein the macrophages are bone marrow, liver, spleen,
Abnormal proliferation in tissues such as the central nervous system causes multiple organ failure, and nervous symptoms such as convulsions and impaired consciousness occur, and the prognosis is poor.

Similar neurological symptoms also appear in severe viral infections. That is, among the viral infections, VAHS (blood-phagocytic syndrome secondary to virus infection: virus-associa
There is an extremely severe form called ted hemophagocytic syndrome, which has neurological symptoms that closely resemble malignant reticulopathy. However, the cause of the onset of neurological symptoms in such cases has not been known at all.

Therefore, there is no fundamental treatment method, and only symptomatic treatments such as exchange transfusion and administration of anticonvulsants have been attempted.

On the other hand, the active ingredient of the therapeutic agent of the present invention, tetrahydrobiopterin and its derivatives are known compounds,
It has been known to be used as a therapeutic agent for malignant hyperphenylalaninemia, depression, and Parkinson's disease. For example, JP-A-59
-25323 and 59-76086.

(Problems to be Solved by the Invention) As described above, a causal therapeutic agent for treating a neurological symptom associated with a malignant tumor or a severe viral infection has not been found hitherto. It is an object of the present invention to elucidate the causes of these neurological symptoms and to provide an agent for removing the causes from the patient. Such drugs reduce neurological symptoms in malignant tumors and severe viral infections, help patients recover from physical exhaustion, and thus increase the effectiveness of antiviral and anticancer drugs, and rescue patients from malignant tumors and severe viral infections It is strongly demanded as a useful medicine.

(Means for Solving the Problems) The present inventors have found that abnormally high blood phenylalanine levels, urinary tetrahydrobiopterin levels in patients with malignant retinopathy accompanied by neurological symptoms, convulsions in VAHS, impaired consciousness, etc. Observations showing abnormally low values were obtained. From this fact, it was presumed that abnormalities occur in the phenylalanine hydroxylation reaction that converts phenylalanine to tyrosine in the body of these patients, which is the cause of neurological symptoms. Therefore, we attempted treatment of malignant reticulosis and neurological symptoms in VAHS patients with tetrahydrobiopterin, which is a coenzyme of aromatic amino acid hydroxylase, which plays a rate-limiting role in the production pathway of amines such as tyrosine. The present inventors have found that abnormal increase in blood phenylalanine level and abnormal decrease in urinary tetrahydrobiopterin level have returned to normal levels, and that neurological symptoms have been significantly improved, and the present invention has been completed.

The present invention provides a compound of formula (I): (Where R is Is shown. A therapeutic agent for improving neurological symptoms associated with malignant tumors and severe viral infections, comprising a compound represented by the formula (1) or a salt thereof as an active ingredient.

The compounds represented by the above general formula (I) which are the active ingredients of the therapeutic agent of the present invention include the following and salts thereof: L-erythro-5,6,7,8-tetrahydrobiopterin Sepiapterin Among the above compounds, preferred is 5,6,7,8-tetrahydrobiopterin or a salt thereof, and among them, the most preferred compound is L-erythro-5,6, 7,8-tetrahydrobiopterin or a salt thereof.

The compound represented by the formula (I) of the present invention is a known substance. For example, JP-A-59-25323 and JP-A-59-760
See No. 86 publication. Salts include pharmacologically non-toxic acids such as
Examples thereof include salts with hydrochloric acid, phosphoric acid, sulfuric acid, boric acid, acetic acid, formic acid and the like, and the above-mentioned salts of the compound of the formula (I) are also included in the active ingredient of the present invention.

The therapeutic agent of the present invention comprises a compound represented by the formula (I) orally, rectally or parenterally (including intravenous and cerebrospinal fluid administration) by a conventional method using a carrier using a general medical agent. It is manufactured by preparing a formulation suitable for administration.

Carriers used in these pharmaceutical preparations generally include excipients, binders, disintegrants and the like, depending on the dosage form used.

Representative examples of the excipient include starch, lactose, sucrose, glucose, mannitol, cellulose, and the like, and examples of the binder include polyvinylpyrrolidone, starch, sucrose, hydroxypropylcellulose, and gum arabic. Examples of disintegrants include starch, agar, gelatin powder, cellulose,
There are CMC and the like, but any other commonly used excipients, binders and disintegrants may be used.

The therapeutic agent of the present invention preferably contains an antioxidant for stabilizing the active ingredient, in addition to the above carrier. The antioxidant is appropriately selected from those generally used in pharmaceutical preparations, and examples include ascorbic acid, N-acetylcysteine, L-cysteine, dl-α-tocopherol, natural tocopherol and the like. The amount used may be that which stabilizes the active compound, but is generally from 0.2 to 1.5 by weight per active compound 1.

Formulations of the present invention suitable for oral administration include tablets, capsules, powders, powders or granules, each containing a predetermined amount of active compound (s), or syrups.
It can be provided as a suspension in a non-aqueous liquid such as an emulsion or a ready-to-use drug.

The granules are obtained by uniformly mixing the active ingredient (one or more) and one or more of the auxiliary ingredients to form a granule,
Provided by sifting the mesh using a sieve.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients.

Capsules are made by filling powders or granules, into which the active ingredient and one or more accessory ingredients are evenly mixed, into suitable capsules using a filler or the like.

Formulations for rectal administration can be presented as a suppository using a conventional carrier such as cocoa butter.

Formulations for parenteral administration may be provided by sealing one or more of the active ingredients as a dry solid in a sterile nitrogen purging container.

At the time of parenteral administration, the dry solid preparation can be dispersed or dissolved in a predetermined amount of sterile water and administered to a patient.

In the preparation of these preparations, it is preferable to add the above-mentioned antioxidants in addition to the active ingredient and the usual auxiliary ingredients, and if necessary, excipients, buffers, flavoring agents, binders, surface One or more auxiliary ingredients selected from activators, thickeners, lubricants and the like may be included in the composition.

The dosage of the active compound, ie the compound of formula (I), will, of course, vary with the route of administration, the condition being treated and the patient being treated, but will ultimately be at the discretion of the physician.

Suitable doses for treating neurological symptoms range from 0.1 to 50 mg / kg body weight / day, with a typical preferred dose being 2 to 20 mg / kg.
Weight is kg / day.

The desired dosage may be such that the active ingredient is administered once a day, or may be administered in 1 to 4 divided doses at appropriate intervals throughout the day.

The active ingredient can be administered alone or as it is without being mixed with other ingredients. However, it is preferable to administer the active ingredient as a pharmaceutical preparation for reasons such as facilitating the adjustment of the dose.

The preparation of the present invention contains, as an active ingredient, at least one selected from the group consisting of 5-vitroxytryptophan (5HTP) and L-DOPA (L-DOPA) as an auxiliary active ingredient, together with the compound of the formula (I). You may. It is generally recognized that by mixing these active ingredients, a more excellent therapeutic effect can be obtained as compared with the case where the active ingredient of the formula (I) is used alone. The ratio of each of the above-mentioned components in the preparation of the present invention is not particularly limited. In the range.

An appropriate dose for treating a neurological symptom associated with a severe viral infection or a malignant tumor with this mixed preparation is in the range of 1.0 to 50 mg / kg / day of the total amount of the active ingredient, preferably 1.0 to 20 mg. / Kg / day.

Upon treatment, selection of a preparation containing the compound of the formula (I) alone as an active ingredient and a preparation containing another active ingredient together is appropriately determined by a physician according to age and symptoms.

The active compound used for the therapeutic agent of the present invention is most preferably optically active L-erythro-5,6,7,8-tetrahydrobiopterin and a salt thereof, and DL-tetrahydrobiopterin, or sepiapterin and these compounds. A similar compound such as a salt may be used. However, L-erythro-5,6,7,8-tetrahydrobiopterin which is present in a living body is most preferable due to problems such as toxicity. Incidentally, the acute toxicity of this L-erythro-5,6,7,8-tetrahydrobiopterin dihydrochloride to rats is 2 g / kg or more by oral administration, and almost no toxicity is found. DL that is not optically active
-Tetrahydrobiopterin also has low toxicity as seen in the treatment of Parkinson's disease in JP-A-59-76086 and JP-A-59-25323, and amino acid metabolism disorders associated with malignant tumors and viral infections. It is possible to use Acute toxicity of compounds of the formula (I) other than these is likewise hardly found.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (Granules, fine granules) 1 part of polyvinylpyrrolidone (Korydone 30) was dissolved in sterile purified water, and 10 parts of ascorbic acid and 5 parts of L-cysteine hydrochloride were added thereto to form a uniform solution. 10 parts of biopterin dihydrochloride was added to make the mixture uniform.

The solution was added to 59 parts of an excipient (mannitol or lactose) and 15 parts of a disintegrant [corn starch or hydroxypropylcellulose (LH-22)], kneaded, granulated, dried and sieved.

Example 2 (Tablets) After 58 parts of lactose and 15 parts of microcrystalline cellulose were mixed with the homogeneous solution of the active ingredient prepared in Example 1, 1 part of magnesium stearate was further added and mixed, followed by tableting.

Example 3 (Capsule) The capsule of the dosage form prepared in Example 1 was filled. However, magnesium stearate is used as a lubricant.
A formulation prepared by adding 2% was used.

Example 4 (Injection) Tetrahydrobiopterin dihydrochloride 1.5 g Ascorbic acid 1.5 g L-cysteine hydrochloride 0.5 g Mannitol 6.5 g The above components were dissolved in sterilized purified water to make 100 ml, and 1 ml of the bacteria were removed. Each 2 ml was taken in a vial or ampoule, freeze-dried and sealed.

Example 5 (Injection) 2.0 g of tetrahydrobiopterin dihydrochloride was dissolved in sterile purified water under oxygen-free conditions, and a 100 ml solution was sterilized.
Sealing was performed in the same manner as in Example 4.

Example 6 (suppository) Tetrahydrobiopterin dihydrochloride 150 parts Ascorbic acid 150 parts L-cysteine hydrochloride 50 parts Using the above ingredients, a uniform powder was used to obtain cocoa oil 9,
Dispersed in 950 parts.

Example 7 (granules) Tetrahydrobiopterin dihydrochloride 5 parts Ascorbic acid 5 parts L-cysteine hydrochloride 2 parts A homogeneous solution was prepared using the above components.

On the other hand, 55 parts of mannitol, 1 part of polyvinylpyrrolidone,
The above solution was added to a mixture obtained by uniformly mixing 14 parts of hydroxypropylcellulose and 5 parts of 5-hydroxytryptophan, kneaded, granulated, dried and sieved.

Example 8 (granules) Tetrahydrobiopterin dihydrochloride 5 parts Ascorbic acid 5 parts L-cysteine hydrochloride 5 parts Mannitol 52 parts Polyvinylpyrrolidone (Korydone 30) 1 part Hydroxypropyl cellulose (LH-22) 12 parts L -DOPA 10 parts Granulated and sieved using the above components in the same manner as in Example 7.
However, instead of 5 parts of 5-hydroxytryptophan, L-
10 parts of DOPA were used.

Example 9 (Granules) Tetrahydrobiopterin 2-hydrochloride 5 parts Ascorbic acid 5 parts L-cysteine hydrochloride 2 parts A homogeneous solution was prepared using the above components.

On the other hand, 5-hydroxytryptophan 5 parts, L-DOPA
10 parts, mannitol 50 parts, polyvinylpyrrolidone (colydone 30) 1 part and hydroxypropylcellulose (LH
-22) The above solution was added to 9 parts uniformly mixed, kneaded, granulated, dried and sieved.

The remarkable effects will be described in detail with reference to clinical examples below. Clinical Examples 1-4 were all malignant tumors and VA
In HS, it is shown that amino acid metabolism abnormality has occurred together with neurological symptoms. In particular, Clinical Example 3 shows that such neurological symptoms and amino acid metabolism abnormality disappear after administration of tetrahydrobiopterin. It is.

(Clinical Example 1) In this case, a 3-year-old boy was diagnosed with malignant reticulopathy by diagnosis. Convulsions, with symptoms of typical malignant reticulopathy
He showed neurological symptoms such as impaired consciousness. At this time, the blood phenylalanine / tyrosine value (Phe / Tyr) was as high as 2.98, and tetrahydrobiopterin was not detected.

(Clinical Example 2) In this case, a 12-year-old girl was diagnosed with malignant reticulopathy by diagnosis. Convulsions, with symptoms of typical malignant reticulopathy
He showed neurological symptoms such as impaired consciousness. At this time, the blood Phe / Tyr value was as high as 3.65, and urinary tetrahydrobiopterin was not detected.

(Clinical case 3) This case was diagnosed as malignant reticulopathy by diagnosis in a 2-year-old girl, and showed typical symptoms such as fever, skin redness, cytopenia, and hepatosplenomegaly, with convulsions and impaired consciousness . The blood Phe / Tyr value was as high as 2.84, and the amount of phenylalanine was abnormally high.
Exchange transfusion reduced Phe / Tyr blood to 2.05. At this point, if 7.5 mg / kg of tetrahydrobiopterin is given orally, the Phe / Tyr value will be 1.35 after 4 hours, and after 8 hours.
It decreased to 1.78. Urinary tetrahydrobiopterin / total biobuterin levels range from 25.0 before administration to 8 hours after administration4
It increased to 4.8, showing a good correlation between an increase in urinary tetrahydrobiopterin and a decrease in Phe / Tyr levels. At the same time, administration of tetrahydrobiopterin eliminated neurological symptoms such as convulsions and impaired consciousness.

(Clinical case 4) This is an 11-year-old girl who did not have access to tetrahydrobiopterin because she was unable to obtain tetrahydrobiopterin. Indicated. Various tests diagnosed VAHS, but no specific virus could be identified. The blood Phe / Tyr ratio was as high as 6.25, and when plasmapheresis was performed for two consecutive days, the Phe / Tyr level decreased and the consciousness level improved, but renal failure and respiratory failure on the fourth day of hospitalization Progressed and died.

(Effects of the Invention) As described above, the present invention has determined the cause of a neurological symptom of a patient associated with a severe viral infection or a malignant tumor, and has provided a therapeutic agent for treatment of the cause. The therapeutic agent of the present invention is expected to increase the cure rate from severe viral infections and malignant tumors by removing the cause of these intractable diseases and comprehensively treating patients.

Claims (5)

(57) [Claims] (1) Formula (I): (Where R is Is shown. A therapeutic agent for improving a neurological symptom associated with severe virus infection or malignant tumor, comprising the compound represented by the formula (1) or a salt thereof as an active ingredient. 2. R is The therapeutic agent according to claim 1, which is: 3. The therapeutic agent according to claim 1, wherein the severe viral infection is VAHS (blood cell phagocytic syndrome secondary to viral infection). 4. The therapeutic agent according to claim 1, wherein the malignant tumor is malignant reticulopathy. 5. The therapeutic agent according to claim 1, comprising L-erythro-5,6,7,8-tetrahydrobiopterin or a salt thereof as an active ingredient.