JP2004315469A - Agent for treatment of citrullinemia - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicine useful for the treatment of citrullinemia, especially adult crisis type-II citrullinemia. <P>SOLUTION: The agent for the treatment of citrullinemia contains arginine and/or its salt as an active component. The arginine used in the agent is L, D, DL, one of their salts or their mixture. The agent is administered to a patient with the citrullinemia at a daily dose of preferably about 3-30 g in terms of free arginine. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a therapeutic agent for citrullinemia, in particular, a therapeutic agent for treating adult-onset type II citrullinemia and a therapeutic agent suitable for oral administration.
[0002]
[Prior art]
Citrullineemia presents with neuropsychiatric symptoms such as disorientation, abnormal behavior, and impaired consciousness, and is a disease associated with an increase in blood citrulline, which was previously called a special type of hepatic brain disease, a juvenile type, or a malnutrition type. It is. Among them, adult-onset type II citrullinemia is a disease with poor prognosis frequently occurring in Japanese, and it is known that the urea cycle enzyme argininosuccinate synthase (ASS) is specifically reduced in the liver. Although the cause has not been elucidated for many years, the present inventors have elucidated the etiological gene (SLC25A13) of the present disease and the protein (citrin) encoding the same in recent years. It was also found that citrin was reduced in patients with this disease (Nature Genetics 22: 159-163, 1999).
[0003]
By the way, in classical citrullinemia (CTLN2), which mainly occurs in neonatal childhood and is based on an abnormality in the ASS gene located on chromosome 9 (9q34), ASS deficiency occurs in all cells and tissues expressing ASS Therefore, arginine, which is a product of the metabolic system, decreases. On the other hand, in adult-onset type II citrullinemia, the ASS protein is specifically reduced in the liver, but the serum arginine level tends to increase because no abnormality is observed in the ASS of the kidney and other tissues. Urinary excretion of argininosuccinic acid, a product of ASS, also increases. Furthermore, it is known that the expression of pancreatic secretory trypsin inhibitor (PSTI) is enhanced in the liver of adult-onset type II citrullinemia cases. On the other hand, there is a similar mutation in idiopathic neonatal hepatitis, and its main symptom is termed neonatal intrahepatic cholestasis caused by citrin definition (NICCD). To date, the only effective treatment for citrullinemia has been known to be liver transplantation, and in fact, blood biochemistry findings of patients after liver transplantation have normalized and the neuropsychiatric symptoms have disappeared . However, liver transplantation has various problems such as securing a donor and rejection after transplantation, and development of an effective treatment method has been desired.
[Non-patent document 1]
Nature Genetics 22: 159-163, 1999.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to provide a drug for treating citrullinemia, particularly a drug for treating adult-onset type II citrullinemia.
[0005]
[Means for Solving the Problems]
The present inventors have studied to solve the above problems, and as a result, have found that arginine leads to the pathological condition of citrullinemia patients, especially to improve the consciousness of patients with consciousness disorder, and based on these various findings, the present invention. Was completed.
That is, the present invention is a therapeutic agent for citrullinemia, comprising arginine and / or a salt thereof as an active ingredient.
The arginine used in the present invention may be any of L-form, D-form and DL-form, may be in the form of a salt, or may be a mixture thereof. The therapeutic agent for citrullinemia of the present invention is particularly effective for adult-onset type II citrullinemia, citrullinemia derived from idiopathic neonatal hepatitis, and the like.
[0006]
BEST MODE FOR CARRYING OUT THE INVENTION
As the arginine used in the present invention, any of its L-form, D-form and DL-form can be used, but the L-form is preferred. Arginine can be used not only in a free form but also in a salt form. Examples of the salt form include acid addition salts, particularly inorganic salts such as hydrochloric acid, sulfuric acid and phosphate, and organic acid salts such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid and monomethyl sulfate. The salt is not limited to these, but it is preferable to select a pharmaceutically acceptable salt.
[0007]
Regarding the access route when arginine is used, there is no particular difficulty in the preparation method when preparing it, and any of them can be easily carried out based on conventional techniques, and their L-form, D-form, DL-form As for the body, there are commercially available products, and it is easy to purchase and use these.
In the present invention, arginine can be used as a drug for various diseases caused by citrullinemia. For example, it can be used as a therapeutic agent for patients with adult-onset type II citrullinemia and idiopathic neonatal hepatitis.
[0008]
In the present invention, at least the above-mentioned arginine may be used in combination with a drug for treating various citrullinemia. In addition, various other necessary components such as an auxiliary agent and a carrier can be optionally blended and used as long as the object of the present invention and the action (effect) exerted by the present invention are not impaired.
The formulation of the therapeutic agent for citrullinemia of the present invention is not particularly limited, and may be an oral preparation or a parenteral preparation (injection). Usually, it is taken orally, but a special (non-oral) means of administration may be used. Further, the active ingredient used in the present invention can be administered orally and parenterally at the same time.
[0009]
The amount of arginine to be used may be appropriately selected according to the patient's symptoms and the degree thereof, the type of dosage form, and the like. However, in the case of oral administration, it is usually preferably about 3 g to 30 g, more preferably 5 g per day in terms of free form. About 20 g, more preferably about 6 to 15 g. When used as an intravenous injection or a drip, an amount of about 1/20 to 1/2 of the amount of the active ingredient used in the preparation for oral administration is sufficient. Of course, in severe cases, the dose can be further increased. However, it is necessary to appropriately adjust the dose according to the patient's symptoms, and it is necessary to determine the dose by paying attention to amino acid overload. The frequency and timing of administration may be once every several days or once a day, but it is usually preferable to administer the administration several times a day, for example, in 2 to 4 divided doses.
[0010]
The preparation of the preparation may also contain various pharmacologically acceptable substances for preparation (as auxiliaries and the like). The substance for formulation can be appropriately selected depending on the dosage form of the formulation. For example, excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, glidants, lubricants, flavors , Sweeteners, solubilizers and the like. Further, specific examples of substances for preparation include magnesium carbonate, titanium dioxide, lactose, mannitol and other saccharides, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, For example, sterile water and monohydric or polyhydric alcohols such as glycerol can be mentioned.
[0011]
The therapeutic agent of the present invention can be prepared in the form of various pharmaceutical preparations known or to be developed as described above, for example, various administration forms such as oral administration, enteral administration, transdermal administration, and inhalation administration. it can. In order to prepare the therapeutic agent of the present invention in the form of these various pharmaceutical preparations, known or future-developed methods can be appropriately adopted.
These various pharmaceutical forms include, for example, suitable solid or liquid forms, such as granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, Drops, solutions for injection, formulations which prolong the release of the active substance and the like can be mentioned.
For example, arginine U granules and arginine U injection are commercially available as arginine-containing preparations. For arginine U granules, 1.3 g of 605 mg of L-arginine hydrochloride and 500 mg of L-arginine (measured as L-arginine). 1000 mg). On the other hand, Argi U injection is a preparation containing 20.0 g of L-arginine hydrochloride in 200 ml.
Even when components other than those described above are used, necessary formulations can be prepared based on these or by using known formulation techniques, and according to various dosage forms.
[0012]
【Example】
Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.
(Example 1)
A special milk is administered at 120 g / day to an encephalopathy patient (body weight 53 kg) due to adult-onset type II citrullinemia, and then from day 30 special milk for citrullinemia (Formula (registered trademark) 7925-A manufactured by Meiji Dairies Co., Ltd.) ) Was increased to 160 g / day. However, even if the ammonia value changes at an average of about 300 μg / dl and the ammonia value temporarily approaches the normal value and the consciousness disorder is improved, the improved state cannot be maintained for a long time. Therefore, when oral administration of an arginine preparation (the above-mentioned argin U granules) was started at a dose of 0.15 g / kg / day as arginine, the ammonia level was maintained at less than 100 μg / dl, encephalopathy disappeared, and the patient was subsequently discharged. did.
[0013]
【The invention's effect】
By administering a therapeutic agent containing arginine as an active ingredient to citrullinemic patients, it was possible to improve the consciousness of patients with consciousness disorder. The therapeutic agent is useful for treating citrullinemia, particularly adult-onset type II citrullinemia.

Claims (4)

A therapeutic agent for citrullinemia, comprising arginine and / or a salt thereof as an active ingredient. The therapeutic agent according to claim 1, wherein the citrullinemia is adult-onset type II citrullinemia. The therapeutic agent according to claim 1, wherein the citrullinemia is derived from idiopathic neonatal hepatitis. The therapeutic agent according to any one of claims 1 to 3, wherein the daily dosage unit of arginine is 3 to 30 g.