JPH07215881A - Therapeutic agent for sjoegren syndrome - Google Patents

Abstract

PURPOSE:To obtain the subject internally administrable therapeutic agent, com prising carbamoyl-beta-D-ribofuranosyl-imidazoliumoleate as an active ingredient, capable of rapidly improving the xerotic conditions of lacrimal and salivary glands and having low toxicity and high safety. CONSTITUTION:This therapeutic agent comprises 4-carbamoyl-1-beta-D- ribofuranosyl-imidazolium-5-oleate (generic name: mizoribine) as an active ingredient. A 25-mg or a 50-mg table of a commercially available pharmaceutical preparation of the mizoribine for oral administration is simply preferably used as the therapeutic agent. The mizoribine in a daily dose of >=150mg is preferably administered for >=4 months so as to afford >=18g total dose.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 4-carbamoyl-1.
Sjogren's syndrome (Sjogr-Synthesis containing -β-D-ribofuranosyl-imidazolium-5-oleate as an active ingredient
en's Syndrome) therapeutic agent.

[0002]

BACKGROUND OF THE INVENTION 4-Carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate is a type of Eupenicillium brefeldianum belonging to the genus Eupenicillium.
cillium brefeldianum) M-21
A nucleic acid-related substance found in the culture solution of the 66 strain (FERM P-1104), which is called the general name Mizoribine, is a weak acidic substance that is easily soluble in water and undergoes brown foaming decomposition at around 200 ° C. Various methods are known, for example J. Antibiotics, 27, (10), 775
(1974), Chem. Pharm. Bull. , 2
3,245 (1975), JP-A-48-56894, JP-A-51-1693, and JP-A-50-121.
No. 275, JP-A No. 50-112276, and the like.

[0003] Further, 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate has an immunosuppressive action, and has been found to be useful, for example, in suppressing rejection in renal transplantation (“transplantation”). , 17 [Supp
l. ], 547, 1982), and the effect of suppressing antibody production against anti-sheep erythrocytes in mice (Transp
lantation, 35 (2): 144, 1983).
Is reported to be useful as a therapeutic agent for rheumatoid arthritis (inflammation,
11 (4), 1991) and usually 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate 2-3 m per 1 kg of body weight as an initial amount.
An anhydrous crystalline substance is used as a tablet of Bredinin (registered trademark; manufactured by Asahi Chemical Industry Co., Ltd.), which is orally administered in an amount equivalent to g and a daily amount equivalent to 1 to 2 mg as a maintenance amount.

[0004]

On the other hand, Sjogren's syndrome is a chronic inflammatory disease characterized by a dry pathological condition due to exocrine insufficiency of the lacrimal gland and salivary gland. That is, the exocrine glands such as the lacrimal glands and the salivary glands are destroyed by the chronic inflammation that is presumed to involve the autoimmune mechanism, and the exocrine fluid is reduced.
A decrease in the lacrimal gland causes xerophthalmia (keratitis sicca), and a decrease in saliva causes xerostomia. In addition, bronchitis and interstitial pneumonia due to nasal and vaginal dryness and exocrine respiratory tract infection are observed.

As described above, it is considered that autoimmune mechanisms are involved in the development of Sjogren's syndrome, and one of the reasons is the expression of autoantibodies. That is,
Anti-SS-A (R _o ) and anti-SS-B (L _a ) antibodies 2
Types of antinuclear antibodies emerge. And the former appears in 70 to 80% of all Sjogren's syndrome, and the latter appears in about 40% of dry syndrome ("Limmunization", Volume 21, Addendum 1).
4, p. 615, 1989).

[0006] Since they also appear in a part of collagen disease which lacks the dry condition, they lack absolute specificity, but are useful for diagnosis. Furthermore, hyperγ-globulinemia, high IgG,
The presence of hyper-IgA blood and the high rate of expression of the rheumatoid factor irrespective of the concurrent occurrence of rheumatoid arthritis provide a clue to diagnosis.

Histopathologically, it is characterized by infiltration of lymphocytes and plasma cells around ducts such as lacrimal glands and salivary glands and around acinar. As a result of such histopathological changes, it is considered that destruction of the acinus and fibrosis occur, resulting in a decrease in exocrine function (Semin Arthritis).
Rheum. , 14, pp77, (1984)). In such Sjogren's syndrome, about half of them are classified into two groups, that is, the dry syndrome only in the dry condition, and the other half in which the dry condition develops together with various collagen diseases such as rheumatoid arthritis. be able to.

The diagnosis of Sjogren's syndrome is to understand the dry pathology. As a standard focusing on this point, 1977
The diagnostic criteria of the Sjogren's disease research group set by the Ministry of Health and Welfare are set for the year. That is, as a definite example, there is a dry symptom of unknown cause. To have keratoconjunctivitis sicca of unknown cause, 2. 2. Abnormal findings characteristic of tear or salivary tissue. An abnormal finding characteristic of salivary angiography is to be recognized, and one or more of these three items are recognized.

As a suspicious example, there is a dry symptom of unknown cause. Suspected keratoconjunctivitis sicca of unknown cause,
2. Decreased salivary secretion (gum test is 10m in 10 minutes)
1.) or less, 3. Having salivary gland swelling that is recurrent or chronic and of no other cause
This is the case when one or more of these three items are recognized.

Based on such criteria, first, the presence or absence of subjective dry symptoms of unknown cause in the eyes and mouth is examined. Regarding dry eye, first, the tear production is measured by Schirmer test, and the degree of keratoconjunctivitis sicca is grasped by Rose Bengal and fluorescent dye test. For xerostomia, salivary secretion is measured by a gum test, etc., and the degree of salivary glanditis is grasped by a labial salivary gland biopsy and parotid gland angiography. When these are positive, they are classified into definite cases and suspected cases depending on their degree, and Sjogren's syndrome (dry condition) is diagnosed.

Other diagnostic criteria include Bloch (Medicine, 44, pp18).
7, 1965), Shearen (Sj
oren's syndrome, Saunders,
Philadelphia, 1971) is known, and the above-mentioned Ministry of Health and Welfare standards are based on clear judgment items not included in these standards.

In addition, the therapeutic policy for Sjogren's syndrome is to control exocrine gland inflammation, which is the cause of the dry condition, and to correct the autoimmune background. The drugs currently used are classified into two types according to their purpose. . The first is to improve exocrine gland inflammation and abnormal immune phenomenon, and includes steroids, non-steroidal anti-inflammatory drugs, and immunosuppressants, and the second is to stimulate exocrine glands and increase exocrine fluid. It is a drug that changes its properties and reduces its viscosity, and includes expectorants and choleretic agents.

As a further example, non-steroidal anti-inflammatory drugs, steroid drugs, and immunosuppressive drugs are, as a general rule, symptomatic for glandular symptoms and, depending on the pathological conditions for extraglandular symptoms,
For complications, the treatment is mainly performed, and symptomatic treatment is also performed for glandular symptoms.For example, mucophazin and chondron are used for dry eye symptoms, and salivate, bisorbone, and prednisolone are used for dry mouth symptoms. Has been done.

However, all of these therapeutic agents have insufficient practical therapeutic effects, and sometimes cause serious side effects such as leukopenia, liver damage and kidney damage when administered for a long time. Therefore, it cannot be said that steroids and immunosuppressants are effective because they cannot be administered for a long period of time.

[0015]

[Means for Solving the Problems] The present inventors have a large therapeutic effect, low toxicity, high safety, long-term administration, and high practicability of oral administration. The present invention has been completed as a result of intensive research and development for developing a therapeutic agent for Sjogren's syndrome.

The present invention relates to 4-carbamoyl-1-β-D
-A remedy for Sjogren's syndrome, which comprises ribofuranosyl-imidazolium-5-oleate as an active ingredient. The Sjogren's syndrome in the present invention means a patient having the above-defined pathological condition, and the treatment thereof may be determined based on the improvement of the dry pathological condition of the subjective dryness symptom.

Further, 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5 used in the present invention.
-Oleit (hereinafter sometimes referred to as Mizoribine)
As mentioned above, it is an immunosuppressant that is already on the market, and its acute toxicity (LD ₅₀ ) is oral> 4883 in mouse males.
mg / kg, subcutaneous> 4883 mg / kg, intravenous> 30
42 mg / kg, intramuscular> 2800 mg / kg, mouse female oral> 4883 mg / kg, subcutaneous> 4883 mg
/ Kg, intravenous> 3042 mg / kg, intramuscular> 280
0 mg / kg, rat male oral> 3100 mg / k
g, subcutaneous> 4161 mg / kg, intravenous> 2572 mg
/ Kg, intramuscular> 2800 mg / kg, rat female oral> 2847 mg / kg, subcutaneous> 3795 mg / kg,
Intravenous> 2608 mg / kg, intramuscular> 2800 mg /
It is a safe drug with low kg and toxicity. It is also known that mizoribine has no nephrotoxicity, has low residual in blood, and has extremely low transfer to the brain (for example,
Applied Pharmacology (1978) 15 (5) 829-835).

In the present invention, it is convenient to use a commercially available formulation for oral administration of mizoribine (registered trademark: Bredinin tablet). Further, it can be appropriately prepared as a preparation for oral administration such as capsules and granules, a suppository, a percutaneously absorbable preparation or an injection by a conventional preparation technique. The amount of mizoribine used in the present invention is, for example, 1 to 10 mg / kg (body weight) as an adult daily dose of 1 to 3 per day.
It may be administered once, for example, preferably with a body weight of 50-60.
Formulation for Oral Administration of Mizoribine to Adults of 25 kg
100 to 300 once using mg or 50 mg tablets
The mg amount of mizoribine may be dividedly administered 2-3 times a day.

With respect to the dose of this active ingredient, the total dose during the treatment period is 15 g or more, preferably 18 g or more, and a suitable dose is 150 mg or more of mizoribine per day for 3 months. Over the time,
It is preferably administered for 4 months or more, and if no clinical abnormality is observed, it may be administered for a period requiring treatment. Since the active ingredient of the composition of the present invention is low toxicity mizoribine, it can be administered for a long period of time, for example, 10 months or more without any trouble.

Next, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. Example 1 As shown in Table 1 below, the dose of mizoribine (50 times 3 times a day) was administered to 6 patients who were certified as Sjogren's syndrome.
mg tablets) and the administration period were examined, and the main clinical symptoms, such as dry mouth, dry eyes, swelling of parotid glands, and improvement symptoms of dry symptoms were examined. 5m for combined predonin
Oral administration of 1-2 tablets of g tablet was carried out daily.

[0021]

[Table 1] As shown in Table 1, out of 6 patients, mizoribine 150 mg
M / day dose for patients up to 3 months treatment period. With the exception of W, improvement in dry symptoms was observed.

The clinical test results of each patient before administration of mizoribine are listed below. No. 1 patient T. K (55 years old)
Table 2 shows the clinical test results.

[0023]

[Table 2] No. 2 patient T. The clinical test results of K (36 years old) are shown in Table 3.

[0024]

[Table 3] No. 3 patients C.I. The clinical test results of Y (50 years old) are shown in Table 4.

[0025]

[Table 4] No. 4 patient S. The clinical test results of A (40 years old) are shown in Table 5.

[0026]

[Table 5] No. 5 patients M. The clinical test results of W (37 years old) are shown in Table 6.

[0027]

[Table 6] No. 6 patients N. The clinical test results of M (46 years old) are shown in Table 7.

[0028]

[Table 7]

The meanings of the symbols of the test items, the range of normal range and the units thereof for each patient are as follows. IgG; normal range 1000 to 1900 mg / dl IgA; normal range 96 to 430 mg / dl IgM; normal range 48 to 350 mg / dl dsDNA (anti-double-stranded DNA antibody); 20 U / ml or less ssDNA (anti-single-stranded DNA antibody) 20 U / ml or less CRP (C-reactive protein); 0.2 mg / dl or less RAHA; 40 times or less

SS-A (anti-SS-A antibody); 20 or less (no unit) SS-B (anti-SS-B antibody); 25 or less (no unit) ANA; 40 times or less CH50; 30-40 U / ml C3 53-115 mg / dl C4; 12-42 mg / dl CD4 + cells; 30-53.7% CD8 + cells; 17.3-43.0% CD5 + cells; 56.3-89.1%;

Among the 6 patients shown in Tables 2 to 7 above, a dose of 150 mg / day of mizoribine was found to improve the dry symptoms characteristic of Sjogren's syndrome in 5 patients with a treatment period of 5 months or more. However, in the course of administration, it was judged that the effect was to be manifested within 4 months of the treatment period, and improvement of the dry symptoms was observed. Moreover, no cases of side effects were observed.

[0032]

As described above, according to the present invention, administration of mizoribine to a patient who has developed Sjogren's syndrome can rapidly improve the dry pathological condition of the lacrimal gland and salivary gland, and is a therapeutic agent for Sjogren's syndrome. Is obtained.

Claims (4)

[Claims] 1. A therapeutic agent for Sjogren's syndrome, which comprises 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate as an active ingredient. 2. The active ingredient is 4-carbamoyl-1-administered with a dose of 15 g or more of 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate.
The therapeutic agent for Sjogren's syndrome according to claim 1, which comprises β-D-ribofuranosyl-imidazolium-5-oleate as an active ingredient. 3. The therapeutic agent for Sjogren's syndrome according to claim 1, wherein the dose is 18 g or more, and the dose is 150 mg or more per day. 4. The therapeutic agent for Sjogren's syndrome according to claim 1, which is amelioration of dry symptoms in the treatment of Sjogren's syndrome.