JPH09194389A - Preventing and treating agent for steroid myopathy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent containing an insulin-like growth factor 1 or its analogue and excellent in preventing and treating effects on steroid myopathy which is adverse effect as muscle weakness, muscle atrophy, etc., accompanied by treatment with steroids. SOLUTION: This preventing and treating agent contains an insulin-like growth factor 1, e.g. derived from human (IGF-1) or its active analogue (e.g. O-glucosylated IGF-1, a variant protein having IGF-1 activity, in which a part of amino acid sequence of IGF-1 is inserted, replaced, loosen or added). The agent is formulated into a form such as a solid preparation e.g. tablet or capsule, a semisolid preparation e.g. ointment or cream, a liquid preparation e.g. solution or suspension, liposome agent, and the resultant preparation is once or dividedly administered in a daily dose of 0.1-10mg/kg, especially 0.2-2mg/kg expressed in terms of IGF-1 amount.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a prophylactic / therapeutic agent for steroid myopathy caused by insulin-like growth factor 1 (hereinafter referred to as IGF-1) or its active analogue.

[0002]

BACKGROUND OF THE INVENTION Steroid myopathy is a variety of steroids (eg, triamcinolone acetonide, dexamethasone, betamethasone, hydrocortisone, etc.) for the treatment of collagen diseases, autoimmune diseases such as polymyositis, asthma and inflammation. Is a lesion that often develops as a side effect when administered continuously. In particular, lesions are likely to appear on type II fibers of muscle. Usually, muscle weakness and muscle atrophy gradually start from the lower limb proximal muscle and then spread to the upper limb proximal muscle, the lower limb and the upper limb distal muscle, the thigh muscle, and the trunk muscle. Although recovery from steroid withdrawal may occur, there are no active preventive or therapeutic agents.

[0003]

An object of the present invention is to provide an effective prophylactic / therapeutic agent for such steroid myopathy. Furthermore, it is to be able to continue the treatment without causing the pain caused by the side effect to the patient in need of the treatment with the steroid.

[0004]

Means for Solving the Problems The present inventors have conducted extensive studies to solve the above problems, and as a result, IGF-1
Further, they have found that the active analog thereof is excellent as a prophylactic / therapeutic agent for steroid myopathy and completed the present invention.

IGF-1 is a naturally occurring polypeptide that can be isolated from many sources. IGF-1 can be produced synthetically or by genetic engineering. IGF
-1 is a mediator when growth hormone (GH) exerts a bone growth promoting action. When GH binds to the GH receptor of the chondrocyte precursor cell membrane existing at the epiphysis of the long bone to transmit a signal, IGF-1 production is promoted. Chondrocyte progenitor cells and chondrocytes not only have the ability to produce IGF-1, but also express IGF-1 receptor on their cell membranes, and thus repeat differentiation and proliferation to promote bone formation and In the vertical direction. GH for treatment of GH deficient short stature
GH is ineffective for the treatment of laron type short stature patients whose administration is effective but whose GH receptor is abnormal, and the treatment with IGF-1 is approved. IGF-1 is also known as a hormone having a blood glucose lowering action together with insulin. Insulin exerts its effect via the insulin receptor, whereas IGF-1
It binds to both the GF-1 receptor and the insulin receptor and exerts its action. Therefore, a therapeutic agent for a patient suffering from diabetes due to impaired insulin receptor and subsequent signal transduction process such as insulin receptor dysfunction type A and B, lipoatrophic diabetes mellitus, spermosis, Loveson-Mendenhol syndrome Is approved for use as IGF-1. However, its use as a prophylactic / therapeutic agent for steroid myopathy is not known.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION IGF-1 used in the present invention
Examples of the IGF-1 derived from mammals such as humans and cows produced by gene recombination technology (see, for example, JP-A-61-1396), peptide synthesis method, cell culture method and the like.
Is included. As an active analog of IGF-1, a mutant protein having IGF-1 activity in which a part of the amino acid sequence has been inserted, substituted, deleted, or added, and O-glucosylated IGF-1 (see WO90 / 02198) ) Etc. are included. Preferable active analogs of IGF-1 include those in which 1 to 5 amino acids have been deleted from the N-terminus as described in WO89 / 05822. In order to avoid an unfavorable immune response, it is preferable to use human-derived IGF-1 or its active analogue.

As an administration method, an appropriate method can be selected from usual methods such as oral administration and parenteral administration (including vein, muscle, subcutaneous, abdominal cavity, rectal, nasal, etc.). The amount of the active ingredient in the pharmaceutical preparation may be an amount sufficient to produce the desired effect, and it varies depending on the age, symptoms, or administration route of the patient, but is usually about 0.1 as IGF-1 per adult per day. 1 to 10 mg / kg, preferably 0.2 to 2
It is about mg / kg, which can be administered once or in divided doses. It is desirable to administer the drug at the same time as the steroid, but before or after the steroid administration I
GF-1 may be administered.

The form of the preparation includes solid preparations such as tablets, capsules, powders, granules, fine granules, troches, pills, suppositories, semisolid preparations such as ointments and creams, solutions,
A suitable dosage form is selected from liquid dosage forms such as suspensions, syrups and elixirs, and conventional dosage forms such as liposomes. The preparation is produced by a conventional means, optionally using a carrier for preparation, an excipient, a stabilizer, other pharmaceutically acceptable additives and the like. In the case of a solid preparation for oral use, it may be coated with an enteric film by a known method.
It may also be in a sustained-release form. In the case of an injection, a solid preparation which can be dissolved before use (eg, a freeze-dried preparation) can be used. Specific examples of these preparations include freeze-dried preparations described in JP-A-4-208228 and JP-A-5-58877.
The nasal preparations and the like described in JP-A No. 1994-200242 can be mentioned.

Test Example (Test Method) SD rats were divided into 3 groups (4 animals in each group), a control group, a steroid administration group, and a steroid +
This is the IGF-1 administration group. Triamcinolone acetonide (manufactured by SIGMA) was selected as the steroid.
75 mg / kg / day is dissolved in dimethyl sulfoxide for administration, and IGF-1 is 2 mg / kg / day in 0.2% BSA-physiological saline solution for administration. All were subcutaneously administered for 2 weeks continuously, and blood samples were collected under anesthesia on the last day, and extensor digitorum longus (hereinafter referred to as EDL) and soleus muscle (hereinafter referred to as Soleus) specimens were prepared, and micrographs were taken. It was photographed and the diameter of the muscle was measured. As a staining method, in addition to hematoxylin-eosin staining (abbreviated as HE in the following Table 1), rutin-ATPase staining specific to type II fibers (abbreviated as Type II in the following table 1) was performed, and the diameter of only type II fibers was also measured. It was measured. The IGF-1 used in this test was obtained by the method described in JP-A-61-1396 and is the same as human IGF-1.

(Test Results) The test results are shown in (Table 1).

[0011]

[Table 1]

In the steroid-administered group, the muscle diameters were all smaller than in the control group, but the degree of decrease was smaller in the group in which steroid and IGF-1 were used in combination. In particular, EDL type II fibers have excellent side effect prevention / treatment effects.

[0013]

EFFECT OF THE INVENTION IGF-1 or its active analogue, which is the active ingredient of the present invention, is excellent in the preventive / therapeutic effect of steroid myopathy.

Claims (2)

[Claims] 1. A prophylactic / therapeutic agent for steroid myopathy containing insulin-like growth factor 1 or an active analogue thereof. 2. Prevention of steroid myopathy according to claim 1, wherein insulin-like growth factor 1 is of human origin.
Therapeutic agent.