JPH0625062B2 - Steroid cataract prevention and treatment - Google Patents

Description

TECHNICAL FIELD The present invention relates to a medical treatment for preventing or treating a cataract that develops in a patient receiving oral steroid therapy, that is, a steroid cataract.

Prior art Chronic rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, which has been receiving strong steroid oral therapy for a long time,
In patients with nephrosis, chronic gastritis, purpura nephritis, and the like, localized cataracts immediately under the posterior lens posterior capsule occur at a high rate.
It is considered that this cataract (steroid cataract) is caused by reduction of reduced glutathione in the lens due to the action of steroid, resulting in oxidation of the cell membrane, resulting in fragility of the cell membrane. Therefore, the steroid cataract has a completely different histological origin from those of senile cataract, in which the constituent fibers of the lens are swollen and opaque, and diabetic cataract.

Steroid cataracts occur between the posterior capsule and the cortex, obstructing the lens suture and spreading into the cortex. Turbidity is minute, whitish yellow, crystalline, mixed with small air bubbles, pearly blue,
Green and red particles are often present in the turbidity.
This cataract develops in both eyes.

Steroid cataract is an iatrogenic disease, but its visual impairment is relatively slight, and its progression is extremely slow.
Compared to the excellent efficacy of steroids, their side effects have not received much attention, and no studies have been conducted on their preventive or therapeutic drugs.

Problems to be Solved by the Invention However, there is a strong correlation between the occurrence of steroid cataracts and the amount and duration of administered steroids (age and sex have little relationship), and steroids can be used for a long time. When I have to take the drug internally, I sometimes go into a situation where I have to undergo a cataract surgery. Therefore, it is necessary to prevent the occurrence of steroid cataract or to effectively suppress the progress thereof while continuing the administration of the steroid drug, and further to absorb the generated lens opacification.

However, although several therapeutic agents have already been developed and are effective for senile cataract and diabetic cataract, effective preventive and therapeutic agents for steroid cataract have not been found yet.

The present inventors have long been earnestly researching a preventive / therapeutic agent for steroid cataracts, but 1-hydroxy-5-oxo-5H-pyrido (which has been conventionally used as a therapeutic agent for senile cataract and diabetic cataract) 3,2-a) Phenoxazine-3-carboxylic acid (1-hydroxy-5-oxo-5H-pyrid
The inventors have found that o (3,2-a) phenoxazine-3-carboxylic acid) or a salt thereof has a preventive and therapeutic action on steroid cataract, and completed the present invention.

Means for Solving the Problems That is, the present invention provides "1-hydroxy-5-oxo-5".
A steroid cataract preventive and therapeutic agent comprising H-pyrido (3,2-a) phenoxazine-3-carboxylic acid or a pharmacologically acceptable salt thereof as an active ingredient. Is the gist.

1-Hydroxy-, which is the active ingredient of the prophylactic / therapeutic agent of the present invention
5-oxo-5H-pyrido (3,2-a) phenoxazine-3-carboxylic acid is saturated, for example, by adding concentrated sulfuric acid to an aqueous solution of 4,5,6,8-tetrahydroxyquinoline-2-carboxylic acid. It is obtained by dropping potassium ferricyanide or sodium dichromate to obtain 4,6-dihydroxyquinolinequinone-2-carboxylic acid, then dissolving this and orthoaminophenol in acetic acid, and concentrating under reduced pressure. Starting material 4,5
6,8-Tetrahydroxyquinoline-2-carboxylic acid can be obtained, for example, by reacting ethyl 5,6,8-trimethoxy-4-hydroxyquinaldinate with hydriodic acid. (See Japanese Patent No. 254823).

1-hydroxy-5-oxo-5H-pyrido (3,2-
The a) phenoxazine-3-carboxylic acid may be a free compound or a pharmacologically acceptable salt. Examples of the salt include alkali metal salts, ammonium salts, amine salts and the like.

The prophylactic / therapeutic agent of the present invention is administered orally or parenterally, and it is most effective to administer it as an eye drop. In the preparation of eye drops, a buffer for adjusting pH (phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, etc.), isotonicity agent (sodium chloride, etc.), Antiseptic / bactericidal agents / preservatives, stabilizers, etc. may be contained.

In the case of eye drops, the dose and frequency of administration are, for example, 1
It is suitable to apply 1 to 2 drops 5 times a day (at wake-up, at bedtime, after each meal) about once.

The acute toxicity of the active ingredient of the present invention is shown in Table 1 below, which shows high safety.

The prophylactic / therapeutic agent of the present invention includes chronic articular rheumatism receiving systemic steroid therapy, systemic lupus erythematosus, psoriatic arthritis,
It is useful for the purpose of preventing the occurrence of steroid cataract in patients with nephrosis, chronic nephritis, purpura nephritis, etc., or effectively suppressing the progress thereof, and further absorbing the generated lens opacification.

Therefore, in patients undergoing steroid therapy, administer this drug prophylactically, and start the administration of this drug immediately if a slight cloudiness is observed in the lens, paying close attention to the condition of the lens. It is preferable to administer the prophylactic / therapeutic agent concurrently with steroid therapy.

The origin of development of morphological abnormalities of the lens by steroids is that steroid drugs cause a decrease in the ability of the epithelial cells to grow in front of the lens, which in turn impairs the differentiation of these cells into lens fibers. It is speculated that the cells will be pushed into the posterior subcapsule from the equator to the posterior pole while accumulating in the form of epithelial cells, accumulating there, and degenerating to form a characteristic opacification. In other words, the steroid cataract has a completely different histological origin from those of senile cataract, in which the constituent fibers of the lens are swollen and opaque, and diabetic cataract.

Thus, reduced glutathione in the lens is reduced by the action of steroids, and the cell membrane becomes oxidized and becomes fragile, but in the present invention, 1-hydroxy-5- which is a compound contributing to the redox system. By the action of oxo-5H-pyrido (3,2-a) phenoxazine-3-carboxylic acid, the oxidation state of the membrane constituting the lens is improved, and as a result, the progression of steroid cataract is effectively suppressed, and Is believed to absorb lens opacity.

EXAMPLES Next, the present invention will be further described with reference to examples.

Formulation Example Formulation Example 1 1-Hydroxy-5-oxo-5H-pyrido (3,2-a) phenoxazine-3-carboxylic acid 5.0 mg Potassium chloride 200 mg Boric acid 1200 mg Borax 4.4 mg p-Hydroxybenzoic acid propyl ester 20 mg was dissolved in sterilized purified water so that the total amount became 100 ml, and then sterile filtered under aseptic conditions to obtain eye drops.

Formulation 2 1-Hydroxy-5-oxo-5H-pyrido (3,2-a) phenoxazine-3-carboxylic acid sodium salt 5.36 mg Glycerin 2600 mg Chlorobutanol 200 mg Methyl p-oxybenzoate 26 mg After dissolving in water to make the total volume 100 ml, sterile filtration was performed under aseptic conditions to obtain eye drops.

Experimental Example The effect of this therapeutic agent on steroid cataract was examined in vitro.

Experimental method Rat lenses were cultured in a basic culture medium containing 850 μg / ml steroid at 37 ° C. for 48 hours, and 1-hydroxy-5-oxo-5H-pyrido (3,2-a) phenoxy in response to steroid-induced lens changes. The effect of sagin-3-carboxylic acid (test compound) was examined.

As the steroid, water-soluble sodium methylprednisolone succinate was used, and the test compound was added to the basal medium at 10 ⁻⁶ M.

The water content as an index of the change in the lens was calculated by the following formula.

Moisture content = [lens wet weight (mg) -lens dry weight (mg)] / lens wet weight (mg) Experimental results are shown in Table 2.

As shown in the above table, it can be seen that the addition of the test compound 10 ⁻⁶ M significantly suppressed the increase in the lens water content due to the steroid.

Clinical trials (patients and therapies) Systemic diseases such as lupus erythematosus, nephrosis, chronic nephritis, purpura nephritis, etc., who have taken medrol or prednin as a steroid for 1 year to 7 years 8-15
A total of 26 eyes of 13 patients up to the age of 6 (6 boys and 7 girls) were given the above-mentioned prescription 1 eye drops 5 times a day (at wake up, at bedtime,
After each meal), eye drops were applied and traces of treatment for 200 to 300 days were performed. Of the 26 eyes, 2 people and 4 eyes did not yet have steroid cataract at the time of the first ophthalmology examination.

(Observation and Recording Method) The pupils were observed once every month with Midrin and the lens was observed with a slit lamp microscope to record the findings in a medical record, and at the same time, the images were taken with a photographing device for a slit lamp microscope.

The degree of opacity of the lens was judged according to the following 6 levels.

++++ Severe most opaque lens all layers +++ Weight turbidity extending to the lens cortex ++ Moderate patchy or nebula fine gray-white particulate turbidity in the posterior pole of posterior capsule There is nodular turbidity in the center of it + Mild mild microscopic opacity in the posterior subcapsule with no nodular opacity or small nodules ± Microscopic turbidity very slight + Asymptomatic crystalline lens that is completely transparent (therapeutic effect evaluation criteria) The therapeutic effect was judged in the following 5 stages.

1. The lens that was cloudy (+) was treated with 1 month treatment (-).
When there is no reappearance of turbidity, (++) becomes (-). Even if it takes 1 month or more for the valid (+) to disappear, it becomes (-). (+++) becomes (++) (++) becomes (+) 3 ． 3. Changes During the follow-up observation, when the opacity of the crystalline lens once disappeared appears again, or the reduced opacity becomes thicker, or the opacity becomes stronger or lighter, 4. 4. No change was observed in the size and shade of the lens opacity during the course of the change. Deterioration Increased opacity of lens (procedure and result of treatment) Table 3 shows the course and result of treatment.

(See Table 3) (Treatment results) Table 4 summarizes the treatment results in Table 3.

That is, it can be seen that a remarkable effect is recognized in about 1/3, and the therapeutic effect is recognized in more than 40% when the effect is included.

Tables 5 to 7 show the relationship between the steroid oral administration period and the therapeutic effect.

(See Table 5 to Table 7) In Tables 5 to 7, those in the diagonal mesh line from the diagonally upper left to diagonally lower right did not change before and after the start of the treatment, and those in the square mesh to the lower left of this diagonal line reduced turbidity by the treatment. Those that enter the square in the upper right of this diagonal line have turbidity due to treatment.

That is, the number of eyes with reduced turbidity is 110 to 130 after the start of instillation.
10 eyes per day, 11 eyes from 200 to 250 days, 12 eyes from 250 to 300 days. In addition, turbidity absorption is especially remarkable
It can be seen that the period of oral administration of steroids is as short as 1 to 2 years.

In addition, it can be seen that the progression of steroid cataract is sufficiently suppressed in consideration of the fact that the administration of steroids is continued while the oral administration is continued even though there is no change before and after the start of treatment.

EFFECTS OF THE INVENTION The prophylactic / therapeutic agent of the present invention is useful as a prophylactic / therapeutic agent for steroid cataracts because it can prevent the occurrence of steroid cataracts, effectively suppress the progress thereof, and absorb opacity of the lens. is there.

Further, the preventive / therapeutic agent of the present invention has 1-hydroxy-5-oxo-5H-pyrido (3,2), which has already been used as a therapeutic agent for senile cataract and diabetic cataract for many years.
-A) Since it uses phenoxazine-3-carboxylic acid or a salt thereof, it is also advantageous in terms of high safety.

Claims (2)

[Claims] 1. A steroid cataract comprising 1-hydroxy-5-oxo-5H-pyrido (3,2-a) phenoxazine-3-carboxylic acid or a pharmacologically acceptable salt thereof as an active ingredient. Preventive and therapeutic drugs. 2. The preventive and remedy for cataract according to claim 1, which is an eye drop.