JPS61126022A - Agent for suppressing migration of leukocyte - Google Patents

Abstract

PURPOSE:To provide a preventive and remedy, containing gamma-linolenic acid as active component, capable of suppressing the migration of leukocyte, especially neutrophilic leukocyte, useful for the remedy of rheumatoid arthritis, psoriasis vulgaris, palmar pustulosis, and nephritis, having low side effects, and administrable for a long period. CONSTITUTION:The objective agent contains gamma-linolenic acid as an active component. gamma-linolenic acid which is an essential fatty acid existing in evening primrose oil, etc. has an action to suppress the migration of leukocyte, especially neutrophilic leukocyte, and can be used as a remedy of rheumatoid arthritis, palmar pustulosis, and nephritis supposed to be caused by the uncontrollable migration of leukocyte, especially neutrophilic leukocyte. Furthermore, it can be applied without necessitating the tonsillectomy nor the administration of steroid preparation, and is usable as a preventive continuously for a long period. The daily dose of gamma-linolenic acid is preferably 5-30mg for adult, corresponding to about 100-500mg of the evening primrose oil, which is an amount to be acceptable without causing the undesirable odor after administration.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a leukocyte migration inhibitor, and further relates to a therapeutic agent for nephritis, rheumatoid arthritis, psoriasis vulgaris, and a prophylactic agent for these.

(b) Prior Art In general, inflammation is a reaction of tissue cells in response to exacerbation of inflammation, followed by the initiation of extravascular permeation of proteins in the microcirculatory system, and the emigration, infiltration, and proliferation of leukocytes. This is a reaction that further passes through granulation formation and ends in healing, but these reactions are considered to be both independent reactions and at the same time a chain reaction that is interconnected.

First, in nephritis, antigen-antibody complexes are deposited in the glomerulus and urinary #Il duct basement membrane, complement is activated, and leukocytes, especially neutrophils, infiltrate, and from here various types of It is thought that inflammatory active substances are absorbed and cause lesions, and in the case of rheumatoid arthritis, antigen-antibody complexes, complement, and neutrophils are present in the joint cavity, so 1. It is thought that activated complement causes neutrophils to gather and release various inflammatory substances, causing lesions in the synovial membrane.

In the case of Ichiki IEi, leukocyte chemotactic factor of complement mesomorphosis is present in the skin, which is thought to cause infiltration of neutrophils.

In this way, when complement is activated, not only leukocyte migration factors but also factors that attract leukocytes from the bone marrow and anaphyllatoxin (anaphyllatoxin), which increases vascular permeability and releases histamine, are released.
phylatoxin) is produced, and locally infiltrated neutrophils release lysosomal enzymes to destroy tissue. In rheumatoid arthritis, the perichondrium is destroyed by lysosomal enzymes, and complement is further activated by islet collagen.

Neutrophils also have a proteolytic enzyme that decomposes complement yJ1 and turns it into a migration factor, so once neutrophils infiltrate and become activated, neutrophils themselves can ! In addition, various inflammatory active substances are produced, and inflammation progresses.

By the way, it is well known that rheumatoid arthritis, palmoplantar pyorrhea, nephritis, etc., can be cured by removing tonsills infected with the focal infection. Despite this, it is characterized by a large amount of neutrophil infiltration, which is caused by some cause such as metal allergy in the palms and heels.
It is thought that the neutrophil'ItL chemotactic factor is generated, resulting in the recruitment of neutrophils to the lesion.

As described above, antibiotics, steroids, anti-inflammatory drugs, etc. are used as therapeutic agents for inflammation caused by the runaway phenomenon of white blood cells, especially neutrophils, that occur in RTI rheumatoid arthritis, pyogenes, and nephritis. However, it is temporary, non-persistent and symptomatic. Moreover, the side effects of these drugs cannot be ignored.

Recently, the precursor free fatty acid of brostaglanson, nohomo-γ-ly/I/I, suppressed the activity of 27 lymphocytes.
It has been reported that neutrophil migration is suppressed without ilJ.

However, nohomo-gamma-linolenic acid exists only in very small quantities in the world, and is extremely expensive, so it is not used as a leukocyte inhibitor that suppresses the periapsis of leukocytes, especially neutrophils. ,
115 for widespread use.

(C) Structure of the Invention The present invention provides a leukocyte inhibitor that suppresses the migration of leukocytes and neutrophils without removing fission lesions or requiring administration of steroids or the like. It is something to do.

The present invention suppresses the prevention of such leukemia DR, thereby treating 13g node richness, psoriasis vulgaris, and palmar pus, which conventionally required tonsillectomy and were difficult to treat. For mania and nephritis, it can be treated without provocative surgery and without the need for steroids, etc. (It is a therapeutic agent that can be used as a prophylactic drug for Lc 3!ll. 0().

That is, the present invention resides in a leukocyte migration inhibitor characterized by containing γ-lylunic acid.

In the present invention, linoleic acid can be used in combination with γ-ly/lenic acid.

In the present invention, the γ-lylunic acid used is not produced within the fIJ body and must be ingested from food, ie, it is an essential fatty acid. For sulfuric acid, linseed oil, cotton sap oil, sunflower 178 seed oil,
Although present in many plants such as sesame oil, peanut oil, olive oil, and corn oil, γ-ly/lenic acid is present only in evening primrose seed oil, evening primrose oil, e.g., Oenothera ′bienn.
is), Enothera lamarchiana (Oenother
aIamarckiana) and Enocera Hata Hockeri
Seed oil of (Oenothera hookeri) as well as Me of Alkanaceae, Sesame/Ciberaceae, e.g. If Alkan-na-7a,
froeclinii), Scrophularia (5ra-yank)
Among these seed oils, which are only present in the seed oils of
In particular, evening primrose oil contains about 6% of the total fatty acids.
%, preferably containing about 72% of phosphoric acid and containing the 7-lyric acid of the present invention, and with γ-phosphoric acid and linoleic acid as the main components. It is preferable to use them together, but γ-ly/lenic acid may be extracted and used alone.

In the treatment of rheumatoid arthritis, psoriasis vulgaris, psoriasis and nephritis, γ-ly/lenic acid is 5 to 30 + r so, and evening primrose oil is about 10
0. to about 50 (l town r) is used.

When taking evening primrose oil at a dosage of -, one cannot help but feel a sense of discomfort or resistance that exists in the raw material evening primrose oil.

This dose is much lower than the conventional dosage of evening primrose oil for the treatment of rheumatoid arthritis, e.g. 2-20 g. and 11,1 Qi (eructation) after taking
In addition, the therapeutic agent of the present invention also refers to preventive treatment, and it is desirable to take it every day. It has the effect of significantly reducing the feeling of resistance.

In addition, the inventor has recently focused on the increase in protein intake and decrease in the intake of unsaturated fatty acids in the Japanese diet as the diet becomes more Westernized. As mentioned above, these symptoms or phenomena can be suppressed by administering γ-lylunic acid, which has been found to be correlated with an increase in the runaway phenomenon of neutrophils.On the other hand, unsaturated fat Since excessive intake of a can worsen infectious diseases, high intake of γ-lylunic acid, adult 1
Intake of more than X00η per day is undesirable, from more than 0 to γ-
A dose of 511y to 30η per day for adults is a necessary and appropriate dose of rinnic acid.

The therapeutic agent of the present invention may be used for oral, enteral, parenteral or local administration, etc. together with a suitable pharmaceutical carrier.

Therefore, 5In is contained in, for example, tablets, capsules, oral a medicines, inhalation liquid medicines, powder pharmaceuticals, suppositories, and the like.

The hydrolyzed injection solution of evening primrose oil is 'i! 1
Use Fulpmin to solubilize the lytic acid! ! I can leave it behind. Further, it is preferable to mix, for example, about 0.1 ffl amount % of la R core x roll into the pharmaceutical product to prevent oxidation.

The results of toxicity and one-drug implantation tests shown below demonstrate that the present invention inhibits neutrophil 'II7.

Acute Toxicity 1 #1 Using 10 mice with 4 withdrawals from LCr1 mice, we investigated the acute Nl toxicity during oral administration of evening primrose oil, and found that LD50 was 500.0η.
/k11 or higher.

Pharmacological test Lewis rats were used, and a group to which evening primrose oil was not administered was established in contrast to a group administered with evening primrose oil.
Every day from 1 pm onwards, 0.75 J/day of evening primrose oil was added to the feed.

Neutrophils were taken out from each group and a ':x' test was performed to compare their migration ability.

For each experiment, neutrophils were collected from 5 to 6 animals in the evening primrose oil administration group and the evening primrose oil non-administration group, and N-formyl-monomethionyl-L-leucil-monophenylalanine (
N-f ormy 1-L -methionyl-
L-1eucyl-L-phenylalanine
(hereinafter referred to as F-met-1eu-phe)) 10-
5 molar solution, F-met-] 10-molar solution of eu-phe, 10-molar solution of F-met-1e up-phe
Migration ability using these as migration factors and Hanks' 4!137 lysis using -9 molar solution Drar+kq
balancccls a It So 1 u
The i71:ability (migration ability in the natural state) was investigated using t i on ).

The experiment was conducted 5 times, and when comparing the data by taking the average of the data from 5 times, it was found that the neutrophils in the Yamaki group without evening primrose oil were significantly lower than the neutrophils in the Yumi group when evening primrose oil was administered. The results showed that the migratory ability was down by more than 60%.

This revealed that evening primrose intake suppressed the migratory ability of neutrophils in Lewis rats.

``'' Example A11 The evening primrose oil used in this example was obtained by extraction with cold hexane, and then purified by deacidification, decolorization, deodorization, etc., and the encapsulated rhinoceros was used for the experiment.

Example 1 Evening primrose oil was administered to a patient who had already experienced 2 m of palmar abscess.

In 5 cases of palmar abscess, the patient was too old or was unable to undergo surgery due to his own will, so one tablet of 250 yen of Tsukimi Fuqu capsules was administered every day per month.

In 5 patients in this administration group, all pages were printed on the model and the heel 2 weeks after administration. It was observed that the development of pus was beginning to be suppressed, and 10 pus were dissolved in 1 month.

Example 2 - Tsukimi r″F and oil injections were administered to patients who had already developed Sjogren's disease.

In seven cases of N.Egren's disease, one evening primrose oil capsule of 250 η was administered daily for two months.

In 7 patients in this administration group, the metal fittings were removed one month after the injection.
Saliva and tear secretion started, and the thirsty feeling in the throat was relieved by ingesting 3 ft of water every day before administration, but this intake was reduced by about half.

(e) Effects The leukocyte migration inhibitor of the present invention naturally inhibits leukocyte migration, particularly neutrophil migration.Due to this inhibitory effect, conventional steroid drugs have been It can be used to treat rheumatoid arthritis, plaque psoriasis, palmar malignancies, nephritis, etc. that require tonsillectomy, without performing focal tonsillectomy, and without requiring the administration of steroids, etc. It is something that can be given.

The leukocyte migration R inhibitor of the present invention exerts not only these therapeutic effects but also preventive effects on the nails. It has a major feature in ζ. Furthermore, the main component is the essential fatty acid γ-
It is lyrinnic acid, which must originally be ingested externally through food, etc., and is excellent as a therapeutic and preventive drug since it has almost no side effects.

In addition, the leukocyte inhibitor of the present invention can be used for one day in adults! Even if a small amount of γ-lylunic acid is as low as 5 to 30η, it can control and normalize leukocyte migration, and such administration can also control and normalize leukocyte migration, thereby preventing rheumatoid arthritis. For psoriasis vulgaris, symptomatic disease, nephritis, etc., do not perform provocative excision of the lesion (and do not require the administration of steroids, etc., which can increase the therapeutic effect). be.

Then, when throwing and receiving γ-ly/lenic acid, γ-
Even if evening primrose oil containing linoleic acid other than linolenic acid is used, the amount is as small as 100 to 500η, so even if it is taken constantly for treatment and P prevention,
Even if γ-lyric/lenic acid is ingested in large quantities (more than 100w), there is no change in the effect, and on the contrary, the infection will worsen, so it is not preferable.
When taking evening primrose oil with a concentration of L500η, there is no discomfort caused by the unpleasant odor accompanying the impure components of evening primrose oil when taking it, and it is easier to take, making it excellent for long-term use.

As the leukocyte migration inhibitor of the present invention, for example, evening primrose oil containing linoleic acid in addition to γ-ly/lenic acid can be used. In this case, γ-lyric acid is produced in the body from phosphoric acid by the action of dehydrogenase in the body, so
It is possible to enhance γ-lylunic acid by increasing the amount of coexisting sulfuric acid. Therefore, for example, even if this function is decreased due to regular alcohol use, etc., the supply of arylinic acid can be continued, so treatment and prevention can be performed regardless of whether or not the γ-lylunic acid production function is decreased. I can do it.

As described above, the present invention is based on leukocyte migration, which has been considered to be an incurable disease (rheumatoid arthritis, psoriasis vulgaris,
a) It enables radical treatment of asahi syndrome and nephritis without the need for provocative removal of lesions, etc., and without the need for administration of steroids, etc.; be.

Claims (1)

[Claims] A leukocyte migration inhibitor characterized by containing γ-linolenic acid.