JP4074640B2 - Preventive or therapeutic agent for endometriosis - Google Patents

Description

  The present invention relates to a preventive or therapeutic agent for endometriosis.

  Endometriosis is a disease in which endometrium or intima-like tissue expands ectopically at sites other than the inner surface of the uterine cavity. The cause of endometriosis is unknown, and treatments such as surgical removal of adhesions, administration of hormones, administration of analgesics, etc. are performed, but these are all symptomatic treatments and are fundamental treatments There is no way.

  An object of the present invention is to provide a drug effective for the prevention and treatment of endometriosis.

  The inventor of the present application stains ectopic endometriosis-like tissue (endometriosis material) of endometriosis patients and tissues collected from similar sites of healthy subjects by various methods, and is observed with a microscope and an electron microscope. I did research. As a result, invasion of mast cells and their degranulation and stromal component increase were observed in the endometriosis material of endometriosis patients. These are typical signs of type I allergy, and therefore the essence of endometriosis was found to be allergic inflammation. Therefore, the present inventor considered that treatment of endometriosis with antiallergic drugs is possible, and administered a plurality of commercially available antiallergic drugs to an endometriosis animal model and examined the therapeutic effect. As expected, it was experimentally confirmed that the symptoms of endometriosis were clearly suppressed by the antiallergic drug, and the present invention was completed.

  That is, the present invention provides a preventive or therapeutic agent for endometriosis containing an antiallergic agent as an active ingredient.

  The present invention revealed that the essence of endometriosis is allergic inflammation, and it became possible to fundamentally treat and prevent endometriosis.

  The present inventor has found for the first time in the world that the essence of endometriosis is allergic inflammation. The present invention has been made based on this new finding. Since the symptoms of endometriosis can be reduced by reducing allergic symptoms, the antiallergic agent contained in the preventive or therapeutic agent for endometriosis according to the present invention is an allergy treatment. And / or any antiallergic agent effective for prevention can be employed.

  The antiallergic agent used in the present invention is a type I allergy reaction inhibitor or antagonist, a chemical transmitter release inhibitor from mast cells, a synthetic enzyme inhibitor, a chemical transmitter antagonist (such as an antihistamine) Is included. Various types of such antiallergic drugs are known, and are used for the treatment of bronchial asthma, allergic rhinitis, allergic dermatitis, and the like, which are typical diseases of type I allergy, and have antihistaminic activity. Some are included and some are not. In the present invention, any of these known antiallergic drugs can be used. Examples of antiallergic agents that can be used in the present invention include cromoglycic acid, tranilast, amlexanox (amlexanox), repirinast, tazanolast, pemirolast K, suplatast, ketotifen, azelastine, oxatomide, terfenadine (terfenadine), mequitazine, Emedastine, epinastine, astemizole, ipdilast, pecilast, ozagrel, seratrodast, pranlukast, ebastine, cetirizine, cyproheptadine, chlorpheniramine, homochlorcyclidine, hydroxyzine and clemastine and their pharmacologically acceptable salts and hydration However, the present invention is not limited to these. Of these, epinastine, ketotifen and pranlukast and their pharmacologically acceptable salts and hydrates are particularly preferred.

  The pharmacologically acceptable salts include acid addition salts such as hydrochloride, sulfate, fumarate, maleate, tartrate, citrate and tosylate and when the active compound is an acid. Although metal salts, such as a sodium salt, potassium salt, and a calcium salt, can be mentioned, It is not limited to these.

  The prophylactic or therapeutic agent for endometriosis of the present invention can be administered by a route recognized for an antiallergic agent which is an active ingredient. As the administration route, oral administration, for example, intravenous administration, subcutaneous administration Any of parenteral administration methods such as intramuscular administration and enteral administration are also included. Oral administration is usually convenient and preferred. The dose is appropriately set according to the degree of symptoms of the patient and the type of antiallergic agent used, but the amount of the active ingredient of the antiallergic agent per day for an adult is, for example, about 10 mg to 20 mg in the case of epinastine hydrochloride. The various active ingredients are effective at dosages that are used to treat allergies.

  For the formulation, any formulation method commonly used in the field of pharmaceuticals can be employed. For example, it can be granulated with additives such as lactose, polyoxyethylene sorbitan fatty acid ester, propylene glycol or sodium lauryl sulfate, and tableted into tablets based on conventional methods, but is not limited thereto. Absent. Since the above-mentioned various antiallergic drugs are commercially available, these prepared antiallergic drugs can be used in the present invention.

  Antiallergic drugs have already been used as therapeutic agents for various allergies such as bronchial asthma, allergic rhinitis, and allergic skin salts, and thus have been confirmed to be safe enough for pharmaceutical products.

  Hereinafter, the present invention will be described more specifically based on examples. However, the present invention is not limited to the following examples.

Reference Example 1 Observation of human endometriosis specimens Collected intrapelvic adhesion lesions of patients with endometriosis (external endometriosis), stained with hematoxylin and eosin or toluidine blue by a conventional method, and examined with an optical microscope Observed. The observation magnification was 10 times for the hematoxylin-eosin stained sample and 20 times or 100 times for the toluidine blue stained sample. Further, the same tissue was stained with uranium and lead by a conventional method, and observed with an electron microscope at a magnification of 3000 to 5000 times.

  As a result, infiltration of mast cells was observed in toluidine blue-stained specimens of endometriosis patient tissues, and degranulation of mast cells was observed along with infiltration of mast cells by electron microscope observation. The main collagen fiber was observed. On the other hand, mast cell infiltration, degranulation, and collagen fibers were not observed in the healthy subjects. Mast cell infiltration and its degranulation are signs of type I allergy. From the above microscopic observation, it was found that the essence of endometriosis is allergic inflammation.

Comparative Example 1 Observation of Endometriosis Specimens in Untreated Endometriosis Model Rats Endometriosis model rats are Michael W. Vernon et al., FERTILITY AND STERILITY, Vol. 44, No. 5, November 1985. It was produced by the method described in 1. That is, endometriosis model rats were prepared as follows. 8 weeks old Sprague-Dawley rats (female) were acclimated for 12 hours in a light and dark environment for 2 weeks, and then the right uterine horn was removed under general anesthesia with sevoflurane and ketamine hydrochloride, 5 x 5 mm uterine tissue A piece was made and autografted with the endometrial surface facing the peritoneum.

  Seven days after the model creation, which is the peak of the model lesion, the peritoneal tissue including the graft was excised to the abdominal muscle and the lesion material was collected. From these materials, optical microscope specimens (hematoxylin / eosin staining, toluidine blue staining) and electron microscope specimens (uranium / lead heavy staining) were prepared, and optical microscope observation was performed as in Reference Example 1 (however, hematoxylin / eosin staining was magnified) 4 times, toluidine blue staining was 20 times magnification) and electron microscope observation.

  As a result, infiltration of mast cells and stromal cell proliferation were observed by toluidine blue staining, and infiltration of eosinophils and lymphocytes was observed in addition to infiltration of mast cells by electron microscope observation.

Example 1 Therapeutic effect of administration of epinastine hydrochloride Endometriosis model rats were prepared by the same method as Comparative Example 1. From 24 hours after model preparation, an antiallergic drug (trade name “Alesion Tablet”, manufactured by Boehringer Ingelheim Co., Ltd.) containing epinastine hydrochloride as an active ingredient is orally administered as epinastine hydrochloride at a dose of 0.04 mg / kg body weight per day for 6 days. After administration, the peritoneal tissue including the graft was excised to the abdominal muscle 7 days after the model preparation, which was the peak of the model lesion, and the pathological material was collected. The collected pathological material was stained in the same manner as in Reference Example 1 and observed with an optical microscope and an electron microscope.

  As a result, a clear inhibitory effect was observed with respect to mast cell infiltration as compared with Comparative Example 1. Furthermore, in the observation with an optical microscope and an electron microscope, apoptosis of fibroblasts was observed, and the effect of suppressing stromal cell proliferation by inducing apoptosis of stromal cells, particularly fibroblasts, was remarkably recognized. These revealed that epinastine is effective in the treatment of endometriosis.

Example 2 Treatment effect by administration of ketotifen fumarate In place of an antiallergic agent containing epinastine hydrochloride as an active ingredient, an antiallergic agent (trade name “Zaditen”, manufactured by Ciba Geigy Japan, Inc.) containing ketotifen fumarate as an active ingredient was administered. Except this, the same operation as in Example 1 was performed.

  As a result, a clear inhibitory effect was observed with respect to mast cell infiltration as compared with Comparative Example 1. Furthermore, in the observation with an optical microscope and an electron microscope, apoptosis of fibroblasts was observed, and the effect of suppressing stromal cell proliferation by inducing apoptosis of stromal cells, particularly fibroblasts, was remarkably recognized. These revealed that ketotifen was effective in treating endometriosis.

Example 3 Treatment effect by administration of pranlukast hydrate Instead of an antiallergic drug containing epinastine hydrochloride as an active ingredient, an antiallergic drug containing pranlukast hydrate as an active ingredient (trade name “ONON capsule”, Ono The same operation as in Example 1 was performed except that the daily dose was 9 mg / kg as pranlukast hydrate.

  As a result, regarding mast cell infiltration, a remarkable inhibitory effect was observed as compared with the case of Comparative Example 1. The effect of suppressing mast cell infiltration was even more prominent than in Examples 1 and 2. Furthermore, in the observation with an optical microscope and an electron microscope, apoptosis of fibroblasts was observed, and the effect of suppressing stromal cell proliferation by inducing apoptosis of stromal cells, particularly fibroblasts, was remarkably recognized. As a result, it was revealed that pranlukast is effective in treating endometriosis.

Claims (1)

  A prophylactic or therapeutic drug for endometriosis comprising epinastine, ketotifen or pranlukast, or a pharmacologically acceptable salt or hydrate thereof as an active ingredient.