JPH0224250B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD The present invention relates to vascular growth inhibitors. More specifically, the present invention relates to a vascular growth inhibitor whose main ingredient is a substance having an anti-inflammatory effect. Blood vessels are important for living organisms, especially animals with closed vascular systems, as sites for physiological functions essential to sustaining life, such as transporting and supplying nutrients to tissues and organs and transporting unnecessary waste products from tissues and organs. Many studies have been conducted on the new construction of the vascular system or the maintenance and improvement of vascular function, focusing on cases of hypertension, ischemic diseases, etc.
Recently, it has been discovered that the vascular system, which controls such essential functions for living organisms, sometimes proliferates abnormally and becomes a factor in triggering or aggravating various pathological conditions. For example, it is known that in a certain percentage of diabetic patients, abnormal growth of capillaries occurs in the vitreous body of the eyeball, sometimes leading to blindness. Currently, it is the number one cause of death in Japan.
It is also known that host blood vessels grow abnormally in the direction of the cancer (J.
Folkman: Bessatsu Science pp. 85-97, Nikkei Science, 1981). Unless there is such abnormal proliferation of host blood vessels, it is impossible for solid tumors to grow beyond a few millimeters in diameter, and no fatal cancer pathology that threatens the host's life is induced. The present inventors came up with the idea that if abnormal growth of blood vessels could be suppressed or prevented, various pathological conditions could be prevented or treated, and after extensive investigation, they found that a substance with anti-inflammatory effect (hereinafter referred to as this substance) The present invention was completed based on the finding that the drug (abbreviation) has antipyretic, analgesic, and antiinflammatory effects as well as pharmacological effects of inhibiting blood vessel proliferation. Conventionally, there has been no invention that has enabled the prevention and treatment of pathological conditions from this standpoint, and the present invention can be said to provide an epoch-making preventive and therapeutic agent. The substance may be any of the steroidal or non-steroidal substances listed below. Steroids: cortisone acetate, hydrocortisone acetate, prednisolone, dexamethasone, dexamethasone sodium phosphate Non-steroids: aniline derivatives: acetalinide, acetaminophene, phenacetin, lactyl phenetidine, busetin, phenyl acetylglycine dimethylamide, bromanilpro Midosalicylic acid derivatives: salicylic acid, sodium salicylate, calcium salicylate, salicylsalicylic acid, aspirin, aluminum aspirate, choline salicylate, methyl salicylate, salicylamide, ethoxybenzamide Quinophene series: quinine ethyl carbonate, quinine hydrochloride, quinine sulfate, quinophene pyrazolone Derivatives: aminopyrine, sulpyrine, aminopropyrone, antipyrine, isopropylantipyrine, miglenin, phenopyrazone, nifenazone, phenylbutazone, oxyphenbutazone, ketophenylbutazone, clofezone, azapropazone, sulfinpyrazone, difenamizole Anthranilic acid series: mefenamic acid , aluminum flufenate, flufenamic acid, niflumic acid, graphenine Phenyl acetic acid series: ibuprofen, alclofenac, ketoprofen, naproxen, flurbiprofen, fenbufen, ibufenac, diclofenac sodium, fentiazac Pyrimidine series: bucolome, mepirizole phenothiazine series Methiazine acid, protidic acid, dimethothiazine Indoleacetic acid type; Indomethacin, Tolmetin sodium, Sulindac, Clidanac Basic type: Tinoridine hydrochloride, Tiaramide hydrochloride,
Perisoxal citrate, benzydamine hydrochloride Others; tribenoside, benfepazone, pheniramidol hydrochloride, cymetride, diphenyldimethylaminoethane hydrochloride, etoheptadine, pentazocine, azahicyclan, propoxyphen hydrochloride, propoxyphen napsylate, colchicine, benzbromarone, probenecid, Imipramine, carbamazepine, bumadizone, piroxicam, fenoprofen calcium, pranoprofen, sazapirin, fueprazone These substances are listed in the Pharmaceutical Directory Comprehensive New Edition (Yakugyo Jihosha, published on May 15, 1976), pp. 70-101; Comprehensive Rinbaku Volume 30 Special Issue (Prescription Planning Method), pp. 55-60 and
pp. 178-180, 1981; Sogo Rinsai Vol. 39 Spring Special Issue, pp. 156-160, 1981; Japanese Pharmaceutical Collection (No. 5)
Edition) Yakugyo Jihosha (1979); drug name search dictionary Yakugyo Jihosha (1981), etc. When the effect of this substance on inhibiting blood vessel growth was investigated using the method described in "Igaku no Ayumi Vol. 122, p. 890, 1982", it was confirmed that abnormal growth of blood vessels derived from experimental animal tumors was significantly inhibited. It was done. In addition, it has been confirmed that blood vessel proliferation is suppressed in the primary lesion and metastatic area of cancer-bearing patients, and abnormal growth of capillaries in the vitreous body is suppressed in symptoms of proliferative retinitis and diabetic retinopathy. was confirmed. As mentioned above, this substance has an inhibitory effect on blood vessel growth, so it can be used to treat proliferative retinitis, rheumatoid arthritis,
It is effective in the prevention and treatment of pathological conditions such as psoriasis, diabetic retinopathy, retinopathy of prematurity, and tumors. When this substance is used as a vascular growth inhibitor, it can be provided in a dosage unit form containing a sufficient amount of the active ingredient to obtain a medicinal effect depending on the symptom.
For oral use, it can take the form of powder, fine granules, granules, tablets, buffered tablets, sugar-coated tablets, capsules, syrups, pills, suspensions, solutions, emulsions and the like. For parenteral use, it can be in the form of an ampule or bottle as an injection solution. It may also be in the form of suppositories or ointments. The substance may be used alone or in admixture with pharmaceutically acceptable diluents and other agents, including solid, liquid, or semi-solid excipients, fillers, binders,
Wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, fragrances, preservatives, solubilizing agents, solvents, and the like may be used. When the substance is used in the form of a formulation, the active ingredient in the formulation is generally 0.01 to 100% by weight, preferably 0.05%.
Contains ~80% by weight. The substance is administered orally or parenterally to humans and animals. Oral administration includes sublingual administration. Parenteral administration includes injection administration (eg, subcutaneous, intramuscular, intravenous injection, infusion), rectal administration, and the like. May be applied. The dose of this substance depends on whether it is an animal or a human, and is influenced by age, individual differences, medical conditions, etc. In some cases, doses outside the range below may be administered, but in general, when administering to humans, The dose of the substance is 1
0.1-1500mg/Kg per day, preferably 1-500mg/
Kg. It may be administered in divided doses 2 to 4 times a day. The present invention will be further explained below with reference to Examples. Example 1 Suppression of abnormal vascular growth and improvement of cancer pathology in mice derived from Sarcoma-180 tumor. Dorsal fascia of 8-week-old ICR mice - tumor cell line (Igaku no Ayumi Vol. 122, p. 890, 1982) in,
Abnormal vascular proliferation in host mice derived from Sarcoma-180 tumors was detected using 5 × 10 ⁶ Sarcoma-180 tumor cells.
When the cells were sealed in a Millipore diffusion chamber (PR000/401, manufactured by Millipore Japan Co., Ltd.) and examined on the 9th day after transplantation, significant abnormal vascular proliferation was observed as shown in FIG. On the other hand, when tolmetin sodium was orally administered at 100 mg/kg/day on the 3rd, 5th, and 8th days after transplantation and examined on the 9th day, no abnormal growth of blood vessels was observed as shown in Figure 2. First, the inhibitory effect on abnormal vascular proliferation was confirmed. Based on this result, ¹⁰⁶ Sarcoma-180 tumor cells were subcutaneously transplanted into ICR mice, and 3, 5, 8 days after transplantation.
On day 1, 100 mg/Kg/day of tolmetin sodium was forcibly administered orally. The control group received 3,
On days 5 and 8, physiological saline alone was orally administered. Table 1 shows the results of determining the tumor growth inhibition rate from the average tumor weight on the 25th day after transplantation (average value of 5 animals in each group). As is clear from Table 1, the tolmetin sodium administration group exhibited a tumor growth inhibition rate of 32.0% compared to the control group, indicating that tolmetin sodium has a significant effect on improving cancer pathology.

[Table] Also, phenylacetylglycine dimethylamide 500mg/Kg, sodium salicylate 500mg/Kg,
Aluminum aspirate 1g/Kg, choline satylate 800mg/Kg, salicylamide 500mg/Kg, aminopyrine 100mg/Kg, sulpirine 1g/Kg, phenylbutazone 200mg/Kg, mefenamic acid 500mg/Kg
Similarly, when oral administration of 500 mg/Kg of aluminum flufenamate, 200 mg/Kg of flufenamic acid, or 50 mg/Kg of diclofenac sodium was observed, the effect of suppressing abnormal vascular growth and improving cancer pathology (effect of suppressing tumor growth) was also observed. It was done. Example 2 Suppression of abnormal blood vessel proliferation and improvement of cancer pathology in mice derived from Sarcoma-180 tumor. Dorsal fascia of 8-week-old ICR mice - tumor cell line (Igaku no Ayumi Vol. 122, p. 890, 1982) in,
Abnormal vascular proliferation in host mice derived from Sarcoma-180 tumors was detected using 5 × 10 ⁶ Sarcoma-180 tumor cells.
When the cells were sealed in a Millipore diffusion chamber (PR000/401, manufactured by Millipore Japan Co., Ltd.) and examined on the 9th day after transplantation, significant abnormal vascular proliferation was observed as shown in Figure 3. On the other hand, when 15 mg/kg/day of hydrocortisone acetate was administered on the 3rd, 5th, and 8th days after transplantation, and the study was conducted on the 9th day, no abnormal proliferation of blood vessels was observed as shown in Figure 4. The inhibitory effect on abnormal blood vessel proliferation was confirmed. Based on this result, ¹⁰⁶ Sarcoma-180 tumor cells were subcutaneously transplanted into ICR mice, and 3, 5, 8 days after transplantation.
On day 1, 15 mg/Kg·day of hydrocortisone acetate was administered intramuscularly. The control group received only physiological saline intramuscularly on days 3, 5, and 8 after transplantation. As a result of calculating the tumor growth inhibition rate from the average tumor weight 25 days after transplantation (average value of 5 animals in each group), the hydrocortisone acetate group was approximately 35% compared to the control group.
It was found that hydrocortisone acetate has a remarkable effect on improving cancer pathology. Also, methiazine acid 250mg/Kg, graphenine 1g/Kg, benzydamine hydrochloride 150mg/Kg, bucolome 500mg/Kg, mepirizole 150mg/Kg, azapropazone 500mg/Kg, tinoridine hydrochloride 500mg/Kg,
Clofezone 500mg/Kg, Sulindac 200mg/Kg,
Naproxen 300mg/Kg or Piroxicam 100
Similarly, when mg/Kg was orally administered, the effect of suppressing abnormal vascular growth and the effect of improving cancer pathology (effect of suppressing tumor growth) were observed. In addition, mouse liver cancer MH-134, Lewis lung cancer cells, rat sarcoma, and Walker 256 cells were used as tumors.
Experimental animals were C3H/He mice, BDF ₁ mice,
Similar results were obtained using Wistar rats. Example 3 Effect of suppressing abnormal vascular growth in BDF ₁ mice derived from Lewis lung cancer cells and improving cancer pathology Effect of suppressing abnormal vascular growth in BDF ₁ mice subcutaneously transplanted with 10 ⁶ Lewis lung cancer cells based on Example 1 When examining the effect of improving cancer pathology, it was found that oral administration of tolmetin sodium at 100 mg/kg/day significantly improved cancer pathology.
Results of calculating survival rate (%) from survival days (5 for each group)
Table 2 shows the average values for each animal.

[Table] *Group receiving only physiological saline Similarly, hydrocortisone acetate was administered at 18 mg/Kg/day;
Or, when aspirin was orally administered at 160 mg/kg/day, the survival rate was 134.1% and 130.1%, respectively. Also, Graphenin 1g/Kg, Clidanac 250
mg/Kg, Ketoprofen 150mg/Kg, Fuenoprofen Calcium 250mg/Kg, Fuentiazak 200
mg/Kg, Fuenbufuen 350mg/Kg, Pranoprofen 150mg/Kg, Flurbiprofen 200mg/Kg
Kg, protidic acid 500mg/Kg, alclofenac
Even when 500 mg/Kg or 1.5 g/Kg of fueprazone was orally administered, similar effects of suppressing abnormal vascular growth and improving cancer pathology were observed. Example 4 Effect on experimental diabetic retinopathy induced in Wistar rats.
mg/Kg of streptozotocin, approx.
After several months, 3,3'-iminodipropionitrile was administered to induce experimental diabetic retinopathy.
The patient began to exhibit abnormal growth of capillaries in the vitreous body, a symptom of proliferative retinitis. Rats that began to exhibit symptoms of proliferative retinitis were selected, and in the group in which 2.5 mg/Kg/day of indomethacin was administered every two days after administration of 3,3'-iminodipropionitrile, on the third day after the start of administration. Abnormal growth of capillaries in the vitreous body was clearly suppressed, and the effect of improving the condition of diabetic retinopathy was observed. Similarly, aspirin administration at 200mg/kg/day also had an effect on improving the condition. Example 5 Effect of improving cancer pathology in cancer patients Patients with liver cancer who are inoperable due to various conditions (Stage
, 57-year-old male) tolmetin sodium 500
When the drug was administered in mg/day and its effect on improving cancer pathology was examined, it was found that a favorable state of improvement in cancer pathology could be maintained for a long period of time. Example 6 Effect on improving the condition of patients with diabetic retinopathy In addition to ticlopidine, 1.5 g/day of aspirin was administered to a 54-year-old male patient with long-term diabetes who had begun to develop capillary proliferation in the vitreous body. As a result, it was confirmed through observation with a fundus camera that the abnormal growth of capillaries, which could not be stopped with other treatments alone, was suppressed, and the progression of the pathology could be completely inhibited by combining it with photocoagulation. Ta. Example 7 Effect on improving the condition of patients with diabetic retinopathy In addition to the administration of ticlopidine, 1 mg/Kg of prednisolone was administered to a 49-year-old male patient with long-term diabetes who had begun to develop capillary proliferation in the vitreous body. However, the abnormal proliferation of capillaries was inhibited, and the progression of the disease state could be almost completely inhibited by combined use with photocoagulation. Preparation proportions 1. 1.5 parts by weight of aspirin, 8.0 parts by weight of single syrup,
100 parts by weight of purified water was added to prepare an oral preparation. Formulation Example 2 40 mg of dexamethasone sodium phosphate was added to sterilized physiological saline to prepare a 10 ml injection. The typical acute toxicity values of this substance are as follows. Acute toxicity values are the values measured when aspirin was orally administered to rats, and prednisolone was measured when administered subcutaneously to mice.

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【table】 [Brief explanation of drawings]

FIGS. 1 and 3 are diagrams showing the state of abnormal vascular growth in the control group, and FIGS. 2 and 4 are diagrams showing the state of inhibition of abnormal vascular growth in the present invention group.

Claims (1)

[Claims] 1. A vascular growth inhibitor characterized by containing a substance having an anti-inflammatory effect as a main component.