WO2009102240A2

WO2009102240A2 - Medicinal agent for treating oncological diseases

Info

Publication number: WO2009102240A2
Application number: PCT/RU2009/000073
Authority: WO
Inventors: Mikhail Vladimirovich Kutushov
Original assignee: Mikhail Vladimirovich Kutushov
Priority date: 2008-02-14
Filing date: 2009-02-13
Publication date: 2009-08-20
Also published as: WO2009102240A3; RU2361587C1

Abstract

The invention relates to the use of fluridone (1-methyl-5-(α,α,α-trifluor-m-tolyl)-3-phenyl pyridinone-4) C19H14F3NO herbicide of structural formula (I) as an agent for treating oncological diseases by a single dose ranging from 0.1 to 5g up to three times a day. In particular cases, fluridone is administered before and after meal in the form of a dry powder or an aqueous solution, fluridone is used diluted in water or in a physiological solution within a range of 10-7-10-3 mmol/l, the fluridone aqueous solution is rectally injected, the 1% fluridone aqueous solution is intravenously or intraperitoneally administered, the 1-5% fluridone ointment is used, fluridone is rectally introduced in the form of 1-2% suppositories and in the form of an aqueous solution by inhalation. The inventive agent for treating oncological diseases is used in the form of a widely available and inexpensive substance which is non-toxic, does not cause side effects during the use thereof in pharmaceutically acceptable doses, reduces the treatment time and enhances the treatment effectiveness.

Description

Oncological medicine

The invention relates to new biologically active substances and can be used in medicine and biology as the basis for the creation of drugs. Currently, there are many anticancer pharmacological drugs used in clinical oncology, the effectiveness of most of which is insufficient, and the spectrum of oncological diseases treated with chemotherapy is significantly limited, due to their toxicity and insensitivity to cancer cells arising from repeated procedures. One of the antitumor drugs widely used in clinical oncology is 5-ftopyracil, which is used to treat ovarian cancer, breast cancer, liver cancer (hapatoma), melanoma, etc. (Safit JN, Vopavida V. // Sapseg Res. - 1992. - VoI.52. - P.6630). Like all cytostatics, 5-ftopyracil is very toxic - with its use, nausea, vomiting, inhibition of bone marrow hematopoiesis, toxic damage to the kidneys, etc. (Mashkovsky MD Medicines. Moscow. - 2001, p. 425).

The drug “Ftopyracil”, which is a white or slightly yellowish, slightly soluble crystalline powder in water and in alcohol, is an antimetabolite, the antitumor activity of which is determined by its transformation in cancer cells into a competitive inhibitor of the enzyme involved in the synthesis of nucleic acids. This drug by intravenous injection is used for inoperable and recurrent cancer of the stomach, cancer of the colon and rectum, breast, ovaries, and pancreas, however, the drug has high toxicity and it can cause inhibition of hematopoiesis, diarrhea, loss of appetite, vomiting, ulcerative stomatitis. In addition, this drug is contraindicated in the general serious condition of the patient, stomach ulcer and duodenum, severe functional failure of the liver. (see, for example, MD Mashkovsky “Medicines)), Moscow, LLC“ New Wave ”, Publisher of the SB. Divov, 2002, v. 2, p. 425). The closest prototype is a drug consisting of chlorocholinchloride (retardant). See RF Patent N ° 2292205 “Use of chlorocholinchloride as an antitumor agent)). 01/27/2007 However, this drug has a short duration of action, is not effective in treating a number of tumors, and is relatively toxic. The alleged invention relates to medicine, namely to medicines used to treat cancer.

The aim of the invention is the creation of funds with high antitumor activity and the absence of side effects. The objective of the invention is to find a drug with a therapeutic effect in relation to various oncological diseases.

The technical result, which provides a solution to the problem, consists in the use of a widely available and inexpensive substance as a means for treating cancer, non-toxic, not causing side effects when used in pharmaceutically acceptable doses, reducing treatment time, increasing the effectiveness of treatment. Such substances include a heterocyclic compound, a chemical substance containing a therapeutic effect was achieved with the use of fluridone herbicide (synonyms: pride, sonar). Ci ₉ H ₁₄ F ₃ NO M.m. 329, l-Methyl-5- (α, α, α-trifter-m-tolyl) -3-phenylshiridinone-4 (EH Lillu) The structural formula, which is as follows:

According to the criterion of acute toxicity, fluridone is a low-toxic compound: LD ₅₀ for rats and mice> 10,000 mg / kg. CK ₅₀ for eared perch 6.3, for rainbow trout 1157 mg / l. It is used to control vegetation in ponds, lakes, canals at consumption rates of 0.1 - 1 mg / l, as well as an excellent herbicide for the control of annual cereal and dicotyledonous weeds in cotton.

The therapeutic mechanism of action of this drug is based on the fact that according to the theory of M.V. Kutushova cancer and plant cells have the same properties and signaling systems. This is due to the fact that cancer cells are a retroevolutionary form of life, and their vegetative properties (continuous growth) confirm their kinship with plants, namely dicotyledons. (MV Kutushov. Cancer can be cured. Pages 399–405. Ed. “Sekachev.” 2005). With the introduction of fluridone, it interacts with the signal structures (receptors) of cancer cells, and as a result, metabolic recovery, normalization of mitosis, and reinvolution of cancer cells. On healthy human cells, herbicides do not have any effect, due to the difference in the structure of hormones and receptors. Herbicidal therapy of malignant tumors and blood cancer has been successfully used by the author for 15 years on volunteers from around the world, in particular, chlorocholine chloride, 2.4 D, MCPA, and their salts are used. The invention consists in the use of the herbicide fluridone (l-Methyl-5- (α, α, α-trifting-m-tolyl) -3-phenylpyridinone-4) Ci ₉ H ₁₄ F ₃ NO with the structural formula:

as a means for the treatment of cancer with a single dose from 0.1 mg to 5 g per reception up to 3 times a day. In special cases, the implementation of fluridone is taken in the form of a dry powder or aqueous solution before or after a meal, apply fluridone in a dilution of 10 ^" to 10 ^" mmol / l in water or saline, an aqueous solution of fluridone is administered rectally, a 1% aqueous solution of fluridone is administered intravenously or intraperitoneally, apply 1-5% ointment of fluridone, fluridone is administered rectally in the form of 1-2% suppositories, fluridone is administered by inhalation in the form of an aqueous solution.

Dosage forms were obtained by methods traditional for the pharmacy using conventional carriers, solvents, and other auxiliary ingredients (I.A. Muraviev, “Pharmaceutical Medicines”, M, 1980, “Pharmaceutical Reference Book” under the editorship of A.I. Tenzova, M., 1981) .

The results of the study of the mechanism of action of the proposed drug are given in examples J \ ° JN ° 1-4, and the possibility of its use for treatment is confirmed by examples JNb 5-13. Example N ° 1. In the test tubes of the experimental group with cancer cells MCF-7

(adenocarcinoma of the mammary gland) in a buffer solution (10 ml), the drug was introduced in a dilution of 10 ^"6 mmol / L in the form of a solution of fluridone. In addition, the drug Doxorubicin 10 ^" mmol, respectively, was introduced into tubes with the same pool of cancer cells / l, in buffer solution as PC (Posivet Soptrol). At the same time, a control group was also formed from the same number of tubes and with the same components, except for cancer cells, instead of which fibroblasts were placed in the tubes of this group.

After thermostating for 3 days at a temperature of 37 ° C, the analysis of the contents of the above tubes was carried out. A review of the results showed:

In the test tubes of the experimental group with the drug, the mitochondrial membranes are almost completely destroyed, and the picture is approximately the same for all variants of the used drug, in the test tubes of this group with the drug Doxorubicin, membranes swell with partial (about 50%) destruction of them, in cells in the test tube with saline, no changes were detected.

In test tubes of the control group, mitochondrial membranes are swollen, but their integrity is preserved. The data obtained indicate that the proposed drug causes a rearrangement of the mitochondrial membranes of cancer cells, but does not change the organelles and structures of normal cells.

Example N ° 2.

In a test tube (10 ml) with transthyretin (protein) of blood plasma (pH-7.0), a concentration of 0.05 mmol / ml, 4 drops of a 0.1% aqueous solution of fluridone were introduced. The tube was placed in a thermostat (incubator) with a temperature

37 ⁰ C.

After 15 minutes measurement of transthyretin concentration and measurement of plasma pH. Transthyretin is not determined, pH 6.0.

It follows that this drug acts on protein denaturation as a drug that changes the structure of the polymer.

This property determines the therapeutic effect of this drug in the treatment of malignant neoplasms. ZhZ example.

Blood of a patient with a sarcoma of the humerus (10 ml) is centrifuged. Part of the obtained plasma is dried and photographed under a polarizing microscope. An aqueous solution of fluridone was introduced into another part of the same plasma, and the resulting and dried mixture was also photographed under a polarizing microscope. Results: In the first composition, light scattering occurs, in the second, birefringence is observed.

These data suggest that this drug returns protein folding altered in cancer to normal.

Example N ° 4. In the culture medium on matrices with the experimental group Colo-205 (colon adenocarcinoma), the drug fluridone was introduced in a dilution from 10 ^'3 to 10 ^"7 mmol / L. The control group was in tubes with the same pool of cancer cells Docopybicin, introduced on the chart as PC, was introduced.

After temperature control for 3 days at a temperature of 37 ° C, an analysis of proliferative activity was carried out.

The results obtained in examples N ° N ° 1-4 are shown in the table:

The effect of test tests on on-line of colo-205 sells

Example N ° 5

Patient 3. 23 years. Diagnosis: Multiforme glioblastoma of the brain on the right. Relapse. One and a half years before the treatment, an operation was performed for glioblastoma of the brain. Complaints of headaches, nausea, vomiting. On an MRI in the projection of a p / operative scar in the substance of the brain, a tumor with uneven edges of 2.8 x 3 cm is determined. Moderate severity, pallor of the skin, aphasia and ataxia. The patient was prescribed 2 g fluridone. per 500 ml. saline in sterile form intravenously, drip. Procedure for 40 minutes. Subsequent procedures were carried out in exactly the same sequence 3 times a week. The course lasted 3 months. During treatment, the tumor decreased in size to 0.1x0, lcm. After two infusions of the drug, nausea and pain decreased. For 6 months, a single injection of the drug was carried out every two weeks. On KT after 12 months of treatment, the tumor is not detected.

Example N ° 6

Patient S. 52 years old. Diagnosis: Primary liver cancer. Relapse. 4 years ago, a portion of the right lobe of the liver with a tumor was resected for hepatoma. In the last six months, there were pains in the right hypochondrium, shortness of breath, ascites, periodic stool retention. The state of moderate severity, low nutrition, yellowness of the skin. On ultrasound, hypoechoic formations in the left lobe of the liver with uneven edges 1x1 cm and 5x5 cm are determined. The patient underwent umbilical vein surgery. For two weeks, twice a day, a sterile preparation of 2 grams fluridone was injected into the catheter. dissolved in 100 ml. saline solution. Subsequent procedures were carried out in exactly the same sequence 2 times a week. Only the drug was administered intravenously. The course lasted 3 months. During treatment, the tumor in the area decreased in size to 0, Zx0.2cm. After 4 months, a connective tissue scar 0, lx0.2cm, remained at the site of the tumor in the liver. In the course of treatment with the help of the drug, there was a positive dynamics in blood tests. General blood test results

Key indicators 12/11/05 19/01/06 14/02/06

Red blood cells 3.51 4.34 4.33 4.43

Hemoglobin 74 80 117 123

Platelets 315 362 286 310

White blood cells 11.2 7.0 5.5 6.2

Basophils 0-1% 1 - - 1

Eosinophils 0-5 1 2 2 1

Pal.nuclear 1-6% 1 1 - -

Segmental 45-70 29 44 63 65

Lymphocytes 18-40% 11 16 23 37

Monocytes 2-9% 15 4.3 4 5

ESR l-15mmch 23 12 10 7

Results of biochemical blood tests

Basic Sod. 10. 11.05 20.12.05 * 04.02.06 07.04.06 indicators are normal

Total protein 65.0-85.0 54 53 75 78

Creatinine Ch 98.5 83 76 57

Urea 44-110 7.5 6.7 3.5 1.8

Cholesterol 1.66-8.3 6.21 5.62 5.75 7.03

Bilirubin 2.90-6.54 11.0 24.2 8.4 8.0 total 8.5-20.5 3.0 22.3 3.3 2.0

Bilirubin up to 25% 8.0 11.9 5.1 6.0 direct up to 25% 82 96 84 90

Bilirubin up to 100 El 107.2 102 89 78.0 indirect 95-110.0 114.0 141 132.8 140.0

Amylase 135.0-3.20 4.3 4.31 4.8 Chlorine 147.0 1.8 0.94 1.32 0.9

Sodium 3.5-6.0 2.34 2.09 2.28 2.11

Potassium 0.98-1.30 7.4 13.4 18.0 27.7

Calcium 2.1-2.55 314.3 395.8 138.0 44.4 ionization. 8.8-27.0 160.4 114.7 54.4 33.7

Calcium 5-40 El 554.5 432.9 111.9 100.4 total 5-40 El 615.8 424 254.2 234

Iron syv. to 104

ACT Eat

ALT 225-450

Phosphatase ate alkali.

LDH

No complaints at this time.

Example -Nb7.

Patient F. 53 years. Diagnosis: Left ovarian adenocarcinoma. MTC in the liver and peritoneum. Four years ago, the uterus was extirpated with appendages. Three years later, pelvic pains and urges to urinate frequently appeared. On KT, a tumor-like formation of 4x5x4cm was determined between the bladder and rectum. In the retroperitoneal tissue, small multiple enlarged lymph nodes are visible .. In the abdominal cavity there is free fluid up to 3 liters. The state of moderate severity, pallor of the skin, cachexia. Drug treatment started according to the scheme of 20 drops

1% solution of fluridone in half a glass of water through the mouth, and in the form of microclysters. 3 times within a month after removal of ascites fluid, 2 grams of fluridone dissolved in 100 ml were intraperitoneally administered. saline solution. In total, the herbicidal course of treatment lasted 4 months. During treatment, the tumor decreased in size to 1.0x0.9x1.0cm. In the second week from the start of treatment, stool returned to normal and pain disappeared. Blood tests on the background of treatment returned to normal within 2x months. A full course of treatment with the drug for 5 months. During therapy, a tumor in the bladder, rectum, ascites, enlarged lymph nodes disappeared. Weight restored. Example 9

Patient A. 48 years. Dz: non-Hodgkin's lymphoma. Cachexia. 3 years ago, a full course of high-dose chemotherapy was performed. Six months ago, tumor-like formations appeared on the neck and under the jaw on the right. An X-ray revealed an expansion of the mediastinum. At the time of treatment, complaints of shortness of breath, sweating weakness. The state of moderate severity, low nutrition, pale skin. In the submandibular region on the right, the tumor formation is 5x3 cm. On the neck on both sides, tumor formations are 2x3x2 cm. Treatment with fluridone according to the scheme. 50 drops of a 1% solution of fluridone dissolved in 150 ml of water was taken by mouth three times a day. The course lasted 4 months. After 12 days from the start of treatment, the patient's submandibular lymph nodes completely disappeared. Within a month, tumors in the neck area decreased in size to O, 5xO, Zcm. After 3 months, none of the changed lymph nodes is detected. Blood and urine tests are normal. Weight restored. There are no complaints. Example 10

Patient D., 57 years old. Dz: Adenocarcinoma of the colon. MTC to the lungs. Ascites.

3 years ago, a large bowel resection was performed with an end-to-end anastomosis. He completed a full course of chemotherapy. 1.5 years after treatment, pain appeared in the lower abdomen, tenesmus. At the time of treatment, she complains of severe weakness, constant abdominal pain, cough, shortness of breath, ascites, and stool retention. The condition is serious, of poor nutrition, the skin is pale with a cyanotic hue, the abdomen is enlarged. In blood tests, there is a decrease in the number of red blood cells, hemoglobin, white blood cells, albumin, an increase in AJlT and ACT. On computed tomography in the right lung, the formation of an irregular shape of 4x5 cm with uneven the edges. In the area of the anastomosis, a volume formation of 3x2.5 cm is determined and free fluid in the abdominal cavity. The patient was prescribed the drug fluridone in the form of intravenous infusions, microclyster and drinking. The infusion solution is 500 mg. sterilized fluridone dissolved in 500 ml. saline solution. Infusions were administered weekly for 3 months. Inhalation of 10 drops of a 1% solution of fluridone daily. Enemas are a mixture of Yugr fluridone per 1500 ml. boiled water. Enemas were taken three times a week for 2x months. To enhance therapy, the drug was taken by mouth in the form of a 1% solution of fluridone per 200 ml. boiled water 20 minutes before meals three times a day. After 20 days from the start of treatment, the patient completely disappeared pain and appetite. In the third week of treatment, shortness of breath decreased. During treatment, the tumor in the anastomotic area decreased in size to 1.2x1, Zcm. After 3 months, a month-long break was made, and then therapy continued for 2x months. During treatment, metastases in the lung and tumor in the anastomotic region are not determined. Marked gradual improvement in blood counts is noted, which is directly related to drug treatment.

Blood test results

The main indicators of October 9, 2006

Red blood cells 3.12 3.34 4.44 4.87

Hemoglobin 74 90 115 128

Platelets 127 213 323 420

White blood cells 9.2 12.0 5.2 5.3

Basophils 0-1% 1 - - 1

Eosinophils 0-5 1 2 0 1

Pal.nuclear 1-6% 0 1 - 2

Segmental 45-70 74 46 56 65

Lymphocytes 18-40% 35 40 34 23

Monocytes 2-9% 13 4 7 9

ESR l-15mmch 36 12 10 5 Results of biochemical blood tests

Basic Sod. 10/09/06 24/11/06 09/12/06 09/10/07 indicators are normal

Total protein 65.0 -80g / 51.23 54.26 60 77

Creatinine 85.0 g / l 118.0 89 74 69

Urea 44-110 48.2 77.4 93.1 92.9

Cholesterol 1.66-8.3 6.21 5.62 5.75 3.03

Bilirubin 2.90-6.54 11.0 14.2 8.4 3.7 Total 8.5-20.5 9.0 20.3 9.3 8.7

Bilirubin up to 25% 34.0 45.9 35.1 26.0 direct up to 25% 22 36 14 20

Bilirubin up to 100 El 107.2 106 89 78.0 indirect 135-147.0 144.0 145 142.8 140.0

Amylase 3-4 4.20 4.3 4.0 4.2

Chlorine 3.5-6.0 3.8 4.9 4.8 4.9

Sodium 0.98-1.30 2.72 2.32 2.28 2.15

Potassium 2.1-2.55 19.4 13.4 18.0 17.7

Calcium ionization. W 8.8 - 314.3 395.8 138.0 64.4

Total calcium 27.0 190.4 104.7 54.8 42.9

Iron syv. 5-40 Eat 265.7 125.8 45.7 29.5

ACT 5-40 Eat 465.8 311 65.2 79

ALT up to 104 El

Phosphatase slit. ldg

Weight restored. There are no complaints. Example N ° 11.

Patient Yu, 34 years old. Dz: Clear cell carcinoma of the left kidney. MTC to the lungs. Three years ago, the left kidney was removed and preventive chemotherapy for clear cell cancer was performed. When examined for KT in the projection of the left kidney, the tumor formation is 3.4 x 4.4 x 3.3 cm, as well as two tumor-like circular formations with a diameter of 3.1 to 3.2 cm in the right and left lung. The condition is severe dyspnea, cyanosis, adynamia. Appointed daily inhalation administration of fluridone in 10 drops of 1% solution per procedure. The drug fluridone was also administered by mouth in the form of a drink of 20 drops of a 1% solution three times a day and in the form of microclysters of 20 drops at night. After 4x weeks of treatment, shortness of breath, and pain, decreased. Blood tests during treatment returned to normal over 3 months. Then, a second course of the drug was carried out, which was injected into the rectum in the form of 1% suppositories and inhaled for 6 months. During therapy, the tumor in the right kidney and metastases in the lungs disappeared. Weight restored.

Example Nb 12. Patient A.54 years.

When handling complaints of pain during urination, delayed and reddened urine. During the examination: ultrasound - prostate - 8 5 cm ³ , a tumor with fuzzy contours 41 x 40 mm ² . PSA 265 mg / ml.

Puncture biopsy - prostate adenocarcinoma. On the Glisson scale 6.5.

Diagnosis: Prostate adenocarcinoma. He refused surgery and chemotherapy. The treatment with the drug - fluridone. For three months, the patient took the drug - fluridone powder 500 mg x 2 times a day with meals. At night, a rectal suppository with 2% of the drug was administered. During this period, pain during urination decreased, the color of the urine returned to normal, after an ultrasound examination, after a month, the prostate volume decreased by 50%, the tumor acquired a clear outline, 10 x 12 mm in size. Then, therapy was continued by taking fluridone for two weeks at 300 mg x 2 times a day with meals. To enhance therapy, therapeutic enemas were prescribed daily at bedtime, at a dose of 2.0 g of fluridone in 30 ml of boiled water. Subsequent examinations of ultrasound, sonography, marked the final disappearance of the symptoms of the disease (pain during urination, urinary retention, etc.). On the control ultrasound six months after the start of treatment: the prostate is 24 cm ³ , the tumor is not detected. PCA - 1.0 mg / ml.

No relapse has been reported in the last two years. Example JVbI 3.

Patient B. 36 years. Dz: Melanoma of the right shoulder, metastasis to the axillary lymph node. In the area of the right shoulder, a swelling neoplasm of dark brown color 5x6x6cm. reinforced venous pattern, perifocal edema and ulceration. In the right axillary region, an enlarged painful lymph node, fused to surrounding tissues.

The histological diagnosis is malignant melanoma. The treatment was performed twice a week, intravenous administration of 200 mg. fluridone per 250 ml. saline solution.

5% ointment based on cocoa butter and fluridone. Within 2x months, the size of the tumor decreased by 60%. The lymph node is not determined. After 4 months, hyperpigmentation and a primary tumor of 0.5x1x1 cm are determined at the site of the tumor. There are no complaints. No relapse for 2x years. As a result of the invention, an agent having high antitumor activity and therapeutic effect in relation to various oncological diseases was created.

At the same time, a widely available and inexpensive substance that is non-toxic and does not cause side effects when used in pharmaceutically acceptable doses is used as an agent for the treatment of oncological diseases. At the same time, the terms are shortened and the treatment efficiency is increased.

Claims

Claim

1. The use of the herbicide fluridone (l-Methyl-5- (α, α, α-trifting-m-tolyl) -3-phenylpyridinone-4) Ci ₉ H ₁₄ F ₃ NO with the structural formula:

as a means for the treatment of cancer with a single dose from 0.1 mg to 5 g per reception up to 3 times a day.

2. The use according to claim 1, characterized in that fluridone is taken in the form of a dry powder or aqueous solution before or after a meal.

3. The use according to claim 1, characterized in that fluoridone is used in a dilution of 10 ^"7 to 10 ^{" 3} mmol / l in water or in physiological saline.

4. The use according to any one of claims 1, 2, characterized in that the aqueous solution of fluridone is administered rectally.

5. The use according to any one of claims 1, 2, characterized in that a 1% aqueous solution of fluridone is administered intravenously or intraperitoneally.

6. The use according to any one of claims 1, 2, characterized in that apply 1-5% ointment fluridone.

7. The use according to any one of claims 1, 2, characterized in that fluridone is administered rectally in the form of 1-2% suppositories.

8. The use according to any one of p. 1.2, characterized in that fluridone is administered inhaled in the form of an aqueous solution.