RU2197957C1 - Preparation and method for removing side effect of antitumor products - Google Patents

Abstract

FIELD: medicine, clinical pharmacology. SUBSTANCE: invention deals with creating a multipurpose preparation which is not of antitumor action itself, but, also, efficiently decreases side effects of different antitumor products, both chemotherapeutical and radiological ones, and development of the method based upon application of such a preparation. Result is achieved due to peroral intake of squalene preactivated either by thermal treatment or UV-, IR-radiation or impact of active oxygen form. Preparation should be used in efficient quantity, optimally - at the dosage of 0.3 ml/kg body weight in case of gastric, intestinal, pulmonary cancers, carcinomas of endo- and exoglands and at leucosis. EFFECT: broadened number of antitumor products. 9 cl, 4 ex, 1 tbl

Description

 The invention relates to the field of medicine, namely to clinical pharmacology, in particular to the creation of a new drug and method of weakening and / or eliminating the side effects of antitumor agents.

 All antitumor (or anticancer) drugs are divided into a number of groups based on their chemical structure, mechanism of action, and sources of production: alkylating substances, antimetabolites, antibiotics, agonists and antagonists of hormones, alkaloids, and other herbal products.

 Along with a specific inhibitory effect on tumors, modern antitumor agents act on other tissues and systems of the body, which, on the one hand, determines their undesirable side effects, and on the other hand, allows them to be used in other areas of medicine. In addition, a significant drawback of modern drugs is the low selectivity of action against tumor cells.

 One of the main side effects of antitumor chemotherapy is the inhibition of hematopoiesis, which requires precise regulation of doses and regimen of drugs; it must be borne in mind that hematopoiesis depression is enhanced with combination therapy - a combination of drugs with radiation therapy, etc. Nausea, vomiting, loss of appetite, diarrhea are often observed, alopecia and other side effects are possible. Some antitumor antibiotics have cardio- (doxorubicin, etc.), nephro- and ototoxicity. With the use of certain drugs, hyperuricemia may develop. Estrogens, androgens, their analogues and antagonists can cause hormonal disorders.

 One of the characteristic features of many anticancer drugs is their immunosuppressive effect, which can weaken the body's defenses and facilitate the development of infectious complications. At the same time, a number of antitumor agents (methotrexate, azathioprine, cyclophosphamide, cytarabine, prospidine, etc.) are used as immunosuppressants for autoimmune diseases.

Recently, medicinal methods have been developed to increase the effectiveness and tolerance of antitumor drugs. So, calcium folinate allows you to optimize the effect of methotrexate and some other antimetabolites (in particular, fluorouracil), new effective antiemetics (blockers of serotonin 5-HT ₃ receptors: ondansetron, tropisterone, etc.) - reduce nausea and vomiting, "colony-stimulating factors" (filgrastim, milgramostim, etc.) - to reduce the risk of neutropenia (Encyclopedia of drugs, ed. 7, 2000, p. 1221).

 Modern developments of antitumor agents include dosage forms that allow a more selective effect on the tumor, reducing the cytotoxic effect of the drug (US Pat. US 6207133, 03/22/2001).

 At present, there are some specific agents that can reduce the side effects of antitumor agents for a specific tumor pathology, these include substances of animal origin (see, for example, US Pat. RF 2099065, 1997) and plant origin (US Pat. RF 2078578, 1997) .

 However, the known drugs are not universal for various tumor pathologies.

 The technical task of the present invention is to provide a universal drug, which not only has an antitumor effect, but also very effectively reduces the side effects of various antitumor agents, both chemotherapeutic and radioisotope. The objective of the invention is to provide a method using such a drug.

 The problem is solved in that a preparation based on natural squalene was created, while it is activated to acquire useful properties by heat treatment or exposure to ultraviolet (UV) radiation, infrared (IR) radiation or exposure to an active form of oxygen. As a result of activation, activated squalene (AS) is obtained, which is an oily liquid having the following physicochemical properties in comparison with native squalene (see table. It is given at the end of the description).

Squalene activation is carried out as follows:
A. Heat treatment: by heating at t from 30 to 200 ^o C, the optimal mode is about 90 ^o C, for 1-6 hours.

 B. Exposure to UV radiation for 1-12 hours, optimally at a wavelength of 250-350 nm for 3-6 hours.

 B. Exposure to IR radiation for 3-12 hours, optimally at a wavelength of 400-800 nm for 6-9 hours.

 G. Exposure to an active form of oxygen selected from the group: ozone, hydrogen peroxide, transmission of molecular oxygen. Treatment with an active form of oxygen is carried out from 3 to 24 hours.

 When working on the present invention, we thoroughly studied and presented the optimal exposure modes to achieve the maximum possible positive results.

 The antitumor properties of activated squalene (AS) as an independent drug and the method for its preparation are described in detail in the previously filed application 2001113007 (05.16.2001). The present application describes the combined use of AS with other known antitumor agents, where AS exhibits the properties of a drug that attenuates and / or eliminates and accelerates the effect of antitumor agents, both chemotherapeutic and radiological.

The drug is activated squalene, i.e. activated by heat treatment, exposure to UV radiation, IR radiation or exposure to an active form of oxygen, activated squalene is a colorless or slightly yellowish viscous liquid having a boiling point of 238-240 ^o C and a specific gravity of 0.853-0.855.

 The use of the drug can be carried out simultaneously with chemo- and radiotherapy by known means, while known means can also be used to reduce the occurrence of side effects, as well as in treated patients, when chemo and / or radiotherapy is manifested in the last side effects.

 Another aspect of the present invention is a method of attenuating and / or eliminating side effects in chemotherapy and radiotherapy of tumors. The method consists in the fact that the patient is prescribed AS in an effective amount.

 The drug is given orally until the desired effect is obtained. The optimal dose is a dose of 0.3 ml / kg of body weight. The duration of administration may vary from 7 to 200 days, in many cases the effect is achieved in a period of 7 to 20 days. The drug was tested on more than 300 patients with various tumor pathologies using both chemo and radio drugs.

 The drug is effective in such pathologies as tumors of the stomach and intestines, lungs, adenocarcinomas of exo- or endocrine glands, metastases of various tumors, leukemia and other tumor pathologies.

 The invention is illustrated by the following examples.

 Example 1

 Patient R., 65 years old, gastric cancer, was admitted to the surgical hospital in a moderate state, with complaints of weakness, fatigue, general malaise, nausea, vomiting after eating, severe pain in the abdomen without accurate localization.

 Sick for the past 8 months, when nausea, general weakness appeared against the background of full health, then expressed pain syndrome, which was not stopped by taking non-narcotic analgesics, joined. An examination revealed a generalized tumor process - cancer of the antrum, adenocarcinoma TzN1M1 with the spread of the process to the peritoneum - carcinomatosis. Case recognized inoperable. Chemotherapy is prescribed.

 When viewed in a hospital - in the mind, is inhibited, comes into contact reluctantly, negative to the medical staff. The skin is of normal color, turgor is reduced, hypotrophy of muscles and subcutaneous tissue. The abdomen is moderately enlarged, symmetrical, slightly swollen, painful with deep palpation in the epigastrium. The liver is at the edge of the costal arch.

 Severe syndrome was stopped by the introduction of narcotic analgesics (promedol, omnopon) up to 7-8 times a day. The patient noted a complete lack of appetite, eating was accompanied by nausea and vomiting.

 The appointment of chemotherapy (dexorubimycin, mitomycin) every 3 days intravenously (12 doses) intensified nausea, vomiting, pain. Difficult pains appeared in the area of the heart, weakness increased. Laboratory records showed a pattern of inhibition of hematopoiesis (the number of leukocytes decreased from 5.2 to 3.4 thousand) and the development of iron deficiency anemia. The liver increased to 2.5 cm from the costal arch. An additional administration of AS at a dose of 0.3 ml / kg of body weight neutralized the toxicosis symptom.

 From the 6th day, a decrease in abdominal pain was noted (1 injection of a narcotic analgesic was enough). By the end of the 7th day, the symptoms of dyspepsia (nausea and vomiting, pain in the liver, appetite) completely disappeared. By the 30th day, the normalization of the blood formula took place.

 On the 25th day from the start of AS administration (against the background of ongoing chemotherapy), the pain syndrome completely disappeared, and the phenomena of cardiopathy were leveled. Taking the drug lasted 120 days, after which the patient was discharged in satisfactory condition.

 Conclusion: AS at a dose of 0.3 ml / kg not only eliminates the negative effects of chemotherapy, but also stops the symptoms of carcinomatosis.

 Example 2

 Patient Sh., 58 years old, colorectal cancer, was admitted to the surgical hospital with complaints of general weakness, moderate bleeding (up to 5 times a day), severe pain during defecation, as well as constant pain in the abdomen.

 An examination revealed a bleeding tumor of the rectum 8 cm from the anus measuring 3 x 5 cm with metastases to the lymph nodes and peritoneum. Diagnosis: Highly differentiated adenocarcinoma with metastases in the liver, peritoneum and lymph nodes. The case was found to be inoperable and the patient was prescribed chemotherapy - the main drug - platinum, at a dose of 150 mg daily. Other drugs, vinblastine (6 mg), were administered at 7-day intervals. The full course of treatment was 30 days, after which the treatment was interrupted. After a 20-day break, a second course was performed.

 At the beginning of the 2nd course, the following symptoms were noted: loss of appetite, hearing loss, weakness, decreased temperature. Laboratory tests revealed leukemia (up to 2.2 thousand leukocytes), thrombocytopenia, a decrease in the number of red blood cells to 2 million, etc. Bleeding intensified. General pain syndrome has not changed significantly.

 The appointment of AS in a dose of 0.3 ml / kg of weight during this period quickly changed the picture of the disease. The pain syndrome was leveled within 10 days of taking the drug. Bleeding stopped on the 7th day, while, despite continuing chemotherapy, the number of leukocytes increased (50th day) to 4.1 thousand, red blood cells - up to 2.5 million, platelets - 1.5 times. The patient developed an appetite, weakness, tinnitus, and paresthesia appeared. This made it possible to continue the course of chemotherapy.

 Conclusion: AS at a dose of 0.3 ml / kg eliminates the negative effects of chemotherapy and the symptoms of carcinomatosis.

 Example 3

 Patient S., 38 years old, metastatic disease of the right lung, was admitted to the hospital for the next chemotherapy course with complaints of weakness, nausea, vomiting, dizziness, general baldness, and numerous subcutaneous hemorrhages.

 Six years ago, the diagnosis was made: Cervical adenocarcinoma. An operation was performed - total removal of the uterus and ovaries, after which stabilization of the process was achieved. However, 5 months ago, the patient developed weakness. Hemoptysis appeared. Computed tomography of the lungs revealed 4 metastases ranging in size from 0.3 to 1.5 square meters. see, 3 courses of chemotherapy were performed (a combination of dexorubimycin hydrochloride and vinblastine), after which the effects of toxicosis were significantly increased, and the size of metastases increased to 3 square meters. see. In the blood - leukopenia, thrombocytopenia, anemia. The platelet count decreased to 50 thousand, resulting in numerous hemorrhages. The appointment of AS in a dose of 0.3 ml / kg body weight for 30 days allowed us to eliminate the negative changes and continue the course of chemotherapy. Repeated examination of the lungs (4 months after the start of the AS cycle) revealed a sharp slowdown in the growth of metastases to 3.2 square meters. cm, and the last (7 months) study recorded a halt in the process. In total, the patient received 8 courses of chemotherapy during the year. Despite this, the patient began hair growth, weakness completely disappeared, and subcutaneous hemorrhages stopped.

 Conclusion: the combination of AS with chemotherapeutic drugs not only reduces the toxic manifestations of the latter, but also enhances the antitumor effect of chemotherapy.

 Example 4

 Patient R., 70 years old. Diagnosis: Stage 3 adenocarcinoma of the prostate (according to Gleason) with metastases to the lymph nodes and bone tissue. He entered the clinic for a course of radiotherapy.

 Sick for more than 2 years, when he noticed a violation of urination and the appearance of pain in the lower abdomen. Ultrasound and palpation examination showed the presence of an extensive tumor with metastases in the nearest lymph node. A tumor biopsy made it possible to diagnose: Prostate adenocarcinoma. The case was found to be inoperable and the patient underwent 6 courses of chemotherapy (estracid, mitoxantrone). However, the pain syndrome and most of the signs of the disease could not be stopped. On the contrary, there were pains in the spine and symptoms of chronic renal and liver failure.

 The introduction of salts of radioactive strontium (strontium 89) in a dose of 150 MBq every 3 months allowed to somewhat reduce the degree of pain. However, a month after the start of treatment, the phenomena of renal hepatic insufficiency intensified, the number of leukocytes decreased from 3.5 to 2 thousand, platelets - 1.6 times.

 The appointment of activated squalene (AS) at a dose of 0.3 ml / kg of the patient's weight led to the complete elimination of the pain syndrome after 14 days from the start of treatment. At the same time, liver function indicators (transaminases) returned to normal and organ volume decreased, and appetite appeared. By the end of the month from the start of treatment, the patient gained 2 kg of weight. After a 60-day treatment, the number of leukocytes in the blood increased to 4.8 thousand, while the number of specific prostatic antigen decreased from 22 to 6 ng / ml.

 An ultrasound examination was performed after 3 months. Revealed a decrease in tumor volume by 22%. Repeated administration of radionucleotides while taking AS allowed to reduce the antigen content to 4 ng / ml.

 Conclusion: the AS preparation, prescribed at a dose of 0.3 ml / kg of weight, not only completely eliminates the effects of intoxication caused by the introduction of radionucleotides, but also has an antitumor effect.

 Thus, the proposed preparation and method for attenuating and / or eliminating the side effect of antitumor agents are universal highly effective means for eliminating the side effect of antitumor therapy.

Claims (9)

1. The drug, weakening and / or eliminating the side effects of antitumor agents based on natural organic compounds, characterized in that as a natural compound contains squalene, which is pre-activated by heat treatment, or exposure to UV radiation, infrared radiation, or exposure to an active form of oxygen , the preparation is a colorless or yellowish viscous liquid with a boiling point of 238-240 ^o C and a specific gravity of 0.853-0.855. 2. The drug according to claim 1, characterized in that it is activated by heat treatment at t ^o = 90 ^o C, or UV radiation at a wavelength of 250-350 nm for 3-6 hours, or exposure to infrared radiation at a wavelength of 400 -800 nm for 6-9 hours, or exposure to an active form of oxygen for 3-24 hours.  3. The drug according to claims 1 and 2, characterized in that it is effective for cancer of the stomach, intestines, lungs, carcinomas of the endo- and exocrine glands, leukemia, metastases of various tumors.  4. The drug according to claim 1, characterized in that it weakens and / or eliminates the side effects of chemotherapeutic and / or radioisotope agents.  5. A method of attenuating and / or eliminating the side effect of antitumor agents by administering to a patient receiving an antitumor therapy a drug of natural origin, characterized in that the patient is administered the drug described in claims 1-4 in an effective amount.  6. The method according to claim 5, characterized in that they attenuate and / or eliminate side effects of chemotherapeutic and / or radioisotope preparations.  7. The method according to PP.5 and 6, characterized in that the drug is used in a dose of 0.3 ml / kg of weight for a person.  8. The method according to PP.5-7, characterized in that the drug is administered per os for a time sufficient to weaken and / or eliminate side effects.  9. The method according to claim 8, characterized in that the drug is administered at a dose of 0.3 ml / kg for 7-200 days for a person.

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