RU2498799C2 - Method for animal tissue radiosensibility enhancement - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to agriculture, particularly to veterinary science, and may be used for the purpose of animal tissue radiosensibility enhancement. That is ensured by the pre-radiation parenteral administration of oxyglycine lithium salt in a dose of 40 to 120 mg per 1 kg of body weight.

EFFECT: invention provides the pronounced radio-sensitizing effect on the animal in experiment.

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Description

The invention relates to agriculture, in particular to veterinary medicine, and can be used in pharmacology, medicine, experimental oncology, radiology and animal husbandry for parenteral administration to agricultural and domestic animals and poultry in order to increase the effectiveness of radiation therapy for malignant neoplasms while reducing the dose of radiation.

It is known from the prior art that one of the components of the complex therapy of malignant neoplasms is the use of ionizing radiation to cause death of cells affected by a malignant tumor. That is why in radiobiological science two aspects of this urgent problem are widely discussed in parallel: 1 task - the development of drugs that help protect healthy tissues surrounding tissue affected by a cancerous tumor; 2 - the task of developing drugs to reduce the radiosensitivity of affected tissues. Both directions suggest an increase in the therapeutic effect in the complex treatment of cancer. Each of these two approaches proceeds from the need to obtain a positive result, resorting to diametrically opposite methods, its achievement. If the first method is being developed to enable the therapeutic use of increased doses of radiation, the second is aimed at achieving a positive effect when using reduced doses of radiation.

Both of these approaches are rapidly developing areas of radiobiological science. In our country, chemosensitization techniques in cancer therapy began to be intensively developed over 30 years ago as part of the All-Union Modifier program.

It is known from the prior art that to achieve the goal, a wide variety of synthetic and natural compounds are widely tested: polysaccharides, nucleic acids, low and high molecular weight substances, sulfhydryl groups, of course, vitamins and antioxidants are traditionally popular. The most widely used electron-withdrawing compounds. The most popular drugs of this group are metronidazole, isometronidazole, tinidazole, etc. A large number of side effects, primarily their pronounced neurotoxicity, are recognized as a limiting factor in the use of these drugs.

The use of hyperbaric oxygenation is a very effective method, but in clinical oncology it encounters serious difficulties due to the technical complexity of the method. Used as a modifier of radiation exposure and drugs that artificially cause hyperglycemia and hyperthermia. However, hyperglycemia is not widely used in the treatment of cancer patients, since the effective concentration of glucose corresponds to the level of hyperglycemic coma, which is very dangerous for the health of patients. Chemotherapy regimens have also been developed that include a combination of 5-fluorouracil and platinum, among many others.

The general conclusion on this complex problem is that the inconsistency of the results, insufficient knowledge of the mechanisms of lethal and radio-modifying effects of existing chemoradio-modifiers, the complexity and danger of use in the clinic, hinder their wide and effective use, which requires the development of new drugs (Chemical radiosensitization of malignant tumors S.L. Daryalova, A.V. Boyko, I.I. Pelevina, V Russian Cancer Conference November 27-29, 2001, Moscow; Radio mode fiction in the combined treatment of non-small cell lung cancer A.Yu. Dobrodeev, A.A. Zavyalov, L.I. Musabaeva.Siberian Oncological Journal. 2006, No. 4.20; Prasad KN, Kumar A, Kochupillai V, Cole WC, High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. J. Am. Coll. Nutr., 1999; 18: 13-25, prototype closest to this work. The authors increased the effectiveness of cancer radiotherapy by administering to animals vitamins A, E, C, carotenoids and antioxidants, including sulfhydryl-containing agents. In the prototype, vitamins and antioxidants were administered in significantly larger doses, and this was done many times, which makes our method more preferable.

The present invention is aimed at solving the technical problem of developing a method of using a new drug that increases the sensitivity of tissues to hard radioactive gamma radiation. The applicant synthesized a new compound - an organic lithium salt with oxyglycine. (Galochkin V.A., Galochkina V.P., Ostrenko K.S., Patent No. 2409556 dated 12/10/2010. Method for the synthesis of an organic compound that prevents the development of stress reactions in animals).

The compound showed a pronounced radiosensitizing effect on the animal organism in the experiment. Both components used for the synthesis of a new organic salt (lithium mineral salt and oxyglycine) are legally approved for use in medical practice.

In the patent and scientific literature there are no indications of the use of the lithium salt of oxyglycine as a substance that increases the radiosensitivity of the body. This circumstance allows us to consider the claimed invention patentable as meeting the condition of patentability “inventive step” (part four of the Civil Code of the Russian Federation No. 230-FZ of 12/18/2007).

Example 1. The experiment was conducted on the basis of the Pharmacotoxicological Laboratory of the Scientific Center of the Institute of Medical Radiology of the Russian Academy of Medical Sciences (Obninsk, Russian Federation). The properties of the synthesized lithium salt with oxyglycine were investigated. The experiment was conducted on 75 rats of the Wistar strain at the age of 6-8 weeks, divided into five similar groups. The animals were irradiated on a gamma ray unit. The radiation dose was 7 Gy. Rats were placed in polyurethane cages with a top of metal rods. Feeding animals was carried out balanced in all nutrients and biologically active substances, full-grain granulated feed. The duration of the experiment is 30 days. A day before the irradiation, the animals were removed feed, leaving only water. At 10 am, the animals were loaded into transport boxes and moved to a specialized room for preliminary preparation. The animals of the experimental groups were injected parenterally (intraperitoneally) with the studied drug in doses of 120, 70 and 40 mg / kg body weight, respectively, of the 1st, 2nd and 3rd experimental groups. The 4th group served as a control, was given a placebo and was irradiated as well as experimental animals, two hours after the injection. The 5th group was intact, i.e. not subjected to any processing. After treatment, the animals were constantly monitored. On the 10th and 20th day, surviving animals were bled for biochemical and hematological analyzes. Morphological studies of organs and tissues were performed in dead animals.

Table 1 Survival of animals after irradiation with lithium oxyglycinate Number of days The number of live animals after treatment with the drug and exposure Doses of the drug administered, mg / kg body weight Placebo Control Intact animals 120 70 40 one fifteen fifteen fifteen fifteen fifteen 5 13 13 fourteen 13 fifteen 10 9 10 10 eleven fifteen fifteen 5 6 5 9 fifteen twenty 3 four four 8 fifteen 25 0 one 0 7 fifteen thirty 0 0 0 7 fifteen

Table 1 presents the dynamics of animal death by five days after drug administration and animal irradiation. There is a very interesting pattern. In the first 5 days after irradiation, the number of dead animals in all three experimental groups was almost the same with the control group. And already from the tenth day, the number of dead animals in the experimental groups begins to gradually exceed mortality in the control group. And this dynamics continues to persist until the end of the experiment. 25 days after irradiation, all animals in all three experimental groups (with the exception of one, in the group with the introduction of 70 mg of the drug / kg body weight) were already dead, and in the control 7 animals remained alive. 30 days after the start of the experiment from three experimental groups, with the introduction of the drug in doses of 120, 70 and 40 mg / kg body weight, respectively, not a single animal was left alive. By this time, animals from the three experimental groups had died completely, and almost half of the animals (7 animals, 46.6%) remained alive in the control group. In the intact group for 30 days of the experiment, not a single case of animal death was noted. The control and experimental groups had one diagnosis, which led to death - the intestinal form of radiation sickness.

Based on the data obtained, it can be concluded about the pronounced radiosensitizing properties of the tested lithium oxyglycine salt. Moreover, these properties were not dose dependent. For all three doses tested, the death of the animals was the same and completely independent of the dosage used. In other words, the minimum of the tested doses of the drug (40 mg / kg body weight) has already exhibited the maximum biological effect.

Previous studies of acute and chronic toxicity (Patent No. 2,409,556 dated December 10, 2010) showed that the lithium salt with oxyglycine belongs to the fourth toxicity class (LD ₅₀ - more than 1000 mg / kg) i.e. it is a low toxic compound, significantly less toxic compared to the known lithium salts with mineral acids that are approved for use in medicine. The studies we conducted to study the effect of the administration of the described doses of the drug confirmed its complete harmlessness over a wide range of hematological, morphological and physiological-biochemical parameters studied in the rat organism.

Against the background of what has been said about the identified positive properties of the lithium salt of oxyglycine, it can be argued that the specific radiosensitization properties shown cannot be considered as a consequence of the toxicity of the drug, and its adverse effect on metabolic processes in animals. However, at the present stage of studying the properties of the lithium salt of oxyglycine, the underlying mechanisms responsible for its ability to increase the radiosensitivity of tissues are still not disclosed.

Claims (1)

A method of increasing the radiosensitivity of animal tissues, involving the use of a biologically active substance, characterized in that, as a biologically active substance, lithium salt of oxyglycine in doses of 40 to 120 mg per 1 kg of body weight is parenterally administered to animals before radiation exposure.