RU2429852C1 - Agent lowering cyclophosphamide toxicity - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to production of an agent for lowering cyclophosphamide toxicity representing Agrimoniin.

EFFECT: agent does not exhibit a toxic effect, reduces general toxic action of cyclophosphamide, improves a survival value of joint treatment as compared with cyclophosphamide monotherapy in 10 times.

1 ex, 1 tbl, 1 dwg

Description

In recent years, the mortality rate from cancer has grown significantly, second only to mortality from diseases associated with cardiovascular disease. Every year, the arsenal of therapies for malignant tumors is rapidly replenishing. New drugs are characterized by high efficiency and better tolerance relative to drugs developed earlier, which, in turn, have not lost their relevance and continue to be widely used for the treatment of tumor processes. These drugs, even in modern conditions, do not find an adequate replacement and are characterized by high efficiency, but at the same time, high toxicity, which leads to poor tolerance for the patient. Such agents include an alkylating cytostatic drug - cyclophosphamide - a derivative of bis- (β-chloroethyl) -amine, which is characterized by high toxicity even in doses close to therapeutic, which causes significant difficulties in its use.

At the same time, interest in drugs derived from plant materials is growing every year. This is due to the complex effect of biologically active substances contained in them, high safety, low toxicity and allergenicity. In this case, special attention is given to medicinal plants, traditionally used in traditional medicine. Such plants include the common cuff - Alchemilla vulgaris L.

Cuff grass is successfully used as official raw material in Western European countries and is included in the pharmacopoeias of Great Britain, France, Germany, Yugoslavia (used in the form of dry grass powder for internal use). A wide range of pharmacological actions has been established for it: anti-inflammatory, hemostatic, lymphotropic, hypotensive, hypoglycemic, etc. [Hager H. Pharmacopoe ia Anglica, Gall ica, Germanae, Hevetica, Russae inter se collatae. Vratistaiae. Impesis Ernesti Gunteri. - MDCCCLXIX. - S.10].

This is due to the rich chemical composition: flavonoids, phenolcarboxylic acids and their esters, tannins, amino acids, as well as essential macro- and microelements such as calcium, potassium, magnesium, phosphorus, chromium, copper, cobalt, etc.

The drawing shows a chromatogram showing the multicomponent polyphenol complex of the herb of the cuff, consisting of gallic acid (1), chlorogenic acid (2), caffeic acid (3), rutin (4), cinnamic acid (5), campferol (6), quercetin (7) and agrimonin (8).

The radical binding mechanism of the action of polyphenols, in particular tannins, on the superoxide radical anion, as well as their inhibitory activity against monoamine oxidase, which plays a role in the oxidative stress of the nervous system, lipogenase, which causes linoleic acid peroxidation, i.e. antioxidant activity of polyphenols, including agrimonin. Therefore, the target product has not only P-vitamin activity, adaptogenic, antioxidant properties, but also antitoxic activity.

The antitoxic effect of plant extracts of chaga and flutonoid rutin is described under the influence of diethynitrosamine (DENA) [A.E. Khubulova, F.K. Dzhioev, A.V. Sergeev, M.Ya. Shashkina. Antimutagenic and antioxidant properties of Cascorutol and Chagovit // Russian Biotherapeutic Journal. - 2009. - No. 2 (8). - S.56-57], as well as a decrease in the toxicity of cyclophosphamide and 5-fluorouracil on the thymus tissue under the action of ferulic acid (M.A. // Development, research and marketing of new pharmaceutical products: collection of scientific papers / under the editorship of M.V. Gavrilin / Pyatigorsk GFA. - Pyatigorsk, 2008. - Issue 63. - S.466-468).

The objective of the invention is the use of agrimonin as a means of reducing the toxicity of cyclophosphamide.

The problem is solved in that male mice of the BDF line ₁ weighing 19-23 g with grafted lung carcinoma Lewis (LLC) were divided into 2 groups of 10 animals: group 1 was administered once cyclophosphamide at a dose of 450 mg / kg intraperitoneally, 2- group I - once cyclophosphamide at a dose of 450 mg / kg intraperitoneally and 10 times an aqueous solution of agrimonium orally at 0.3 ml / mouse (10 mg / kg) with an interval of 24 hours.

Example 1. Pharmacological activity of the drug.

The study was carried out on male mice of the BDF ₁ line weighing 19-23 g. Lewis lung carcinoma (LLC) was used as a model. The tumor is solid, non-immunogenic, metastasizes to the lungs. Inoculated subcutaneously with a suspension of tumor cells of 60 mg in 0.5 ml of culture medium per mouse.

Animals were divided into 2 groups of 10 animals: the 1st group was injected once with cyclophosphamide at a dose of 450 mg / kg intraperitoneally, the 2nd group was administered once with cyclophosphamide at a dose of 450 mg / kg intraperitoneally and 10 times with an aqueous solution of agrimonin orally 0.3 ml / mouse (10 mg / kg) with an interval of 24 hours.

The criteria for evaluating the general toxic effect were taken as the average life expectancy (LSS). Animals were monitored by assessing their average life expectancy (LSS). During the experiment, in the 1st group of animals receiving only cyclophosphamide, 83% of the mice fell on the 11th day of the experiment, in the 2nd group with combined use of cyclophosphamide with an aqueous solution of agrimonin - 0%. It was found that the toxicity of mice in the 1st group fell on average on the 5th day, and in the 2nd group on the 11th day of the experiment, all mice were alive. Animals of the 2nd group fell from the tumor on the 50th day. Death from toxicity is not fixed.

The data in the table indicate the high ability of agrimonin isolated from the cuff grass to reduce the general toxic effect of cyclophosphamide.

Table The effect of agrimonin isolated from cuff grass on life expectancy (LSS) of mice with Lewis lung carcinoma (LLC) Group of mice No. Treatment regimen SG, days one 450 mg / kg X 1 cyclophosphamide intraperitoneally 6.1 ± 0.5 2 450 mg / kg X 1 cyclophosphamide intraperitoneally + 0.3 ml / mouse (10 mg / kg) X 10 aqueous solution of agrimonin per os 53.8 ± 0.3

1. Toxicity test. The agent at a dose of 10 g / kg did not show a toxic effect.

2. Agrimonin, isolated from the grass of the cuff, reduces the general toxic effect of cyclophosphamide. The survival rate and general condition of the animals in the group receiving combined treatment with an aqueous solution of agrimonium are higher than in the group receiving monotherapy with cyclophosphamide 10 times.

The data obtained allow us to conclude that agrimonin obtained from cuff grass can be used as a means of reducing the general toxic effect of antitumor drugs in the treatment of malignant neoplasms.

Claims (1)

The use of agrimonin as a means to reduce the toxicity of cyclophosphamide.

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