Cytostatic composition with antioxidant activity

FIELD: medicine.

SUBSTANCE: invention concerns pharmacology, veterinary science and medicine and covers a cytostatic composition containing coordination compounds of platinum, ascorbic acid and phenanthroline derivatives where as coordination compound of platinum, it contains cisplatin, as ascorbic acid and phenanthroline derivatives - ascorbate phenanthrolinate complex of platinum of formula [PtPhen2]Asc and ascorbate phenanthrolinate complex of europium of formula EuAscNO3Phen·4·H2O at the following mass ratio: cisplatin - 1; ascorbate phenanthrolinate complex of platinum - 2; ascorbate phenanthrolinate complex of europium - 3.

EFFECT: composition with antioxidant activity.

1 cl, 1 dwg, 2 tbl, 4 ex

 

The invention relates to coordination compounds of metals with biological activity, and can be used in Oncology for cytotoxic chemotherapy.

Well-known and widely used in practice Sol platinum cisplatin (CIS-dichlorodiammineplatinum) [1].

The disadvantage of this drug is toxic side effects on the body when used in its pure form.

Known composition for antibiotically therapy for patent RF №2192861, 2001, upon receipt of which the use of coordination compounds of platinum, for example cisplatin, and 1,10-phenanthrolin and ascorbic acid at a weight ratio of 1:1:1-1:1:10 (composition selected for the prototype).

The disadvantage of this arrangement is the high toxicity phenanthroline, which limits the possibility of therapeutic use of the composition for injection.

The technical problem of the invention is a composition based on coordination compounds of metals having high cytotoxic and antioxidant activity and low toxic side effects on the body. For this purpose it is desirable to free themselves from the presence of toxic components - 1,10-phenanthrolin or to reduce its toxic effects.

The problem is solved by using for the preparation of compositions of the following known is the shaft components: 1 - the platinum drug cisplatin, 2 - askorbatperoksidazy platinum complex with the formula [PtPhen2]Asc, and 3 - the mixed-ligand complex of rare earth element europium with phenanthroline and ascorbic acid with the formula EuAscNO3Phen·4H2O when the mass ratio of 1:2:3.

Methods of obtaining the above salts of rare earth elements, as well as cytotoxic effects [PtPhen2]Asc known and we have published previously [3].

Examples of the biological activity of the composition and its components.

Example 1. Tested antiproliferative action of the composition on immunocompetent cells in the reaction of blast transformation of human lymphocytes stimulated by phytohemagglutinin (PHA) after the action of the composition in a concentration range of 0.05-5.0 mg/ml assessing the impact of drugs on lymphocyte proliferative activity in spontaneous and induced PHA test conducted in accordance with the methodological recommendations of farmkomiteta of the RF Ministry of health [Bulletin of the pharmacological Committee, 1999, No. 1].

The results of the test products in the reaction of blast transformation of lymphocytes (rbtl) is represented in the drawing.

The testing established that the claimed composition in the above range of concentrations has an inhibitory effect on PHA induced proliferation act shall want to make lymphocytes, that testifies to its cytotoxic action is not inferior to the prototype. When the concentration of the composition of 1.0 mg/ml and more comes total destruction of cells.

Example 2. Conducted a series of studies of the cytotoxic effect of the claimed composition on tumor cells of Ehrlich carcinoma mice in a wide range of concentrations (see table 1).

Table 1
The results of determination of the cytotoxic effect of the claimed composition on tumor cells of Ehrlich carcinoma after 48 hours incubation
DoseThe percentage of viable cells (%)Control (without drug)
0,051087
0,5087
5,0087

Of materials table 1 shows that the inventive composition is almost completely suppresses the viability of tumor cells. Analysis of the data obtained in all series of experiments, allows us to conclude that in case of joint application of cisplatin, Scola is attentant of platinum complexes, and europium, there are marked manifestation of the cytotoxic activity of the composition, evidence cancerostatic mechanism of action of the claimed composition.

Example 3. Comparative Toxicological study of the components of the claimed compositions performed on mice BALB/c mice weighing 18-20 g by the method of probit analysis intraperitoneal injection of its physiological solution. The value of LD50ascorbocinchoninate complex of europium EuAscNO3Phen·4H2O amounted to 610 mg/kg, and its mixture with ascorbocinchoninate complex of platinum in the ratio 3:2 - 520 mg/kg, whereas LD501,10-phenanthroline was 82.5 mg/kg, i.e. acute toxic effects on the body of the claimed components several times lower than that of phenanthroline.

Further investigated the antioxidant activity of the claimed composition. Antioxidant activity was determined using the method of cathodic voltammetry, in particular the process of electroreduction of oxygen (EV O2) [3]. The effect was evaluated on a temporary, or so-called kinetic criterion of antioxidant activity, which reflects the efficiency of interaction of the sample with oxygen radicals and is determined by the formula:

where is the criterion of antioxidant activity, µmol/l min;

Co2the oxygen concentration in the original solution without substance, µmol/l;

Ii- the current value of the electroreduction Of2, MCA;

Ibegthe maximum current electroreduction About2in the absence of a substance in solution, MCA;

T - time of the process, minutes

The antioxidant activity of the claimed compositions are presented in table 2.

Table 2
Study drugWithslaveTo
(g/l)(µmol/l·min)
Ascorbic acid5·10-41,4
The claimed composition5·10-40,7

Hereslave- working concentration of drugs chosen by analogy with the test EV O2for ascorbic acid.

From the table 2 values and It can be seen that the inventive composition has antioxidant activity, which is comparable (50%) with activity indicator standard antioxidant ascorbic acid.

In the literature there is no information about the use claimed it is notizie in clinical practice, indicating the novelty of technical solutions, and non-obviousness cytotoxic and antioxidant activity of the composition at relatively low toxicity allows you to talk about according to his criterion of "inventive step".

Used sources of information

1. Medmaravis. Medicines, Vol.2. M.: 2002, n.218.

2. Composition for antibiotically therapy. RF patent №2192861, MKI AC 31/4745, publ. 2002.11.20.

3. Yevtushenko D.N., Skorik N.A., carpenters V.M. study of the interaction of europium, samarium and platinum with ascorbic acid and 1,10-phenantroline. Inch, 2002, t, No. 11, s-1882.

4. E.I.Korotkova, Y.A.Karbainov, ..Avramchik, ..Bakibaev. New electrochemical sensor for antioxidant activity determination. / In book: "Instrumental Methods of Analysis. Modern Trends and Applications. Conference Proceedings of 3-rd International conference". ZITI, Greece, 2003, P.707-710.

Cytostatic composition with antioxidant activity, containing coordination compounds of platinum, derivatives of ascorbic acid and phenanthroline, characterized in that as the coordination compounds of platinum selected cisplatin and derivatives of ascorbic acid and phenanthroline presents ascorbocinchoninate the platinum complex of the formula [PtPhen2]Asc and ascorbocinchoninate complex of europium formula EuAscNO3Phen·4·H2O when the next mass ratio of components:

cisplatin1
askorbatperoksidazy complex platinum2
askorbatperoksidazy complex of europium3



 

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