Method for correction of toxic damages caused by doxorubicin

FIELD: medicine, oncology.

SUBSTANCE: method involves every day administration thiotriazoline on the background of doxorubicin treatment that is administrated once per a week for 4 weeks. Method provides carrying out correction of toxic damage of heart based on the complex anti-ischemic, membrane-stabilizing, antioxidant and immunomodulating effects of thiotriazoline. Invention can be used in correction of doxorubicin cardiomyopathy.

EFFECT: improved correction method.

3 tbl, 2 ex

 

The invention relates to medicine, in particular to the treatment of hematological malignancies, lymphoproliferative diseases and malignant neoplasms of different localization with the use of anthracycline antibiotics row.

Known use for the treatment of hematological diseases anthracycline antibiotic number of "Adriamycin" [1].

Adriamycin shows antineoplastic activity, but toxic in the treatment causes a number of side effects and complications, damaging healthy organs (suppression of hemopoiesis, damage to the digestive tract, lung, heart).

Known use in the treatment of hematological diseases anthracycline antibiotic number "Doxorubicin" (DOH) [2, 3].

Doxorubicin has the highest anti-tumor activity, but he, like the above analogy, characterized by high toxicity, which is the main limiting factor adequate cytotoxic therapy, and she is so serious that requires discontinuation of treatment before reaching the optimal antitumor effect [4].

To reduce the toxic action of antibiotics to patients concurrently administered protivomoskitnye drugs.

Known use in the treatment of cancer antibiotics, such as doctor is bezina in complex with dexrazoxane, which is an antioxidant agent [5, 6] and, to some extent, reduces cardiotoksicnae properties of anthracycline antibiotics.

On community features, intended and achieved the effect accept this method as a prototype. The disadvantage of the prototype is the narrow range of pharmacological actions dexrazoxane, because he does not possess hepatoprotective activity has insufficient cardioprotective, anti-ischemic and membrane-stabilizing properties, and, in addition, acquire it for currency.

The basis of the invention is the task of developing a method for correcting toxic lesions in the treatment of hematological diseases, providing the maximum reduction in the toxic effects of antibiotics.

The solution of this problem provides a way of correcting toxic lesions in the treatment of hematological diseases, comprising the administration to a patient of anthracycline antibiotic series, such as doxorubicin, and antioxidant, anti-ischemic drug thiotriazoline. Pharmacological effect thiotriazoline due to anti-ischemic, membrane stabilizing, antioxidant and immunomodulatory properties. The drug enhances compensatory activation of anaerobic glycolysis reduces suppression processes oxide is placed in Krebs cycle with preservation of intracellular Fund ATP. Thiotriazoline activates the antioxidant system and inhibits the oxidation of lipids in ischemic myocardial areas, stabilizes and decreases, respectively necrosis and myocardial ischemia, prevents the development of human isoenzymes cardiospecific - lactate dehydrogenase and creatine phosphokinase, reduces the sensitivity of the myocardium to catecholamines, prevents progressive suppression of contractile function of the heart and the development of impaired heart rate. The drug exerts antianginal action, comparable with drugs group organic nitrates, calcium antagonists, beta-blockers, reducing the need of oxygen.

When doxorubicin is administered at 3.0 (for rabbits) to 5.0 (rats) mg / kg once a week for four weeks, and thiotriazoline at 20-100 mg/kg daily during this period.

Thiotriazoline is an antioxidant, hepatoprotective, cardioprotective, anti-inflammatory, immunomodulatory, anti-ischemic, membrane stabilizing agent.

The effect of inventions

The method of correction of lesions in the treatment of hematological diseases according to the invention considerably reduce the symptoms of toxic action the Oia antibiotics.

Example 1. The effect of doxorubicin (DOH) on the lipid peroxidation in the myocardium and liver of rats.

Studies have been conducted on 53 white rats male, Wistar, weighing 150-180 g, which were kept on a standard diet of the vivarium.

Animals were divided into three groups. The control were intact rats (group I), group II - animals with modeling cardiomyopathy induced by intraperitoneal injection of doxorubicin at a dose of 5 mg/kg once a week for four weeks, group III - animals, which on the background modeling doxorubicinol cardiomyopathy daily for four weeks was introduced thiotriazoline at a dose of 100 mg/kg intraperitoneally.

The intensity of free radical processes lipoperoxidation was estimated by a spectrophotometric method for the accumulation in the myocardium and liver of rats thiobarbiturates products, the main of which is malonic dialdehyde (MDA), a secondary product FLOOR as if not spontaneous induced and induced fermentativnaya the process, using as a prooxidant system Fe (II)- NaDPH.

The obtained results were processed by the method of variation statistics using t-test, t-test and are shown in tables 1, 2.

Analysis of the obtained data shows that doxorubicin causes a drastic intensification lipop is Rosedale as in the myocardium, and in the liver of rats (tab. 1, 2). This significantly increases the intensity of the spontaneous uninitiated perekonomian of lipids (Pol): in the liver by 41%in the myocardium of rats by 21%, and fermentativnogo lipoproteine 24% in the liver and 70% in the myocardium of rats.

The results of the experiments indicate a significant increase in the accumulation of MDA in the myocardium (70%). This can be explained by trapnest doxorubicin to cardiolipin, representing the mitochondrial phospholipid membranes of cardiomyocytes.

The high level of MDA in the myocardium in experimental rats was evidence about the depletion attack on polyunsaturated fatty acids, which are the main substrates of the FLOOR. In the heart tissue acidosis occurs, increases the permeability of cell membranes, and cell receives an additional amount of ions of CA2+. Formed the wrong set of interconnected lipid and ionic homeostasis. There is an additional activation of proteases, phospholipases, the formation of free fatty acids, production of prostaglandins and leukotrienes.

In the myocardium of rats a possible decrease in MDA level (50.4%) thanks to thiotriazoline happened when fermentativnaya lipoprotein (tab. 2)when spontaneous lipoperoxidative observed decrease in MDA level by 19%. In the liver of rats the MDA level underthe influence of thiotriazoline reduced by 34.5%, in spontaneous lipoprotein, when fermentativnaya - 26.5% (tab. 1).

Based on the performed experiments, we can conclude that the leading mechanism of action thiotriazoline is antioxidant effect. The drug inhibits the formation of initial and final products of lipid peroxidation restores balanced relationship between oxidant and antioxidant systems in the pathologically changed tissues, thereby protects the structural and functional integrity of membranes of tissues.

td align="center"> I
Table 1
Spontaneous and fermentativnaya lipid peroxidation in the myocardium of rats with doxorubicinol cardiomyopathy and its correction by thiotriazoline.
№p/pExperienced groupQty

animals
MDA
Spontaneous lipid peroxidationEnzyme dependent lipid peroxidation
mmol/g of tissue%mmol/g of tissue%
IIntact rats1766±3.0 100137±17,7100
IIModel doxorubicinol cardiomyopathy1780,4±4,0*the level of 121.8233±16,0*USD 170.1
IIIModel + thiotriazoline1968.5±2.8to 103.8164±14,7**119,7
* significant change compared with group I (intact rat)
** - significant changes in comparison with group II (model).
Table 2
Spontaneous and fermentativnaya lipid peroxidation in rat liver under the influence of doxorubicin and its correction by thiotriazoline
№p/pExperienced groupQty

animals
MDA
Spontaneous lipid peroxidationEnzyme dependent lipid peroxidation
mmol/g of tissue%mmol/g of tissue%
Intact rats17162±10.5100656±, and 33.8100
IIModel doxorubicinol cardiomyopathy17229±20,3*141,3815±25,5*124,2
IIIModel + thiotriazoline19173±to 12.0106,84641±30,6**97,7
* significant change compared with group I (intact rat)
** - significant changes in comparison with group II (model)

Example 2. The effect of doxorubicin on the indices of cardio - and hemodynamics rabbits.

The experiments were carried out on 24 rabbits of the Chinchilla breed, weight 2,6-4.5 kg, contained in standard vivarium conditions.

Rabbits were divided into groups: group I - intact animals, group II - rabbits with doxorubicinol cardiomyopathy, group III - rabbits that concurrently with doxorubicin was injected thiotriazoline.

In the experiment used doxorubicin produced by OJSC "Kiever the parathas and thiotriazoline production of JSC "Galichfarm".

Modeling of cardiomyopathy in rabbits was carried out by intravenous (into the ear vein) of doxorubicin at the dose of 3.0 mg/kg once a week for 4 weeks. Cumulative dose DOH corresponded to 12 mg/kg, thiotriazoline - 100 mg/kg of body weight daily for four weeks.

All rabbits conducted a comprehensive study of the functional state of the system circulation using the method of catherization left ventricle of the heart (LIS) to determine the maximum pressure (Rmah) and well-known method thermodilution to determine cardiac output (IOC). These indicators, as well as systemic blood pressure (SBP) in the femoral artery and heart rate (HR) were recorded on a device Hewlett Packarel. Cardiac index (SI), systolic index (FIC), total peripheral resistance (OPS), work index left ventricular (wheat ridge), a working stroke index of the left ventricle (RUILI), debit heart (L) determined by the calculation method.

Studies have shown that under the conditions of this pathology changes of most indicators of cardio - and hemodynamics are depressive in nature. The most affected contractile activity of the myocardium, as evidenced by a pressure drop in LV by 20.5%, and the working of the index and the working of the shock index by 29% and 26.5%, respectively the military.

Smaller violations identified by the Central hemodynamics. So heart and systolic index fall by only 9.8% and 5% respectively. The decreasing trend of the IOC 10.6% and OPS 11.6% leads to a fall in the GARDEN of 16.4%. Heart rate with virtually no changes.

Analysis of results indicates that when doxorubicinol cardiomyopathy significantly reduced the contractile activity of the myocardium. To a lesser extent such amendments relate to the Central hemodynamics.

Thiotriazoline in exchange introduction prevents violations of most of the indicators that have undergone changes in conditions doxorubicinol intoxication. This concerns, first of all, maximum pressure, systemic arterial pressure, the work index of the left ventricle, the working drums index of the left ventricle, which remained practically at the level of performance of the control group.

List of used information

1. Galenko-Jaroszewski N.A., Chekman I.S., Gorchakov N.A. Essays pharmacology funds metabolic therapy. - M.: Medicine, 2001, 240 S.

2. Kapelko VI, Popovich M.I. Metabolic and functional basis of experimental cardiomyopathies. // Kishinev: shtiintsa, 1990.

3. Johnson, S.A., D.S. Richardson Anthracylines in haematology: pharmakinetics and clinical studies //Blood Rev. - 1998. - vol.12 - p.52-71.

4. Grenier J.J., Lipshultz SE Epidemiology of antracyckine cardiotoxicity on children and adults //Semin oncjl - 1998, vol.25 - p.72-85.

5. Chekman I.S., Gorchakov N.A. Drugs metabolic actions in cardiology // Treatment i and diagnostics. - 2003. No. 4. - p.52-56.

6. Mashkovsky PPM Medicines. 2002. T-2, str.

The correction method doxorubicinol cardiomyopathy antioxidant drug, characterized in that the antioxidant drug use thiotriazoline, while doxorubicin is administered once a week for four weeks, and thiotriazoline daily for a specified period.



 

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