The Influence of Cytoprotective Therapy with Tizole on the Processes of Regeneration of Myeloid Tissue and Jejunal Epithelium under Ionizing Radiation Exposure

The dissertation is devoted to the study of the influence of cytoprotective therapy with the drug Tizole (aquacompleks of glycerosolate of titanium) on the processes of regeneration of myeloid tissue and jejunal epithelium under ionizing radiation exposure. The research is conducted in the context of searching for new active drugs capable of enhancing tissue regeneration under extreme conditions. Tizole, recommended by the Ministry of Health of the Russian Federation for local use as an anti-inflammatory agent, has previously demonstrated radioprotective, anti-inflammatory, bactericidal, and amoebicidal activity; however, its effect upon parenteral administration under physiological and pathological conditions has not been sufficiently studied.

The work addresses tasks related to evaluating the effect of various doses of Tizole on the regenerative and mutagenic activity of the intestinal epithelium and hematopoiesis, determining the characteristics of regenerative processes in myeloid tissue and the epithelium of the small intestine after ionizing radiation exposure, and evaluating the possibility of combining Tizole with dermatin to enhance the cytoprotective effect in post-radiation exposure. The scientific novelty lies in the identification of the anti-apoptotic action of Tizole on radiosensitive tissues and the demonstration of the dose-dependent nature of this effect, as well as in substantiating the advantages of combined therapy with Tizole and dermatin.

Relevance of the Problem. The elucidation of new mechanisms of tissue regeneration under extreme conditions makes it possible to identify and implement new principles of pathogenetic therapy and to search for new active factors influencing these processes. For this purpose, biologically active substances that affect mitogenic activity and possess adaptogenic, interactor, and other properties are used (Gorizontov P.D., 1976; Meerson F.Z., 1986; Yastrebov A.L., 2005).

However, the problem of restoring tissue regeneration under the influence of extreme factors remains relevant today, and its successful resolution depends to a large extent on the search for new active drugs capable of enhancing tissue regeneration.

In this regard, our attention was drawn to the aquacompleks of glycerosolate of titanium (Tizole). The drug Tizole is recommended by the Ministry of Health of the Russian Federation (R 001667/01-2002) as a medicinal product for local use due to its anti-inflammatory activity, which served as a stimulus for the active introduction of Tizole into clinical practice and its inclusion in the State Register of Medicines of the Ministry of Health of the Russian Federation (Larionov L.P., Emelyanova I.V., 2003). Chemical formula of Tizole: Titanium (C₄H₅NO₅)₂·(H₂O)ₙ, molecular weight 2054.

Tizole was developed and is manufactured by the enterprise "OLIM" (Society of Laboratory Research of Medical Preparations, Yekaterinburg; Emelyanova I.V., Lopatina G.L., Filatova E.A., 1988).

On the basis of previously conducted experimental studies, it has been established that Tizole possesses radioprotective, anti-inflammatory, bactericidal, and amoebicidal activity, as well as conduit activity when used in combination with other medicinal products (Znamensky V.V., Berzin S.A., Gerasimov V.B., Larionov L.P., 2003). The drug Tizole potentiates the action of anti-inflammatory drugs (Kostina O.A., Fedorova N.P., 2003) and of drugs possessing antimicrobial activity (Spector S.I., Zobnina G.A., 2003).

Tizole is non-toxic and is not a potential allergen. It has been shown that upon parenteral administration, Tizole is deposited in the cells of parenchymal organs and in the cells of rapidly renewing tissues (myeloid tissue, intestinal epithelium). After two weeks, the content of Tizole in the organism (based on titanium quantification) corresponds to normal values, indicating rapid elimination of the drug from the body (Larionov L.L., 1989).

It has also been demonstrated that Tizole exerts a pronounced radioprotective effect when administered parenterally to experimental animals prior to radiation exposure. However, parenteral administration of the drug Tizole is not yet used in clinical practice, due to the absence of experimental data on its influence on organs and systems under both physiological conditions and pathological processes, as well as under the influence of extreme factors.

It is known that the resultant rate of cell renewal, which provides the basis for evaluating tissue regeneration, is determined by accounting for cell proliferation and programmed cell death (apoptosis). In this regard, it could not be excluded that Tizole might prove active with respect to both processes.

It may also be hypothesized that the effect of the drug Tizole on tissue regeneration could be enhanced by the combined use of cytoprotective drugs whose action is directed at the genetic apparatus of the cell (dermatin, leukogen, etc.). However, such a combination of Tizole with stimulators of cell proliferation has not been studied, whereas their combined action could prove highly favorable for the outcome of cellular repair under the influence of extreme factors.

Among extreme factors, our attention was focused on the action of ionizing radiation, since its damaging effect is directed primarily at rapidly renewing tissues that require maintenance of a high regenerative potential.

All of the above constituted the basis for formulating the main goal and objectives of the present study.

Goal of the Study. To investigate the effect of the drug Tizole upon its parenteral administration under physiological conditions and under conditions of ionizing radiation exposure.

Objectives of the Study:

1. To investigate the effect of various doses of Tizole on the regenerative and mutagenic activity of the intestinal epithelium, and to study the state of hematopoiesis and regeneration of the intestinal epithelium under physiological conditions at various time periods after parenteral administration of Tizole.

2. To determine the characteristics of regenerative processes and mutagenic activity in myeloid tissue and the epithelium of the small intestine after exposure to various doses of ionizing radiation and administration of Tizole.

3. To evaluate the possibility of using the drug dermatin in post-radiation exposure to enhance the cytoprotective action of Tizole.

4. To characterize the cytoprotective effect of combined parenteral administration of Tizole and dermatin under conditions of ionizing radiation exposure.

5. To provide a comparative characterization of the mechanism of cytoprotective action of Tizole and dermatin under conditions of ionizing radiation exposure.

Scientific Novelty. In the present work, for the first time, it has been demonstrated that upon parenteral administration, the drug Tizole exerts a pronounced anti-apoptotic effect on radiosensitive tissues (myeloid tissue, jejunal epithelium). It has been shown that the reduction in apoptosis during Tizole therapy is dose-dependent.

The anti-apoptotic effect of Tizole is enhanced after combined administration of the cytoprotectors Tizole and the drug dermatin.

Against the background of therapy with Tizole, dermatin, and combined therapy with Tizole and dermatin, a reduction in mutagenic activity was noted. However, upon combined administration of the drugs, the reduction in mutagenic activity in the jejunal epithelium was significantly more pronounced.

Theoretical and Practical Significance of the Work. In the experiment, a therapeutic effect on radiosensitive tissues (myeloid tissue and jejunal epithelium) was demonstrated during therapy with the cytoprotector Tizole and combined therapy with Tizole and dermatin. In this regard, the use of combined therapy is considered most preferable, since in addition to the anti-apoptotic effect, a more pronounced reduction in mutagenic activity was observed.

The possibility of combined administration of a cytoprotector possessing anti-apoptotic activity and a drug stimulating regeneration for the therapy of post-radiation syndrome preceding intensive chemotherapy has been substantiated.

Presentation of the Work. The main provisions of the dissertation were reported and discussed at:

1. Scientific and Practical Conference "Man and Health: Application of Biocorrectors," Moscow, 2005.

2. Scientific Conference of Young Scientists "Current Issues of Clinical and Experimental Medicine," Saint Petersburg, 2006.

3. IX All-Russian Scientific and Practical Conference "Man and His Health," Saint Petersburg, 2006.

4. 61st Scientific Conference of Students and Young Scientists "Current Issues of Modern Medical Science and Healthcare," Yekaterinburg, 2006.

5. X Russian Oncological Congress, Moscow, 2006.

Publications. Eight works on the topic of the dissertation have been published.

The following provisions are submitted for defense:

1. Tizole, upon parenteral administration under conditions of ionizing radiation exposure, exerts an anti-apoptotic effect and stimulates cell renewal processes. The anti-apoptotic effect of Tizole is dose-dependent, as evidenced by the reduction in the severity of apoptosis with an increase in the dose of the administered drug.

2. Tizole, upon parenteral administration under conditions of ionizing radiation exposure, reduces induced mutagenic activity.

3. Combined use of Tizole and the reparant dermatin under conditions of post-radiation damage exerts the most significant cytoprotective effect. The cytoprotective action of dermatin is realized through stimulation of mitotic activity and reduction of induced mutagenesis, whereas Tizole possesses a predominant effect on the reduction of apoptosis.

Scope and Structure of the Dissertation. The dissertation comprises 208 pages of text typed in the MS Word 2000 word processor, contains 99 tables and 11 figures. The dissertation consists of an introduction, a literature review, a description of research methods, two chapters of original research, a general conclusion, conclusions, and a reference list comprising 86 works in Russian and 146 in foreign languages.