Sorption Detoxification as an Addition to Conventional Therapy of Acute Radiation Sickness and Iatrogenic Leukopenia

Leukopenia is an essential part of the clinical course of acute radiation sickness and is a side effect of anti-cancer treatment. In both situations, the main factors which determine the survival are the degree of bone marrow suppression and gastrointestinal tract damage due to the presence of a large pool of fast-dividing cells. Leuko- and neutropenia are main limiting factors which may contribute to chemotherapy failure. Hematopoietic cytokines the part of conventional therapy in this field, but their effects require boosting. That is why the use of means and methods of adsorption therapy is considered promising. Sorption therapy creates a basis for sorption detoxification, a doctrine of curative measures directed to the removal of toxic endogenous or exogenous compounds from body fluids. The most widely used types are the purification of blood or its components (hemosorption), oral administration of sorption materials (enterosorption) and application-sorption therapy of wounds and burns. In this chapter, the results of early and recent research and prospects for the use of carbon adsorption therapy for the treatment of acute radiation sickness and cytostatic myelosuppression are discussed

Blood coagulation parameters in rats with acute radiation syndrome receiving activated carbon as a preventive remedy

Radiation-induced coagulopathy (RIC) is one of the major causes of death during acute radiation syndrome (ARS). The aim of this study was to characterize the responses of the hemostasis system to ARS of a moderate level on the 1st and 9th days after irradiation. We aimed to identify molecular markers of the blood coagulation system that are most affected by ARS and to estimate the enterosorption effect on the development of irradiation-induced changes. Platelet aggregation rate, activated partial thromboplastin time (APTT) and fibrinogen concentration were determined by standard methods. Level of protein C (PC) was measured using­ chromogenic substrate S2366 (p-Glu-Pro-Arg-pNa) and Agkistrodon halys halys snake venom activa­ting enzyme. Functionally inactive forms of prothrombin (FIFPs) were determined using two activators in parallel – thromboplastin or prothrombin activator from Echis multisqumatis venom. Rats of both irradia­ted groups had a higher risk of intravascular clotting in comparison to both control groups. Statistically significant shortening of clotting time in the APTT test (24 ± 4 s vs. 33 ± 5 s) and increased fibrinogen concentration (4.2 ± 0.6 mg/ml vs. 3.2 ± 0.3 mg/ml) were detected. Both parameters were normalized on the 9th day after irradiation. However the platelet count was decreased (0.3∙106 ± 0.05∙106 1/μl vs. 0.145∙106 ± 0.04∙106 1/μl) due to the impaired megakaryocytic function. The level of PC was decreased after X-ray irradiation (70 ± 10%) and partly restored on the 9th day after irradiation (87 ± 10%). Administration of activated carbon (AC) inhibited the drop in the PC concentration after X-ray irradiation (86 ± 15%) and accelerated its restoration on the 9th day (103 ± 14%). The statistically significant accumulation of FIFPs was detected in blood plasma of irradia­ted rats at the 1st and 9th days after irradiation. No FIFPs were found in any irradiated rat treated with AC. Characterization of the hemostasis system of rats that were exposed to a semilethal dose of X-rays allowed us to select parameters that can be used for monitoring of ARS development. Apart of from basic coagulation tests (APTT) and the measurement of platelet aggregation, fibrinogen and protein C level we can recommend the determination of FIFPs as a useful tool for estimation of the hemostasis response after irradiation with X-rays. This test indicates the intravascular thrombin generation and can help predict thrombotic complication or disseminated intravascular coagulation. Determination of FIFPs in blood plasma of irradia­ted rats allowed us to study the enterosorption effect on the development of irradiation-induced changes. It was shown that enterosorption with AC prevented accumulation of FIFPs which appears to be a newly discovered anti-thrombotic effect of therapy with AC. ARS influenced hemostasis by inducing thrombin generation (indicated by FIFPs generation), low-grade inflammation (indicated by PC concentration decrease) and thrombocytopenia. Enterosorption with AC minimizes inflammation and pro-coagulant processes caused by a moderate dose of X-ray irradiation. Accumulation of FIFPs can be assumed to be one of the most sensitive markers of the blood coagulation response to X-ray irradiation

MYELOPROTECTIVE ACTIVITY OF TWO GRANULOCYTE COLONY STIMULATING FACTORS ON MODEL OF CYTOSTATIC MYELOSUPPRESSION

Myelosuppression during intensive chemotherapy frequently is a reason of therapy disruption and rising of patients’ lethality. Effective method for prevention and treatment of neutropenia today is granulocyte colony stimulating factor (G-CSF) drugs. The aim of study – a comparison of myeloprotective activity of original preparation of recombinant G-CSF (rG-CSF), developed by IEPOR stuff, and officinal medication Filgrastim. Materials and Methods. Experiments were performed on healthy inbred white rats, 200 ±20 g. Melphalan (L-PAM, Alkeran, GlaxoSmithKline) was used to cause the myelosuppression at dose of 4 mg/kg one time intravenously. Filgrastim (Neupogen, Hoffman-La Roche Ltd,Switzerland) was used as a referent-drug. Dose of G-CSF was 50 mcg/kg. Animals were randomly distributed into 4 groups: 1 – intact group; 2 – rats who got L-PAM (L-PAM); rats of group 3 and group 4 except L-PAM got Filgrastim (L-PAM + filgrastim) and rG-CSF (L-PAM + rG-CSF). Cytokine was injected subcutaneously once a day during 4 days after melphalan injection. All data were analyzed using StatSoft STATISTICA 10 software. Results and Discussion. Melphalan caused prominent myelosuppression and thrombocytopenia: white blood cells count decreased by 75.6 %, erythrocytes count by 10.3 %, platelets count – by 59.9 %, hemoglobin level was without significant changes. Analysis of the ratio of blood cells showed that absolute count of neutrophils decreased by 53.8 % and lymphocytes – by 86.8 %. Both preparations of G-CSF caused significant rising of white blood cells count by 57.0 % (filgrastim) and by 53.9 % (rG-CSF). Also we observe the increasing of absolute count of neutrophils by 67.0 and 61.1 % at leukocytes formula. There were no changes of the other blood cells sprouts. Conclusions. Data of our study showed that both preparations of granulocyte colony stimulating factor demonstated significant myeloprotective effect. Ukrainian domestic preparation has the same efficacy as an officinal drug Figrastim. Such results are the base for further investigation of its efficacy and safety parameters and implementation into clinical practice

Chapter Sorption Detoxification as an Addition to Conventional Therapy of Acute Radiation Sickness and Iatrogenic Leukopenia

Leukopenia is an essential part of the clinical course of acute radiation sickness and is a side effect of anti-cancer treatment. In both situations, the main factors which determine the survival are the degree of bone marrow suppression and gastrointestinal tract damage due to the presence of a large pool of fast-dividing cells. Leuko- and neutropenia are main limiting factors which may contribute to chemotherapy failure. Hematopoietic cytokines the part of conventional therapy in this field, but their effects require boosting. That is why the use of means and methods of adsorption therapy is considered promising. Sorption therapy creates a basis for sorption detoxification, a doctrine of curative measures directed to the removal of toxic endogenous or exogenous compounds from body fluids. The most widely used types are the purification of blood or its components (hemosorption), oral administration of sorption materials (enterosorption) and application-sorption therapy of wounds and burns. In this chapter, the results of early and recent research and prospects for the use of carbon adsorption therapy for the treatment of acute radiation sickness and cytostatic myelosuppression are discussed