[STUDYING THE ACUTE TOXICITY OF DEXTRAN POLYALDEHYDE CONJUGATE WITH ISONICOTINIC ACID HYDRAZIDE.]

The acute toxicity of a new antubercular drug, dextran polyaldehyde conjugate with isonicotinic acid hydrazide (dextrazide), has been studied on animals, HepaRG cell line, and FRSN human skin fibroblasts. Average tolerable doses (LD(10), LD(16)), half-lethal doses (LD(50)), and lethal doses (LD(84)) of dextrazide have been determined for intraperitoneal introduction in mice and rats and intravenous injection in rabbits.

Experimental study of the efficiency of oxidized dextran for prevention of influenza A/H5N1.

Oxidized dextran is suggested for prevention of infection induced by influenza A/H5N1 viruses, methods of its use and doses are determined. Two intravenous injections of dextran 3 and 1 days before experimental infection of outbred mice by influenza A/H5N1 A/goose/Krasnoozerskoye/627/05 virus resulted in a high preventive dose-dependent effect: the mean lifespan was 25% prolonged, the mortality decreased 3-fold.

Phagocytosis of hybrid molecular nanosomal compositions containing oxidized dextrans conjugated with isonicotinic acid hydrazide by macrophages.

We studied phagocytic activity of macrophages towards hybrid molecular nanosomal compositions consisting of 150-800-nm nanoliposomes containing oxidized dextrans with a molecular weight of 35 and 60 kDa obtained by chemical ("permanganate") and radiochemical oxidation of dextran conjugated with isonicotinic acid hydrazide (dextrazides, intracellular prolonged antituberculous drugs). Phagocytic activity of macrophages towards hybrid molecular nanosomal compositions containing dextrazides obtained by chemical oxidation of dextrans is higher than activity towards hybrid molecular nanosomal compositions containing dextrazides prepared by radiochemical oxidation and depends on the size of hybrid molecular nanosomal compositions and molecular weight of oxidized dextrans.

Phagocytic activity of macrophages against liposomes with conjugates of oxidized dextrans and isonicotinic acid hydrazide during modeling of phagocytosis disturbances in vitro.

We studied phagocytic activity of macrophages against molecular-liposome hybrid compositions consisting of liposomes (diameter 200-450 nm) containing oxidized dextrans with a molecular weight of 35 or 60 kDa conjugated with the basic antituberculosis preparation isonicotinic acid hydrazide (dextrazides) during modeling of various disturbances of endocytosis function of phagocytic cells in vitro. Preincubation of macrophages with trypsin, colchicine, or sodium azide did not change the parameters of adhesion of molecular-liposome hybrid compositions to macrophages. It was found that preincubation of cells with colchicine or sodium azide reduced parameters of phagocytosis of the molecular-liposome hybrid compositions; this reduction did not depend on the molecular weight of dextrans entering the composition of the molecular-liposome hybrid compositions.

Effects of molecular liposomal hybrid compositions with oxidized dextrans and isonicotinic acid hydrazide on production of granulocytic macrophage colony-stimulating factor by macrophages.

The effects of molecular liposomal hybrid compositions consisting of liposomes (200-450 nm) containing oxidized dextrans (dextranals; 35-60 kDa) conjugated with isonicotinic acid hydrazide (dextrazides), their components, and native dextrans on the production of granulocytic macrophage CSF by peritoneal macrophages were studied in vitro. Dextranals proved to be more potent inductors of granulocytic macrophage CSF than native dextrans. Conjugation of nicotinic acid hydrazide with dextranals did not modify their capacity to stimulate the production of granulocytic macrophage CSF. Liposomes in the molecular liposomal hybrid compositions did not attenuate the dextrazide capacity to stimulate the production of granulocytic macrophage CSF. Molecular liposomal compositions containing 60 kDa dextrazide exhibited the most potent stimulatory effect on macrophage production of granulocytic macrophage CSF.

Effect of oxidixed dextrans on oxidative and metabolic function of mouse peritoneal macrophages in vitro and in vivo.

We compared the effects of dextrans with a molecular weight of 35 kDa oxidized by chemical (OD(ch)) and radiochemical (OD(r)) methods on oxidative and metabolic functions of peritoneal macrophages from BALB/c mice in vitro and in vivo. It was found that none type of dextrans exhibits chemiluminescent properties. In vitro study showed that OD(ch) had a priming effect on mouse peritoneal macrophages, while OD(r) did not potentiate the oxidative and metabolic response of cells to zymosan. Being injected intraperitoneally, OD(r) more markedly enhanced chemiluminescent response of mouse peritoneal macrophages and reduced their viability than OD(ch). Thus, both dextrans are biocompatible, but in OD(ch) this parameter is higher.

In vitro effect of oxidized dextrans on peritoneal cells.

We studied the dependence of in vitro dextran biocompatibility on the method of oxidation of 35-kDa dextran. The biocompatibility of dextran oxidized with potassium permanganate was higher compared to that obtained by radiochemical oxidation. It was related to the formation of peroxide compounds during radiochemical oxidation.

Comparative study of the in vitro effect of nanoliposomes with oxidized dextrans on peritoneal cells.

We studied the in vitro effect of hybrid molecular-nanosomal biocompatible compositions on cultured peritoneal cells. The compositions consisted of oxidized dextrans with a mean molecular weight of 35 and 60 kDa, which were obtained by chemical and radiochemical oxidation of dextran. Hybrid nanoliposomal compositions of chemically oxidized dextran (permanganate method) had greater biocompatibility and tropic activity to macrophages compared to nanoliposomes of radiochemically oxidized dextran.

In vitro effects of molecular nanosomal hybrid compositions with oxidized dextrans, conjugated with isonicotinic acid hydrazine on peritoneal macrophages.

The effects of molecular nanosomal hybrid compositions consisting of nanoliposomes with oxidized dextrans (mol. weights 35 and 60 kDa) conjugated with isonicotinic acid hydrazine (dextrazides) on peritoneal macrophages were studied in vitro. Incubation of peritoneal cells with molecular nanosomal hybrid compositions modified the immunological phenotype of macrophage populations, which reflected an increase in their functional activity. Molecular nanosomal hybrid compositions containing dextrazide with 60-kDa dextran more effectively activated macrophages.

Radiation technology in the preparation of polyethylene oxide hydrophilic gels and immobilization of proteases for use in medical practice.

This paper deals with the development of a technology for making a hydrophilic gel of polyethylene oxide reception in which radiating ability is employed to cause cross-linking of polymers in a water solution. The gel of polyethylene oxide was shown to be non-toxic, contain 5-50% of polymer and be useful in composite medicinal forms along with biologically active substances including Bac. subtilis proteases. Proteases immobilized in the gel possess high thermal stability and proteolytic activity and are readily applied in medicine. The effect of immobilized proteolytic and glucolytic enzymes of Bac. subtillis (Immozimase) on the warm ischemia-reperfusion (I/R) which can cause hepatic and jejunum injury was also studied. These enzymes were immobilized on water-soluble polymer polyethylene glycol by means of an electron beam. The number of degranulated mast cells as well as serum ALT after I/R in the group with Immozimase was decreased to almost half as compared with the control group. Pretreatment with Immozimase resulted in significant reduction of hepatic and gut neutrophil accumulation as compared with control animals. It was concluded that Immozimase has a protective effect for hepatic and gut ischemia/reperfusion, and this effect seems to be associated with prevention of leukocyte accumulation.