A. V. Dushkin

Polysaccharide arabinogalactan from larch Larix sibirica as carrier for molecules of salicylic and acetylsalicylic acid: preparation, physicochemical and pharmacological study

Abstract Inclusion complexes of salicylic acid (SA) and acetylsalicylic acid (aspirin, ASA) with polysaccharide arabinogalactan (AG) from larch wood Larix sibirica and Larix gmelinii were synthesized using mechanochemical technology. In the present study, we have investigated physicochemical properties of the synthesized complexes in solid state and in aqueous solutions as well as their anti-aggregation and ulcerogenic activity. The evidence of the complexes formation was obtained by nuclear magnetic resonance (NMR) relaxation technique. It was shown that in aqueous solution the molecules of SA and ASA are in fast exchange between the complex with AG macromolecules and solution. The stability constant of aspirin complex was calculated. It was shown that mechanochemically synthesized complexes are more stable when compared to the complex obtained by mixing solutions of the components. Complexes of ASA show two-fold increase of anti-platelet effect. It allows to reduce the dose of the antithrombotic drug and its ulcerogenic activity. These results substantiate the possibility to design new preparations on the basis of ASA with increased activity and safety.

Arabinogalactan, a plant polysaccharide, as a new tool for pharmacon clathration.

The ability of the carbohydratecontaining naturalmetabolites to bind drugs by formation of complexes(clathration) attracts attention because this allows thepharmacon dose and toxicity to be reduced, with theirpleiotropic properties improved and the basic effectretained.We demonstrated previously that this ability wascharacteristic of glycosides of higher terpenoids, suchas glycyrrhizinic acid [1, 2], stevioside, and rebaudioside [3].In this study, we have demonstrated that thepolysaccharide arabinogalactan (AG), which is ametabolite of the endemics of Siberian forest floralarches

Gel chromatographic and toxicological studies of the mechanochemical transformations of water-soluble polysaccharides

Changes in the molecular weight characteristics of polysaccharide macromolecules - arabinogalactan, hydroxyethyl starch 200/0.5, Fibregum, and dextrans 10, 40, and 70 - were studied during mechanochemical processing. A preference for “gentle” conditions for mechanical processing (~1 g) were established, as these conditions do not lead to destruction of polysaccharide macromolecules. An additional advantage of these mechanical processing regimes is that they can be scaled up to industrial flow mills. Mechanochemical processing had no adverse effect on the toxicity measures of the polysaccharides studied. Toxicological studies of mechanically processed arabinogalactan, hydroxyethyl starch 200/0.5, Fibregum, and dextrans 10, 40, and 70 showed that these polysaccharides and the products of their mechanochemical processing can be classified as class 4 (low-toxicity) substances.

The efficacy of the supramolecular complexes of niclosamide obtained by mechanochemical technology and targeted delivery against cestode infection of animals

Niclosamide is an anthelmintic that is widely used to treat cestode infection of animals. The efficacy of the supramolecular complexes of niclosamide obtained by mechanochemical technology and targeted delivery was studied in hymenolepiosis of mice and monieziosis of sheep. The efficacy of new substances of niclosamide with polyvinylpyrrolidone polymer in different ratios (1:10; 1:5; 1:2) was determined by the results of helminthological necropsy of the small intestine of sheep and mice. Pre-treatment eggs per gram (EPG) were not significantly different (P>0.1) among groups. The controlled test was used to evaluate the efficacy. A high efficacy (>95% efficacy) of the supramolecular complexes of niclosamide with PVP (SCoNwPVP) was shown in different ratios (1:10; 1:5 and 1:2) at a dose of 20mg/kg of body weight at oral administration against Hymenolepis nana in mice and Moniezia expansa in sheep. Whereas the basic drug - substance of niclosamide was effective at a dose of 100mg/kg of b/w. No adverse effects of the drugs on animal health were detected during the study.

Physicochemical properties and anti-opisthorchosis effect of mechanochemically synthesized supramolecular complexes of Albendazole with the polysaccharide Arabinogalactan from Larix sibirica and Larix gmelinii.

212 Opisthorchosis provoked by trematodes Opisthorchis felineus is one of the most widely spread helminthiasis in Russia, which affects at least 50–80% of the population of Western Siberia [1]. In the past decades, opisthorchosis has been treated with large action spectrum drugs, such as Praziquantel and Albendazole (ABZ). One of significant disadvantages of these preparations is their high toxicity [2]. More over, risks of teratogenic and carcinogenic effects of these preparations should also be taken into account. Praziquantel exhibited positive effects upon treatment of acute opisthorchosis, though it was not sufficiently effective in cases of most widely spread chronic opisthorchosis. Therefore, the development of novel antihelminthic agents and/or increase in efficiency of the existing ones is considered to be a challenging problem.

Efficient and safe medicines developed by Siberian scientists

Results of pharmacological and physico-chemical studies of supramolecular drug delivery systems on the basis of plant metabolites, viz. polysaccharides and glycyrrhizinic acid are summarized. The prospects of developing of safe and efficient medicines are outlined.

About the mechanism of membrane permeability enhancement by substances in their intermolecular complexes with polysaccharide arabinogalactan from larches Larix sibirica and Larix gmelinii

9 The inclusion of drug molecules (DMs) into inter molecular complexes with the water soluble polysac charide arabinogalactan (AG) isolated from the wood of larches Larix sibirica and Larix gmelinii makes it possible to significantly (sometimes manifold) enhance their pharmacological activity at peroral administration or reduce the doses with retaining the basic effects. These complexes are synthesized by the solid phase mechanochemical method and are char acterized by an increased water solubility. Their exist ence in aqueous solutions is also confirmed by the dynamic NMR spectroscopy data [1]. Despite the considerable amount of pharmacological and physic ochemical data [2], the mechanism underlying the increase in the pharmacological activity of DM–AG complexes remains unclear. A possible explanation for this change is the direct absorption of the DM–AG complex from the gastrointestinal tract into the blood stream and the delivery of DMs to the target receptors. The complex protects DMs from metabolization and prevents their accelerated excretion from the body, thereby increasing their effective concentration. Another explanation is the creation of an increased concentration of DMs in the aqueous phase both in the free state and in complexes DM–AG in the gas trointestinal tract. The decline in the absorbed DMs is rapidly compensated by the dissociation of these com plexes. As a result, the absorption rate increases, which increases the concentration of DMs in the bloodstream. Such a mechanism is also applicable to explain the observed enhancement of the pharmaco logical effect. The aim of this study was to investigate the possible mechanism of increasing the penetrability of DMs from the solutions of their complexes with AG. Since AG macromolecules have no characteristic groups that allow tracking their fate in the body, AG was functionalized using the “spin label” method [3]. A number of stable nitroxyl radicals R1–R3 served as DM models (table). Compounds R1 I, R2, and R3 were obtained by the methods described in [4]. The covalently bound adduct R1 O AG (I) was obtained by mechanochemical treatment of a mixture of radical R1 I with AG (TU 9363 021 39094141 08) in the presence of NaOH in an AGO 2 planetary ball mill [5]. The intermolecular complexes R2–AG (II) and R3–AG (III), in which the molecules were not covalently bound, was also obtained by mecha nochemical treatment of the components of mixtures in a weight ratio of 1/50. The solubility of R2 and R3 and the molecular weight of AG were determined as described in [1]. The study was performed with male Wistar rats weighing 180–230 g, which were obtained from the nursery of the Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences. All manipulations with animals were performed in accor dance with the European Convention for the Protec tion of Experimental Animals. Aqueous suspensions (I), (II), and (III) were administered intragastrically or intraperitoneally. After administration, blood sam ples (100 μL) were taken from tails of rats at different time intervals. Blood samples were diluted with 100 μL of phosphate buffer (pH 7.4) containing 150 mM NaCl, 250 U/mL heparin, and 50 μM diethylene tri amine pentaacetic acid (DTPA). Then, 5 h after the drug administration, the animals were anesthetized by About the Mechanism of Membrane Permeability Enhancement by Substances in Their Intermolecular Complexes with Polysaccharide Arabinogalactan from Larches Larix sibirica and Larix gmelinii