Modeling of Benign Prostatic Hyperplasia in Rats with a High Dose of Testosterone.

In order to optimize the testosterone model of benign prostatic hyperplasia, we studied the effect of castration and different doses of testosterone on the induction of the proliferative process in the prostate of Wistar rats. It was shown that 4-week subcutaneous administration of testosterone propionate in a dose of 20 mg/kg causes pronounced proliferative and hemodynamic disorders in the dorsolateral gland morphologically similar in castrated and non-castrated males. Administration of testosterone in a dose of 3 mg/kg had no significant effect on the dynamics of the pathological process in non-operated rats and normalized the structure of the gland in castrated animals. Morphological study showed that castration of males provides no visible advantages in reproducing the testosterone model of benign prostatic hyperplasia. The proposed non-traumatic modification of the model with a high dose of testosterone has good reproducibility and sensitivity to therapeutic agents, as shown by the example of finasteride.

Prostatotropic Action of Glycyrrhizic Acid Disodium Salt in Benign Prostatic Hyperplasia Models.

The prostatotropic activity of glycyrrhizic acid disodium salt (Na2GA) was studied in the models of benign prostatic hyperplasia (BPH) induced by chronic injection of sulpiride (40 mg/kg intraperitoneally for 8 weeks) or testosterone propionate (20 mg/kg subcutaneously for 4 weeks) in the Wistar rats. The oral administration of Na2GA in a dose of 100 mg/kg produced a moderate antiproliferative effect in both BPH models resulting in reduced volume density of prostatic epithelium (in the testosterone model) and increased volume density of the glandular lumen (in both models). The observed prostatotropic effects of Na2GA were similar to those of Permixon and finasteride, but they were less pronounced as confirmed by smaller drops in epithelial volume density and epithelial-to-stromal ratio compared to the effects of both reference drugs.

Morphological Assessment of Prostatotropic Activity of (3,5-Dimethyl-4-Hydroxy)Benzyl Thiododecane on a Model of Benign Prostatic Hyperplasia in Rats.

Prostatotropic activity of (3,5-dimethyl-4-hydroxy)benzyl thiododecane (T-DD) was evaluated on a model of benign prostatic hyperplasia induced in Wistar rats by chronic (2 months) intraperitoneal administration of sulpiride (40 mg/kg). Morphometric analysis of the dorsolateral lobe of the prostate showed that after the 2-month course of intragastric T-DD (100 mg/kg) administered in parallel with sulpiride, the volume density of glandular epithelium decreased by 1.7 times, while the volume density of prostate stroma increased by 2 times. After administration of the reference drug Permixon at a dose of 50 mg/kg, the volume densities of epithelium decreased by 1.3 times and stromal volume density increased by 1.5 times. The observed effects are presumably related to suppression of 5α-reductase activity and modulation of estrogen receptors in the prostate.

Physicochemical Properties and Anti-Opisthorchosis Effect of Mechanochemically Synthesized Solid Compositions of Praziquantel with Glycyrrhizic Acid Disodium Salt.

The mechanochemical preparation of solid compositions of praziquantel with plant saponin (glycyrrhizic acid disodium salt) is described. The study of a number of physicochemical parameters showed that dissolving solid compositions in water is accompanied by the inclusion of praziquantel molecules into micelles, which are formed in the solution of the glycyrrhizic acid disodium salt. Using the opisthorchiasis model caused by Opisthorchis felineus, we found a 4- to 11-fold increase in the anthelmintic activity of praziquantel in the composition as compared to the official praziquantel. According to the pharmacokinetic data, the use of the composition increased the bioavailability of praziquantel 3 times.

Specific Features of Progression of the Parasitic Invasion, caused by Opisthorchis felineus, in Golden Hamsters.

The influence of Opisthorchis felineus invasion on the development of pathological changes in the hepatobiliary system was studied in 120 golden hamsters in a long-term experiment (42 weeks) after single infection per os in the dose of 50 metacercariae per animal. The animals were sacrificed on weeks 4, 8, 12, 16, 28 and 42. Chronic experimental infestation with O. felineus triggered a cascade of morphogenetic processes in both extrahepatic and intrahepatic biliary systems. At the early stages of the experiment, polyps and strictures of bile ducts were formed in the lobar bile ducts; in portal tracts, hyperplasia and adenomatous transformation of the newly formed epithelial structures were observed. At the later stages, third-degree biliary intraepithelial neoplasia developed in the lobar bile ducts; in the intrahepatic bile ducts, increased epitheliocyte hyperplasia and invasive growth of cell cords were observed, that impaired tissue architectonics. Progressing cell atypia can be classified as cholangiocellular cancer.

Amide of Lambertian Acid Suppresses Hyperactivation of Inotropic Glutamate Receptors, but not Synaptic Potentiation in Hippocampal Sections.

Amide of lambertian acid suppresses hyperactivation of inotropic glutamate receptors in hippocampal sections induced by a decrease in the level of magnesium ions (a selective blocker of glutamate NMDA receptors). Treatment of the sections with amide of lambertian acid in standard physiological saline does not prevent development of NMDA-dependent synaptic potentiation. Lambertian acid isolated from needles and turpentine of Siberian pine (Pinus sibirica R. Mayr), and its derivatives may become a source of substances with glutamatergic mechanism of action for treatment of cognitive and neurodegenerative disorders.

Cardiotoxic and Dyslipidemic Effects of Doxorubicin and Betulinic Acid Amide.

Changes in the blood lipid spectrum and structural reorganization of the rat myocardium in response to injection of a single sublethal dose of doxorubicin (7 mg/kg) alone and in combination with course administration of betulonic acid amide (100 mg/kg/day for 14 days) were studied. Betulinic acid amide in the specified dose exhibited less pronounced cardiotoxic (necrobiotic impairment of cardiomyocytes) and dyslipidemic (increase of cholesterol and triglyceride levels) effects in comparison with doxorubicin. Combined treatment with betulinic acid amide and doxorubicin led to more pronounced remodeling of the myocardium, which was shown by a significant increase of the connective tissue/cardiomyocyte volume ratio detected by day 14 of the experiment.

[Curare-Like Camphor Derivatives and Their Biological Activity].

The synthesis and evaluation of muscle relaxant activity of series of dimeric camphor derivatives are described. Compounds in which the quaternary nitrogen atoms are separated by aromatic chain exhibited the highest efficiency as muscle relaxant. It was shown the screening of a charged atom and counter-ion does not have a significant role on the activity of the studied agents.

[Synthesis and Anti-Inflammatory activity of the propargylamino derivatives of naphthoquinonlevopimaric acid].

Modification of naphthoquinonlevopimaric acid was carried out by introducing of propargylamino residues. Anti-inflammatory activity Mannich bases were studied.

[Synthesis of new analogues of combretastatin A-4 and the study of their anti-inflammatory activity].

New approach to synthesis of analogs of natural Combretastatin A-4 based on interaction of α-acetylenic ketones with secondary amines (diethyl amine, pyrrolidine, piperidine, morpholine) is offered. Unknown analogs of Combretastatin A-4 with ß-aminovinylcarbonyl bridges are received earlier. Anti-inflammatory activity of the received connections is studied.

Hepatoprotective properties of betulonic acid amide and heptral in toxic liver injury induced by carbon tetrachloride in combination with ethanol.

Toxic liver injury with the development of fibrosis and cirrhosis was modeled in Wistar rats by intragastric administration of 0.1 ml/kg CCl4 in combination with 5% ethanol with glucose 3 times a week for 6 weeks. The animals were treated with betulonic acid amide (50 mg/kg in Tween aqueous solution) and heptral (6 mg/kg) as hepatoprotective compounds. It was found that betulonic acid amide stimulated the regenerative response in hepatocytes under conditions of combined toxic exposure and promoted recovery of their qualitative and quantitative characteristics, which was accompanied by a significant decrease in the severity of liver fibrosis and the absence of cirrhotic transformation of the liver.

Role of cAMP- and IKK-2-Dependent Signaling Pathways in Functional Stimulation of Mesenchymal Progenitor Cells with Alkaloid Songorine.

The role of cAMP- and IKK-2-dependent pathways in stimulation of the growth capacity of mesenchymal progenitor cells with alkaloid songorine was studied in vitro. Inhibitors of adenylate cyclase and IKK-2 were shown to abolish the increase in proliferative activity of progenitor cells. Moreover, blockade of the inhibitory kinase complex was accompanied by a decrease in the intensity of progenitor cell differentiation.

Involvement of PI3K, MAPK ERK1/2 and p38 in Functional Stimulation of Mesenchymal Progenitor Cells by Alkaloid Songorine.

We studied the role of intracellular signaling molecules PI3K, МАРK ERK1/2, and р38 in stimulation of realization of the growth potential of mesenchymal progenitor cells by alkaloid songorine in vitro. Inhibitors of PI3K, ERK1/2 and р38 canceled the increase in proliferative activity of progenitor cells, the blockers of ERK1/2 and р38 reduced the intensity of progenitor cell differentiation.

Role of NF-κB/IKK-dependent signaling in functional stimulation of mesenchymal progenitor cells by alkaloid songorine.

We studied the role of NF-κB/IKK-mediated signaling in the stimulation of growth potential of mesenchymal progenitor cells by alkaloid songorine in vitro. Specific NF-κB inhibitor oridonin abolished activation of proliferation and differentiation of progenitor cells. Aurothiomalate, a selective blocker of IKK-2, also suppressed mitotic activity of fibroblast precursors, but had no effect on the rate of the differentiation.

[Role of opisthorchis felineus on induction of bile duct cancer].

Opisthorchis felineus (Trematoda) is widespread in the Russian Federation, especially in Siberia, and other countries of Europe. Infestation of endemic area population with O. felineus reaches 80%. On animal models of the infection of closely related Opisthorchis viverrini combined with the nitrosamines' intake it has been shown that the parasite induces cholangiocarcinoma. However carcinogenic potential of O. felineus is still poorly studied. The present study is aimed to investigate the role of O. felineus in cholangiocarcinoma carcinogenesis in hamster treated additionally by dimethylnitrosamine (DMN). Golden hamsters were divided into 4 groups (15 specimens in the control group and 20 for other groups): (I) untreated control, (II) 12.5 ppm DMN solution intake, (III) infected with 50 metacercariae of O. felineus and (IV) infected with 50 metacercariae of O. felineus and 12.5 ppm DMN solution intake. According to the histological data, in the. O. felineus-infested group significant hyperplastic and dysplastic biliary changes were found considered as a precancerogenic state. Such pathological changes of bile ducts were more severe in group treated with both factors, with cholangiocarcinoma being found out at 18th week in all the animals of this group. These results demonstrate that O. felineus could play promoting role in two-step model in cholangiocarcinoma carcinogenesis and may be used to define the O.felineus group in the International Agency for Research on Cancer classification of agents, mixtures and exposures (IARC categories).

Complex investigation of the effects of lambertianic acid amide in female mice under conditions of social discomfort.

The effects of chronic administration of a new substance lambertianic acid amide and previously synthesized methyl ester of this acid were compared in female mice living under conditions of social discomfort. For modeling social discomfort, female mouse was housed for 30 days in a cage with aggressive male mouse kept behind a transparent perforated partition and observed its confrontations with another male mouse daily placed to the cage. The new agent more effectively than lambertianic acid methyl ester improved communicativeness and motor activity of animals, reduced hypertrophy of the adrenal glands, and enhanced catalase activity in the blood. These changes suggest that lambertianic acid amide produces a pronounced stress-protective effect under conditions of social discomfort.

Effect of 2-aminoadamantane derivatives on behavior of mice in a modified light/dark test.

The effects of two derivatives of 2-aminoadamantane, enantiomers J447H and J579, on the behavior of male and female C57Bl/6J mice were studied using a modified light/dark test. The substances differed by their effects on the behavior of male mice. J579 reduced the number of rearings. J447H in a dose of 1 mg/kg affected more parameters: it reduced exploratory activity 1 h after administration and stimulated exploratory and motor activity in 2 h. In female mice, J447H significantly reduced the number of peepings into holes in 2 h after administration. The results indicate that further analysis of the effects of J579 and especially J447H is required.

[Synthesis of aminopropylaminoderivatives of betulinic and oleanolic acids].

On the basis of betulinic and oleanolic acids triterpenoids with different with different amine fragments: (3-aminopropoxy)-, 3-acetyl-(3-aminopropyl)amino-, 6-[bis(3-aminopropyl)amino]hexylamino-, (3-aminopropyl)-4-aminosulfonyl-4-phenylamino- at positions C3 and C28 were synthesized. It is shown that betulonic acid amide with 4,4'-diaminodiphenylsulfonic substituent don't render antitumor effect in mice with transplantable Lewis lung carcinoma, but possess significant anti-inflammatory activity.

[Antitumor activity of dihydrobetulonic acid amides in vitro and in vivo].

Amides with homopiperidinic and piperazinic cycles were synthesized from dihydrobetulonic acid which was obtained by dihydrobetulin oxidation. All substances have shown high antitumor activity (CCID50 3.5-36.2 microM) in vitro in lymphoid (CEM-13, U-937) and monocytic (MT-4) human cell lines. Amides with methyl- and ethyl-piperazinic residues don't influence viability of Lung Lewis Carcinoma cell in culture and haven't any significant effect to its transplantates in C57BL/6 mice. But such amides inhibit efficiently the metastatic elaboration in lung of these mice. The antimetastatic activity increases followed by the change of aliphatic residue length in piperazinic cycle from methyl to ethyl.

[Hepatoprotective activity of betulonic acid amides containing a piperidine or pyrrolidine nitroxide moiety].

Betulonic acid amides containing a nitroxyl radical moiety possess antiholestatic effects in mice. Introduction ofpiperidine nitroxide moiety into lupan core increases its hepatoprotective activity. Oral administration of piperidine nitroxide derivative in dose 50 mg/kg doesn't stimulate transplanted tumor growth and raises a lifespan of mice.