[PHARMACOLOGICAL CORRECTION OF APOPTOSIS LEVEL OF CORTICAL NEURONS IN AGED HER2/NEU TRANSGENIC MICE].

Neurodegenerative changes and neuronal death are the basis for development of the nervous system aging. We investigated the mechanism of apoptosis of the sensorimotor cortex neurons of transgenic mice HER2/neu during aging, changes in the cortex function and the participation of exogenous neurometabolites (cytoflavin, piracetam) in regulation of neuronal death and locomotor and psycho-emotional status of mice. The level of apoptosis and expression of apoptosis markers (TUNEL, immunohistochemistry, Western blotting) in HER2/neu transgenic mice as compared to wild type mice (FBV line) were determined. In aging FBV mice the basal activity was shown to decrease and anxiety to increase correlating with the high level of neuronal apoptosis. We identified behavioral characteristics of transgenic HER2/neu mice and found that their low basal activity does not change with aging. Previously we have shown that in this strain of mice the apoptosis level is low, without any age-related changes, due to the suppression, first of all, of the p53-dependent pathway by HER2 (tyrosine kinase receptor) overexpression. Cytoflavin and piracetam were revealed to possess a marked neuroprotective effect, preserving and restoring functions of the nervous system (improving locomotion and psychological status) in both strains of mice. The effect of neurometabolites studied on neuronal apoptosis is ambiguous. In case of its low level it is a moderate stumulation of apoptosis via the external p53-dependent pathways with activation of caspase-3 in transgenic HER2/neu mice with high carcinogenesis level that can possibly prevent tumor development. On the contrary, in old wild-type animals we observed a significant decrease of age-dependent apoptosis level (by stimulating expression of the anti-apoptotic protein Mcl-1), which prevents neurodegeneration.

[Comparative experimental study of the influence of drugs that improve brain metabolism (angiogen, cytoflavin) on neuronal apoptosis and function of cerebral cortex during aging].

The safety of cortical neurons and their functional activity is essential for organism at all stages of ontogenesis. However, aging changes leading to an increase in apoptosis level may cause considerable damage to cerebral cortex function, including sensorimotor. We have studied the role of exogenous neurometabolites (angiogen, cytoflavin) in apoptosis regulation and correction of age-related motor and behavioral disturbances. To study the regulation of neuronal morphofunctional activity, we used accelerate-senescent transgenic HER2 mice in comparison to wild type FBV mice. Functional changes in cerebral cortex were studied by the Suok test and open field test, the level of neuronal apoptosis was assessed by TUNEL method, the expression of apoptosis-modulating proteins was detected by immunohistochemistry and Western blotting. We have revealed differences in psycho-emotional and locomotor activity of these strains of mice. In addition, results of our study showed morphological differences: increase in the apoptosis level of cortical neurons in aged FBV type mice, but no changes in aged HER2 mice. The investigated drugs induce cell death of cortical neurons in transgenic mice of both ages and in young wild-type mice by p53-dependent pathway. Increased apoptosis in the cortex of old transgenic mice has important clinical implications, because reduced apoptosis during aging is one of the causes of cancer. The treatment of old wild-type animals reduces elevated neuronal apoptosis, which decreases risk of age neurodegeneration. Thus, revealed morphological changes in the cerebral cortex are the basis for involutional disabilities (including reduced locomotor activity and increased anxiety level). The use of angiogen and cytoflavin treatment improves functional activity of the cortex and protects normal structure of nervous tissue.

Pathways of apoptosis regulation in hepatocytes induced by first-line antitubercular drugs.

We studied pathways of apoptosis regulation during experimental hepatopathy caused by treatment with antitubercular drugs and involvement of some hepatoprotectors and immunomodulators in the regulation of hepatocyte apoptosis induced by antitubercular drugs. The intensity of apoptosis and expression of apoptosis-associated molecules were evaluated. It was shown that antitubercular drugs induce apoptosis in hepatocytes by triggering external signaling pathway and p53-dependent signaling pathway and simultaneously reducing the level of anti-apoptotic Bcl-2 protein. Runihol, remaxol, and cycloferon reduced degenerative effects in the liver, though the level of apoptosis remained high. Ademetionine in tablets and reamberin improved the microstructure of the liver by inhibiting both apoptotic pathways induced by the antitubercular drugs; in other words, they have distinct hepatoprotective and apoptosis-protective effects, which is especially important at the late stages of ontogeny.

[The morphofunctional state of the liver and the possibilities of pharmacotherapy for its disease in small bowel obstruction].

OBJECTIVE: To study the results of liver morphological studies in 40 Vietnamese pot belly pigs with simulated small bowel obstruction. MATERIALS AND METHODS: Liver morphofunctional changes in acute strangulation ileus were investigated in an experiment on 40 Vietnamese pot belly pigs weighing 15-20 kg. Five animals were used as a control. RESULTS: In simulated acute ileus, the found morphofunctional changes in hepatocytes were characterized by toxic dystrophy of the organ with the signs of secondary hepatitis. CONCLUSION: During the experiment, the course of the disease and surgical restoration of small bowel patency have been found to be accompanied by significant histological and ultrafine structural disorders of the liver, which is a rationale for intensive antihypoxant, antioxidant, and hepatoprotective therapy in the pre- and postoperative periods.

[The hepatotropic activity of runihol and ademethionine against experimental liver damage caused by first-line antituberculosis drugs].

Experiments on 62 male albino outbred rats investigated the impact of 14-day use of the oral hepatotropic agents ademethionine and runihol in different doses in liver damage caused by a antituberculosis combination (HRZ). HRZ-induced liver damage was shown to be accompanied by the development of cytolysis and cholestasis. The test drugs in the doses under study had a mixed effect, by reducing the magnitude of biochemical manifestations of these syndromes. Both drugs favored the recovery of the structure of the liver and the reduction of the extent of carbohydrate, protein, and fat dystrophies of the organ. As in previous investigations, ademethionine was found to have enhanced activity of alterative processes in the liver.

[Meglumine acridonacetate and complex therapy of patients with newly identified advanced pulmonary tuberculosis].

Clinical and immunological efficacy of meglumine acridonacetate (cycloferon) tablets was evaluated in complex treatment of patients with newly diagnosed advanced pulmonary tuberculosis. It was shown that the use of cycloferon according to our scheme increased the efficacy of the therapy (earlier disappearance of the disease symptoms and bacteria isolation, shorter-terms of cavern healing, more pronounced positive radiographic dynamics vs. the patients under the etiotropic therapy). The use of cycloferon normalized the number of gamma interferon receptors, increased the gamma interferon serum levels, reduced the incidence of the side effects (liver damage) due to the use of TB drugs. Such a use of cycloferon was cost effective. The use of sycloferon is possible in the complex treatment of outpatients with advanced pulmonary tuberculosis.

[Pulmonary vasculitis as a clinical mask of HCV infection: efficiency of interferon-free antiviral therapy].

The paper describes a clinical case of pulmonary vasculitis caused by hepatitis C virus (HCV). Its diagnosis was established on the basis of in-depth laboratory testing and an investigation of the molecular biological markers of viremia (polymerase chain reaction--PCR--HCV RNA) in peripheral blood mononuclear cells. By taking into account of extrahepatic HCV replication and contraindications to interferon therapy, the female patient was given an interferon-free antiviral therapy cycle using an interferonogenic inductor in combination with ribavirin. Pathogenic therapy (methylpred and ursodeoxycholic acid) was additionally performed. An interferon-free regimen of cycloferon + ribavirin led to sustained remission of HCV infection running with its systemic manifestations. The therapy could improve the function of not only the liver, but also the lung. In suspected extrahepatic HCV infections, an investigation of molecular biological markers for viremia (HCV RNA PCR) in the peripheral blood mononuclear cells is an essential diagnostic technique. Interferonogenic inductors, cycloferon in particular, should be used in combination with ribavirin when a chronic hepatitis C patient with the extrahepatic manifestations of HCV infection has contraindications to conventional therapy with recombinant interferon-α.

[Role of hepatoprotectors and immunomodulators in regulation of hepatocyte apoptosis induced by antituberculosis treatment].

UNLABELLED: It was currently shown that hepatopathy due to drug toxicity is associated with increased apoptosis of hepatocytes. Therefore, development of drugs which regulate cell death is of great importance. AIM: To involve some hepatoprotectors (ademethionine, reamberin, remaxol) and immunomodulators (cycloferon) into regulation of apoptosis in experimental models of liver first-line antituberculousis drugs (isoniazid, rifampicin, pyraztinamide). MATERIALS AND METHODS: Levels of apoptoasis (TUNEL), expression of CD95 (receptor of tumor necrosis factor - by immunohistochemistry), expression of caspase-8, caspase-3 and pS3 (Western-blotting) were measured. RESULTS: Exposition offirst-line antituberculousis drugs leads to dysthrophia of liver parenchyma cells with increased apoptosis of hepatocytes and activation of CD95, caspase-8 (external way) and overexpression of p53 and caspase-3. It was found that reamberin, cycloferon and remaxol have hepatoprotective effect improving liver histology; ademethionine administered by intraperitoneal injection showed no positive effects. Reamberin demonstrated apoptosis-inhibiting effect in the experiment whereas other drugs were found to be apoptosis inductors for hepatocytes in toxic hepatopathy. CONCLUSIONS: Legulation of apoptosis by cycloferon and remaxol mediated by external and p53-dependent pathway is confirmed by increased expression of CD95 and p53 protein. Ademethionine might induce apoptosis by the intrinsic pathway.

[The hepatoprotective activity of remaxol and S-adenosyl-L-methionine for liver damage caused by reserve-series antituberculosis drugs].

Experiments on male albino outbred rats investigated the hepatoprotective activity of remaxol and ademethionine in liver damage caused by reserve-series antituberculosis drugs. The test drugs had a mixed action, by reducing the degree of cytolytic and cholestatic syndromes. Remaxol and ademethionine assist in diminishing the degree of liver structural and functional impairments occurring with reserve-series antituberculosis drugs, by restoring the girder structure of lobes and decreasing the magnitude of dystrophic changes to stimulate reparative processes. Histological examination of liver tissue sections from rats receiving ademethionine revealed the enhanced activity of alterative processes in the liver.

[Hepato- and endothelioprotective action of runihol and ademetionine in experimental liver injury induced by TB drugs in combination with alcohol].

Hepato- and endothelioprotective action of runihol and ademetionine in 66 male rats with liver disease induced by essential and second-line antituberculosis drugs in combination with alcohol were studied. One-directed affirmative action study drugs, shown to reduce the level of biochemical markers of cytolysis and cholestasis in conjunction with a significant reduction in symptoms of fatty, hyaline droplet and hydropic degeneration. In this runihol had a more pronounced anticytolitic effect, while under the influence of ademethionine the normalization endothelial dysfunction was established.

[Antioxidant properties of remaxol, reamberin, and ademetionine in patients with drug-induced liver injury on the background of antituberculous therapy].

The antioxidant properties of remaxol, reamberin and ademetionine have been studied in comparison to 5 % glucose solution in a group of 120 patients with drug-induced liver injury. It is established that the inclusion of this drugs in the composition of complex therapy contributed to restoration of the antioxidant potential of the cells, which was manifested by increased activity of glutathione peroxidase and superoxide dismutase and integral indices of antioxidant protection (total antioxidant capacity and total antioxidant status) with a relative stabilization of the level of glutathione-S-transferase. Maximum pharmacotherapeutic effect with respect to all of the studiea indices has been achieved by the use of remaxol.

[Immunotropic and antihypoxant therapy of experimental drug-sensitive and drug-resistant tuberculosis].

The results of pre-clinical research of cycloferon, remaxol and runihol on the model of experimental generalized tuberculosis, caused by the MBT with a different spectrum of drug sensitivity are presented. A considerable increase of the curative effect of the therapy with the used of cycloferon and remaxol. There was manifested the strengthening of lung clearance from the office, reducing the prevalence of specific inflammation in the lungs of the index of lung damage, stimulation of sorption and destructive ability of peritoneal macrophages, inhibited in the course of development of experimental tuberculosis infection. Runihol has no impact on the effectiveness of chemotherapy in the absence of a stimulating influence on the phagocytic function of the peritoneal macrophages.

[The clinical efficacy of a succinate-containing infusion drug during pharmacotherapy for hepatic lesions of varying genesis: results of meta-analysis].

AIM: To pool the published results of trials of the new infusion hepatoprotector remaxol for the integral quantification of the magnitude of its clinical efficacy. SUBJECTS AND METHODS: The authors made a systematized review of the published results of randomized clinical trials of the succinate-containing infusion hepatoprotector remaxol in diseases associated with hepatic lesions (chronic hepatitis B and C, severe ethanol intoxication in the presence of alcohol dependence, drug-induced liver lesion during treatment of tuberculosis, and metabolic syndrome). The pooled database included information on 935 patients. The combined control group (n = 447) received traditional pharmacotherapy drugs (active placebo), the treatment group (n = 628) additionally took remaxol. RESULTS: Meta-analysis of the frequency characteristics of positive outcomes (the rate of disappearance of major clinical symptoms and complications) and the activity range for the enzymes characterizing hepatocyte cytolysis (alanine aminotransferase and aspartate aminotransferase) and cholestasis (alkaline phosphatase and gamma-glutamate transpeptidase) in the compared groups could provide an integral evaluation of the clinical efficacy of remaxol, which was 1.57 for enzymatic activity and 1.78 for the frequency characteristics of outcomes. The odds ratio of positive outcomes was 2.9 (range 1.9 to 3.9) and the number of patients who needed to be treated with remaxol during the follow-up to prevent a poor outcome in one patient was 6 (range 4 to 8). CONCLUSION: The succinic acid-based infusion hepatoprotector remaxol provides a statistically and clinically significant therapeutic effect in the drug correction of hepatic lesions of varying genesis.

[Mechanism of hepatocyte apoptosis in experimental toxic liver injury].

One of the causes of drug hepatopathy is hepatocyte apoptosis, the mechanisms of which are still unclear. The experiments were performed in 24 Wistar rats to study the role of hepatoprotectors in the regulation of hepatocyte apoptosis in liver damage induced by administration of antituberculosis drugs (ATD). The level of apoptosis (TUNEL) was evaluated, and the expression of apoptosis-associated molecules was detected by immunohistochemistry and Western blotting. It was shown that a signaling cascade induced by ATD involved the activation of cell surface receptors (CD95) and caspase-8, i.e. apoptosis was mediated by extrinsic pathway. In addition,ATD induced p53 oncosuppressor synthesis with further activation of caspase-3 effector. Runihol administration during ATD treatment administration improved the condition of the liver, despite some apoptosis stimulating effect, mediated by an intrinsic pathway. It was found that runihol blocked both FAS- and p53-dependent pathways. Ademethionine during drug intoxication acts as a hepatoprotector, blocking extrinsic and p53-dependent pathways.

[Pharmacological activity of runihol and S-adenosyl-L-methionine in rats with experimental liver damage by reserve antituberculosis drugs].

The hepatoprotective action of runihol and S-adenosyl-L-methionine (ademethionine) has been studied in a group of 47 white outbred male rats with model liver injury induced by reserve antituberculosis drugs (PAS, prothionamide, cycloserine). The ability of test drugs to correct structural and functional liver disorders is established. Both runihol and ademethionine favored decrease in the signs of structural and functional liver disorders induced by reserve antituberculosis drugs, Showing mixed type of action, the test drugs promoted recovery of the liver parenchyma and reduced manifestations of hepatocyte dystrophy to the same extent, without manifestations of necrobiotic processes and a mononuclear infiltration.

[Virus infections and interferon inducers in the complex therapy].

Interferon inductors of various chemical groups, belonging to antivirals, and induction of several types of endogenous interferon in blood serum are described. Cycloferon was shown efficient in the complex treatment of chronic hepatitis C, tuberculosis in HIV-infected subjects, arbovirus diseases, influenza and acute respiratory virus infections.

[Comparative efficacy of clinical use of reamberin, remaxol and ademethionine in patients with tuberculosis of the respiratory organs and liver drug-injury].

The efficacy ofreamberin, remaxol, S-adenosyl-L-methionine (ademethionine) and 5% glucose solution was estimated in the treatment of patients with tuberculosis of the respiratory organs and drug hepatotoxicity signs confirmed by higher activity of liver indicative enzymes and nitrogen oxide levels. Remaxol showed a pronounced positive effect on the cytolytic syndrome signs, evident from lower activity of alanine aminotransferase and aspartate aminotransferase. At the same time ademethionine was superior to remaxol in the effect on the cholestatic signs and inferior in the effect on the cytolytic signs. By the effect on the activity of alanine aminotransferase and aspartate aminotransferase, reamberin was inferior to remaxol and superior to ademe-thionine, its effect on the cholestasis markers level vs. the other drugs being superior only to that of 5% glucose solution. As compared to reamberin, ademethionine and 5% glucose solution, remaxol promoted higher integral indices of the host antioxidant protection (total antioxidant capacity and total antioxidant status), that partially explained the drug pronounced hepatoprotective effect.

[Effectiveness of the hepatoprotective activity of reamberine, remaxol, and ademethionine and risk assessment in their use in patients with respiratory tuberculosis and drug-induced liver injury].

AIM: To comparatively evaluate the hepatoprotective activity of reamberine, remaxol, and exogenous ademethionine and a risk for unfavorable/favorable outcomes of their use in patients with liver injury during antituberculosis chemotherapy. SUBJECTS AND METHODS: One hundred and eighty patients with new-onset respiratory tuberculosis were examined and divided into 4 groups (45 patients in each group): Study Group 1 (SG1): patients who took reamberine; Study Group 2 (SG2): those who received remaxol; Study Group 3 (SG3): those who had ademethionine; and a Comparative Group (CG): those who received 5% glucose solution. The test drugs were intravenously administered in a dropwise manner once daily for 10 days. The laboratory hepatic injury severity index (LHISI) was estimated according to the method described by T.N. Kalachnyuk and the risk for a favorable/unfavorable outcome was assessed, by calculating the average cost of the used hepatotropic agents. RESULTS: LHISI increased statistically significantly with the development of liver injury induced by antituberculosis agents. There was a statistically significant reduction in LHISI during therapy with the test hepatotropic agents versus glucose solution, the most pronounced activity being shown by remaxol. Relative risk (RR) and odds ratio (OR) assessments revealed the high likelihood of a favorable outcome (a reduction in LHISI) when each of the 3 test drugs versus glucose solution was administered; the highest RR and OR were also found in the use of remaxol. Estimation of costs and the number of patients to be treated (NPBT) in order to avoid a case of none LHLIS reduction could reveal the highest efficacy of remaxol. CONCLUSION: The test agents (reamberine, remaxol, and ademethionine) are effective in treating tuberculosis patients with drug-induced liver injury. The administration of remaxol demonstrated the highest positive effect (as estimated by LHISI) in terms of both RR and NPBT.

[Antihypoxants in current clinical practice].

Hypoxia is a universal process accompanying and determining the development of various pathological conditions. In the most general form hypoxia can be defined as the incompatibility between energy requirements of the cell and energy production in the system of mitochondrial oxidative phosphorylation. The energetic status of the cell can be improved by such pharmacological products as antihypoxants of 5 groups: inhibitors of fatty acid oxidation, succinate-containing and succinate-producing agents, components of the natural respiratory chain, artificial redox-systems, and macroergic compounds. This paper is focused on the mechanisms of action of these products, their major effects, and results of clinical studies. Special emphasis is laid on succinate-containing products combining properties of a balanced polyionic solution and an antihypoxant (reamberin, cytoflavin, remaxol). They are known to be effective against various pathological conditions including ischemic stroke, toxic, hypoxic and dyscirculatory encephalopathies, infectious diseases, posthypoxic lesions in the central nervous system of newborns, various intoxications), etc.

[Hepatotropic therapy in treatment of liver injury].

At present, the conception of the use, efficacy and safety of hepatotropic agents in treatment of drug-induced liver injury, in particular due to antituberculosis drugs is not yet final, which is conditioned by extremely rare clinical trials on the subject adequate to the up-to-date principles of the conclusive medicine. The review presents data on the hepatotoxic effect of antituberculosis drugs, analysis and systematization of the data on the use of hepatotropic agents in liver injury induced by antituberculosis drugs, the principles and characteristics of their clinical use. The mechanism of action of remaxol, a new original hepatotropic agent and the indications of its use are discussed. The experimental findings on the remaxol ability to decrease the antituberculosis drug-induced liver injury through lowering the carbohydrate, albuminous and fatty degeneration and activating the organ reduction are presented. The clinical trials are evident of the most efficient action of remaxol on the signs of toxemia, as well as cytolysis and cholestasis, which along with its antiasthenic and antidepressant action allows to use remaxol as an universal hepatotropic agent in the treatment of diverse drug-induced liver injuries in both the therapeutic and prophylactic schemes.