[The results of phase III multicenter open randomized controlled study REM-Chol-III-16 in patients with intrahepatic cholestasis syndrome caused by chronic diffuse liver diseases].

AIM: To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology. MATERIALS AND METHODS: In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course. RESULTS: The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment. CONCLUSION: Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.

[Vilon effect on consequences of repeated radioactive and mercuric impact in small doses].

The purpose of the study was to determine the efficacy of vilon administration in rats after reiterated exposure to ecotoxicants (mercury in concentration near to maximum allowable one and gamma-radiation in small dose). In 24 hours after repeated radioactive and mercuric impact (RMI) and for 30 consecutive days the animals reported lymphopenia. At the same time the indices of DNA leucocytes content and structure did not differ from the parameters of intact animals, this could evidence the development of adaptation reactions. Vilon administration led to the normalization of the lymphocytes number by the 30th day after repeated irradiation (contrary to the radioactive- chemical control), while the number of granulocytes in the test group was higher than that in the intact control group. Study of the survival rate in rats revealed that Vilon reduced morbidity of rats in the course of 15 months after RMI.

[Geroprotective effect of thymalin and epithalamin]. / Geroprotektornaia éffektivnost' timalina i épitalamina.

Researchers of the St. Petersburg Institute of Bioregulation and Gerontology of the North-Western Branch of the Russian Academy of Medical Sciences and the Research Institute of Gerontology of the Ukrainian Academy of Medical Sciences (Kiev) clinically assessed the geroprotective effects of thymic and epiphyseal peptide bioregulators (Thymalin and Epithalamin, correspondingly) in 266 elderly and older persons during 6-8 years (the bioregulators were applied for the first 2-3 years of observation). The obtained results convincingly confirmed the ability of the bioregulators to normalize the basic functions of the human organism, i.e. to improve the indices of the cardiovascular, endocrine, immune, and nervous systems, homeostasis, and metabolism. The restoration of homeostasis in the patients was accompanied by a 2.0-2.4-fold decrease in acute respiratory disease incidence, reduced incidence ischemic heart disease clinical manifestations, hypertension, deforming osteoarthrosis, and osteoporosis, as compared to the control group. Such a significant improvement in the somatic state of the peptide-treated patients corresponded to a decrease in their mortality rate during the observation period: 2.0-2.1-fold among the Thymalin-treated patients, 1.6-1.8-fold--in the Epithalamin-treated group, and 2.5-fold--in the patients treated with Thymalin combined with Epithalamin, as compared to the control group. A separate group of patients was treated with Thymalin combined with Epithalamin annually for 6 years. We registered a 4.1-fold mortality decrease in this group as compared to the control level. The results of our research confirmed the conclusion on the high geroprotective efficacy of Thymalin and Epithalamin and the expediency of their application in medicine and social care as the means of health maintenance and age-related pathology prevention in persons over 60 years old enabling the prolongation of the active period of their lives.

Effect of peptide Lys-Glu on interleukin-2 gene expression in lymphocytes.

Lys-Glu in vitro stimulated interleukin-2 gene expression in mouse spleen lymphocytes. This effect depended on peptide concentration and duration of treatment. It is hypothesized that this peptide is the shortest regulatory fragment promoting the transport of trans-acting factors into the nucleus. It can not be excluded that Lys-Glu is a structural component of trans-acting factor active centers, which are necessary for the activation of interleukin-2 gene transcription in lymphocytes.

Effect of vilon on biological age and lifespan in mice.

Subcutaneous administration of vilon (Lys-Glu) to female CBA mice starting from the 6th month of life increased physical activity and endurance, decreased body temperature, prolonged the lifespan, and prevented the development of spontaneous neoplasms. Vilon had no effect on age-related changes of estrous function and free radical processes. Long-term administration of vilon caused no unfavourable effects on animal development. The obtained results show safety of chronic vilon administration and allow to use this preparation for geroprotection and prophylaxis of age pathology.

Immunomodulatory synthetic dipeptide L-Glu-L-Trp slows down aging and inhibits spontaneous carcinogenesis in rats.

Immunomodulatory molecule L-Glu-L-Trp was isolated from natural calf thymic peptide complex Thymalin by reverse-phase high performance liquid chromatography. On the basis of the synthesized dipeptide a pharmaceutical was designed containing this compound, which later receives the brand name Thymogen. The agent activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced changes in intracellular composition of cyclic nucleotides, and activated neutrophilic chemotaxis and phagocytosis. The effect of dipeptide on survival, life span and spontaneous tumor development was studied in female rats. Seventy-six, five-month-old outbred female rats were randomly subdivided into two groups and were subcutaneously injected with 0.2 ml of normal saline (controls, 32 rats) or with 5 micrograms/rat of the dipeptide L-Glu-L-Trp, dissolved in 0.2 ml of saline (44 rats), 5 times per week for 12 months. Animals were monitored up to their natural death and all the tumors discovered were studied microscopically. Mean life span of rats in both groups was similar but that of 10% maximum survived control rats constituted 949 +/- 16.1 days, whereas in the dipeptide-treated rats this value was 1048 +/- 21.1 days (P < 0.001). Six out of 44 rats treated with the drug survived over the maximum life span of control rats (965 days). The aging rate indicated as alpha in the Gompertz equation, was 0.0071 days-1 in controls and 0.0041 days-1 in rats exposed to L-Glu-L-Trp. Total tumor incidence was 1.5 times lower (P < 0.01), malignant tumor incidence 1.7 times lower (P < 0.01), and hematopoietic malignancies (leukemias and lymphomas) 3.4 times lower (P < 0.02) in rats exposed to the dipeptide in comparison with controls. Thus, treatment with L-Glu-L-Trp delayed aging rate and decreased spontaneous tumor incidence in rats.

[Cortexin effectiveness in circulatory encephalopathy]. / Effektivnost' primeneniia korteksina pri distsirkuliatornykh éntsefalopatiiakh.

A clinical trial of cortexin, a new peptide bioregulator of cerebral functions, in combined therapy of dyscirculatory encephalopathy (DE) stage I-II was made in 76 patients. They were divided into two groups: a control group of 31 patients on standard therapy and the study group of 45 patients on standard therapy with adjuvant cortexin delivered via nasal electrophoresis (NE). The effect was estimated by clinical symptoms, psychophysiological tests, computed EEG, quantitative parameters of rehabilitation. Cortexin NE produced a positive effect on psychoemotional state, neurological status, intellectual-mnestic and CNS functions. Adjuvant cortexin aroused efficiency of rehabilitation in DE stage I and II by 22.7%. The response of intellectual-mnestic and CNS functions was the highest. Cortexin improves attention, perception, memory, thinking, cortical neurodynamic processes. It is well tolerated and has no side effects. Cortexin is recommended as a drug of choice in combined treatment of patients with DE stage I-II.

[The effect of brain peptides on nerve tissue cells in vitro]. / Vliianie peptidov golovnogo mozga na kletki nervnoi tkani in vitro.

The effect of cortexin and epithalamin on the cell growth rate was investigated in the organotypic tissue culture of dorsal root ganglia (DRG), and of cortex and subcortical structures of 10-11-day old chick embryos. Cortexin in concentrations of 20 and 100 ng/ml is active, inducing a more intensive neurite outgrowth in DRG, compared to the control. Epithalamin was active in concentrations 20 and 200 ng/ml. Cortexin (100 ng/ml) was active in the cortex tissue culture, but inhibited the neurite growth in the subcortical structures culture. The stimulation of this culture to development was evident after using 200 ng/ml epithalamin. The neurite stimulating effect of cortexin and epithalamin is presumably associated with neurotrophic factors.

Natural and synthetic thymic peptides as therapeutics for immune dysfunction.

Natural thymic peptides have been isolated from calf thymus by mild acid extraction. Pharmaceutical containing natural peptides (Thymalin) was put into practice as immunocorrector. One of the immunomodulatory molecules (L-Glu-L-Trp) has been isolated from Thymalin by reversed-phase high performance liquid chromatography. Pharmaceutical containing this agent (Thymogen) was designed on the base of synthesized dipeptide. A novel immunomodulatory dipeptide was synthesized and termed Vilon. Both natural and synthetic pharmaceuticals activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced the changes in intracellular composition of cyclic nucleotides and cytokine [interleukin (IL-2), interferon (IFN)] excretion of blood lymphocytes. Synthetic dipeptides activated neutrophil chemotaxis and phagocytosis. They had no influence on antioxidant response in thymocytes in comparison with natural peptides. Thymalin and Thymogen were used in persons with chronic pathology and immune dysfunction. The results indicate that thymic peptides participate in the regulating mechanisms of inflammatory processes as cytokine antagonists and show the difference between natural and synthetic products. It is important for the drugs designed to prevent immune dysfunction development.

Study of the post-natal effects of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. II. Influence of low-molecular-weight polypeptide factors from the thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex and brain white substance.

The influence of the polypeptide factors extracted from thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex or brain white substance on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day of gestation. The polypeptide factors were given to the offspring as a series of s.c. injections, at a dose of 0.5 mg/rat/day, starting at one or 2.5 months of age and continuing throughout the whole of post-natal life. ENU induced tumors of the brain, spinal cord, peripheral nerves and kidneys in 94-98% of the offspring exposed to the carcinogen, with an average number of 2.3-2.6 tumors per rat, and an average survival time of 294 days. Post-natal thymus factor or pineal gland factor administration was followed by an increase in mean lifespan of approximately 2 months and a significant decrease (P < 0.05) in the total tumor number per tumor-bearing rat, as well as the incidence and multiplicity of spinal cord tumors. Pineal gland factor also decreased the incidence of peripheral nerve and kidney tumors and their number per tumor-bearing rat. Brain cortex factor and brain white substance factor treatment was followed by a decrease in total tumor multiplicity of 1.2- to 3.3-fold, and a decrease in incidence of brain tumors of 10 to 33% per rat in comparison to the controls. Brain cortex factor also decreased the total tumor incidence. At the same time, brain white substance factor administration increased the incidence of peripheral nerve tumors and decreased the mean lifespan. Both bone marrow factor and anterior hypothalamus factor did not have any modifying effects on any of the ENU-induced tumors and mean lifespan. Thus, our results show the possibility of attenuation of transplacental ENU-induced carcinogenesis with post-natal administration of some polypeptide substances.

[The diagnostic value of different test systems for the screening determination of antibodies to the human immunodeficiency virus]. / Diagnosticheskaia tsennost' razlichnykh test-sistem dlia skriningovogo opredeleniia antitel k virusu immunodefitsita cheloveka.

Evaluation of the quality of enzyme immunoassay (EIA) systems by their sensitivity and specificity is inadequate, mainly due to the impossibility of detecting early or latent HIV infection in humans as it manifests by seroconversion only to a few HIV proteins. The additional evaluation criterion (confirmation rate) has been introduced, and an original method for the integral evaluation of the quality of assay systems intended for the diagnosis of HIV infection by EIA techniques has been proposed.

[The use of DNA polymerase from Thermus thermophilus]. / Primenenie DNK-polimerazy iz Thermus termophilus.

National DNA polymerase from Thermus thermophilus was used in polymerase chain reaction (PCR). The synthetic oligonucleotides (primers) to the basic structural HIV genes GAG, ENV, the genome DNA of donor peripheral blood lymphocytes were used, and the controls included the plasmid DNA with cloned HIV genome and the genome DNA of peripheral blood lymphocytes from HIV-infected persons confirmed by ELISA and Western blot analysis. The PCR technique and evaluation of the obtained results are described. The expediency of using PCR for different contingents is discussed.

[The effect of the synthetic immunomodulator thymogen on radiation-induced carcinogenesis in rats]. / Vliianie sinteticheskogo immunomoduliatora timogena na radiatsionnyi kantserogenez u krys.

Five month-old female rats were given a mixture of Sr-90 and Cs-137 in drinking water in the dose of 0.1 and 0.2 microCi/day per animal over 12 months. Some animals received 12 monthly courses of a synthetic immunomodulating dipeptide--thymogen in the dose of 5 micrograms/animal for 5 consecutive days. Radionuclide-treated rats showed higher occurrence of tumors on the whole and of breast adenocarcinoma, in particular. Thymogen was shown to inhibit Sr-90- and Cs-137-induced radiation carcinogenesis, namely, a decrease in the total tumor and cancer occurrence was observed. The animals receiving thymogen alone showed longer life span, slower rate of aging and lower overall tumor and cancer occurrence. In this study, the ability of a synthetic peptide immunomodulator--thymogen to inhibit spontaneous and radionuclide-induced carcinogenesis in female rats was first established.

[The correction of secondary radiation-induced immunodeficiencies]. / Korrektsiia vtorichnykh radiatsionnykh immunodefitsitov.

The influence of the ionizing radiation upon the human organism is accompanied by the formation of the secondary radiative immunodeficiencies, which can be treated with the help of immunomodulating preparations of microbiotic, animal and plant origin, as well as compounds obtained by chemical synthesis. The comparative analysis of the various immunomodulators has shown that the peptide preparations of thymos and bone marrow, referred to the cytomedinum class (thymalinum, thymogenum, haemalinum) were most perspective for the correction of the secondary radiative immunodeficiencies. The scheme of thymalinum application in the treatment of radioactive affections of immune system is enclosed.

[The effect of thymalin on biochemical and immunological indices of lymphocyte differentiation and functional activity]. / Vliianie timalina na biokhimicheskie i immunologicheskie pokazateli differentsirovki i funktsional'noi aktivnosti limfotsitov.

Polypeptide preparation thymalin obtained from thymus was found to normalize the LDH isoenzyme spectrum and cyclase system in lymphocytes of patients. Thymalin contributed also to expression of differentiation antigens on T-lymphocytes surface. As a result of this functional activity of T-lymphocytes was restored, which correlated with improvement of the patients clinical state. Biochemical and immunological patterns of lymphocytes differentiation may be used both in diagnosis and control of treatment efficiency in patients with acquired immunodeficiency syndrome.