Effect of 2-Isobutyl-4,6-dimethyl-5-hydroxypyrimidine on the Growth of Lewis Lung Carcinoma and Survival of Mice.

Experiments on male C57Bl/6 mice with transplantable Lewis lung epidermoid carcinoma were performed to evaluate the effect of early or delayed administration of compound SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) on tumor growth and animal survival. Intraperitoneal injection of SNK-411 in doses of 25 and 50 mg/kg on days 2-8 of tumor growth was followed by significant inhibition of tumor growth (by 1.8 and 2.2 times, respectively, in comparison with the untreated control). Administration of this compound on days 8-15 of tumor development had little effect on tumor growth. SNK-411 in doses of 25 and 50 mg/kg (both dosing regimens) significantly increased survival rate and lifespan of animals with tumors. The drugs for verification of this model (Fluorofur, 400 mg/kg; and doxorubicin hydrochloride, 4 mg/kg) were injected intraperitoneally on days 2-4 and 8-10 of tumor development. Administration of Fluorofur and doxorubicin hydrochloride at the late stage was accompanied by significant inhibition of tumor growth (by 1.6 and 1.4 times, respectively). The increase in the survival rate of animals receiving the cytostatic according to standard dosing regimens was less significant than in experiments with SNK-411.

Effects of 5-Pyrimidinol Derivative SNK-41 on Cytokine Profile of Mice with Lewis Lung Carcinoma.

We studied the effects of SNK-411, a new 5-pyrimidinol derivative, on serum cytokine profile of C57Bl/6 mice with Lewis lung carcinoma. The compound was injected intraperitoneally in doses of 25 and 50 mg/kg. A significant (by 3.5 times) increase in serum IL-4 content was detected in mice with tumors on day 9 of tumor development. In mice receiving SNK-411 in doses of 25 and 50 mg/kg, IL-4 content significantly decreased (by 4.0 and 3.6 times) on days 2-8 of carcinoma development; IL-2 content decreased by 1.4 and 1.2 times and IL-6 content decreased by 2.7 and 1.6 times, respectively, in comparison with control mice with tumors. Injections of SNK-411 in the same doses on days 8-15 of carcinoma development led to a significant decrease in IL-4 levels (by 2.2 and 4.5 times, respectively, in comparison with control mice with tumors) and did not affect serum levels of other cytokines.

Correcting effect of ladasten on variations in the subpopulation composition of T lymphocytes in C57BL/6 mice on the experimental model of an anxious-depressive state.

We studied the effect of Ladasten (30 mg/kg intraperitoneally for 5 days) on the subpopulation composition of T cells in immunocompetent organs of male C57Bl/6 mice during modeling of an anxious-depressive state (chronic zoosocial stress). Stress exposure of animals for 30 days was followed by a decrease in the relative weight of the thymus, increase in the weight of the spleen, reduction of the percentage of T cell populations, and shift in the CD4(+)/CD8(+) ratio toward cytotoxic T cells. Administration of Ladasten had a normalizing effect on the relative weights of study organs and subpopulation composition of T cells in immunocompetent organs, which returned to the control level.

[The magnitude of fatigue and its association with depression, pain, and inflammatory activity in rheumatoid arthritis].

AIM: To analyze the rate of clinically significant fatigue and to search for its predictors in patients with rheumatoid arthritis (RA). SUBJECTS AND METHODS: The investigation included 95 patients with a valid RA diagnosis. The majority of the patients were women (87.4%); mean age was 46.7 +/- 1.2 years; mean disease duration was 135.5 +/- 11.6 months. The authors evaluated RA activity by the Disease Activity Score (DAS28), magnitude of fatigue by the Fatigue Severity Scale (FSS), that of pain by the Brief Pain Inventory, and functional status and quality of life by the Health Assessment Questionnaire and EQ-5D. A psychiatrist diagnosed mental disorders in accordance with ICD-10 and using the psychiatric and psychological scales and procedures. RESULTS: 80% of the patients felt clinically significant fatigue (FSS scores of > or = 4). Multivariate analysis yielded a prognostic model that made it possible to state that clinically significant fatigue was primarily associated with the magnitude of depression by the Hospital Anxiety and Depression Scale, the presence of a depressive episode, the duration of anxiety and depressive spectrum, the magnitude of pain (Ritchie index), DAS28, and the presence of osteoporosis. CONCLUSION: The presence and magnitude of depression along with the magnitude of pain are an important factor that influences the formation of fatigue in RA, which gives rise to evident functional failure and a low quality of life. Combination therapy for RA may be effective when mental disorders, mainly the anxiety and depressive spectrum, are timely diagnosed.

[Perception of pain in rheumatoid arthritis: relation to inflammation, psychic disorders, functional status, and quality of life].

Pain perception was analyzed depending on the inflammatory activity of rheumatoid arthritis (RA), variants and manifestations of psychic disorders (including depressive, anxious and moderate cognitive ones), chronic fatigue, changes in the functional status and quality of life. The study included 125 patients (mean age 47.4 +/- 1.01 yr) with definitive diagnosis of RA 138.4 +/- 10.1 months in duration. RA activity was estimated from the DAS28 index, pain intensity and degree of fatigue by BPI and FSS scales respectively, the functional status and life quality by HAQ and EQ-5D. Psychic disorders were diagnosed by a psychiatrist in accordance with ICD-10 with the use of relevant psychiatric and psychological scales and methods. Pain perception was unrelated to the patients' age and RA duration. The multifactor analysis provided a basis for the prognostic model suggesting that the most severe pain in RA is related to the functional status and quality of life (VAS of general health status), hsCRP level, inflammatory activity index RA DAS28, peripheral platelet count, degree of fatigue (FSS) and depression (YADS), female sex. Depression and its severity is one more factor influencing pain perception in RA and accounting for functional insufficiency and low quality of life. Early diagnostics of psychic disorders (in the first place anxious and depressive ones) is mandatory to ensure effective combined therapy of pain in RA patients.

[An experimental study of the anti-inflammatory action of noopept and its effect on the level of cytokines].

The anti-inflammatory effects of noopept (dipeptide analog of piracetam) upon a single intraperitoneal (i.p.) administration at doses of 1, 5, and 10 mg/kg in comparison to the reference drug diclofenac (10 mg/kg, i.p.) have been studied on a model of acute exudative inflammation induced by carrageenan in outbred rats and concanavalin A (Con A) in CBA mice. The level of cytokines was studied on the lipopolysaccharide (LPS) model (single administration, 100 mg/kg, i.p.) with 5-day administration of noopept at a dose of 5 mg/kg (i.p., before endotoxin injection) in C57BL/6 mice. The administration of noopept led to a significant suppression of the inflammatory response to both carrageenan and Con A. The administration of Con A caused a 16-fold increase in the level of IL-6 interleukin in the blood serum of mice as compared to control. Noopept (5 mg/kg) reduced the level of IL-6 by a factor of 1.8 in the inflammatory response to Con A. The administration of LPS led to pronounced increase in the levels ofpro-inflammatory IL-6 and TNF-alpha in the blood serum of test mice as compared to intact animals. The course administration of noopept (5 mg/kg) significantly decreased the level of IL-6 and reduced by half the level of TNF-alpha.

[Effect of antiasthenic drug ladasten on the level of cytokines and behavior in experimental model of anxious depression in C57BL/6 male mice].

Effects of the antiasthenic drug ladasten [N-(2-adamantyl)-N-(para-bromophenyl)amine] on the profile of cytokines, behavior, and indexes of immunity organs was studied on zoosocial stress model in depressed C57BL/6 male mice. The anxious depression state in male mice was formed by repeated agonistic interactions according to the sensory contact model. Ladasten (30 mg/kg, i.p.) and reference drug imipramine (10 mg/kg, i.p.) were administered either once after 3-day stressor interaction or for 5 days after 10-day interaction. The concentration of cytokines in blood serum was determined by flow cytometry method. The behavioral changes were studied using an actometer and the elevated plus-maze test. The parameters were studied 24 h after last drug injection. Different stages of depression were manifested by behavioral impairments, increased concentration of pro-inflammatory cytokines IL-6, IL-17, and IL-4, and decreased indexes of immunity organs. Ladasten induced (more significantly than imipramine) a decrease in the level of pro-inflammatory cytokines IL-6, IL-17 and IL-4, removed behavioral changes, and restored indexes of immunity organs. Thus, the antiasthenic drug ladasten limits development of the anxious depressive state and suppresses the level ofproinflammatory cytokines IL-6, IL-17 and IL-4. These findings suggest that ladasten is a possible candidate drug for adjuvant therapy of depressive disorders.

Effect of ladasten on the content of cytokine markers of inflammation and behavior of mice with experimental depression-like syndrome.

The effects of ladasten and reference product imipramine (10 mg/kg) on the content of cytokines TNF-α, IL-6, IL-10, IL-1α, IL-2, IL-4, IL-5, IL-17, IFN-γ, and GM-CSF and behavior of male C57Bl/6 mice were studied on the model of a depression-like state induced by a single intraperitoneal injection of bacterial LPS in a dose of 100 µg/kg. Ladasten was injected 5 times in doses of 30 and 50 mg/kg. LPS was administered 1 h after the last injection of the test agents. Behavioral disturbances and significant increase in the concentration of TNF-α and IL-6 in blood plasma were observed 2 h after LPS treatment. Ladasten was more potent than imipramine in decreasing the content of proinflammatory cytokines TNF-α and IL-6 and preventing the development of behavioral disturbances in mice. Antiasthenic drug ladasten was shown to decrease the elevated level of proinflammatory cytokines TNF-α and IL-6 after LPS treatment. Further studies should be performed to develop new indications for the use of ladasten in adjuvant therapy of depression.

Study of anti-inflammatory effects of GB-115, a glycine-containing retropeptide cholecystokinin analog.

Anti-inflammatory effects of GB-115 compound (N-phenylhexanoyl-glycyl-L-tryptophan amide) injected intraperitoneally in doses of 0.1, 1, and 10 mg/kg were demonstrated on the model of ConA- and carrageenan-induced inflammation. Intraperitoneal injection of GB-115 in a dose of 1 mg/kg to C57Bl/6 female mice with experimental autoimmune encephalomyelitis significantly alleviated the pathological symptoms, improved spontaneous locomotor activity, promoted recovery of thymus weight, and reduced edema and neutrophil infiltration of the perivascular space of the brain tissue. Intraperitoneal injection of GB-115 in a dose of 1 mg/kg suppressed generation of active oxygen forms by neutrophils in the chemiluminescence test.