Anti-inflammatory and immunomodulating effects of the bacterial lysate in the <em>in vivo</em> models of aseptic lymphadenitis and pneumococcal pneumonia

Bacterial lysates may produce immunoregulatory effects in the inflammatory diseases that are not directly caused by infectious agents; they may also stimulate the immune response against pathogens which are not a part of the lysate composition. Imudon® is a polyvalent bacterial lysate that is available in orodispersible tablets. However, the influence of this drug product on aseptic inflammation and immune defense against the infectious agents, the antigens of which are not contained in this preparation have not been studied so far. The aim of this study, therefore, was to determine the anti-inflammatory and immunomodulating effects of Imudon® using the models of aseptic lymphadenitis (in Wistar rats) and pneumococcal pneumonia (in Balb/c mice), i.e., the conditions not related to the specific components of the bacterial lysate. Lymphadenitis was induced in rats by administration of λ-carrageenan into a cervical lymph node via an open operative approach. Whereas pneumonia was induced in mice by administering Streptococcus pneumoniae suspension intranasally. The choice of pneumococcus was determined by the absence of pneumococcal antigens in Imudon®, i.e., it cannot be a direct inducer of adaptive immune response against pneumococcal infection. Imudon® was administered intragastrically as a crushed tablet suspension following a therapeutic-preventive regimen (for 14 days daily until the induction of inflammation and for 3 [in the lymphadenitis model] or 5 days [in the model of pneumonia] in three doses thereafter). In the lymphadenitis model, Imudon® demonstrated both local and systemic anti-inflammatory responses manifested in the reduced number of circulating leucocytes and lower TNFα levels and by ameliorated histological features of inflammation in the operated lymph node. In rats, the anti-inflammatory effect was most pronounced when the product was administered at a dose of 2.2 mg/kg (equivalent to a human therapeutic dose) and 6.6 mg/kg. In the model of pneumonia, administration of Imudon® at 4.44 mg/kg (equivalent to a human therapeutic dose) and 13.32 mg/kg demonstrated a trend towards increased survival rate as compared to the control group. On Day 5 after infection Imudon® (4.44 and 13.32 mg/kg) decreased significantly the severity of inflammation and bacterial titer in the lungs. The titer of anti-pneumococcal immunoglobulins A in the bronchoalveolar lavage fluid were found to be higher in the Imudon® treated group (13.32 mg/kg) compared to control group. The results of this study showed high antiinflammatory and immunomodulatory activities of Imudon® and provided an insight into the mechanisms that underlie the clinical effects of this drug in various inflammatory diseases

A TWO-YEAR STUDY OF CANCEROGENIC POTENTIAL OF THE NEW OPIOID RECEPTOR ANTAGONIST ONDELOPRAN IN RATS

Opioid receptor antagonists are widely used for the treatment of alcohol dependence. Currently, original drug Odelepran (INN: ondelopran) with a unique binding profi le to all three types of human opioid receptors (μ, κ, δ) is being developed by R-Pharm.Aim of the study. To investigate a cancerogenic potential of the new opioid receptor antagonist ondelopran in a twoyear study in ratsMaterials and methods. The study cancerogenic potencial was performed in male and female Wistar rats at the age of 8–10 weeks at the start of experiment. All animals were allocated to 8 groups. Each group consisted of 50 animals of each sex. Test item (ondelopran fi lm-coated tablets, 125 mg), was administered to the animals intragastrically as a tablets suspension in 1% starch solution daily, 5 days a week for 24 months in two doses: 10 mg/kg (equivalent therapeutic dose for humans) and 100 mg/kg. Animals of control groups were administered with placebo and vehicle (1% starch solution). Clinical observation and examination of animals were conducted weekly to detect any signs of intoxication; dynamics of the body weight and registration of animal deaths were also assessed. To assess the rate of the pathological changes, the macro- and microscopic examination of inner organs and neoplasms was conducted.Results. During the study the mortality rates did not diff er between the groups. Clinical signs ts.and symptoms of intoxication upon administration of the tested item and placebo were not observed. Neoplasms were found in the organs of all groups of animals. More than 30 variants of neoplasms were identifi ed upon pathomorphological examination. The identifi ed tumors are typical for rats and considered as spontaneous age-related pathology. There was no statistically signifi cant diff erences between groups in the total incidence of tumors.Conclusion. To conclude the above said, the test item of the ondelopran fi lm-coated tablets, 125 mg have no carcinogenic properties