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The major feature of COVID-19 is intensive virus-induced inflammation in vital body organs and spatiotemporal dysregulation of pro- and anti-inflammatory cytokines and chemokines synthesis. All this leads to unpredicted clinical progression and high risk of "cytokine storm" development. The "cytokine storm" is the pathogenetic basis for further development of life-threatening complications. Thus, there is a huge need to select effective and safe approaches that allow to control virus-induced inflammation as a part of preventive anti-inflammatory therapy. This article presents toxicological characteristics of the original low-molecular compound XC221GI (1-[2-(1-methylimidazole-4-yl)-ethyl]perhydroazin-2,6-dione) from pre-clinical studies. The obtained results demonstrate that the XC221GI does not have any toxic effect in repeated long-term administration. The compound was well tolerated by all animals. The no-observed-adverse-effect level (NOAEL) was 30 mg/kg per day for dogs and 450 mg/kg per day for rats. There were no effects of XC221GI on blood count, hematopoiesis and hemostasis. As well as no cytotoxic, mutagenic, genotoxic, carcinogenic properties or anaphylactogenic and immunotoxic activity were revealed for XC221GI. All known data enable to classify XC221GI as a low toxic compound and consider its safety profile as reasonably favorable.

Chronic cough heavily affects patients' quality of life, and there are no effective licensed therapies available. Cough is a complication of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection, asthma, and other diseases. Patients with various diseases have a different profile of tussive responses to diverse cough triggers, thereby suggesting sundry mechanisms of neuronal dysfunctions. Previously, we demonstrated that the small molecule drug XC8 shows a clinical anti-asthmatic effect. The objective of the present study was to investigate the effect of XC8 on cough.We studied the antitussive effect of XC8 on cough induced by agonists activating human transient receptor potential (TRP) cation channels TRPA1 or TRPV1 in guinea pigs. We checked the agonistic/antagonistic activity of XC8 on the human cation channels TRPA1, TRPV1, TRPM8, P2X purinoceptor 2 (P2X2), and human acid sensing ion channel 3 (hASIC3) in Fluorescent Imaging Plate Reader (FLIPR) assay.XC8 demonstrated clear antitussive activity and dose-dependently inhibited cough in guinea pigs induced by citric acid alone (up to 67.1%) or in combination with IFN-γ (up to 76.4%). XC8 suppressed cough reflexes induced by the repeated inhalation of citric acid (up to 80%) or by cinnamaldehyde (up to 60%). No activity of XC8 against cough evoked by capsaicin was revealed. No direct agonistic/antagonistic activity of XC8 on human TRPA1, TRPV1, TRPM8, P2X2, or hASIC3 was detected.XC8 acts against cough evoked by the activation of TRPA1 (citric acid/cinnamaldehyde) but not TRPV1 (capsaicin) channels. XC8 inhibits the cough reflex and suppresses the cough potentiation by IFN-γ. XC8 might be of significant therapeutic value for patients suffering from chronic cough associated with inflammation.

Introduction A significant number of patients with moderate asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS). These patients do not yet meet the criteria for oral corticosteroids (OCS) and monoclonal antibodies. The new anti-chemokine oral drug XC8 could represent an alternative treatment option for these patients. The objective of this trial was to evaluate the effect of different doses of the XC8 in patients with partly controlled asthma in a phase 2a clinical trial. Methods A double-blind, parallel-group, randomized, multicenter, phase 2a trial was conducted at 12 sites in Russia. Patients with asthma were randomized into four groups (n = 30 each) to receive XC8 at 2 mg, 10 mg, 100 mg or placebo once-daily for 12 weeks in addition to low-dose ICS with or without LABA. Efficacy and safety parameters were evaluated at weeks 0, 2, 6, and 12. Results No statistically significant difference between the treatment arms in the number of patients with adverse events was observed. The primary endpoint, improvement of forced expiratory volume in 1 s (FEV1) % predicted over 12 weeks compared to placebo, was not statistically significant. The treatment of patients with XC8 (100 mg) resulted in statistically and clinically significant improvements in FEV1 compared to baseline (7.40% predicted, p 300 cells/μl) or serum interferon-γ (IFN-γ) level (> 100 pg/mL) treated with XC8 (100 mg) achieved a statistically significant improvement in FEV1 (11.33% predicted or 8.69% predicted, respectively, p

Background:Corticosteroids are the preferred option to treat asthma, however, they possess serious side effects and are inefficient in 10% of patients. Thus, new therapeutic approaches for asthma treatment are required.Objective:To study the efficacy of a novel glutarimide derivative XC8 in a Sephadex-induced lung inflammation in rats as well as in acute and chronic ovalbumin-induced allergic asthma in guinea pigs.Method:Rats were treated with 0.18-18 mg/kg of XC8 intragastrically 4 times (24 h and 1 h prior to and 24 h and 45 h after endotracheal administration of Sephadex). The number of inflammatory cells in bronchoalveaolar lavages (BAL) was determined. Guinea pigs were treated with 0.045 -1.4 mg/kg (acute asthma) or with 1.4 and 7.0 mg/kg of XC8 (chronic asthma) intragastrically following the sensitization with ovalbumin and during aerosol challenge. Lung inflammation, numbers of eosinophils (BAL and lung tissue), goblet cells, degranulating mast cells and specific airway resistance (sRAW) were determined. The comparator steroid drug budesonide (0.5 mg/kg for rats and 0.16 mg/kg for guinea pigs) was administered by inhalation.Results:XC8 reduced influx of eosinophils into BAL in Sephadex-induced lung inflammation model in rats (by 2.6-6.4 times). Treatment of acute asthma in guinea pigs significantly reduced eosinophils in guinea pigs in BAL (from 55% to 30%-39% of the total cell count) and goblet cells in lung tissue. In a model of acute and chronic asthma, XC8 reduced significantly the number of eosinophils and degranulating mast cells in the lung tissue. Treatment with XC8 but not with budesonide decreased the specific airway resistance in acute and chronic asthma model up to the level of naive animals.Conclusion:XC8 induced a profound anti-inflammatory effect by reducing eosinophils in BAL and eosinophils and degranulating mast cell numbers in the airway tissue. The anti-asthmatic effect of XC8 is comparable to that of budesonide. Moreover, in contrast to budesonide, XC8 was capable to reduce goblet cells and airway resistance.

The effect of the peptide substance on the induced production of histamine by culture of basophile, interaction of the preparation with the H1-histamine receptors and possible sedative effect on animal models were studied. The introduction of the peptide substance in cell culture of basophile didn’t have a significant effect on the histamine release. Study of the interaction of the polypeptide substance with H1-histamine receptors of guinea pig ileum showed that the preparation inhibits the response of unstriated muscles to histamine. The effect was similar to antihistamine drug - ketotifen. In the models of “open field” and “elevated criss-cross labyrinth” it was found that the peptide preparation hasn’t a sedative effect.