Curtailing virus-induced inflammation in respiratory infections: emerging strategies for therapeutic interventions.

Acute respiratory viral infections (ARVI) are the most common illnesses worldwide. In some instances, mild cases of ARVI progress to hyperinflammatory responses, which are damaging to pulmonary tissue and requiring intensive care. Here we summarize available information on preclinical and clinical effects of XC221GI (1-[2-(1-methyl imidazole-4-yl)-ethyl]perhydroazin-2,6-dione), an oral drug with a favorable safety profile that has been tested in animal models of influenza, respiratory syncytial virus, highly pathogenic coronavirus strains and other acute viral upper respiratory infections. XC221GI is capable of controlling IFN-gamma-driven inflammation as it is evident from the suppression of the production of soluble cytokines and chemokines, including IL-6, IL-8, CXCL10, CXCL9 and CXCL11 as well as a decrease in migration of neutrophils into the pulmonary tissue. An excellent safety profile of XC221GI, which is not metabolized by the liver, and its significant anti-inflammatory effects indicate utility of this compound in abating conversion of ambulatory cases of respiratory infections into the cases with aggravated presentation that require hospitalization. This drug is especially useful when rapid molecular assays determining viral species are impractical, or when direct antiviral drugs are not available. Moreover, XC221GI may be combined with direct antiviral drugs to enhance their therapeutic effects.

The Hidden Pandemic of COVID-19-Induced Organizing Pneumonia.

Since the beginning of the COVID-19 pandemic, clinical, radiological, and histopathological studies have provided evidence that organizing pneumonia is a possible consequence of the SARS-CoV2 infection. This post-COVID-19 organizing pneumonia (PCOP) causes persisting dyspnea, impaired pulmonary function, and produces radiological abnormalities for at least 5 weeks after onset of symptoms. While most patients with PCOP recover within a year after acute COVID-19, 5-25% of cases need specialized treatment. However, despite substantial resources allocated worldwide to finding a solution to this problem, there are no approved treatments for PCOP. Oral corticosteroids produce a therapeutic response in a majority of such PCOP patients, but their application is limited by the anticipated high-relapse frequency and the risk of severe adverse effects. Herein, we conduct a systematic comparison of the epidemiology, pathogenesis, and clinical presentation of the organizing pneumonias caused by COVID-19 as well as other viral infections. We also use the clinical efficacy of corticosteroids in other postinfection OPs (PIOPs) to predict the therapeutic response in the treatment of PCOP. Finally, we discuss the potential application of a candidate anti-inflammatory and antifibrotic therapy for the treatment of PCOP based on the analysis of the latest clinical trials data.

The Effect of Anti-Chemokine Oral Drug XC8 on Cough Triggered by The Agonists of TRPA1 But Not TRPV1 Channels in Guinea Pigs.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Lung Fibrosis after COVID-19: Treatment Prospects.

At the end of 2019, a highly contagious infection began its ominous conquest of the world. It was soon discovered that the disease was caused by a novel coronavirus designated as SARS-CoV-2, and the disease was thus abbreviated to COVID-19 (COVID). The global medical community has directed its efforts not only to find effective therapies against the deadly pathogen but also to combat the concomitant complications. Two of the most common respiratory manifestations of COVID are a significant reduction in the diffusing capacity of the lungs (DLCO) and the associated pulmonary interstitial damage. One year after moderate COVID, the incidence rate of impaired DLCO and persistent lung damage still exceeds 30%, and one-third of the patients have severe DLCO impairment and fibrotic lung damage. The persistent respiratory complications may cause substantial population morbidity, long-term disability, and even death due to the lung fibrosis progression. The incidence of COVID-induced pulmonary fibrosis caused by COVID can be estimated based on a 15-year observational study of lung pathology after SARS. Most SARS patients with fibrotic lung damage recovered within the first year and then remained healthy; however, in 20% of the cases, significant fibrosis progression was found in 5-10 years. Based on these data, the incidence rate of post-COVID lung fibrosis can be estimated at 2-6% after moderate illness. What is worse, there are reasons to believe that fibrosis may become one of the major long-term complications of COVID, even in asymptomatic individuals. Currently, despite the best efforts of the global medical community, there are no treatments for COVID-induced pulmonary fibrosis. In this review, we analyze the latest data from ongoing clinical trials aimed at treating post-COVID lung fibrosis and analyze the rationale for the current drug candidates. We discuss the use of antifibrotic therapy for idiopathic pulmonary fibrosis, the IN01 vaccine, glucocorticosteroids as well as the stromal vascular fraction for the treatment and rehabilitation of patients with COVID-associated pulmonary damage.

Bisamide Derivative of Dicarboxylic Acid Contributes to Restoration of Testicular Tissue Function and Influences Spermatogonial Stem Cells in Metabolic Disorders.

Metabolic syndrome can lead to several challenging complications including degeneration of the pancreas and hypogonadism. Recently, we have shown that Bisamide Derivative of Dicarboxylic Acid (BDDA) can contribute to pancreatic restoration in mice with metabolic disorders via its positive effects on lipid and glucose metabolism, and by increasing the numbers of pancreatic stem cells. In the present study, we hypothesized that BDDA might also be effective in restoring hypogonadism caused by metabolic syndrome. Experiments were performed on male C57BL/6 mice with hypogonadism, where metabolic disorders have been introduced by a combination of streptozotocin treatment and high fat diet. Using a combination of histological and biochemical methods along with a flow cytometric analysis of stem and progenitor cell markers, we evaluated the biological effects of BDDA on testicular tissue, germ cells, spermatogonial stem cells in vitro and in vivo, as well as on fertility. We demonstrate that in mice with metabolic disorders, BDDA has positive effects on spermatogenesis and restores fertility. We also show that BDDA exerts its therapeutic effects by reducing inflammation and by modulating spermatogonial stem cells. Thus, our results suggest that BDDA could represent a promising lead compound for the development of novel therapeutics able to stimulate regeneration of the testicular tissue and to restore fertility in hypogonadism resulting from complications of metabolic syndrome.

Antifibrotic and Regenerative Effects of Treamid in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by interstitial fibrosis and progressive respiratory failure. Pirfenidone and nintedanib slow down but do not stop the progression of IPF. Thus, new compounds with high antifibrotic activity and simultaneously regenerative activity are an unmet clinical need. Recently, we showed that Treamid can help restoring the pancreas and testicular tissue in mice with metabolic disorders. We hypothesized that Treamid may be effective in antifibrotic therapy and regeneration of damaged lung tissue in pulmonary fibrosis. In this study, experiments were performed on male C57BL/6 mice with bleomycin-induced pulmonary fibrosis. We applied histological and immunohistochemical methods, ELISA, and assessed the expression of markers of endothelial and epithelial cells in primary cultures of CD31+ and CD326+ lung cells. Finally, we evaluated esterase activity and apoptosis of lung cells in vitro. Our data indicate that Treamid exhibits antifibrotic activity in mice with pulmonary fibrosis and has a positive effect on capillaries of the lungs. Treamid also increases the number of endothelial progenitor cells in the lungs of animals with pulmonary fibrosis. Lastly, Treamid increases esterase activity and decreases apoptosis of CD31+ lung cells in vitro. Based on these findings, we suggest that Treamid may represent a promising compound for the development of new antifibrotic agents, which are capable of stimulating regeneration of lung endothelium in IPF patients.

New Anti-Chemokine Oral Drug XC8 in the Treatment of Asthma Patients with Poor Response to Corticosteroids: Results of a Phase 2A Randomized Controlled Clinical Trial.

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 < 0.001). Patients with elevated peripheral blood eosinophil count (PBEC, > 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 < 0.05) as compared to the baseline versus the placebo. The strongest effect was observed in patients with both high PBEC and IFN-γ level. Pharmacodynamic engagement was demonstrated through the reduction of serum levels of C-C motif ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10). Treatment with XC8 (100 mg) alleviated resistance to maintenance ICS therapy in patients with elevated IFN-γ level. CONCLUSIONS: Given the high safety, oral route of administration, and efficacy, XC8 may provide a promising treatment option for patients with mild-to-moderate asthma. TRIAL REGISTRATION: 795-30/12/2015 (Ministry of Health Russian Federation), NCT03450434 (ClinicalTrials.gov).

Antidiabetic Effects of Bisamide Derivative of Dicarboxylic Acid in Metabolic Disorders.

In clinical practice, the metabolic syndrome can lead to multiple complications, including diabetes. It remains unclear which component of the metabolic syndrome (obesity, inflammation, hyperglycemia, or insulin resistance) has the strongest inhibitory effect on stem cells involved in beta cell regeneration. This makes it challenging to develop effective treatment options for complications such as diabetes. In our study, experiments were performed on male C57BL/6 mice where metabolic disorders have been introduced experimentally by a combination of streptozotocin-treatment and a high-fat diet. We evaluated the biological effects of Bisamide Derivative of Dicarboxylic Acid (BDDA) and its impact on pancreatic stem cells in vivo. To assess the impact of BDDA, we applied a combination of histological and biochemical methods along with a cytometric analysis of stem cell and progenitor cell markers. We show that in mice with metabolic disorders, BDDA has a positive effect on lipid and glucose metabolism. The pancreatic restoration was associated with a decrease of the inhibitory effects of inflammation and obesity factors on pancreatic stem cells. Our data shows that BDDA increases the number of pancreatic stem cells. Thus, BDDA could be used as a new compound for treating complication of the metabolic syndrome such as diabetes.

Safety, pharmacokinetics and pharmacodynamics of a novel anti-asthmatic drug, XC8, in healthy probands.

INTRODUCTION: XC8 (histamine glutarimide) is a novel agent which targets eosinophilic migration and mast cell degranulation and has shown anti-asthmatic effects in animal studies. OBJECTIVE: The objective of this placebo-controlled phase 1 study was to assess the safety of oral XC8 and to evaluate its pharmacokinetic and pharmacodynamic properties. METHODS: 32 healthy volunteers in three dose-escalation treatment groups (10 mg [n = 8], 50 mg [n = 8] and 200 mg [n = 16]) were randomized in a 3:1 ratio to XC8 or placebo respectively. The subjects received a single dose of the drug at Day 1 and then once-daily for 14 days (Days 8-21). RESULTS: No severe adverse events occurred. The number of adverse events was similar in the treatment arms compared to placebo and all subjects completed the study as planned. No clinically significant changes occurred in hematologic and biochemical blood tests in subjects receiving XC8. The pharmacokinetic data showed similar dose and time dependent mean plasma XC8 concentrations after single (Day 1) and multiple (Day 21) dosing. The mean maximum concentrations were 114-1993 ng/mL after single and 115-2089 ng/mL after multiple dosing. The mean times to maximum concentration were 0.68-1.01 and 0.67-0.98 h, respectively. There was no evidence for accumulation of XC8 after multiple dosing. CONCLUSION: XC8 was safe and well tolerated. A phase 2 study is being performed to further evaluate the potential role of XC8 in asthma treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02882217.

A Novel Oral Glutarimide Derivative XC8 Suppresses Sephadex-Induced Lung Inflammation in Rats and Ovalbumin-induced Acute and Chronic Asthma in Guinea Pigs.

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.

Synthesis, anti-MRSA, and anti-VRE activity of hemin conjugates with amino acids and branched peptides.

The increasing prevalence of antibiotic-resistant bacterial strains has necessitated the synthesis of novel antibacterial agents. It was previously shown that naturally occurring metalloporphyrin hemin possesses dark antibacterial activity against Gram-positive bacteria. To improve hemin antibacterial activity, we synthesized a number of hemin conjugates with amino acids and branched peptides. Arginine-containing hemin conjugates demonstrated high antibacterial activity against Gram-positive bacteria including methicillin- and vancomycin-resistant strains in vitro. Most of the synthesized conjugates showed low toxicity against human erythrocytes and leukocytes.

Activity of Ingavirin (6-[2-(1H-Imidazol-4-yl)ethylamino]-5-oxo-hexanoic Acid) Against Human Respiratory Viruses in in Vivo Experiments.

Respiratory viral infections constitute the most frequent reason for medical consultations in the World. They can be associated with a wide range of clinical manifestations ranging from self-limited upper respiratory tract infections to more devastating conditions such as pneumonia. In particular, in serious cases influenza A leads to pneumonia, which is particularly fatal in patients with cardiopulmonary diseases, obesity, young children and the elderly. In the present study, we show a protective effect of the low-molecular weight compound Ingavirin (6-[2-(1H-imidazol-4-yl)ethylamino]-5-oxohexanoic acid) against influenza A (H1N1) virus, human parainfluenza virus and human adenovirus infections in animals. Mortality, weight loss, infectious titer of the virus in tissues and tissue morphology were monitored in the experimental groups of animals. The protective action of Ingavirin was observed as a reduction of infectious titer of the virus in the lung tissue, prolongation of the life of the infected animals, normalization of weight dynamics throughout the course of the disease, lowering of mortality of treated animals compared to a placebo control and normalization of tissue structure. In case of influenza virus infection, the protective activity of Ingavirin was similar to that of the reference compound Tamiflu. Based on the results obtained, Ingavirin should be considered as an important part of anti-viral prophylaxis and therapy.

Efficacy of metmyoglobin and hemin as a catalyst of lipid peroxidation determined by using a new testing system.

A new quantitative approach to investigate the capability of iron heme complexes (HEM), metmyoglobin and hemin, to catalyze lipid peroxidation was elaborated. The oxidation of methyl linoleate in micellar solutions was used as a testing model. The key point was the determination of the rate of free radical generation, RIN, calculated from the rate of oxygen consumption. The HEM catalytic activity was characterized by two independent parameters: by reactivity and by its resistance to degradation. Both parameters were found to be pH-dependent. The reactivity was expressed as the effective rate constant for the reaction of HEM with lipid hydroperoxide. The resistance to degradation was characterized by the rate of the decrease in RIN with time and also by the regeneration coefficient, which shows how many active free radicals can be generated by one molecule of HEM. Both Hemin and metMB were found to be very effective catalysts even at nanomolar concentrations. The effective regeneration of active forms of HEM was observed. The catalytic activity of HEM was rapidly reduced with time. The kinetic scheme of the process under consideration was suggested, and this was applied for kinetic computer simulations.