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

Abstract

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

“…Acid is known to activate the TRPV1 and TRPA1 channels, but the activation of the airway sensory nerve depends on the magnitude and rate of pH change [ 14 ]. Before we found that the most pronounced anti-asthmatic effect of XC8 on guinea pigs was observed in the dose range of 1.4–7.0 mg/ kg, which corresponds to 20–100 mg per day for humans [ 33 ]. In phase 2a clinical trial, the highest anti-asthmatic effect of XC8 was observed for a dose of 100 mg per day [ 35 ].…”

“…The small molecule drug XC8 (glutarimide derivative) developed by Pharmenterprises LLC was shown to affect the influx of eosinophils into bronchoalveolar lavage (BAL) in a model of lung inflammation or asthma in rats and guinea pigs [ 33 ]. We demonstrated the complete safety of XC8 in healthy probands in phase 1 clinical trial [ 34 ].…”

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

“…Subjects underwent a screening period of up to 14 days, during which their eligibility was assessed. Thirty-two healthy subjects were allocated to 3 dosing groups (10,50, and 200 mg dosing) and randomized to treatment with XC8 or placebo in a 3:1 ratio (6 subjects receiving 10 and 50 mg XC8 and 2 placebo in treatment groups 1 and 2 and, and 12 subjects receiving 200 mg XC8 and 4 placebo in treatment group 3). Due to the dose escalating design (see 2.2 Study conduct) investigators and subjects were double-blinded regarding the randomization to active treatment and placebo, but not to the dosing group.…”

“…XC8 (histamine glutarimide) is a novel anti-asthmatic agent which targets eosinophilic migration and mast cell degranulation by inhibition of maturation of chemokines (CCL2, CCL7, CCL8, CCL13). A previous study has shown that XC8 reduces airway resistance and eosinophil counts in bronchoalveolar lavage and lung tissue in sephadex induced lung inflammation in rats and ovalbumin induced asthma in guinea pigs [10].…”

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

“…We have shown earlier that the derivatives of biogenic amines (peptidoamines) are effective against some inflammatory diseases [20][21][22]. We have found that the glutarimide derivative XC8 reduces the influx of eosinophils into bronchoalveolar lavage (BAL) in a Sephadex-induced lung inflammation model in rats [23]. In a model of acute and chronic asthma, XC8 significantly reduced the number of eosinophils in BAL, degranulating mast cell and goblet cell number in the lung tissue and specific airway resistance.…”