Imidazobenzodiazepine Asthma Drug Reduces Lung Inflammation without Affecting Systemic Immune Function
Mentor 1
Alexander Arnold
Location
Union Wisconsin Room
Start Date
5-4-2019 1:30 PM
End Date
5-4-2019 3:30 PM
Description
Asthma is a common health ailment, but established modes of treatment leave much to be desired, and invite novel pharmaceutical approaches. The role of the GABA (γ-aminobutryic acid) in the central nervous system has long been recognized, but both the neurotransmitter and its receptors are widespread outside the nervous system. Cells pertinent to asthma pathogenesis have been found to express GABA A receptor (GABAAR) subunits, namely airway epithelial cells, airway smooth muscle (ASM) cells, CD4+ T-cells, and alveolar macrophages. Some of the receptor’s subunits exist in multiple isotypes, and the specific composition of GABAARs varies between tissues and cell types, allowing subunit-specific small molecule ligands to target particular cells and tissues to the exclusion of others. Evidence indicates that subunit-selective, orally-administered imidazobenzodiazepines are a viable means of asthma treatment. One, the drug development candidate MIDD0301, induces ASM relaxation, and reduces cytokine secretion and eosinophilia in the lungs, thereby reducing inflammation. However, its immunomodulatory properties had prompted investigation of its potential for immunotoxicity. Two 28-day studies were conducted. In the first, MIDD0301 was administered to an experimental group twice daily at 100 mg/kg. Relative to ad libitum and vehicle controls, the experimental group did not differ significantly along any of the immunological, hematological and histological variables examined. In the second, MIDD0301 was administered daily at 200 mg/kg to an experimental group, along with a positive control receiving prednisone at 5 mg/kg, and a vehicle group. Concurrently, an immunization protocol induced a humoral response in all groups. Using the same battery of tests, the MIDD0301 treated-group, unlike the positive control, did not differ significantly from vehicle group values. Together, these studies demonstrate that MIDD0301 produces neither hypersensitivity nor immune system suppression, respectively. MIDD0301 shows promise as an anti-inflammatory agent that selectively reduces inflammation in the lungs without compromising systemic immune function.
Imidazobenzodiazepine Asthma Drug Reduces Lung Inflammation without Affecting Systemic Immune Function
Union Wisconsin Room
Asthma is a common health ailment, but established modes of treatment leave much to be desired, and invite novel pharmaceutical approaches. The role of the GABA (γ-aminobutryic acid) in the central nervous system has long been recognized, but both the neurotransmitter and its receptors are widespread outside the nervous system. Cells pertinent to asthma pathogenesis have been found to express GABA A receptor (GABAAR) subunits, namely airway epithelial cells, airway smooth muscle (ASM) cells, CD4+ T-cells, and alveolar macrophages. Some of the receptor’s subunits exist in multiple isotypes, and the specific composition of GABAARs varies between tissues and cell types, allowing subunit-specific small molecule ligands to target particular cells and tissues to the exclusion of others. Evidence indicates that subunit-selective, orally-administered imidazobenzodiazepines are a viable means of asthma treatment. One, the drug development candidate MIDD0301, induces ASM relaxation, and reduces cytokine secretion and eosinophilia in the lungs, thereby reducing inflammation. However, its immunomodulatory properties had prompted investigation of its potential for immunotoxicity. Two 28-day studies were conducted. In the first, MIDD0301 was administered to an experimental group twice daily at 100 mg/kg. Relative to ad libitum and vehicle controls, the experimental group did not differ significantly along any of the immunological, hematological and histological variables examined. In the second, MIDD0301 was administered daily at 200 mg/kg to an experimental group, along with a positive control receiving prednisone at 5 mg/kg, and a vehicle group. Concurrently, an immunization protocol induced a humoral response in all groups. Using the same battery of tests, the MIDD0301 treated-group, unlike the positive control, did not differ significantly from vehicle group values. Together, these studies demonstrate that MIDD0301 produces neither hypersensitivity nor immune system suppression, respectively. MIDD0301 shows promise as an anti-inflammatory agent that selectively reduces inflammation in the lungs without compromising systemic immune function.
