An Immunotoxicity Safety Study of MIDD0301
Mentor 1
Alexander Arnold
Location
Union Wisconsin Room
Start Date
27-4-2018 1:00 PM
Description
Asthma is among the most common of health ailments, but established modes of treatment leave much to be desired, and invite novel pharmaceutical approaches. Evidence indicates the promise of orally administered, subunit-selective, positive GABAA receptor (GABAAR) modulators as a means of inducing the relaxation of airway smooth muscle (ASM) cells. In contemporary drug discovery, immunotoxicity studies are advised as a way of determining whether the administration of a drug candidate produces undesired immune system suppression or activation. Here, one such positive GABAAR modulator, the subunit-selective imidazobenzodiazepine drug candidate dubbed MIDD0301, was examined with regard to this immunotoxic aspect of its preclinical trials, in order to see whether chronic administration would evoke immune system activation. The compound was orally administered to a segment of a population of mice twice daily over a period of 28 days. Post mortem analysis of the treated mice, along with positive (vehicle) and negative (ad libitum) controls, was conducted at three points during this period, and consisted of the animals’ total weights, the weights and histological profiles of the lymphoid organs (thymus, spleen, and Peyer’s patches), blood serum protein electrophoresis, and the relative prevalences of cell types in whole blood. In all indicators examined, no statistically significant differences were observed between the treatment groups. Because the expected indicators (e.g. white blood cell and lymphoid tissue proliferation, increased γ-globulin presence) were unobserved, it may be concluded that chronic administration of the compound is safe, at least insofar as it fails to evoke an immune activation response. Before progressing on to other forms of evaluation however, it will be necessary to confirm that the drug fails to suppress an artificially induced immune response, an effort currently in the pilot stage.
An Immunotoxicity Safety Study of MIDD0301
Union Wisconsin Room
Asthma is among the most common of health ailments, but established modes of treatment leave much to be desired, and invite novel pharmaceutical approaches. Evidence indicates the promise of orally administered, subunit-selective, positive GABAA receptor (GABAAR) modulators as a means of inducing the relaxation of airway smooth muscle (ASM) cells. In contemporary drug discovery, immunotoxicity studies are advised as a way of determining whether the administration of a drug candidate produces undesired immune system suppression or activation. Here, one such positive GABAAR modulator, the subunit-selective imidazobenzodiazepine drug candidate dubbed MIDD0301, was examined with regard to this immunotoxic aspect of its preclinical trials, in order to see whether chronic administration would evoke immune system activation. The compound was orally administered to a segment of a population of mice twice daily over a period of 28 days. Post mortem analysis of the treated mice, along with positive (vehicle) and negative (ad libitum) controls, was conducted at three points during this period, and consisted of the animals’ total weights, the weights and histological profiles of the lymphoid organs (thymus, spleen, and Peyer’s patches), blood serum protein electrophoresis, and the relative prevalences of cell types in whole blood. In all indicators examined, no statistically significant differences were observed between the treatment groups. Because the expected indicators (e.g. white blood cell and lymphoid tissue proliferation, increased γ-globulin presence) were unobserved, it may be concluded that chronic administration of the compound is safe, at least insofar as it fails to evoke an immune activation response. Before progressing on to other forms of evaluation however, it will be necessary to confirm that the drug fails to suppress an artificially induced immune response, an effort currently in the pilot stage.
