"Oral
LY411575 at 50 mg/kg body weight for 5 d decreased the noise-induced threshold shift at 4, 8 and 16 kHz (
Figure S2A). Outer hair cell numbers were increased and the new hair cells had stereociliary bundles (
Figure S2B). The treated mice suffered significant side-effects (
Figure S2B). A lower dose (10 mg/kg body weight) had no therapeutic benefit. "
and
"Due to the dose-limiting toxicity after systemic administration of the drug, we tested direct delivery to the inner ear via the round window membrane, a permeable cellular barrier between the middle and inner ear"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573859/
I clicked on supplemental data figure s2B.
"Of 12 mice administered 50 mg/kg for 5 d, 6 could be tested for ABR at 3 months, the final time point of the LY411575 treatment. The rest died within the first week due to severe diarrhea and weight loss. Mice that survived also suffered from weight loss (approximately 15% loss in 3 d), with a loss of epithelial cells of their stomach and increase in secreting cells in all gastro-intestinal tract from esophagus to colon and severe atrophy in the spleen in a week; immunosuppression with an atrophy of thymus (total number of the cells were dramatically decreased to 1/40 and double positive fraction of CD4 and CD8 was decreased from 78.6% to 1.23%), changes in the skin color in the next week. Those changes resulted from Notch inhibition reported by previous papers (
Hadland et al., 2001;
Wong et al., 2004)"
So it looks like it isn't itself toxic, but systemic (oral) administration of the notch inhibitor is the cause of unwanted side effects.
Maybe we are just going to have to wait for FrequencyTX to do their work and get FDA approved.
Hopefully it doesn't take too much longer.
)
Member
