SBIR-STTR Award

Contrasting in vitro and in vivo systems will be used to evaluate the anti-inflammatory/analgesic activity and side-effects of a family of phosphatidylcholine (PC) – associated NSAIDs. Previous studies indicate that PC-NSAIDs have equivalent and/or enhanced therapeutic activity while GI ulceration/bleeding is remarkably reduced. Dr. Susan Carlton’s lab will measure the effect of our test NSAIDs (PC-NSAID vs unmodified NSAIDs) on calcium signaling of rodent dorsal root ganglia cells in response inflammatory mediators. Her lab also will electrophysiologically measure the effect of test NSAIDs on nociceptive C-fiber activity of a rodent skin-nerve preparation. Dr. Catherine Ambrose will investigate the effect of the test NSAIDs on growth/apoptosis of human osteoblasts in culture. During the Option period, Dr. Lenard Lichtenberger’s lab will utilize a rodent model of adjuvant-induced joint inflammation that provides information on the anti-inflammatory/analgesic activity of the test NSAIDs and their ability to induce GI ulceration/bleeding. The synovial fluid eicosanoids will be measured by HPLC/MS. Dr. Carlton also will evaluate the anti-inflammatory/analgesic activity of PC-NSAIDs using a rodent hindlimb incision model. In Phase II we plan to expand our in vivo evaluation of PC-NSAIDs using an array of rodent model systems available in the labs of the Co-Investigators.

Keywords:
Nsaids, Gastrointestinal Tract, Anti-Inflammatory, Analgesic, Ulcers, Bone-Remodeling, Nociceptive, Dorsal Root Ganglia

We have developed a novel class of phosphatidylcholine (PC)-associated nonsteroidal antiinflammatory drugs (NSAIDs) to treat inflammation and pain with reduced GI side-effects. In Phase I studies using a number of in vitro systems monitoring the activity and threshold of nociceptive fibers under basal conditions and after exposure to inflammatory mediators, we demonstrated that a number of PC-NSAIDs were more effective than the unmodified drugs in reducing the activity of pain sensory nerves. Interestingly, preliminary analysis of in vitro primary human osteoblasts suggest that PC-NSAIDs may have favorable effects on bone remodeling compared with unmodified NSAIDs Based upon these studies, we propose to investigate in Phase II the therapeutic actions of the most effective PC-NSAID we have identified, Indomethacin-PC (vs. unmodified indomethacin) in rodent models of joint and nerve inflammation, post-operative incisional pain (to both mechanical and thermal stimulation) and bone healing. We also propose to evaluate the GI toxicity of the test NSAIDs in the above in vivo model systems to confirm Indomethacin-PC’s superior GI safety. The parenteral and oral formulations of Indomethacin-PC will be optimized by the scientists at PLx Pharma in close consultation with our industrial advisors and our Co-investigators at the two University of Texas institutions.

Keywords:
Non-Steroidal Anti-Inflammatory Drug Pain Analgesics Nsaid Inflammation