Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis

Leila Gobejishvili,1 Walter E Rodriguez,1 Philip Bauer,2 Yali Wang,1 Chirag Soni,2 Todd Lydic,3 Shirish Barve,1 Craig McClain,1 Claudio Maldonado4 1Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA; 2Endoprotech, Inc., Louisville, KY, USA; 3Lipidomics Center, Michigan State University, East Lansing, MI, USA; 4Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USACorrespondence: Claudio Maldonado, Department of Physiology, School of Medicine, University of Louisville, 500 S. Preston Street, HSC A-1115, Louisville, KY, 40292, USA, Tel +1 (502) 852-1078, Email claudio.maldonado@louisville.edu Leila Gobejishvili, Department of Medicine, School of Medicine, University of Louisville, 505 S. Hancock Street, CTR 516, Louisville, KY, 40202, USA, Tel +1 (502) 852-0361, Fax +1 (502) 852-8927, Email l0gobe01@louisville.eduIntroduction: The phosphodiesterase 4 (PDE4) inhibitor, rolipram, has beneficial effects on tissue inflammation, injury and fibrosis, including in the liver. Since rolipram elicits significant CNS side-effects in humans (ie, nausea and emesis), our group developed a fusogenic lipid vesicle (FLV) drug delivery system that targets the liver to avoid adverse events. We evaluated whether this novel liposomal rolipram formulation reduces emesis.Methods: C57Bl/6J male mice were used to compare the effect of three doses of free and FLV-delivered (FLVs-Rol) rolipram in a behavioral correlate model of rolipram-induced emesis. Tissue rolipram and rolipram metabolite levels were measured using LC-MS/MS. The effect of FLVs-Rol on brain and liver PDE4 activities was evaluated.Results: Low and moderate doses of free rolipram significantly reduced anesthesia duration, while the same doses of FLVs-Rol had no effect. However, the onset and duration of adverse effects (shortening of anesthesia period) elicited by a high dose of rolipram was not ameliorated by FLVs-Rol. Post-mortem analysis of brain and