S-Nitrosothiol-Based Rinse/Aerosol Solutions for Treatment/Prevention of Rhinosinusitis (Phase II)

AbstractChronic rhinosinusitisCRSis estimated to affectof the US populationwith annual health care direct costs of nearly $billion per yearyet there are few effective therapies for CRSDetection of Staphylococcus aureus and or Pseudomonas aeruginosa biofilm in the sinus mucosa is associated with severe CRS presentationHealthy cells that line the nasal passages normally emit significant levels of nitric oxideNOa potent and natural antimicrobial molecule that stimulates mucociliary clearance and reduces bacterial biofilm formationReduced levels of NO in the exhaled nasal breath of CRS patients suggest that boosting local NO concentrations within the sinuses may be quite beneficialIn Phase I of this projectNOTA LaboratoriesLLCclearly demonstrated that a naturally occurring and inexpensive NO releasing agentS nitrosoglutathioneGSNOcan be incorporated into a typical saline bicarbonate sinus rinse solution and generate adequate levels of NO to significantly reduce levels of live bacteria counts for two biofilm forming CRS microbesSaureus and PaeruginosaIn these experimentsthe bacterial biofilms were grown on the surface of human upper airway epithelial cellsWe further demonstrated that the levels of GSNO and concomitant NO released do not harm the underlying human cellsas assessed by monitoring the levels of a toxicity associated cytokineILIn additionNOTA demonstrated that the release rates of NO from GSNO can be enhanced by the presence of ascorbateAscvitamin Cand that the resulting powder formulations of GSNO Asc can be stored for more thanmonthsatCwhile retaining rtof their NO release capabilityVia Phase II SBIR fundingNOTA willFurther optimize the concentration of the GSNO Asc mixture within an isotonic NaCl NaHCOEDTA solution and frequency of application for the in vitro disruption of Saureus and Paeruginosa biofilms formed on human upper airway epithelial cells overd test periodsExplore a commercial packaging processin polymer film lined aluminum pouchesand test the resultingyear stability of a dry packaged GSNO Asc NaCl NaHCOEDTA mixed powder that will be reconstituted in plastic sinus flush bottles withmL of pure water immediately before use by patientsConduct animal studies in rabbits to determine if NOTA s reconstituted RSNO Asc NaCl NaHCOEDTA formulationgiven as an aerosol spray twice daily over ad periodsignificantly decreases bacterial counts in the sinus cavities of infected rabbitswith CRSvscontrolsonly NaCl NaHCOEDTAandBegin the regulatory process by obtaining expert assessments of the role of the FDA in approval of the new GSNO formulations as a potential over the counter product for the CRS marketThe completion of these efforts during Phase II will enable NOTA to plan the first human subject clinical trials at the University of Michigan Sinus Center as part of Phase III studies