Novel Use of Volatile Anesthetics as Topical Treatment for Painful Inflammatory Conditions: Interactions with Integrins and In Vivo Anti-inflammatory Effects.

Summary Abstract Problem of painful inflammatory diseasesPersistent or inappropriate inflammation underlies a broad range of painful diseases including musculoskeletal conditionswounds and burnsMuch of the pain associated with these diseases is due to the release of nociceptive mediators from leukocytes at the site of inflammationThough treatments such as NSAIDsNon Steroidal Anti inflammatory Drugsare availablethey are often inadequate due to limited efficacy and undesirable side effectsVapogenixVPXis a clinical stage pharmaceutical company specializing in developing a novel class of locally acting nonnarcotic analgesics based on new usesformulations and routes of administration of already approved volatile anestheticsVAsparticularly topical application to treat localized painCurrent knowledgeVPX and others have demonstrated anti nociceptive activity of VAs when applied topicallySome VAs have also been shown to have anti inflammatory effectsboth in vivo and in vitroRecent publications suggest that this anti inflammatory effect may be due to allosteric inhibition of integrin functionspecificallyLandMintegrinsActivatedintegrins are known to be key players in inflammationparticularly by facilitating leukocyte migration to the damaged tissueHypothesisOur hypothesis is that topical VAs have a dual benefitcombining anti nociceptive and anti inflammatory effectsand may reduce inflammation and associated pain through direct interactions with integrinsAimsThe overall aim of the proposed SBIR Phase I study is to identify the most promising VA for future development as a novel antiinflammatory product for topical application in painful inflammatory conditionsThis will be accomplished by establishing the pharmacological profile of VA interactions with integrins and by characterizing the functional effects using in vitro assaysSpecific Aimand also by demonstrating anti inflammatory effects of locally administered VAs in vivo using a mouse model of acute inflammationSpecific AimMethodsSpecific Aimwill be achieved by testing the interactions of six VAs with a panel of integrins using cell adhesion assays and by studying further these interactions using cell signaling and cell migration assaysFor Specific Aimtwo VAs will be tested in the mouse air pouch model for their ability to reduce inflammation when applied topically and when injected at the site of inflammationAssessments will include total and differential cell counts and cytokine profilingLong term objectivesThe overall goal of this programand a possible SBIR Phase II proposalis the development of a novel topical formulation of a VA to treat painful inflammatory conditionsThe final product will have dual anti inflammatory and antinociceptive effectsand a topical application will provide a good safety profileInflammatory painful conditions affect millions of Americans and no ideal treatment is availabletherefore the clinical need and the commercial opportunity associated with funding this effort is substantial Narrative The proposed research is relevant to public health because persistent or inappropriate inflammation underlies a broad range of painful diseasesand though numerous treatments are availablethey are often ineffective or have serious side effects or bothVapogenix is a pioneer in the field of developing novel pharmaceuticals for painwith or without inflammationand specializes in leveraging recently discovered properties of inhaled volatile anesthetics as topical analgesicssome which may also have anti inflammatory propertiesIn this studywe will examine the molecular mechanisms by which these compounds interact with immune cellsand examine their anti inflammatory potentialas a first step in turning them into a two prongedanalgesic and anti inflammatorytopical therapy for painful inflammatory diseases