Problem of painful inflammatory diseases: Persistent or inappropriate inflammation underlies a broad range of painful diseases including musculoskeletal conditions, wounds and burns. Much of the inflammation and pain associated with these diseases is due to the release of mediators from leukocytes at the site of injury. Current treatments are often inadequate due to limited efficacy and undesirable side effects. Vapogenix (VPX) is a clinical-stage pharmaceutical company developing a novel class of locally acting non-opioid analgesics based on new uses, formulations and topical administration of volatile anesthetics (VAs). Current knowledge: VPX and others have demonstrated anti-nociceptive activity of VAs when applied topically. Some VAs have also been shown to have anti-inflammatory effects, both in vivo and in vitro. Recent publications suggest that this anti- inflammatory effect may be partly due to the inhibition of key players in inflammation, specifically ?L?2 and ?M?2 integrins, which are known to facilitate leukocyte migration to the damaged tissue. During SBIR Phase I studies, we showed that 5 VAs inhibited adhesion of the integrin ?L?2 to intercellular adhesion molecule-1 (ICAM-1), and locally injected sevoflurane inhibited neutrophil migration while reducing the levels of numerous proinflammatory cytokines in the mouse air pouch model. Based on these data, sevoflurane was chosen for formulation development. Hypothesis: Our hypothesis is that topical formulated sevoflurane will have a dual (anti- inflammatory and anti-nociceptive) benefit.
Aims : The objective of this study is to identify a development formulation of sevoflurane for topical application in painful inflammatory conditions. This will be accomplished by developing and evaluating sevoflurane formulations in appropriate models (Aim 1); and by generating pharmacology data to compare locally administered sevoflurane to known anti-inflammatory agents to support an IND submission (Aim 2). Finally, we will prepare a briefing package for a pre-IND meeting with the FDA (Aim 3). Methods: Sevoflurane formulations will be developed and screened for penetration profile in vitro (human skin permeation model) and anti-inflammatory activity in vivo (mouse air pouch model). The selected lead formulation will be tested in the mono-iodoacetate-induced painful inflammation model arthritis model in rats. Additionally, the anti-inflammatory profiles of sevoflurane in comparison to diclofenac and dexamethasone will be examined by phenotyping leukocyte subpopulations and cytokine expression in vivo using flow cytometry and single cell analysis. Finally, we will prepare a pre-IND briefing package in order to seek FDA feedback on our full development program. Long term objective: VPX?s long-term goal is to develop a novel VA-based topical product with dual anti-inflammatory and anti-nociceptive effects to treat painful inflammatory conditions with an improved safety profile compared with currently used analgesics. Since painful inflammatory conditions affect millions of Americans, the clinical need and commercial opportunity associated with funding this effort is substantial.
The proposed research is relevant to public health because persistent or inappropriate inflammation underlies a broad range of painful diseases, and current treatments are often ineffective or have serious side effects or both. Vapogenix, a pioneer in the field of developing novel pharmaceuticals for pain, is leveraging recently discovered properties of some inhaled volatile anesthetics as topical analgesics as well as anti-inflammatory agents. In this proposal we will develop a formulation of the volatile anesthetic, sevoflurane and confirm its anti-inflammatory effectiveness in a disease-relevant animal model, in order to develop a two-pronged (analgesic and anti- inflammatory) topical therapy for painful inflammatory diseases.
