"Off-Label" Use of Common Medicines Could Target the Vulvodynia Mechanism. (1st August 2022) - Falsetta, M
ABSTRACT: Introduction: Vulvodynia is a devastating disease that significantly impairs the quality of life of our patients. Although there is at least limited evidence for the use of various therapeutics, none target the underlying causes of disease, perhaps save surgical excision of the affected tissue. One of our goals is to elucidate the poorly understood causes of vulvodynia to improve treatment and possibly avoid surgical intervention. This approach can be used to identify new targets for less invasive medical therapies. Inflammation has been implicated in the vulvodynia mechanism, and targeting different aspects of this mechanism or augmenting the resolution of inflammation are reasonable strategies for treatment. Objective: We have identified several agents that have the capacity to alleviate vulvar allodynia, but these will need to undergo lengthy drug development steps. Therefore, we also wish to identify FDA-approved agents that could act on the vulvodynia mechanism. Methods: We conducted a lipidomic screen of nearly 200 lipids involved in inflammation and its resolution in vulvar biopsies collected from a group of 10 localized provoked vulvodynia (LPV) cases and 10 controls without vulvar pain. Paired biopsies were taken from painful sites within the vulvar vestibule and non-painful sites within the external vulva. Anatomically identical sites were also biopsied in asymptomatic controls, allowing us to compare lipid profiles at painful and non-painful sites within cases and between cases and controls. This screen was followed up with enzymatic assays, gene expression profiling, and enzyme-linked immunosorbent assays to further explore these pathways and identify new candidate therapies. Results: We found that lipid profiles in painful areas showed reduced expression of pro-resolving lipids, such as 14, 15-epoxyeicosatrienoic acid, while proinflammatory mediators, such as prostaglandin E2 were elevated, pointing to an alteration in arachidonic acid metabolism. Arachidonic acid is a polyunsaturated fatty acid that serves as a substrate for the production of proinflammatory and pro-resolving lipids. In LPV, it appears that arachidonic acid metabolism is skewed towards heightened production of inflammatory mediators associated with pain. We found that the activity and expression of enzymes involved in proinflammatory mediator expression is comparatively higher in painful areas, while enzymes involved in producing pro-resolving lipids are less active. We identified three enzymes families involved in this bioactive lipid mechanism: lipoxygenase, cyclooxygenase (COX), and cytochrome P450 (CYP450). Both COX and CYP450 can be targeted with FDA-approved agents. Conclusions: The vulvodynia mechanism is complex, but it offers several targets for therapeutic intervention. We have identified targets for both drug development and "off-label" use of existing therapies. The use of medicines "off-label" may result in faster alleviation of symptoms, even if only as a stop-gap to stave off surgery until new drugs are introduced. Disclosure: No