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Possible Therapeutic Targets for Laminitis Therapy on the Horizon
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This scientific burst characterized by the exponential increase of publications regarding different aspects of equine laminitis is like fertile soil for the development of new strategies in controlling and treating this devastating disease. Currently the Barbaro Memorial Fund from the National Thoroughbred Racing Association is granting three exciting proposals testing new treatments, each one directed toward a specific aspect of the pathophysiology of laminitis.
In 2007, two proposals were funded. "Targeting 5-HT in Equine Laminitis," by Dr. Douglas Allen, et al at the University of Georgia is a study based on the vascular nuances and is testing an available serotonin blocker. Serotonin is a potent vasoconstrictor mediator, which can be release by microthrombi formed by platelet deposition within the veins of laminar dermis during the prodromal stage. It is certainly an important study since previous studies demonstrated that laminitis can be prevented by administration of a competitive inhibitor of platelet aggregation. The other was studied funded by the Barbaro Memorial Fund was the "Treatment of Equine Laminitis with Doxycycline," by Dr. Susan Eades, et al at Louisiana State University and is based on the use of MMPs inhibitors such as doxycycline since there has been substantial evidence regarding the involvement of these enzymes in the basal membrane degradation.
In 2008, the proposal "Effect of Digital Hypothermia on Inflammatory Injury in Laminitis," by Dr. James Belknap, et al at the Ohio State University was funded. In this multicenter project,
the effects of cold therapy and the relevance of laminar inflammation in the development of laminitis will hopefully be clarified and further detailed.
Moreover, there are many potential therapeutic targets based on extensive research about SIRS and MODs in rodent model. One point of particular interest should be blocking leukocyte accumulation in the developmental phase. More than a therapeutic option, this strategy could be useful to determine the role of those cells on epidermal detachment and basal membrane destruction. Currently there is project involving the Universidade Federal de Minas Gerais and the Ohio State University in the development and testing of chemokine and adhesion molecule blockers in CHO-induced laminitis.
Corticoids, which have been used in the past for the treatment of horses with laminitis, are currently contraindicated based on reported cases of laminitis after treatment of normal horses with long-acting corticosteroid agents. However, Brazilian studies have shown that hydrocortisone, a short-acting glucocorticoid, is effective in reducing local lesions observed during experimental intestinal ischemia-reperfusion in different models, and also prevents lung leukocyte accumulation in horses subjected to small colon distention. Recent studies conducted at Faculdade de Ciências Agrárias e Veterinárias (UNESP Jaboticabal) using a model of jejunum distention demonstrated horses treated with hydrocortisone had decreased laminar indices of MMP and markers of neutrophil accumulation compared with untreated control horses. Although these findings are still preliminary, a therapeutic and/or preventive effect of hydrocortisone on horses with or predisposed to laminitis should be considered in upcoming studies.
Another interesting concept is using regional intravenous perfusion (RIP) as a method of delivering therapies to the affected digits in order to obtain therapeutic levels in the digits while avoiding systemic effects. This has the possibility of being a great advantage to equine clinicians treating laminitis versus physicians treating visceral organ injury in human septic patients where their only avenue is the systemic use of potent anti-inflammatory drugs to counteract the inflammatory damage to the visceral organs. This has resulted in severe immunosuppression leading to fatality from expansion of the septic focus which originally initiated the systemic inflammatory response. Thus, our advantage of having the “target organ” located more peripherally may allow us to deliver high doses of drugs to the affected laminae without devastating systemic consequences. One of the first concerns that need to be addressed is whether the short time that a tourniquet needs to be applied to the distal limb for RIP will exacerbate laminar injury owing to increased venous and thus capillary hydrostatic pressure and whether this could contribute to or exacerbate laminar edema and further pathology. [...]
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