Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds

Abstract

Chronic wounds are among the most devastating and difficult to treat consequences of diabetes. Dysregulation of the skin renin-angiotensin system is implicated in abnormal wound healing in diabetic and older adults. Given this, we sought to determine the effects of topical reformulations of the angiotensin type 1 receptor blockers losartan and valsartan and the angiotensin-converting enzyme inhibitor captopril on wound healing in diabetic and aged mice with further validation in older diabetic pigs. The application of 1% valsartan gel compared with other tested formulations and placebo facilitated and significantly accelerated closure time and increased tensile strength in mice, and was validated in the porcine model. One percent of valsartan gel-treated wounds also exhibited higher mitochondrial content, collagen deposition, phosphorylated mothers against decapentaplegic homologs 2 and 3 and common mothers against decapentaplegic homolog 4, alpha-smooth muscle actin, CD31, phospho-vascular endothelial growth factor receptor 2, and p42/44 mitogen-activated protein kinase. Knockout of the angiotensin subtype 2 receptors abolished the beneficial effects of angiotensin type 1 receptor blockers, suggesting a role for angiotensin subtype 2 receptors in chronic wound healing.

Angiotensin‐converting enzyme inhibitor works as a scar formation inhibitor by down‐regulating Smad and TGF‐β‐activated kinase 1 (TAK1) pathways in mice

“…Although the losartan group had the similar results at the final day, as we wanted to focus on the effect of ACEI, the further studies were not involved. Interestingly, recent study reported that applying valsartan (one of angiotensin receptor blockers) topically was a favourable treatment for chronic diabetic wounds (Abadir et al, ). Future studies should elucidate the effects of angiotensin receptor blockers on scar formation.…”

“…Patients who are already on an ACEI for hypertension or other cardiovascular conditions would be benefit from it, and this would have been a good indication for ACEIs. Since wound healing could be better achieved in both mice and pigs by giving valsartan topically (Abadir et al, ), we also should explore the topical application for scar management, like transdermal administration. Further, a comparison between systemic and topical administration of ACEI will be needed in addition to further experiments in order to clarify if ACEI may also represent a novel therapeutic approach to other dermatological disorders in humans.…”

Use of topical valsartan as a novel treatment for complicated leg ulcers

“…Therefore, innovative therapies are needed. Recently, the role of the renin–angiotensin system (RAS) in wound healing has been characterized in animal models . Given the availability and excellent safety profile of various RAS modulators, successful repurposing of these drugs to improve healing of chronic ulcers may prove useful in clinical settings.…”

“…Given the availability and excellent safety profile of various RAS modulators, successful repurposing of these drugs to improve healing of chronic ulcers may prove useful in clinical settings. Considering recent reports supporting a mechanism of action for RAS modulation for the improvement of healing, we hypothesized that topical delivery of a RAS modulator would improve wound healing. Herein we report our experience of treating VLUs with a topical formulation of valsartan 1% ointment.…”

“…tRAS is known to be dysregulated in ageing and diabetes, with increased AT1 and decreased AT2 expression. In diabetic aged mice and diabetic pigs, topical valsartan 1% gel significantly accelerated wound healing by selective blockage of AT1 . It has been suggested that systemic AT1 receptor blockers impair fibroblast migration and delay wound healing .…”