Topical valsartan speeds up healing in chronic wounds

A topical gel formulated from a medication commonly used for hypertension accelerated and improved healing when applied to chronic wounds in mice and pigs, researchers reported in a study published in the Journal of Investigative Dermatology.

If validated in human clinical trials, the treatment could be used for diabetic foot ulcers, an increasing and costly health care problem. The researchers are hoping to eventually submit the treatment for approval from the US Food and Drug Administration (FDA).

“The FDA has not issued any new drug approval for wound healing in the past 10 years,” said the study’s first author Peter Abadir, MD, associate professor of medicine at Johns Hopkins University School of Medicine, Baltimore, MD. “Using medicines that have been available for more than 2 decades, we think we have shown that this class of medicines holds great promise in effectively healing chronic wounds that are prevalent in diabetic and aged patients.”

Normal wound healing involves complex biological signaling in which the renin-angiotensin system (RAS) plays a crucial role. The RAS furthers the inflammatory response, collagen deposition, and the transforming growth factor-beta (TGF-β) signaling necessary for wound healing. In contrast, dysregulation of RAS is implicated in abnormal wound healing in diabetic and older adults.

The researchers speculated that angiotensin receptor blockers—normally used for treating hypertension—might accelerate wound healing and collagen deposition via the TGF-β signaling pathway. They reformulated two angiotensin type 1 receptor blockers, losartan and valsartan, from oral formulations into topical gels. The investigators applied the gels directly to wounds on young diabetic and older nondiabetic mice, as well as older diabetic pigs.

They administered 5% topical losartan in three groups of diabetic mice corresponding to three different phases of wound healing:

• Inflammatory phase: treatment up to day 3 post-wounding
• Proliferative/remodeling phase: treatment starting on day 7 post-wounding
• All phases of healing: treatment from day 1 until closure

Mice treated during the proliferative/remodeling phase had the fastest healing rate, the researchers found.

Next, the researchers compared the efficacy of different concentrations of losartan gel (1%, 5%, and 10%) with comparable concentrations of valsartan gel (0.5%, 1%, and 5%), which they applied to diabetic mice during the proliferation/remodeling phase of wound healing.

Results showed that valsartan was more effective in accelerating wound healing than losartan, with no significant difference in healing time between any of the valsartan doses. Among all the agents, 1% valsartan had the greatest overall impact on total wound closure. However, 10% losartan was associated with worse wound healing, possibly due to toxicity from the higher dose, the researchers suggested.

Thick-skinned

Given that 1% valsartan showed the best overall results during the proliferation/remodeling phase in diabetic mice, the researchers tested its effects against placebo on wounds in older diabetic pigs. Pig skin has similar properties to human skin and is a good model of human wounds.

The investigators found that wounds treated with 1% valsartan gel showed faster closure rates than wounds treated with placebo gel. All 1% valsartan-treated wounds were closed by day 50, compared with none of the placebo-treated wounds. Also, no valsartan was detectable in the blood in the later part of the treatment course, indicating that the drug wasn’t absorbed systemically.

Lastly, the researchers investigated the impact of 1% valsartan gel on the quality, not just the speed, of wound healing by testing collagen content, tensile strength, and other histological changes in pig skin. They found that the accelerated wound healing rate in valsartan-treated skin was associated with significantly thicker epidermal and dermal collagen layers and a more organized collagen fiber arrangement than placebo-treated wounds.

The increased collagen deposition and improved collagen arrangement also resulted in significantly stronger skin with a higher tensile strength, “suggesting more resilience against wound dehiscence and recurrence, a highly relevant concern in diabetic patients,” Dr. Abadir and colleagues wrote.

A different approach

“Our strategy for specifically targeting the biology that underlies chronic wounds in diabetics and older adults differs greatly from other approaches to wound care thus far,” said senior author Jeremy Walston, MD, professor of medicine and co-director of the Biology of Healthy Aging Program at Johns Hopkins. “The topical gel likely enables a cascade of positive biological effects that facilitate and accelerate chronic wound healing.”

The investigators are readying clinical trials in humans. Dr. Abadir, Dr. Walston, and co-investigator Neal Fedarko, PhD, also of Johns Hopkins, filed an international patent application for their topical RAS blocker treatment for wound healing. They’ve licensed it to Gemstone Biotherapeutics, a Baltimore-based start-up company focused on developing treatments for advanced wound care.

“Hopefully, this medication will be available for public use in a few years, if further research bears out our results,” Dr. Walston said.