Thrombin peptide Chrysalin^® stimulates healing of diabetic foot ulcers in a placebo‐controlled phase I/II study

Abstract

Thrombin and thrombin peptides play a role in initiating tissue repair. The potential safety and efficacy of TP508 (Chrysalin) treatment of diabetic foot ulcers was evaluated in a 60-subject, prospective, randomized, double-blind, placebo-controlled phase I/II clinical trial. Chrysalin in saline or saline alone was applied topically, twice weekly, to diabetic ulcers with standardized care and offloading. A dose-dependent effect was seen in the per-protocol population where 1 and 10 mug Chrysalin treatment resulted in 45 and 72% more subjects with complete healing than placebo treatment. Chrysalin treatment of foot ulcers more than doubled the incidence of complete healing (p<0.05), increased mean closure rate approximately 80% (p<0.05), and decreased the median time to 100% closure by approximately 40% (p<0.05). Chrysalin treatment of heel ulcers within this population resulted in mean closure rates 165% higher than placebos (p<0.02) and complete healing in 86% (6/7) of ulcers compared with 0% (0/5) of placebo ulcers (p<0.03). Local wound reactions and adverse events (AEs) were equal between groups with no reported drug-related changes in laboratory tests or serious AEs. These results indicate the potential safety and efficacy of Chrysalin for treatment of diabetic foot ulcers.

Thrombin Peptide (TP508) Promotes Adipose Tissue-Derived Stem Cell Proliferation via PI3 Kinase/Akt Pathway

“…We have shown previously that ASCs differentiated into vascular cells when injected into infarcted hearts [34]. In light of previous reports that TP508 promotes wound healing [12,13,14,15,16,17,18], our findings suggest that the beneficial effect of TP508 may be mediated by stem cells. To this end, it has been shown that autologous mesenchymal stem cells increase vascularity and reduce wound size of nonhealing diabetic ulcer [35].…”

“…To this end, it has been shown that autologous mesenchymal stem cells increase vascularity and reduce wound size of nonhealing diabetic ulcer [35]. Importantly, a recent report showed that TP508 also stimulates healing of diabetic foot ulcers in a placebo-controlled phase I/II study [18]. It would be interesting to find out whether the beneficial effects of TP508 on diabetic ulcer are mediated by endogenous stem cells.…”

“…TP508 also accelerated repair of rat fresh fractures [15] and promoted bone formation in rabbit critical-size segmental bone defects [16] and in a rabbit model of distraction osteogenesis [17]. TP508 stimulates healing of diabetic foot ulcers in a placebo-controlled phase I/II study [18]. …”

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

“…In addition, many of the serine proteases, for example, thrombin, downstream of FVIIa in the coagulation cascade elicit intracellular signaling, which regulates gene transcripts that are involved in wound healing (38). For example, administration of a 23-residue peptide derived from thrombin has been shown to accelerate wound repair (39), and enhancement of TF expression via gene transfer in wounds in diabetic mice restored the delayed wound closure times found in these mice to those of nondiabetic mice (37).…”

The Diabetic Foot

“…Topical application of doxycycline may have benefit. A thrombin peptide, chrysalin, has shown some evidence of improve-ment in wound healing (23). Topical adenosine agonists may improve wound healing, as neutrophil adenosine A2 receptors inhibit phagocytosis and secretion of inflammatory molecules and reduce oxidative stress, with these agents potentially increasing IL-10 secretion by monocytes, leading to anti-inflammatory effects and enhanced platelet aggregation.…”