Abstract
IntroductionThe treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis.MethodsCathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA) was subsequently performed on the forearm skin of healthy men (n = 5).ResultsIn rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC0–20 were 44032.2±12277 and 14957.5±23818.8 %BL.s, respectively; P = 0.01). In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans.ConclusionsThis study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.
Highlights
The treatment of scleroderma-related digital ulcers is challenging
Neither cathodal nor anodal iontophoresis of bosentan 10–2 M or sitaxentan 1022 M induced any significant change in skin blood flux compared to NaCl (Table 1; Figure 1)
We observed no significant effect of bosentan or sitaxentan at 1023 M or 1024 M
Summary
The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. Systemic sclerosis (SSc) is a rare disease affecting digital microcirculation, leading to finger ulcers and in some cases to amputation [1]. A non specific endothelin receptor antagonist (ERA), has been indicated to prevent digital ulcers in patients at risk, but it has no efficacy on existing ulcers [2]. Some authors have highlighted the potential interest of iontophoresis of vasodilating drugs as a treatment for digital ulcers in SSc [6,7] and previous work from our laboratory has suggested that PGI2 analogues are appropriate candidates [8]. Iontophoresis of ERAs could be interesting but, to our knowledge, it has never been tested either in animals or in humans
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