Iontophoresis of endothelin receptor antagonists in rats and men |
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Authors: | Matthieu Roustit Sophie Blaise Claire Arnaud Marcin Hellmann Claire Millet Diane Godin-Ribuot Boris Dufournet Jean Boutonnat Christophe Ribuot Jean-Luc Cracowski |
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Institution: | Clinical Pharmacology Unit, Inserm CIC03, Grenoble University Hospital, Grenoble, France. MRoustit@chu-grenoble.fr |
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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. |
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