Cathodal iontophoresis of treprostinil and iloprost induces a sustained increase in cutaneous flux in rats

Abstract

BACKGROUND AND PURPOSE The treatment of scleroderma‐related digital ulcers is still a therapeutic challenge. The most effective drugs are prostacyclin analogues. However, their usage is limited to an intravenous route of administration and by their frequent side effects. The objective of this study was to test whether treprostinil, iloprost and epoprostenol can induce sustained vasodilatation in rats when delivered locally using cutaneous iontophoresis. EXPERIMENTAL APPROACH Treprostinil, iloprost and epoprostenol were delivered by cathodal and anodal iontophoresis onto the hindquarters of anaesthesized rats (n= 8 for each group). Skin blood flow was quantified using laser Doppler imaging and cutaneous tolerance was assessed from day 0 to day 3. KEY RESULTS Cathodal but not anodal iontophoresis of treprostinil (6.4 mM), iloprost (0.2 mM) and epoprostenol (1.4 mM) induced a significant and sustained increase in cutaneous blood flow. The effects of treprostinil and iloprost were significantly different from those of treprostinil vehicle. Only weak effects were observed when both drugs were applied locally without current. Skin resistance was unchanged in areas treated with prostacyclin analogues. Finally, skin tolerance was good, with no evidence of epidermal damage. CONCLUSIONS AND IMPLICATIONS Cathodal iontophoresis of treprostinil and iloprost increases cutaneous blood flow with a good local tolerance. The effects of cathodal iontophoresis of these drugs should be investigated in humans, as they could have potential as new local therapies for digital ulcers in patients with scleroderma.

Anodal Iontophoresis of a Soluble Guanylate Cyclase Stimulator Induces a Sustained Increase in Skin Blood Flow in Rats

“…Taken together, these data suggest that the partition coefficient and the concentration are crucial parameters to enhance iontophoresis. This is consistent with the good iontophoretic transfer of treprostinil (M r 390.51 and logD 6 1.4) in the same rat model (Blaise et al, 2011).…”

“…Indeed, despite a large and sustained vasodilator response at 7.5 mM, the response was not as prolonged as that previously described with treprostinil, for which a plateau was still present at least 60 minutes after the end of iontophoresis (Blaise et al, 2011). This could be due to an elevated subcutaneous clearance of A-350619, or to a transient pharmacodynamic effect.…”

“…In addition, although sodium nitroprusside, an indirect nitric oxide (NO) donor, can be delivered through iontophoresis (Blaise et al, 2010), its short half-life does not make it a promising candidate. On the other hand, the iontophoresis of prostacyclin analogs (iloprost and treprostinil) showed promise at inducing a sustained increase in cutaneous flow in rats (Blaise et al, 2011). A first study with iloprost in healthy volunteers was performed to confirm these results in humans; unfortunately, the study was aborted because of significant side effects.…”

“…Before iontophoresis, each rat was inspected to ensure that the hairless skin on the back and the hind legs was intact. Rats were then equipped with three 1.2-cm 2 circular iontophoresis AgCl electrodes (LI 611, PeriIont System; Perimed, Järfälla, Sweden) containing drugs or vehicles, as described previously (Blaise et al, 2011). Passive electrodes (PF 384, PeriIont System; Perimed) were placed on the back of the neck, and both electrodes were connected to a current generator (PF 382b, PeriIont System; Perimed).…”

“…Rats were kept in a day/night cycle of 12/12 hours with food and water at will. Rats were shaved as previously described (Blaise et al, 2011;Roustit et al, 2012).…”