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.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Figures

Figure 1

Experimental setup: three iontophoresis chambers (A) connected to power supplies (B) were placed on the back and the hind legs of two shaved rats placed in the prone position on a thermal pad (C), temperature being maintained at 37.5°C and adjusted using a rectal probe (D) in one rat. Laser Doppler imaging (E) was performed over the area including all iontophoresis chambers. Cutaneous resistance was determined during iontophoresis with an amperometric biosensor unit (F).

Figure 2

Effects of iontophoresis (A) in the cathodal direction and (B) in the anodal direction, of iloprost 0.2 mM, treprostinil 6.4 mM, epoprostenol 0.028 mM at pH 12 and pH 6.5, NaCl 0.9 % and sodium nitroprussiate (SNP) 57.8 mM, on cutaneous blood flow expressed as % of baseline.

Figure 3

Paired analysis of the effect of treprostinil 6.4 mM and iloprost 0.2 mM in comparison with treprostinil buffer at the cathode, on cutaneous blood flow expressed as % of baseline.

Figure 4

Paired dose-dependent effect of cathodal iontophoresis of (A) treprostinil at 6.4 mM, 0.64 mM and 0.064 mM and (B) iloprost at 0.2 mM, 0.02 mM and 0.002 mM, on cutaneous blood flow expressed as % of baseline.

Figure 5

Effect of the passive transdermal diffusion of iloprost 0.2 mM and treprostinil 6.4 mM on cutaneous flux expressed as % baseline blood flow.

Figure 6

Histopathological examination of a full-thickness skin biopsy taken after iontophoresis of treprostinil 6.4 mM. The sample was embedded in paraffin and stained with haematoxylin, eosin and safran (x40).