title: Effect of continuous vs pulsed iontophoresis of treprostinil on skin blood flow.
abstract: BACKGROUND
  Systemic sclerosis (SSc) is a rare disease affecting digital microcirculation, leading to finger ulcers and in some cases to amputation. Prostacyclin analogues can be used intravenously but their therapeutic effect is counterbalanced by potentially serious vasodilatation-induced side effects. Iontophoresis of treprostinil could be a promising local therapeutic alternative for SSc-related digital ulcers. Iontophoretic drug delivery is complex, and whether continuous or periodic current should be used remains debated. The objective of the present work is to compare the effect of continuous vs pulsed iontophoresis of treprostinil in rats.
  
  
  METHODS
  Treprostinil (0.64 mM and 0.064 mM) and NaCl were delivered by cathodal iontophoresis onto the hindquarters of anaesthetized rats. Three protocols delivering the same quantity of current were compared: one was continuous (100 μA during 20 min) and two were periodic (B: twenty 1-min cycles with 200 μA during 30 s followed by 30 s Off; and C: twenty 1-min cycles with 600 μA during 10s followed by 50s Off) (n=8 for each protocol with each concentration). Skin blood flow was quantified using laser Doppler imaging and skin resistance was calculated with Ohm's law.
  
  
  RESULTS
  All protocols induced a significant increase in skin blood flow. At the lower concentration (0.064 mM treprostinil) the pulsed 10/50 sequence significantly enhanced cutaneous blood flow (Table 1; Fig. 1B) compared to continuous iontophoresis or the 30/30 sequence. We noted that the pulsed iontophoresis of NaCl (10/50 sequence) induced a significant early increase in cutaneous blood flow in comparison with continuous iontophoresis. Skin resistance measures were negatively correlated with current intensity delivered.
  
  
  CONCLUSIONS
  In conclusion, pulsed iontophoresis of treprostinil with a 10 s/50 s (On/Off) protocol at 600 μA increases the efficacy of iontophoresis at 0.064 mM but not at a tenfold higher concentration. Pulsed iontophoresis could be used to optimize treprostinil iontophoresis, to provide similar efficacy with decreased costs, and should now be tested on humans.
authors.affiliation: Clinical Pharmacology Unit, INSERM CIC1406, Grenoble University Hospital, Grenoble, France; Univ. Grenoble Alpes, Grenoble, France. Electronic address: skotzki@chu-grenoble.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Kotzki
authors.affiliation: Clinical Pharmacology Unit, INSERM CIC1406, Grenoble University Hospital, Grenoble, France; UMR 1042-HP2, INSERM, Grenoble, France; Univ. Grenoble Alpes, Grenoble, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Roustit
authors.affiliation: UMR 1042-HP2, INSERM, Grenoble, France; Univ. Grenoble Alpes, Grenoble, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Arnaud
authors.affiliation: UMR 1042-HP2, INSERM, Grenoble, France; Univ. Grenoble Alpes, Grenoble, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Godin-Ribuot
authors.affiliation: Clinical Pharmacology Unit, INSERM CIC1406, Grenoble University Hospital, Grenoble, France; UMR 1042-HP2, INSERM, Grenoble, France; Univ. Grenoble Alpes, Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007478:Iontophoresis / Q000379:methods*; D008297:Male; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects*; D012867:Skin / Q000098:blood supply / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D011464:Epoprostenol; C427248:treprostinil
keywords: Continuous current; Iontophoresis; Microcirculation; Periodic current; Prostacyclin