Kotzki Sylvain, Roustit Matthieu, Arnaud Claire, Godin-Ribuot Diane, Cracowski Jean-Luc
Clinical Pharmacology Unit, INSERM CIC1406, Grenoble University Hospital, Grenoble, France; Univ. Grenoble Alpes, Grenoble, France.
Clinical Pharmacology Unit, INSERM CIC1406, Grenoble University Hospital, Grenoble, France; UMR 1042-HP2, INSERM, Grenoble, France; Univ. Grenoble Alpes, Grenoble, France.
Eur J Pharm Sci. 2015 May 25;72:21-6. doi: 10.1016/j.ejps.2015.02.012. Epub 2015 Feb 21.
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.
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.
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.
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.
系统性硬化症（SSc）是一种罕见疾病，会影响手指微循环，导致手指溃疡，在某些情况下还会导致截肢。前列环素类似物可静脉使用，但其治疗效果会被潜在的严重血管扩张引起的副作用所抵消。曲前列尼尔离子导入可能是治疗SSc相关手指溃疡的一种有前景的局部治疗方法。离子导入给药很复杂，对于应使用连续电流还是周期性电流仍存在争议。本研究的目的是比较曲前列尼尔连续离子导入与脉冲离子导入在大鼠中的效果。
通过阴极离子导入将曲前列尼尔（0.64 mM和0.064 mM）和氯化钠输送到麻醉大鼠的后肢。比较了三种输送相同电量的方案：一种是连续的（20分钟内100 μA），两种是周期性的（方案B：二十个1分钟周期，30秒内200 μA，随后30秒关闭；方案C：二十个1分钟周期，10秒内600 μA，随后50秒关闭）（每种浓度每种方案n = 8）。使用激光多普勒成像对皮肤血流进行定量，并根据欧姆定律计算皮肤电阻。
所有方案均导致皮肤血流显著增加。在较低浓度（0.064 mM曲前列尼尔）下，与连续离子导入或30/30序列相比，10/50脉冲序列显著增强了皮肤血流（表1；图1B）。我们注意到，与连续离子导入相比，氯化钠的脉冲离子导入（10/50序列）引起皮肤血流早期显著增加。皮肤电阻测量值与输送的电流强度呈负相关。
总之，曲前列尼尔以600 μA的10秒/50秒（开/关）方案进行脉冲离子导入可提高0.064 mM浓度下的离子导入效果，但在浓度高出十倍时则不然。脉冲离子导入可用于优化曲前列尼尔离子导入，以降低成本提供相似疗效，目前应在人体上进行测试。
