Guigui Alicia, Mazet Roseline, Blaise Sophie, Cracowski Claire, Beau-Guillaumot Myrtille, Kotzki Sylvain, Roustit Matthieu, Cracowski Jean-Luc
Grenoble Alpes University Hospital, Clinical Pharmacology, Grenoble, France.
Univ. Grenoble Alpes, Grenoble, France.
J Clin Pharmacol. 2020 Jun;60(6):758-767. doi: 10.1002/jcph.1574. Epub 2020 Feb 20.
Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer.
指端皮肤溃疡是系统性硬化症的一种严重并发症。一线治疗方法是静脉注射伊洛前列素，但它会引发剂量限制性不良反应。通过皮肤离子电渗疗法局部给予曲前列尼尔可能是一种安全的替代方法。我们在健康志愿者和系统性硬化症相关指端溃疡患者中进行了一项两阶段、随机、安慰剂对照的单剂量递增研究。我们进一步探讨了该方法对皮肤血流量的影响。在第一组健康受试者中，在三个部位（即六个皮肤位点）进行曲前列尼尔和安慰剂离子电渗疗法：脚底、腿部和手指。我们使用了浓度为1mg/mL的曲前列尼尔水凝胶。然后，我们以3:1的比例用曲前列尼尔或安慰剂随机治疗系统性硬化症相关指端溃疡。我们使用的浓度范围为0.1至1mg/mL。根据不良事件通用术语标准（CTCAE）记录并评定所有不良事件，而用激光散斑对比成像记录皮肤微血管血流量。在12名健康志愿者中，我们观察到60例局部不良反应：烧伤、皮肤疼痛、红斑和瘙痒，根据5分制CTCAE量表评定为1级或2级。曲前列尼尔离子电渗疗法显著增加了腿部的皮肤血流量（AUC分别为88460%±6436%和基线血流量·分钟时的12730%±3397%；P<0.001）以及脚底的皮肤血流量（AUC分别为20124%±6119%和基线血流量·分钟时的3142%±3036%，P=0.018），手指部位有增加趋势。在5例系统性硬化症相关指端溃疡患者中，报告了2例局部治愈性不良反应。曲前列尼尔水凝胶离子电渗疗法在患有指端溃疡的系统性硬化症患者中是安全的。
