Trial of a novel prostacyclin analog, UT-15, in patients with severe intermittent claudication

Abstract

Abstract:Prostacyclin is an endothelially derived vasodilator and inhibitor of platelet aggregation. Despite its therapeutic potential for peripheral arterial disease, the short half-life and chemical instability are barriers to routine therapy. Accordingly, prostacyclin analogs are being evaluated in patients with peripheral arterial disease. State-of-the-art non-invasive ultrasonography allows for serial testing of the hemodynamic effects of vasoactive drugs. The safety, efficacy and hemodynamic effects of UT-15, a novel, long-acting prostacyclin analog, were studied in patients with severe intermittent claudication. A total of eight patients with stable severe intermittent claudication, Fontaine classes IIb-III, were admitted to the hospital for intravenous infusion of UT-15. A symptom-limited, dose-escalation protocol was instituted, beginning with placebo and then with increasing dosage at 60-min intervals, followed by a 2-h period of maintenance dose at the maximum well-tolerated infusion rate. The hemodynamic response in the lower limbs was assessed with serial ultrasonography, segmental arterial pressures and pulse volumes. Blood flow in the common femoral artery increased 29% (p = 0.003) by the end of the maintenance period and remained above baseline throughout the washout period (p = 0.044). Blood velocity in the lower limb increased in most of the peripheral arteries. These increases achieved statistical significance in the common femoral artery (p = 0.025) and anterior tibial artery (p = 0.019), and approached significance in the popliteal artery (p=0.062). In two of four patients in whom blood flow was undetectable before the infusion, arterial blood flow at the ankle level became apparent on ultrasonography during maintenance infusion. UT-15 infusion improved the pulse volume recording (p = 0.016) but the ankle/brachial index did not change significantly. Common side effects at peak dose included headache and nausea. There were no serious adverse events attributable to UT-15 treatment. In most patients, the optimal infusion rate was 10-20 ng/kg per min. In conclusion, ultrasonography is a novel approach for assessing the hemodynamic response to vasoactive agents. UT-15 is well tolerated when given for up to 2 h and increases arterial blood flow and velocity in patients with severe intermittent claudication.

Treprostinil Sodium (Remodulin), a Prostacyclin Analog, in the Treatment of Critical Limb Ischemia: Open-Label Study

“…This pilot trial did not limit the size or location of wounds to be assessed, and baseline wounds were quite variable in size (from 0.2 cm 2 to 63.8 cm 2 ) and the degree of necrosis and/or gangrene. Given the findings in this report—complete healing of small wounds in three subjects—and positive data with intravenous prostanoids in previous work, 4,8,9,12 there may be a role for treprostinil in ischemic wound healing in CLI patients. Continuous subcutaneous administration of treprostinil was clearly manageable for these subjects in an outpatient setting.…”

“…If larger wounds are to be treated, more aggressive dosing and a longer duration of treatment should be considered. Future trials could also include skin perfusion and ultrasound measurements to extend previous work in patients with lower limb ischemia 12 and provide information about the mechanism of action.…”

“…Treprostinil at the maximum well-tolerated doses of 10 to 20 ng/kg/min produced potentially clinically significant increases in lower limb blood flow in serial ultrasonography (blood velocity and flow), segmental arterial pressure, and pulse volume recording assessments in these subjects. 12 Treprostinil has not previously been tested chronically in patients with CLI. Given the results of the acute trial and the extensive literature describing the use of prostacyclin and its analogs in CLI, a pilot safety and dose range-finding trial evaluating chronic subcutaneous treprostinil in subjects with CLI and no planned vascular interventional procedure was conducted.…”

“…Treprostinil at the maximum well-tolerated doses of 10 to 20 ng/kg/min produced potentially clinically significant increases in lower limb blood flow in serial ultrasonography (blood velocity and flow), segmental arterial pressure, and pulse volume recording assessments in these subjects. 12…”

Prostanoid therapies in the management of pulmonary arterial hypertension

“…Treprostinil, a benzindine prostanoid, was initially studied for potential use in congestive heart failure, 36 transplantation, 37 and peripheral vascular disease. 38 Support for treprostinil’s utility in PAH was sealed with a large subcutaneous infusion clinical trial. 39 …”