Trial of a novel prostacyclin analog, UT-15, in patients with severe intermittent claudication.
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.
Mohler
E R
ER
Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, USA.
Klugherz
B
B
Goldman
R
R
Kimmel
S E
SE
Wade
M
M
Sehgal
C M
CM
D000368:Aged; D001775:Blood Circulation / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D005263:Femoral Artery / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007383:Intermittent Claudication / Q000188:drug therapy* / Q000503:physiopathology; D007866:Leg / Q000098:blood supply / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011150:Popliteal Artery / Q000502:physiology; D016909:Tibial Arteries / Q000502:physiology; D018616:Ultrasonography, Doppler, Duplex; D014665:Vasodilator Agents / Q000627:therapeutic use*
D014665:Vasodilator Agents; D011464:Epoprostenol; C427248:treprostinil