defibrotide and Peripheral-Vascular-Diseases

Defibrotide has been evaluated in patients with peripheral arterial disease (PAD) of the lower limbs, with coronary artery disease (CAD), and with Raynaud's phenomenon (RP). In PAD patients, defibrotide improved physical performance, restored deficient fibrinolysis, and affected rheology and blood flow. Further events-oriented trials are needed. For CAD patients, defibrotide could be applicable as an adjunct treatment following thrombolysis, instead of heparin. Defibrotide does not increase bleeding risk. There is a need to study other medications together with defibrotide for their synergistic effects. In patients with RP, defibrotide restored deficient fibrinolysis, but its true clinical potential needs to be assessed.

Topics: Antifibrinolytic Agents; Clinical Trials as Topic; Coronary Disease; Humans; Peripheral Vascular Diseases; Polydeoxyribonucleotides; Raynaud Disease; Vascular Diseases

In 103 patients with peripheral arterial disease (PAD) of the lower limbs, coagulation and fibrinolytic parameters were evaluated to identify hemostatic abnormalities characteristic of this patient population. PAD was defined as clinically stable Leriche stage 2 (based on clinical history, peripheral pulses, ankle-arm index, and treadmill test) for at least 3 months, walking distance > 100 m, and no other major illnesses, rest pain, or trophic lesions. Defibrotide, a polydeoxyribonucleotide derivative with vascular effects, was administered to the patients as part of a multicenter trial. The PAD patients exhibited a prothrombotic state as evidenced by high D-dimer in all but 24% of the patients (average 797 +/- 802 vs. 163 +/- 54 ng/mL normal population; p < 0.001) and high thrombin-antithrombin III complex (TAT) levels (10.2 +/- 8.9 vs. 2.5 + 1.5 ng/mL; p < 0.001) with low to normal levels of protein C (86 +/- 25 vs. 102 +/- 18%; p < 0.01) and plasminogen activator inhibitor-1 (PAI-1) antigen (5.9 +/- 4.5 vs. 1.3 + 0.7 ng/mL; p < 0.001) were elevated in 79% of the patients. These results suggest that there is ongoing thrombosis in the majority of PAD patients. Differences from normal controls were observed for t-PA, PAI-1, protein C, and protein S; however, it is not certain that the thrombosis in patients with PAD is due to these factors.

Topics: Adult; Aged; Antithrombin III; Biomarkers; Blood Coagulation; Double-Blind Method; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Fibrinolytic Agents; Humans; Male; Middle Aged; Peptide Hydrolases; Peripheral Vascular Diseases; Plasminogen Activator Inhibitor 1; Polydeoxyribonucleotides; Prognosis

In a random double-blind study versus placebo, 60 ambulatory patients with peripheral occlusive disease of the lower limbs and claudicatio intermittens (Leriche's stage 2), were treated for 60 days with defibrotide (400 mg b.i.d., oral, n = 30) or placebo (n = 30). Patients in the defibrotide group received additional treatment with the same drug at the reduced rate of 400 mg once daily for another 120 days for maintenance (total treatment duration 180 days). All patients were assessed at intake and 60 days for relative and absolute walking distance (RWD and AWD) in a standard treadmill test and for the Winsor Index (WI) at rest and after exercise; patients of the defibrotide treatment group were retested in the same way at 90-180 days. In a subgroup of patients (defibrotide = 11, placebo = 12), blood samples were obtained for the assessment of whole blood and plasma viscosity at intake and after 60 days of treatment. These samples could not be collected properly in the remaining cases, for technical reasons. At day 60, we compared the effects of the two treatments on physical performance: mean (SE) values of RWD were for defibrotide 148 (9.7) and 179 (12.4) m in basal and post-treatment conditions, respectively, and 209 (16.2) and 212 (17.1) m for placebo. Similar changes were observed for AWD: for defibrotide 206 (13.4) and 241 (15.2) m and for placebo 270 (22.9) and 272 (23.1) m. The mean changes were significantly larger with defibrotide: for RWD + 33 (7.1) vs. + 0.3 (3.8) m (p < 0.01) and for AWD + 34 (9.2) and -2 (6.6) m (p < 0.01). The overall gain of walking distance after maintenance therapy with the reduced defibrotide dosage amounted to approximately + 50% over basal (after 180 days). Blood and plasma viscosity improved in patients on defibrotide but the change fell short of statistical significance versus placebo. All findings confirm the potential usefulness of defibrotide in the treatment of peripheral arterial disease, at the same time encouraging further studies of the involved mechanisms of action.

Topics: Aged; Arterial Occlusive Diseases; Blood Viscosity; Double-Blind Method; Female; Fibrinolytic Agents; Hemorheology; Humans; Intermittent Claudication; Leg; Male; Middle Aged; Peripheral Vascular Diseases; Placebos; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Walking

Defibrotide, a polydeoxyribonucleotide of mammalian origin, has been shown to reduce the blood level of the plasminogen activator inhibitor, and so to increase the activity of tissue plasminogen activator without any adverse effect. A randomized, double-blind, placebo-controlled study has been done in 22 patients, 14 with peripheral vascular disease, 6 with coronary heart disease and 2 with cerebrovascular disease. Patients were given defibrotide 400 mg b.d. or identical placebo for 30 days and the parameters of fibrinolysis were evaluated before and after the treatment. A significant increase in tissue plasminogen activator activity at rest and after venostasis was observed after defibrotide; tissue plasminogen activator antigen at rest and after venostasis was not affected by either treatment. Defibrotide significantly reduced plasminogen activator inhibitor activity and antigen at rest. Only one patient complained of gastric pain after placebo treatment. The study shows that defibrotide has profibrinolytic property and that it could be used to explore the role of plasminogen activator inhibitor in venous and arterial thrombosis.

Topics: Administration, Oral; Aged; Blood Coagulation Tests; Cerebrovascular Disorders; Coronary Disease; Double-Blind Method; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Plasminogen Inactivators; Polydeoxyribonucleotides; Tissue Plasminogen Activator

To evaluate the hemorheological influence on oxygen release after a period of 4 months of suspension from smoking and of antihypertensive treatment with amlodipine 10 mg o.d. and defibrotide 400 mg o.d. we have studied 14 smokers with II moderate hypertension (according to the World Health Organization) with hypertensive retinopathy II and slight left ventricular hypertrophy and II stage type a peripheral arterial disease according to Leriche-Fontaine classification. The total suspension for a period of 4 months from smoking associated with a Ca-antagonist such as amlodipine and an hemorheological, antithrombotic drug such as defibrotide together could bring about an improvement on the treatment of hypertension and a notable reduction in the risks linked to the complications found in hypertensives with PAOD II type a.

Topics: Amlodipine; Antihypertensive Agents; Blood Gas Monitoring, Transcutaneous; Blood Viscosity; Calcium Channel Blockers; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Peripheral Vascular Diseases; Polydeoxyribonucleotides; Smoking; Smoking Cessation