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In a controlled study of 100 patients, mean age 65 years old, suffering from chronic peripheral obliterative arterial disease, Leriche's stage II, were randomised in two groups treated respectively with defibrotide (400 mg bid) or heparan-sulfate (40 mg bid) by the oral route for a period of 6 months. At basal and after 30, 90 and 180 treatment days, patients were assessed for pain, paresthesias, rigidity and or tiredness in the leg, Winsor index (WI) relative and absolute walking distance (RWD, AWD), and time of recovery from pain. In order to evaluate microcirculation the following parameters were tested: resting flow (RF), standing flow (SF), veno-arteriolar reflex (VAR) and a capillaroscopy study was conducted. All patients showed an improvement in the clinical and instrumental parameters but more pronounced in the defibrotide group; the difference between the beginning and the end of the therapy was significantly better for defibrotide (p < 0.01). The tolerability observed was good, no side-effects were reported during the study.

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.

The authors report on the pharmacological employment of defibrotide in the treatment of a case of deep vein thrombosis (DVT) of the left iliac-femoral veins in a patient with a high-risk of hemorrhage (haematuria from kidney neoplasm, rupture of basilar artery aneurysm, urethral bleeding from catheter trauma). Alternatively to the traditional thrombolytic and anticoagulants, not indicated here for their haemorrhagic risk potential, defibrotide promptly resolved the DVT without any major effect on blood coagulation parameters. Initially, 1 gr of defibrotide in 250 ml of glucose-1-phosphate solution was administered twice-daily for the first two days when improvement had been observed. An additional 5 days of therapy was continued under the same regimen, then 400 mg intravenously every 2 hours for 14 days, and 400 mg intramuscularly every 24 hours until the 30th day. The patient was dismissed from the hospital on therapy with indobufen 200 mg orally, and elastic support stocking. After 6 months the patient is well. An echo color Doppler evaluation showed a normal venous blood flow through the femoral, iliac and caval veins, and venous blood reflux in the iliac-femoral and femoral saphenous veins due to valvular insufficiency. Caval filters, although recognized by many institutions as a preferred method of protection against pulmonary thromboembolism especially in patients with a contraindication to anticoagulation therapy or recurrent pulmonary embolism, was not used in this case, since the patient was critically ill. From this case report and the review of the literature it seems that defibrotide may represent a valid alternative therapy in the treatment of DVT, especially in high risk haemorrhagic patients.

Defibrotide pharmacokinetics were studied in 6 voluntary healthy subjects and in 10 uremic patients undergoing dialysis during which (instead of heparin) defibrotide was administered to prevent fibrino-formation in the circuit. Blood concentrations of the drug were assessed (expressed with reference to the residual glycidic deoxyribose) during a standard dialysis using defibrotide, 3.5, 15, 30, 45, 60 and 90 minutes after the defibrotide bolus (200 mg) had been injected into the arterial channel. The half-lives of the alpha and beta plasmatic phases were found to be equal at 3.79 and 41.4 min in dialysed subjects and at 1.13 and 16.54 in healthy volunteers. These results indicate that in uremic patients undergoing dialysis at intervals using defibrotide, a longer time is required to eliminate the drug from the circulation. This variation does not however appear to be significant in terms of the therapeutic use of the drug during dialysis.

Twenty patients, submitted to internal arteriovenous fistula procedure, were randomly assigned to one of the following treatments: defibrotide 400 mg b.i.d. IM (starting the day before surgery and continuing for the following 7 days); calcium heparin 5,000 IU t.i.d. SC (since the day of surgery and for the following 7 days). No deep venous thrombosis or thrombosis of the fistula were noticed during both treatments and no side effects were observed. In the defibrotide group, ELT showed a significant decrease (-40%) attesting an improvement of fibrinolysis without a plasminogen abatement. These findings indicate that defibrotide represent an effective alternative to calcium heparin for antithrombotic prophylaxis of A-V fistula in uremic patients.

With the aim of preventing deep vein thrombosis after radical or modified mastectomy, 100 patients were randomly assigned to one of two different groups: the first group was treated with defibrotide (400 mg b.i.d. e.v.) starting from the day before the operation and continuing for the following seven days. The second group was given calcium heparin (5,000 IU b.i.d. by s.c. route) from day 0 to the 7th post-operative day. Neither side effects nor DVT or PE were observed. The quantity of fluids from the drainages rapidly decreased in both groups from the first day to the third one, while the quantity of blood cells was negligible starting from the second post-operative day. On this basis defibrotide may be considered an effective and well tolerated drug for the prevention of DVT.

Forty-one surgical patients at risk of deep venous thrombosis (DVT) were treated with defibrotide (400 mg/b.i.d./i.v.) or with heparin (5000 UI/t.i.d./s.c.). Neither DVT nor pulmonary embolism was evidenced. In the heparin group the healing rate was longer and during the first three days bleeding from the surgical wound was more pronounced. In particular one patient of the heparin group had to interrupt the treatment for haemorrhage.

The latest research into the prevention of peri- and postoperative thromboembolic disease has found orthopaedic surgery patients to be most at risk. As the genesis of deep venous thrombosis (DVT) is due to haemodynamic, hemorheologic and parietal factors, various prophylactic measures have been considered in the past, measures which have not proved able to provide satisfactory protection in orthopaedics. The results obtained with Defibrotide in a random and controlled clinical study versus calcium heparin involving 211 patients of both sexes candidates to receive total hip arthroplasty and presenting at least one major thromboembolic risk factor are reported. The patients were assigned at random to one of the following treatments: 1) Defibrotide at a dose of 400 mg b.i.d. i.v. in 50 ml phleboclysis in 5 minutes (n = 108); 2) calcium heparin at a dose of 5000 IU t.i.d. subcutaneously (n = 103). The treatment began the day before operation and continued on average up to the eighth day for the Defibrotide group. With the control group it continued until discharge (usually on the 15th day) and at home for about three weeks until the completion of the physiotherapy cycle. In the 108 patients treated with Defibrotide only one case of DVT was reported and in none of these patients were symptoms or signs of pulmonary embolism encountered. In the group treated with calcium heparin 2 cases of clinically and radiologically diagnosed pulmonary embolism and 4 cases of DVT were observed. Although the differences were not statistically significant, the tendency favours Defibrotide. Statistically significant (p less than 0.01) was the difference in postoperative bleeding evaluated with particular attention in patients of advanced age. Further, in the Defibrotide group, scarring was considered excellent in 96% of cases while in the heparin group scarring was excellent in 85% (p less than 0.05). To conclude, the sure clinical effectiveness, tolerance, handiness and lack of interference with clotting functions make Defibrotide a really useful drug for the prevention of thromboembolic episodes in patients undergoing major orthopaedic surgery.

Deep venous thrombosis (DVT) can be a significant complication of the postoperative course in gynaecological surgery, because of traumatism and compression to which the vascular pelvic structures are subjected. A protocol was therefore designed to evaluate the effectiveness and tolerability of defibrotide, a new antithrombotic and profibrinolytic drug, compared with low-dose heparin. The study was conducted on 102 women, undergoing major gynaecological surgery for benign and malignant affections, randomly assigned to the following two treatment groups. A) defibrotide (400 mg i.v./i.m. b.i.d., starting the day before the surgery for 8 days); B) calcium heparin (5000 IU s.c. b.i.d., starting on the day of surgery, for/days). Clinical, haematological and instrumental (Doppler ultrasound) parameters were assessed and no major events were noted in either of the two treatment groups though in the calcium heparin group, 2 patients showed clinical signs of DVT (not confirmed by Doppler ultrasound) and no side effects were noticed, except for a cutaneous rash in one defibrotide patient and an episode of bleeding on the third postoperative day in a patient treated with calcium heparin. Defibrotide proved as effective as calcium heparin in the prevention of DVT in gynaecological surgery.

The efficacy and tolerability of defibrotide (800 mg/i.v.) and calcium heparin (15,000 UI/s.c.) in the prophylaxis of post-surgical deep venous thrombosis (DVT) and pulmonary embolism (PE) were compared in a multicentre trial involving 60 Italian surgical institutions (general surgery, obstetrics and gynecology, urology). Total enrollment was 2,250 patients (defibrotide: 1.194; calcium heparin 1.056). According to the protocol, the clinical suspicion of DVT and/or PE led to in-depth diagnostic evaluations (DVT: Doppler ultrasound velocimetry; PE: chest X-rays; ECG, pulmonary scintigraphic scanning). The incidence of post-surgical DVT was similar in the two groups (defibrotide: 8 patients; calcium heparin: 10 patients). A trend towards a lower incidence of DVT in the defibrotide group no PE; calcium heparin: 4 cases (chi 2 = 4.530, p less than 0.05). The local and systemic tolerability of both treatment was excellent. This trial, carried out in routine surgical practice, establishes the profibrinolytic approach to DVT prophylaxis as a sound and effective alternative to the traditional interference with the coagulation cascade.

The efficacy of defibrotide in the treatment of acute thrombophlebitis of the legs has been investigated in 140 patients, randomized into two groups. All patients received defibrotide either alone or as an addition to conventional therapies. Two different schemes of administration were selected and carried out in each group, according to the time of onset of thrombophlebitis. Defibrotide demonstrated a good clinical efficacy in both groups, with a highly significant reduction in those patients receiving defibrotide and conventional therapies. The clinical result were outstanding in two subgroups: extensive thrombophlebitis and brachioaxillary phlebitis.

The effectiveness and tolerability of defibrotide in the prevention of post-surgery deep vein thrombosis (DVT) were compared with those of heparin in a multicentric randomized controlled study. One hundred-eight-four both sexes patients submitted to thoracic surgery were randomly allocated to defibrotide (400 mg b.i.d. by IV route, n = 94) or to calcium heparin (5000 I.U. t.i.d. s.c., n = 90); both treatments were started the day before the operation and withdrawn when patients were allowed to stand up (i.e., after 7 days). No patients developed DVT in the defibrotide group, while a single case of DVT was detected in the heparin group; furthermore, a more prominent bleeding was observed in the latter, in the early post-operative period (normal bleeding: 2nd day: defibrotide 70/92 pts, heparin 53/90 pts, p less than 0.02; 3rd day: defibrotide 87/92 pts, heparin 76/90 pts, p less than 0.05, chi 2 test), while the healing rate of surgical wounds was similar in the two groups. No relevant modifications in laboratory parameters were seen throughout the observation period. Thus, these preliminary data suggest that defibrotide is at least as effective as heparin in the prevention of post-thoracic surgery DVT and that the former drug has a possibly better tolerability profile, due to a lesser tendency to bleeding.

In an open multicenter comparative study aimed at the evaluation of the efficacy of defibrotide and calcium heparin in the prophylaxis of postoperative deep vein thrombosis (DVT) and pulmonary embolism (PE) an evaluation has been made on 4810 patients. 2810 patients received defibrotide (800 mg/die: 400 mg b.i.d. or 200 mg q.i.d. by IV route); 2000 patients received calcium heparin (500 IU b.i.d. or t.i.d. by SC route) till the 7th post-operative day. The diagnosis of DVT or pulmonary embolism (PE) was made according to clinical routine criteria. The incidence of DVT has been 33/2810 (1.17%) in the defibrotide group and 47/2000 (2.35%) in the heparin group (chi 2 p = 0.002), while the cases of suspected or ascertained PE have been respectively 15/2810 (0.53%) and 23/2000 (1.15%) (p = 0.025). The post-operative course was totally normal in both groups; no significant adverse reactions were noticed. The obtained results suggest the effectiveness of defibrotide as an alternative to heparin in the prevention of post-operative DVT.

In an open multicenter comparative study aimed at the evaluation of the efficacy of defibrotide in the prophylaxis of postsurgical deep vein thromboses (DVT) an ad interim evaluation has been made on 2626 patients thus far enrolled. 1323 had received defibrotide (200 mg q.i.d. by IV route from day -1 to day +7th postoperative), 941 calcium heparin (5000 IU b.i.d. or t.i.d. by SC route from day 0 to day +7 postoperative) and 362 other treatments (antiaggregating agents, placebo or no therapy). This group has not been included in the final evaluation, due to its limited size. The diagnosis of DVT or pulmonary embolism (PE) was made according to clinical routinary criteria. The incidence of DTV has been 15/1323 (1.13%) in the defibrotide group and 21/941 (2.23%) in the heparin group (chi-square, p = 0.056) while the cases of suspected or ascertained PE have been respectively 3/1323 (0.22%) and 10/941 (1.06%) (p = 0.02). The incidence of adverse effects with defibrotide was less than 1%; occasional cases of increased serum transaminase levels were seen with heparin. These preliminary results supports the effectiveness of defibrotide in the prevention of post-surgery DVT, its effects being similar or more prominent than those of calcium heparin, currently regarded as the standard medication.