Effects of defibrotide after oral and parenteral administration in patients with peripheral obliterative arterial disease (POAD).

Defibrotide (D) a polidesoxyribonucleotidic derivative provided with fibrinolytic and antithrombotic activity has already proven effective when administered by parenteral route in patients with peripheral obliterative arterial disease (POAD). Bioavailability studies gave evidence that the drug is absorbed by 50-70% when administered orally. Thus, aim of this trial was to evaluate whether the drug might exert similar clinical and biological effects after oral/parenteral dosing in a 2:1 ratio. This was a randomized cross-over study including 17 out patients with POAD (Leriche stage II). D was administered by oral (400 mg b.i.d.) and intramuscular route (200 mg b.i.d.), both treatments lasting 15 days. In basal conditions and at the end of both treatments the following evaluations were made: (1) absolute walking distance (tread mill); (2) Doppler ultrasonographic examination (Winsor index); (3) strain-gauge plethysmography (rest flow and peak flow). In addition in the same occasions plasma samples were collected for the assessment of plasminogen (chromogenic assay) and fibrinolytic activity (fibrin plates). Defibrotide administration was followed by a significant increase in walking distance both after oral and parenteral administration [basal conditions (IRL): 232.7 +/- 23.0 meters; oral: 273.1 +/- 28.1 m; i.m.: 277.9 +/- 26.8 m, p less than 0.01 - (IRA) basal conditions: 380.1 +/- 25.6; oral: 437.1 +/- 31.5 m; i.m.: 442.5 +/- 34.0 m, p less than 0.01] and by a significant increase in peak flow (basal conditions: 9.66 +/- 1.04; oral: 10.90 +/- 0.90; i.m.: 11.12 +/- 0.98, p less than 0.05), while Winsor index and rest flow were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

[Factor VII and cardiovascular risk in obese subjects]. / Fattore VII e rischio cardiovascolare negli obesi.

We investigated whether or not obesity is related to increased factor VII activity. We studied 70 obese subjects (aged 25 to 50 years, 25 males and 45 females, body mass index (BMI): mean +/- SD = 32.44 +/- 5.44) and 33 non-obese subjects (aged 25 to 50 years, 12 males and 21 females, BMI: mean +/- SD = 21.80 +/- 1.70). None of them were smokers or affected by hyperlipidemia, diabetes mellitus, impaired glucose tolerance or arterial hypertension. Factor VII activity was measured by the coagulometric method. We found higher factor VII activity in obese subjects (115.74 +/- 26.10%) than in healthy subjects (98.55 +/- 23.49%, p less than 0.005). Increased factor VII levels could determine a thrombophilic state involved in the genesis of cardiovascular accidents in obesity.

[Relations between overweight, thrombophilia and cardiovascular risk]. / Relazione tra sovrappeso corporeo, trombofilia e rischio cardiovascolare.

Seventy-one healthy subjects, aged 20 to 60, 19 males and 52 females, body mass index (BMI) 19 to 40, were enrolled in the study. None of them were smokers, or affected by hyperlipidemia, arterial hypertension or impaired glucose tolerance. We measured plasminogen activators inhibitor (PAI) activity, C-peptide levels, plasma fibrinolytic activity. We found a correlation between BMI and plasma fibrinolytic activity (r = -0.382, p less than 0.005), between BMI and PAI (r = 0.353, p less than 0.005), between BMI and C-peptide (r = 0.694, p less than 0.001) and between PAI and C-peptide (r = 0.404, p less than 0.02). Our data show a correlation between obesity and low fibrinolytic activity, probably due to high PAI levels. In obesity impaired fibrinolytic activity, maybe linked to hyperinsulinemia, could induce thrombophilic state.

[Hemorrheologic disorders of red cells in subjects at risk for atherosclerosis]. / Le alterazioni emoreologiche del globulo rosso in soggetti a rischio per aterosclerosi.

Cigarette smoking, hypercholesterolaemia, hypertriglyceridaemia, are all known risk factors for atherosclerotic vascular lesions. Often they are associated with alterations mainly due to increased haematocrit (smoking) or to the influence of triglycerides and cholesterol on the erythrocyte membrane or plasma viscosity. In order to eliminate these factors, washed red blood cells, poor in leucocytes and platelets, in a suspension with phosphate saline buffer were studied. 20 heavy smokers, 40 patients with hyperlipidaemia (26 II a or b; 14 IV) and 50 healthy people were considered. Red blood cell viscosity was calculated at 4 shear rate between 0.37 and 69.5 sec-1. Red blood cell deformability, as an indicator of cell filtration through Nucleopore membranes was also studied. There was no difference in the filtration index among the subjects under study. Red blood cell viscosity increased in smokers and in patients with hyperlipidaemia.

[Hemorrheologic disorders in obese patients. Study of the viscosity of the blood, erythrocytes, plasma, fibrinogen and the erythrocyte filtration index]. / Le alterazioni emoreologiche negli obesi. Studio della viscosità ematica, eritrocitaria, plasmatica, del fibrinogeno e dell'indice di filtrazione eritrocitaria.

Risk factors for atherosclerosis are often associated with haemorheological changes. On this point, obesity (recently advocated as an independent risk factor) was not much studied and with not univocal results. We have studied 70 obese patients (BMI greater than 30) and 50 healthy subjects (BMI less than 25). Among obese 26 had no more pathologies, 29 had hypertension, 3 suffered from ischemic heart disease, 3 suffered from occlusive arteriopathy, 9 were hyperlipidemic, 10 were smokers. We determined plasma viscosity and whole blood viscosity (at haematocrit corrected to 45% too). Washed erythrocytes, poor in leucocytes and platelets and resuspended in phosphate-buffered saline, were used for study of erythrocyte viscosity and deformability. Obese patients showed raised mean blood viscosity values when compared to healthy controls (p less than 0.01); an even more significant increase (p less than 0.001) was found concerning plasma viscosity and fibrinogen. Erythrocyte viscosity and red blood cell filterability index did not show any significant difference. We found no significant correlation between viscosity values and presence of hypertension, hyperlipidemia and smoking habit among obese. In conclusion, the higher vasculopathy incidence might be caused by an increase in blood viscosity, mostly due to plasmatic component. This fact appears to be independent from the presence of atherosclerosis complications or other risk factors.

[Increase in erythrocyte and plasma viscosity in patients with atherosclerotic vasculopathy of different sites]. / Aumento della viscosità eritrocitaria e plasmatica in pazienti affetti da vasculopatia aterosclerotica a diversa localizzazione.

Peripheral atherosclerotic arteriopathies are characterised by increased blood viscosity and, according to some, by a reduction in red blood cell deformability. Red blood cell viscosity was studied in 40 atherosclerosic patients (14 carotid and 26 aortoiliacofemoral lesions). All patients were subjected to the standard diagnostic examination (Doppler velocimetry, etc.). Fifty healthy non-smokers of the same sex and 20 heavy smokers were studied as controls. The viscosity of the whole blood, and plasma and blood fibrinogen were assayed. In studying erythrocyte viscosity, cells poor in leucocytes and platelets suspended in a saline phosphate buffer were employed. The atherosclerotic patients presented significantly higher mean levels of erythrocyte viscosity (p less than 0.01) and the increase in plasma viscosity and blood fibrinogen was also statistically significant. The viscosity of the whole blood was also increased in these patients (p less than 0.001). The increase in blood viscosity in subjects with peripheral arteriopathies therefore appears to be attributable to the plasma and to rheological alterations in the red blood cells.

[Blood, plasma, erythrocyte viscosity and index of erythrocyte filtration in subjects with hyperlipemia]. / La viscosità ematica, plasmatica, eritrocitaria e l'indice di filtrazione eritrocitario in soggetti affetti da iperlipemia.

40 hyperlipidaemic patients (26 type II a and b, 14 type IV) and 50 healthy controls were studied. The patients were not suffering from any other pathology of note and were under no drug treatment. Blood viscosity at natural Ht and at Ht 45% and plasma viscosity were measured. Red blood cell viscosity and deformability was studied on washed red cells, poor in leucocytes and platelets and suspended in a saline phosphate buffer. The patients with hyperlipidaemia had blood viscosity higher than healthy people. Red blood cell and plasma viscosity were higher in subjects with hyperlipidaemia. There was no difference in the filtration index between the people under study. The increased blood viscosity found in people with hyperlipidaemia appears to be attributable to changes in both the plasma and the erythrocytes.