G.L. Messa

Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration

SummaryIn 6 normal volunteers given single oral doses of 250, 500 and 1000 mg ticlopidine (T), the peak plasma level of unchanged drug was reached after about 2 h. There was no correlation between the plasma T level and its inhibitory effect on platelet function, expressed as % inhibition of ADP-induced aggregation. By means of HPLC and GC/MS significant concentrations of T were demonstrated in washed red cells, platelets and neutrophils, with a marked difference in the time course of the appearance of cell-associated drug. The time course of platelet-associated T very accurately fitted that of the antiaggregatory activity.After subacute oral administration (250 mg b. d. for 7 days), the maximum effect on platelet function was observed after 3 to 4 days, when a significant concentration of platelet-associated T had been reached. The pharmacological effect persisted as long as drug was detectable in platelet.An in vitro study strongly suggested that the antiaggregating effect was retained by treated washed platelets but not by treated plasma. It is suggested that the platelet compartment represents the pharmacological target of T via a specific uptake system.

Pharmacodynamic Effects of Sulodexide on Profibrinolytic and Haemorrheological Patterns

SummaryTwenty-four patients with vascular disorders, randomly divided into 3 dosage groups of 8 patients, were treated with a single oral dose of sulodexide (50, 100 or 200mg) and placebo. Tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1) activity and antigen, euglobulin lysis time, α2-antiplasmin, plasminogen, fibrinogen, blood and plasma viscosity, and whole blood filtration rate were determined before administration and over the following 24 hours. Sulodexide significantly increased t-PA activity linearly with the dose over the range of 50 to 200mg. At the same time, it also significantly decreased the concentration of PAI-1 linearly and proportionally with the dose. No clear effects were observed on the other monitored parameters, although euglobulin lysis time and plasma viscosity showed a tendency to decrease after the administration of sulodexide. These results justify the clinical activity of sulodexide. Indeed, the concomitant increase of t-PA and decrease of PAI-1 activity and antigen might increase the natural fibrinolytic activity with a physiological potentiation, without other adverse effects. The known activity of sulodexide in decreasing plasma viscosity during long term treatment is, however, not immediately explicable by the single-dose effects.

Effect on rheological and some peripheral haemodynamic parameters of defibrotide in POAD patients

Received 1.12.1986; Accepted 19.1.1987 by Editor T. DiPerri) In ten POAD patients, 800 mg. of Defibrotide (polideoxynucleotide extracted from mammalian lung, with antitrombotic and fibrinolytic activity) were infused i.v. Blood and plasma viscosity, haematocrit, blood filterability and fibrinogen concentration were controlled, in basal conditions and after one hour from the end of infusion. Haemodynamic parameters: rest flow, peak flow, time to peak flow, half time and total time of reactive hyperemia by means of strain gauge pletismography, were controlled at lower limbs before infusion and after 1 h., 2 h., 6 h., from the end of infusion. The present investigation showed an improvement of rheological parameters and a decrease of total time and half time of reactive hyperemia. These data demonstrate a rheological activity of Defibrotide as well as the fibrinolytic one.

Defibrotide Therapy for Thrombophlebitis -Controlled Clinical Trial

Deep venous thrombosis is a common disease with significant danger of both acute and chronic complications. Widely accepted therapies are based on anticoagulant (heparin and/or anticoagulant agents) or early fibrinolytic therapy. All these therapies frequently have severe side effects. Defibrotide is a new drug with antithrombotic and profibrinolytic activities but without anticoagulant activity and major side effects. To evaluate the efficacy of this drug against acute thrombophlebitis, we treated a group of 10 patients with 200 mg defibrotide intravenously three times a day for 15 days. Fibrinolysis parameters were monitored every other day. The indices of venous function by strain-gauge plethysmography and venous occlusion were evaluated every 7 days. The drug induced a significant improvement in plethysmographic indices and a significant profibrinolytic activity. Defibrotide-treated patients showed a fast disappearance of clinical and instrumental signs of thrombophlebitis. No side effects were reported during the study.

Inhibition of platelet aggregation in man by indobufen (K 3920).

A complete crossover trial was undertaken in six healthy volunteers to gain information on dose-effect responses to indobufen by assessing the intensity and duration of the effect of 3 single oral doses of the drug on platelet aggregation induced by threshold concentration of ADP and by 3 added doses of collagen. The results of the study confirm that the activity is dose-related and is reversible since 24 hours after administration it has practically disappeared. The effect of the same dose of indobufen differed significantly according to the amount of collagen added to plasma, whereas increasing doses of indobufen provoked a significantly more marked effect when the amount of inducer employed was the same.

New in vivo model to assess venous endothelial cell functions. Effect of defibrotide

In the past few years there has been increasing interest in the role of the vascular endothelium as an active modulator of biological responses. Endothelial cells exert antithrombotic activity by the release of prostacyclin [23] and adenine nucleotides [16], the availability on the cell surface of heparin-like substances [3], and thrombomodulin-mediated activation of protein C [8]. In addition, endothelium is involved in the regulation of fibrinolysis by releasing soluble factors, such as tissue plasminogen activator (tPA; [10]) and plasminogen activator inhibitor (PAI; [22, 11]), as well as in the control of vascular responsiveness by the production of smooth muscle relaxing and contracting factors. Endothelial cells have also been shown to synthesize and to express procoagulant activities [18].Many data on endothelial cell functions has been obtained from two experimental models, namely endothelial cell cultures and perfused segments of animal and human vessels. Both are subject to methodological criticism since they only represent in part in vivo conditions, and the necessary experimental manipulations and laboratory procedures greatly modify the naturally occurring cellular functions.In order to overcome such difficulties as far as possible, a new in vivo model has been employed to provide easily assessable and reliable data on the properties of endothelial cells in man. A venous segment was isolated functionally by cannulating a dorsal vein in the hand and a cubital vein in the same arm. Changes observed ex vivo in blood from the cubital vein following infusion into the hand vein of an active drug, can mainly be attributed to its local effect on the venous wall. At the same time, a cubital vein in the other arm was cannulated in order to provide information to distinguish systemic from regional effects.

CIRCADIAN VARIATION OF PLATELET AGGREGATION AND BLOOD RHEOLOGY

Many vascular pathologies have been reported to follow a diurnal rhythm (AMI, angina, stroke, sudden cardiac death, pulmonary thromboembolism) with a peak in the early morning. Aim of the study was to evaluate the existence of a diurnal rhythm of platelet aggregability and blood rheology. The study was carried out in 12 subjects; blood withdrawings were performed every 3 hour for 24 hours and in each blood sample platelet aggregation (on PRP and on washed platelets) and haemorheological parameters (blood viscosity, blood filterability, haematocrit and fibrinogen) were measured. Moreover systolic and diastolic blood pressure was recorded by dynamiC monitoring. The results show that a circadian rhythm of the above mentioned parameters does exists. Even if our data do not prove a strict correlation between these parameters and the incidence of the vascular pathology, it could be interesting to keep in mind the existence of a temporal parallelism when starting preventive therapy.

Multicentre comparative trial of tienilic acid and hydrochlorothiazide in hypertensive patients

SummaryTo compare the clinical and metabolic effects of a new diuretic uricosuric agent, tienilic acid, with those of hydrochlorothiazide, a multicentre double-blind trial was performed in 56 hypertensive patients. Twenty — eight patients were randomly assigned to take tienilic acid and 28 to take hydrochlorothiazide. The diuretic and anti-hypertensive actions of the two compounds were similar. No significant differences were observed between tienilic acid and hydrochlorothiazide in their effects on urinary and serum electrolytes, hepatic and renal function tests, and fasting lipids. The patients who received tienilic acid showed a significant fall in serum uric acid, mediated by the uricosuric effect. The availability of an agent combining diuretic, anti-hypertensive and hypouricemic effects offers promise in the treatment of arterial hypertension.