C. Frigerio

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.

Pharmacokinetics of exogenous adenosine in man after infusion

SummaryThe plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 μg·kg−1 respectively) and after infusion of 200 μg·kg−1 in 10 min followed by 400 μg·kg−1 in 10 min.As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min−1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l).After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 μg·ml−1), but the mean clearance and half-life were significantly different (12.1 l·min−1 and 0.63 min respectively).In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.

EVIDENCE OF AN ADENOSINE‐DEPENDENT MECHANISM IN THE HYPOTENSIVE EFFECT OF l‐ARGININE IN MAN

1. The hypothesis that endogenous adenosine could play a role in the haemodynamic response to l‐arginine is investigated.

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.

Determination of Plasma Concentrations of Cyclandelate and Mandelic Acid in Patients with Generalized Atherosclerotic Vasculopathy Treated with Oral Cyclandelate

Cyclandelate, a vasoactive substance consisting of the mandelic acid ester of 3,3,5-trimethylcyclohexanol, was administered to 10 patients with cerebrovascular and/or peripheral vascular disease. Blood specimens were collected at 1 − 6 h after oral administration of 1600 mg cyclandelate, and the ester and acid were extracted from plasma in acid medium using n-hexane/isopropyl alcohol. The concentrations were determined by a high-performance liquid chromatography isocratic system. The highest plasma cyclandelate concentrations were detected at the third hour, whereas plasma mandelic acid concentrations were still increasing 6 h after administration.