Serotonin-thromboxane interactions and platelet function

Background: Serotonin is known to potentiate the pro-aggregatory and vasoconstrictor effects of thromboxane A2. Storage pool deficiency of platelets which is characterised by low intraplatelet serotonin is associated with a bleeding diathesis. In a previous trial, administration of a selective serotonin reuptake inhibitor (SSRI) decreased intraplatelet serotonin which in turn inhibited platelet plug formation under shear stress. A potentiating effect of serotonin and thromboxane A2 was described previously in animal trials. We therefore plan to investigate possible potentiating effects of cyclooxygenase (COX-I) inhibition by acetylic salicylic acid and SSRI in healthy volunteers. Aims: The study is designed to examine the to describe a potentiating effect of serotonin and thromboxane A2 on platelet activation, and hence potentiation of the antiplatelet effects of SSRI and aspirin. A combination therapy of an SSRI and aspirin could represent a new therapeutic modality for thrombotic diseases. Rationale: An interaction of COX-I inhibition and selective serotonin reuptake inhibition might be exploited for the treatment of cardiovascular patients. The acute effects of serotonin re-uptake inhibition on serotonin plasma levels are quantified because a transient increase in plasma serotonin concentrations may represent a risk for patients with cardiovascular diseases. It is also important to characterise a drug-interaction between aspirin and SSRI to avoid adverse events like an increased probability of bleeding events. Study design: A randomized, placebo-controlled, double blind, two-way cross-over trial with a wash-out period of 17 days between treatment periods. Subjects & study medication: The trial will be performed in 20 healthy male smoking volunteers because intraplatelet serotonin concentrations are increased in smokers (> 20 cigareftes/d will be included). As a representative of the SSRI group, paroxetine (20mg/d) will be administered for a total of 18 days. Starting on day 15, volunteers will receive additional treatment with 100 mg aspirin for four days, to study the interaction between aspirin and SSRI. Then the subjects will cross-over to the alternative treatment period. Primary outcome variables platelet plug formation measured with the PFA-100 to describe the degree of platelet inhibition during pharmacological blockade of the thromboxane and serotonin pathways Secondary outcome variables -thrombin receptor activating peptide stimulated expression of CD62/63 measures of serotonin metabolism, thromboxane A2 levels, activation markers of coagulation, endothelium and platelets

Background: serotonin is a platelet agonist and potent vasoconstrictor that has recently received attention concerning its potential role in acute coronary artery thrombosis. The selective serotonin re-uptake inhibitor paroxetine decreased platelet serotonin storage and platelet function in human beings and therefore it might be exploited for patients with cardiovascular and/or cerebrovascular diseases. The acute effects of paroxetine on serotonin plasma levels were quantified because a transient increase in plasma serotonin concentration may represent a risk for patients with cardiovascular diseases and post stroke state. Methods: Healthy male smoking volunteers received 20mg/d paroxetine for 3 weeks in a randomized, double-blind, placebo-controlled, two-way cross over trial. Results: There was no significant differences at baseline and during the whole treatment period in plasma serotonin concentrations compared to the placebo group (p>0.05). Conclusion: The results demonstrate that paroxetine has a favourable safety profile because it fails to transiently increase plasma serotonin concentration.