Platelet activation clinical trials

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Tab. 12.1 NO donors examined in clinical trials for anti-platelet/anti- thrombotic activity.

Reminiscent of the trend with laboratory studies, most (33 out of 43 cited above) uncontrolled clinical trials with either healthy volunteers or cardiovascular patients suggest that oral and intravenous NO donors at therapeutic doses acutely inhibit platelet activation in vivo (vide supra). Aside from their lack of long-term dosing and a placebo control group, several considerations restrict the predictive clinical value of these uncontrolled clinical studies limited numbers of subjects nonuniform criteria for subject entry and treatment outside of the trial induction of adrenaline or... 

Some studies have shown increased risks of violent death and depression in subjects with reduced serum cholesterol concentrations. Serum and membrane cholesterol concentrations, the microviscosity of erythrocyte membranes, and platelet serotonin uptake have been determined in 17 patients with hypercholesterolemia (21). There was a significant increase in serotonin transporter activity only during the first month of simvastatin therapy. This suggests that within this period some patients could be vulnerable to depression, violence, or suicide. This is an important paper, in that it explains why mood disorders are not regularly seen in clinical trials with statins, as has been summarized in a recent review (3). 

A DTI offers several advantages over conventional heparin. They act independent of AT and are capable of inactivating free and clot-bound thrombin equally well. As a group, these agents inhibit thrombus growth and thrombin-mediated platelet activation. Several direct thrombin inhibitors have now been studied in clinical trials. 

Numerous concerns about the safety of hemoglobin preparations have been presented in the literature. Some of the historical safety concerns have been addressed and are no longer issues with respect to the hemoglobin formulations now in advanced clinical trials. For example, effects such as neutrophil and macrophage activation, the formation of microthrombi, and platelet aggregation appear to have been eliminated from these Hb formulations. However, new safety concerns, centering on effects that have been observed clinically, have been raised. Three principal concerns will be discussed here 1) Mb s pressor activity 2) the potential for acellular Hb to exacerbate injury and 3) the potential for Hb to potentiate or exacerbate infection. 

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