Platelet inhibition

Although an initial dose of 160 to 325 mg is required to achieve rapid platelet inhibition, long-term therapy with doses of 75 to 150 mg daily are as effective as higher doses. In addition, doses of less than 325 mg daily are associated with a lower rate of bleeding.29,30 The major bleeding rate associated with chronic aspirin administration in doses less than 100 mg per day is 1.6%, whereas the rate with doses more than 100 mg per day is 2.3%.30 Therefore, a daily maintenance dose of 75 to 160 mg is recommended.2... 

J.E. Freedman, J. Loscalzo, M.R.M.R. Barnard, C. Alpert, J.F. Keaney, and A.D. Michelson, Nitric oxide released from activated platelets inhibits platelet recruitment. J. Clin. Invest. 100, 350-356 (1997). 

The higher antiaggregatory and antithrombotic activity can be explained by the fact that the NO-release from sydnonimines can occur in the blood plasma independently of the presence of activating cellular cofactors. The antithrombotic activity of C89-4095 has been reported to be inhibited by oxyhemoglobine, thus demonstrating a clear sGC- and cGMP-mediated mechanism for platelet inhibition. C4144 90 showed a... 

In summary, the contribution of cGMP-independent mechanisms in NO-donor-mediated platelet inhibition is still not clear. Another unsolved question is, why cGMP-independent mechanisms of platelet inhibition are not common to all NO donors. In the following, the specific differences between various NO donors with regard to platelet effects will be discussed. 

NO donors have been used for more than a century in the treatment of cardiovascular diseases. Clearly, the NO/cGMP system plays a major role in platelet inhibition in vivo and in vitro, however, the complex regulation of cGM P levels, as well as the crosstalk to the cAMP system, makes it a signaling network that is not yet fully understood. The contribution of cGMP-independent mechanisms in NO signaling in platelets is far from clear. Careful use of the crucial genetically altered mouse models, the variety of NO donors with clear differences in biochemistry and functional platelet effects as well as the many so-called specific activatory or inhibitory research tools will certainly help to elucidate the still unknown areas of NO signaling in platelets in the near future. 

Poland, platelet-inhibiting effects have been observed with bisarylpyridazines of type (70, R = H, Me, Br, Cl R2 = H, Me) [270]. In France, the arylidenedi-hydropyridazines (71) and (72) have been investigated [271, 272]. They have been found to inhibit thromboxane biosynthesis. 

Platelet Inhibition Ginger extract has been found to inhibit platelet aggregation induced by arachidonic acid, epinephrine, ADP, and collagen (Srivastava 1984). The extract s ability to inhibit cyclooxygenase activity and thromboxane levels correlated well with inhibition of platelet aggregation (Srivastava 1984 Mustafa et al. 1993). The type of preparation used also affects platelet inhibition, because roasted and charcoal of ginger were effective, while ether extracts of raw and dried ginger were not (Wu et al. 1993). 

Ginger s platelet inhibition effect was demonstrated with oral doses in humans (Srivastava 1989). Although this was not confirmed in a later study, it highlights the importance of dosage and preparation (Janssen et al. 1996). The effect is dose dependent, and while fresh ginger is effective, dried ginger is not (Lumb 1994). 

Clopidogrel is indicated for prevention of vascular ischaemic events in patients with symptomatic atherosclerosis. It is also used, along with aspirin, for the prevention of thromboembolism after placement of an intracoronary stent. Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose is usually administered. Although rare, severe neutropenia and also thrombotic thrombocytopenic purpura may occur. 

Lipoxygenase (platelet) inhibition. Hexane extract of the dried fruit, administered to rats at a concentration of 700 mg/mL, had no effect on arachidonic acid transforma-... 

The effect with which PPT modulate the response of platelets is also pertinent to vascular disease, in particular, thrombosis. Resting platelets inhibit the respiratory burst of neutrophils whereas thrombin-activated platelets increase the respiratory burst. Quercetin and resveratrol at picomolar concentrations attenuate this response by preserving endothelial CD39/ATP-dase," " and on present evidence (see above) such concentrations might be achieved locally following deglucuronidation at a site of inflammation. 

The physiological importance of nitric oxide should also be mentioned. It plays an important role in smooth muscle relaxation, platelet inhibition, neurotransmission, immune regulation, and penile erection (Nobel Prize in 1998 for the discovery of its role in the cardiovascular system). The importance of NO in biological systems stimulated the development of electrochemical sensors and the investigation of the electrochemical behavior of that compound. 

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