1,721,134 research outputs found
Multiple effects of dipyridamole on neutrophils and mononuclear leukocytes: adenosine-dependent and adenosine-independent mechanisms
No full textDipyridamole is an antithrombotic drug that has been shown to influence not only platelet function but also some aspects of leukocyte activation. In this study we demonstrate that dipyridamole effectively inhibits superoxide anion generation by neutrophils, mononuclear leukocytes, and whole blood stimulated with N-formyl-methionyl-leucyl phenylalanine and calcium ionophore A23187. In addition, the drug, at concentrations as low as 1 mumol/L, inhibits the expression of procoagulant activity--basal and stimulated--by mononuclear leukocytes. It is shown that, similar to its effect on platelets, dipyridamole influences these leukocyte functions indirectly, that is, through an increase of extracellular adenosine that in turn inhibits both superoxide anion generation by leukocytes and the expression of procoagulant activity by mononuclear leukocytes. In fact, adenosine deaminase, which metabolizes adenosine to inactive product, prevents the effects of dipyridamole on superoxide anion generation and on the expression of procoagulant activity by leukocytes. Experiments carried out with 8-phenyl-theophylline indicate that the adenosine-dependent effects of dipyridamole may involve multiple pathways, only some of which are dependent on the interaction of adenosine with its receptors. Dipyridamole also dose-dependently inhibits the synthesis of leukotrienes B4 and C4 by stimulated neutrophils and mononuclear leukocytes through a mechanism that is not mediated by the presence of adenosine in the extracellular medium. The reported effects of dipyridamole on separate and distinct pathways involved in leukocyte activation are of relevance in the overall evaluation of the antithrombotic activity of this drug
Influences of lipid-modifying agents on hemostasis
No full textDrugs affecting lipid metabolism may influence, to a variable extent, the hemostatic system, that is, platelet activation, fibrinogen, and fibrinolysis. These effects may or may not be linked to the activity of these compounds on the lipid/lipoprotein profile. For this reason it may be important to consider the effects of hypolipidemic drugs on the different aspects of hemostasis, because this may allow a better understanding of their clinical use, as well as, eventually, a more proper selection in individual patients. Among the major lipid-lowering agents, fibric acids belong to a multifaceted series of abnormal fatty acids known to interact with a liver nuclear receptor, in turn activating fatty acid catabolism. A similar activity may be exerted by n-3 fatty acids from fish, as well as by other chemically related or unrelated compounds. Among fibric acids all but gemfibrozil can reduce fibrinogen levels; this last drug can, however, apparently activate fibrinolysis. Among the selective cholesterol-lowering medications, both resins and HMG CoA reductase inhibitors may reduce, in some patients, over prolonged periods of treatment, platelet sensitivity to major aggregants. This effect may be seen best with non-liver-selective agents (e.g., simvastatin), although recent data cast doubt on its constancy. A direct comparative evaluation of different HMG CoA reductase inhibitors on platelet aggregability has never been carried out. These last drugs may also reduce the circulating levels of the tissue factor pathway inhibitor (TFPI), transported by LDL in plasma, which is a potentially negative effect. A lipid-lowering molecule with antioxidant activity, for example, probucol, may also possibly play a role in controlling platelet activation.(ABSTRACT TRUNCATED AT 250 WORDS
Mode of action of PGI2 and of its stable derivative iloprost on platelets and leukocytes
No full textAtherosclerosis and thrombosis. Old and new drugs
No full textThanks to the increasing knowledge of the pathogenesis of atherosclerosis, much effort has been made in the last years to develop new drugs aimed at controlling risk factors correlated with the disease as well as to investigate more deeply their mechanism of action. In particular, this brief review will describe some new aspects of the mechanism of action of drugs widely used in the control of risk factors like hyperlipemia, hypertension and blood viscosity. Among drugs active on plasma lipid profile, HMG-CoA reductase inhibitor are, at present, under study for their promising activity in the modulation of the interaction between the cells of the arterial wall and circulating blood elements. Indeed, these compounds have been found to control the proliferation of smooth muscle cells and other events related to the formation of atheroma. As far as antithrombotic drugs are concerned, the efficacy of low doses of aspirin has emerged by recent clinical trials. The successful use of low doses of aspirin has been possible following the comprehension of the mechanism by which this compound inhibits TXA-dependent platelet function, thus allowing a dose-dependent dissociation of the antithrombotic activity from other undesirable effects. Also for calcium antagonist an antiatherogenic effect which deserves further investigations has been recently clarified. Indeed it has been demonstrated that calcium antagonists have a protective effect against vascular lesions because they inhibit smooth muscle cell proliferation, lipid uptake by macrophages and the production of collagen and elastin. Another class of drugs which represents a new approach in the control of some risk factors is represented by n-3 fatty acids. Besides their activity on triglycerides, these compounds exert a positive effect on hemostatic and thromboembolic event, by reducing platelet aggregation and blood viscosity. Also for those molecules which appear to exert promising antiatherosclerotic and antithrombotic action, further studies will define their exact mechanism of action.Thanks to the increasing knowledge of the pathogenesis of atherosclerosis, much effort has been made in the last years to develop new drugs aimed at controlling risk factors correlated with the disease as well as to investigate more deeply their mechanism of action. In particular, this brief review will describe some new aspects of the mechanism of action of drugs widely used in the control of risk factors like hyperlipemia, hypertension and blood viscosity. Among drugs active on plasma lipid profile, HMG-CoA reductase inhibitor are, at present, under study for their promising activity in the modulation of the interaction between the cells of the arterial wall and circulating blood elements. Indeed, these compounds have been found to control the proliferation of smooth muscle cells and other events related to the formation of atheroma. As far as antithrombotic drugs are concerned, the efficacy of low doses of aspirin has emerged by recent clinical trials. The successful use of low doses of aspirin has been possible following the comprehension of the mechanism by which this compound inhibits TXA-dependent platelet function, thus allowing a dose-dependent dissociation of the antithrombotic activity from other undesirable effects. Also for calcium antagonist an antiatherogenic effect which deserves further investigations has been recently clarified. Indeed it has been demonstrated that calcium antagonists have a protective effect against vascular lesions because they inhibit smooth muscle cell proliferation, lipid uptake by macrophages and the production of collagen and elastin. Another class of drugs which represents a new approach in the control of some risk factors is represented by n-3 fatty acids. Besides their activity on triglycerides, these compounds exert a positive effect on hemostatic and thromboembolic event, by reducing platelet aggregation and blood viscosity. Also for those molecules which appear to exert promising antiatherosclerotic and antithrombotic action, further studies will define their exact mechanism of action
GYKI 14,451, a synthetic tripeptide inhibitor of thrombin: "in vitro" and "in vivo" studies
No full textStatins in atherothrombosis
No full textClinical studies have shown that hydroxy-methyl glutaryl coenzyme A reductase inhibitors (statins) may favorably affect atherothrombosis. In addition to their potent cholesterol-lowering properties, statins reduce atheroma progression as well as the incidence of acute thrombosis-related vascular events and their dreadful clinical consequences. Available data indicate that statins exert significant antithrombotic effects in clinical practice by reducing the occurrence of vascular atherothrombotic events, with a more prominent effect in high-risk patients. The mechanisms by which statins inhibit thrombosis have been extensively investigated, and several pathways appear to be involved. In particular, statins have been proposed to reduce platelet activation and to exert favorable effects on fibrinolysis, but no clear-cut conclusion can be drawn from available studies. Moreover, statins do not consistently influence fibrinogen or factor VII levels in plasma. In contrast, in vitro and in vivo data indicate that these compounds profoundly affect thrombin generation driven by tissue factor/factor VII pathway. In vitro studies indicate that this effect is not dependent on plasma cholesterol lowering but, rather, on the inhibition of isoprenoid biosynthesis. The relative contribution of reduced levels of prenylated proteins and of cholesterol pathway to the modulation of tissue factor expression is, however, hardly to be established in clinical settings
- …
