Antiplatelet and Antileukocyte Effects of Cardiovascular,Immunomodulatory and Chemotherapeutic Drugs

Abstract

In vitro and ex vivo interactions of betaadrenoceptor blocking drugs, antihistamines and chloroquine with blood platelets and polymorphonuclear leukocytes resulted in different alterations of regulatory functions of these blood cells. Inhibition of platelet aggregation, arachidonate regulatory pathway, 5-hydroxytryptamine transportation, removal of platelet membrane receptors, inhibition of second messenger pathways at subcellular level and suppression of phagocytosis are indicative of nonreceptor rather than specific receptor interactions. Binding of drugs with biomembranes is reversible depending on the ionic charge of the molecule and hydrophobicity of the bilayer, partition coefficient, pH and pKa of the amphiphilic molecules and other physico-chemical properties of amphiphilic drugs. Alterations in the drug molecule structure alters the drug-phospholipid binding profile. Any change in the metabolism of membrane phospholipids directly or indirectly influences one or more of the important components of the phospholipid-signalling pathway. In addition to changes in phospholipase A, C and D activities, protein kinase C, calmodulin-phosphodiesterase, Ca2+,Mg2+-ATPase, Na+,K+-ATPase and other messengers were found to be changed in cells and tissue after cationic amphiphilic drug (CAD) administration. Although not much has been understood of the mechanism by which some CAD affect immune functions, there are good reasons to suggest that these effects might occur. CADs share sufficient similarities in their structure even though they come from diverse pharmacological classes. CADs affect ion transport, immune functions, tumour growth, serotonin metabolism and several other functions in the body. Extensive therapeutic use and associated side effects have generated a great deal of interest in understanding the nonreceptor interactions with CADs.

Comparative investigations of the influence of H1-antihistamines on the generation of reactive oxygen species by phagocytes

“…Inhibition of CL in neutrophils due to the oxidative burst with DIT and LOR appeared both at extra-and intracellular level indicating a complex effect of H 1 -antihistamines [7]. Since structure-activity relationships play an important role in the inhibition of cell function by H 1 -antihistamines [8], the results obtained in this study require further detailed analysis at the molecular level.…”

Further studies on the mechanism of antiphagocyte-antioxidative effect of H1-antihistamines

“…However Lor was equipotent on both extra and intracellular ROM generation with 60 % inhibition of CL. At 100 µmol/L, Dit and Lor completely inhibited extra-and intracellular part of CL, indicating that Dit and Lor may not only act on extracellular generated ROM but also interfere with intracellular metabolic pathways regulated by proteinkinase C after activation of neutrophils with PMA [6].…”

Minimizing Ischemia Reperfusion Injury in Xenotransplantation

“…During IRI, platelet activation occurs through a multitude of receptors including platelet collagen receptor, adenosine diphosphate receptor, glycoprotein-IIb/IIIa (GPIIb/IIIa), Pselectin, and G-proteins. Additionally, complement byproductmediated, histamine-mediated, and thromboxane-mediated pathways exist which lead to platelet activation (194)(195)(196)(197). Activated platelets release ROS, serotonin, and platelet activating factors, as well as interact with leukocytes and endothelial cells, propagating sterile inflammation, coagulation, and IRI (194).…”