TY - JOUR
T1 - Investigational new drugs among glycoprotein IIb/IIIa-receptor antagonists
AU - Kondo, K.
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2000
Y1 - 2000
N2 - Glycoprotein IIb/IIIa receptors play an important role in platelet aggregation by binding fibrinogen. Drugs that antagonize this binding have been developed for the treatment of thrombotic diseases including acute coronary syndrome. These drugs are of four main types: [1] monoclonal antibody, [2] synthetized peptide, [3] non-peptide, and [4] oral antagonist. Since these drugs inhibit the final step in platelet aggregation, i.e., binding of fibrinogen to the platelet membrane, they were expected to 1) have high specificity for inhibiting platelet aggregation, 2) inhibit any kind of aggregation regardless of stimulation, 3) have high potency in aggregation suppression. As a result of large clinical trials, however, monoclonal antibody alone was revealed to be effective, but non-peptide and oral antagonists were ineffective. The possible mechanisms that lead to such inefficiency are: 1) difference in binding duration to platelets, 2) concomitant suppression of other adhesion molecules beside IIb/IIIa, 3) difference in binding site in the receptor and presence of a partial agonist effect, 4) aggregation promotion or induction of apoptosis via caspase-3 activation, 5) modified aggregation by gene polymorphism. New findings on platelet physiology through studying ways to overcome the above problems will lead to the development of new drugs and treatment.
AB - Glycoprotein IIb/IIIa receptors play an important role in platelet aggregation by binding fibrinogen. Drugs that antagonize this binding have been developed for the treatment of thrombotic diseases including acute coronary syndrome. These drugs are of four main types: [1] monoclonal antibody, [2] synthetized peptide, [3] non-peptide, and [4] oral antagonist. Since these drugs inhibit the final step in platelet aggregation, i.e., binding of fibrinogen to the platelet membrane, they were expected to 1) have high specificity for inhibiting platelet aggregation, 2) inhibit any kind of aggregation regardless of stimulation, 3) have high potency in aggregation suppression. As a result of large clinical trials, however, monoclonal antibody alone was revealed to be effective, but non-peptide and oral antagonists were ineffective. The possible mechanisms that lead to such inefficiency are: 1) difference in binding duration to platelets, 2) concomitant suppression of other adhesion molecules beside IIb/IIIa, 3) difference in binding site in the receptor and presence of a partial agonist effect, 4) aggregation promotion or induction of apoptosis via caspase-3 activation, 5) modified aggregation by gene polymorphism. New findings on platelet physiology through studying ways to overcome the above problems will lead to the development of new drugs and treatment.
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U2 - 10.1254/fpj.116.263
DO - 10.1254/fpj.116.263
M3 - Review article
C2 - 11215375
AN - SCOPUS:0033768004
SN - 0015-5691
VL - 116
SP - 263
EP - 268
JO - Folia Pharmacologica Japonica
JF - Folia Pharmacologica Japonica
IS - 5
ER -