Differential changes in potency of platelet-aggregation inhibitors after preincubation in platelet-rich plasma.
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Adenosine Diphosphate↗
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Rhodocetin, a novel platelet aggregation inhibitor from the venom of Calloselasma rhodostoma (Malayan pit viper): synergistic and noncovalent interaction between its subunits.
A novel platelet aggregation inhibitor, rhodocetin, was purified from the crude venom of Calloselasma rhodostoma. It inhibited collagen-induced platelet aggregation in a dose-dependent manner, with an IC50 of 41 nM. Rhodocetin has a heterodimeric structure with alpha and beta subunits, which could be separated on a nonreducing denaturing gel or reverse-phase HPLC column. Individually neither subunit inhibited platelet aggregation even at 2.0 microM concentration. Titration and reconstitution experiments showed that, when these subunits are mixed to give a 1:1 complex, most of its biological activity was recovered. The reconstituted complex inhibited platelet aggregation with an IC50 of 112 nM, about 3-fold less effective than the native molecule. Circular dichroism analysis revealed that the reconstituted complex had a spectrum similar to that of the native protein. By using surface plasmon resonance studies, we established that the stoichiometry of binding between the two subunits is 1:1 and the subunits interact with a Kd of 0.14 +/- 0.04 microM. The complete amino acid sequences of the alpha (15956.16 Da, 133 residues) and beta (15185.10 Da, 129 residues) subunits show a high degree of homology with each other (49%) and with the Ca2+-dependent lectin-related proteins (CLPs) (typically 29-48%) isolated from other snake venoms. Unlike the other members of the family in which the subunits are held together by an interchain disulfide bond, rhodocetin subunits are held together only through noncovalent interactions. The cysteinyl residues forming the intersubunit disulfide bridge in all other known CLPs are replaced by Ser-79 and Arg-75 in the alpha and beta subunits of rhodocetin, respectively. These studies support the noncovalent and synergistic interactions between the two subunits of rhodocetin. This is the first reported CLP dimer with such a novel heterodimeric structure.
Amino Acid Sequence↗
[Platelet aggregation inhibitors in the comprehensive treatment of bronchial asthma].
Platelet aggregation in infectious bronchial asthma patients was examined in vitro and in vivo upon administration of disaggregation agents trental, curantyl, sermion. A significant disaggregation related to trental and sermion action was recorded in vitro and in vivo as shown by hemolysate-aggregation test, ADP-induces aggregation, plasma levels of the platelet factor IV. Introduction of disaggregation agents in to combined therapy of infectious bronchial asthma contributes to more rapid arrest of bronchoconstriction in relevant patients.
Adolescent↗
PI-200 and PI-201, new platelet aggregation inhibitors produced by Streptomyces sp. A7498. Taxonomy, fermentation, isolation, physico-chemical properties, structure determination and biological properties.
Two new platelet aggregation inhibitors, PI-200 and PI-201 were isolated from the fermentation broth of Streptomyces sp. A7498. PI-200 and PI-201 inhibited ADP-induced aggregation of rabbit platelets with an IC50 of 3.8 x 10(-4) M and 7.1 x 10(-4) M, respectively.
Animals↗
A potent platelet aggregation inhibitor purified from Agkistrodon halys (mamushi) snake venom.
By means of gel filtration on Sephadex G-75, DEAE-Sephadex A-50 column chromatography and three gel filtrations on Sephadex G-75, a potent platelet aggregation inhibitor was purified from Agkistrodon halys snake venom and shown to be a single peptide chain, as judged by SDS-polyacrylamide gel electrophoresis. The purified platelet aggregation inhibitor was an acidic protein with a molecular weight of 14,000 and possessed phospholipase A2 activity. Its inhibitory activity on platelet aggregation was heat stable (at 96 degrees C, 30 min) in an acidic medium (pH 5.5), while its phospholipase A enzymatic activity was heat labile under the same conditions. Its inhibitory activity on platelet aggregation induced by thrombin, sodium arachidonate, collagen or ionophore A-23187 was non-competitive and dose-dependent with a similar ID50 (approximately 11 micrograms/ml). It exerted its inhibitory action without pre-incubation with platelet suspension, however, its inhibitory effect could be moderately increased after longer incubation (30 min).
Amino Acids↗
Ornatins: potent glycoprotein IIb-IIIa antagonists and platelet aggregation inhibitors from the leech Placobdella ornata.
The purification and characterization of six isoforms of ornatin, potent glycoprotein IIb-IIIa (GP IIb-IIIa) antagonists and platelet aggregation inhibitors are described. These isoforms were purified from whole leech homogenates of the leech Placobdella ornata, a North American leech commonly known as the turtle leech, by trichloroacetic acid precipitation, Sephadex G-50 size exclusion chromatography, GP IIb-IIIa affinity chromatography, and C18 reverse-phase HPLC. Each of the five completely sequenced isoforms, which range from 41 to 52 residues in length, contains the Arg-Gly-Asp (RGD) sequence, a common recognition sequence in adhesion proteins, as well as 6 cysteine residues; the positions of both of these features are conserved in the primary sequences. The amino acid sequences of ornatin isoforms B, C, D, and E are highly conserved, whereas ornatin A2 and A3 are less similar and lack 9 residues at the N-terminus. The ornatins are approximately 40% identical with decorsin, a GP IIb-IIIa antagonist isolated from the leech Macrobdella decora [Seymour, J. L., Henzel, W. J., Nevins, B., Stults, J. T. & Lazarus, R. A. (1990) J. Biol. Chem. 265, 10143-10147]; furthermore, the RGD sequence and 5 out of 6 cysteine residues are maintained in the same relative positions in both decorsin and ornatin. The ornatin isoforms do not exhibit significant similarity to any members of the snake-venom-derived family of GP IIb-IIIa antagonists [Dennis, M. S., Henzel, W. J., Pitti, R. M., Lipari, M. T., Napier, M. A., Deisher, T. A., Bunting, S. & Lazarus, R. A. (1990) Proc. Natl Acad. Sci. USA 87, 2471-2475] except in the RGD region of these proteins. The ornatin isoforms inhibit the binding of GP IIb-IIIa to immobilized fibrinogen with IC50 values ranging over 2.9-5.3 nM; ornatin isoforms A2, C, and E inhibit ADP-induced human platelet aggregation with IC50 values of about 130, 280, and 440 nM, respectively.
Amino Acid Sequence↗
A three-residue cyclic scaffold of non-RGD containing peptide analogues as platelet aggregation inhibitors: design, synthesis, and structure--function relationships.
Antagonists of fibrinogen at the GPIIb/IIIa receptor, which is the most abundant membrane protein on the platelet surface, are under active investigation as potential antithrombotics. The critical interaction between GPIIb/IIIa and fibrinogen can be inhibited by either linear or cyclic RGDS-containing peptides, which have been proved as lead compounds in the design of platelet aggregation inhibitors. In this study we present the design and construction of a new class of cyclic (S,S) non-RGD containing peptide sequences, using two Cys as a structural scaffold for the development of antiaggregatory agents. The (S,S)-CDC- sequence was incorporated as a conformational constraint, in molecules bearing at least one positive charge with the general formula (S,S)XCDCZ, where X = Ac-Arg, Pro-Arg, Pro-Ser-Lys, and Pro-Ser-Arg, and Z = -NH(2) and Arg-NH(2). Investigation of the structure-function relationships was performed on the basis of (a) the local conformation induced by the (S,S)-CDC motif, (b) the distance of the positively (R-C(zeta) or K-N(zeta)) and negatively (D-C(gamma)) charged centers, (c) the presence of a second positive or negative charge on the molecule, and (d) the orientation of the basic and acidic side chains defined by the pseudo dihedral angle (Pdo), which is formed by the R-C(zeta), R-C(alpha), D-C(alpha), and D-C(gamma) atoms in the case of (S,S)-RCDC and by the K-N(zeta), K-C(alpha), D-C(alpha), and D-C(gamma) atoms in the case of (S,S)-KCDC.
Amino Acid Sequence↗
Sch 38519, a novel platelet aggregation inhibitor produced by a Thermomonospora sp. Taxonomy, fermentation, isolation, physico-chemical properties, structure and biological properties.
The complex containing a new platelet aggregation inhibitor, Sch 38519, was recovered from the fermentation filtrate of Thermomonospora sp. SCC 1793. A chemically defined medium was developed which favored the production of Sch 38519. The antibiotic was isolated from the fermentation filtrate by absorption on macroreticular resin and further purified by ion exchange chromatography and reverse phase HPLC. Sch 38519 is an isochromanequinone structurally related to medermycin, lactoquinomycin and granaticin. It inhibits thrombin-induced aggregation of human platelets with an IC50 of 68 micrograms/ml. Sch 38519 is also active against Gram-positive and Gram-negative bacteria.
Actinomycetales↗
Platelet aggregation inhibitors in prevention and treatment of coronary thrombosis.
Platelet aggregation plays a key role in the development of complications of atherosclerosis. By inhibiting platelet aggregation in a pharmacological way complications such as myocardial infarction and sudden death may be prevented. This goes for primary as well as secondary prevention. The most relevant substances for this goal are aspirin, clopidogrel and the new glycoprotein IIb/IIIa inhibitors.
Coronary Thrombosis↗
Design and synthesis of piperidine-3-carboxamides as human platelet aggregation inhibitors.
A detailed structure-activity analysis was carried out using eight 1-alkyl(aralkyl)nipecotamides (type 5), 33 bis-nipecotamidoalkanes and aralkanes (type 6), and 7 N,N'-bis(nipecotoyl)-piperazines (type 7) as inhibitors of human platelet aggregation. Steric factors played an important role in determining the activity of type 5 compounds possessing an an appropriate degree of hydrophobic character. Types 6 and 7 compounds were more potent than the corresponding type 5 molecules. Hydrophobic character appeared to influence the activity of type 6 compounds. A 3-substituent on the piperidine ring was necessary for antiplatelet activity; the substituent should be preferably an amide with its C attached directly to the ring. 3,5-Disubstitution and 2-substitution led to a decline in activity. Optimal activity was attained when the two nipecotoyl ring N atoms were connected by an aralkyl group, and separated by approximately 7 A. It is suggested that van der Waals forces and pi interactions may govern the inhibitor-platelet interaction. The most potent type 6 inhibitor was alpha,alpha'-bis[3-(N-ethyl-N-butylcarbamoyl)piperidino]-p-xylene (6i). The most potent type 5 compound was 1-decyl-3-(N,N-diethylcarbamoyl)piperidine (5a). Any substitution on the piperazine ring of type 7 compounds led to a decline in activity, the most active analog being N,N'-bis(1-decylnipecotoyl)piperazine (7a). It is suggested that nipecotamides interact with anionic platelet sites located 7 A from each other and connected by a hydrophobic well.
Adult↗
Echistatin. A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus.
A 49-residue protein, echistatin, which inhibits platelet aggregation, was purified from the venom of the saw-scaled viper Echis carinatus. The purification procedure included gel filtration on Sephadex G-50, cation-exchange chromatography on Mono S, and C18 reverse-phase high pressure liquid chromatography. The purified protein was homogeneous as judged by polyacrylamide gel electrophoresis, isoelectric focusing, reverse-phase high pressure liquid chromatography, and NH2-terminal sequence analysis. Echistatin is a single-chain polypeptide with a molecular weight of 5400 and a native isoelectric point of 8.3. The most abundant amino acid, cysteine, accounts for 8 of the 49 residues in the protein. A 10-residue segment of echistatin shows 90% identity to a portion of the sequence of trigramin, a platelet aggregation inhibitor from the green tree viper Trimereserus gramineus (Huang, T.-F., Holt, J. C., Lukasiewicz, H., and Niewiarowski, S. (1987) J. Biol. Chem. 262, 16157-16163). Echistatin contains the sequence arginine-glycine-aspartic acid, which is common to proteins which bind to the glycoprotein IIb/IIIa complex. It also contains the sequence proline-arginine-asparagine-proline, which is found in the A alpha chain of human fibrinogen at position 267-270. The purified protein inhibits fibrinogen-dependent platelet aggregation initiated by ADP with an IC50 of 3 x 10(-8) M and also prevents aggregation initiated by thrombin, epinephrine, collagen, or platelet-activating factor. Reduction of echistatin abolished its inhibitory activity.
Amino Acid Sequence↗
Nucleotide sequence of a full-length cDNA encoding a common precursor of platelet aggregation inhibitor and hemorrhagic protein from Calloselasma rhodostoma venom.
The nucleotide sequence of a full-length cDNA encoding the common precursor of a platelet aggregation inhibitor, rhodostomin and a hemorrhagic protein from Calloselasma rhodostoma snake venom is presented. The 1.98-kb cDNA contains an open reading frame encoding 478 amino acid residues. The complete structure of the precursor protein encoded by the cDNA is elucidated.
Amino Acid Sequence↗
[Hamostasiological changes induced by platelet-aggregation-inhibitors, tested in children with congenital heart disease (in vitro and in vitro examinations) (author's transl)].
This report has delt with in vivo and in vitro examinations in the cases of sixteen children suffering from cyanotic congenital heart disease, and who had been placed under extended therapy with platelet-aggregation-inhibitors. The pharmacological effect of acetylsalicylic acid and dipyridamol has been discussed--as far as it is known. The discrepancy between in vivo and in vitro therapy-effect in the treatment with platelet-aggregation-inhibitors has been subjected to criticism. Consistant treatment of all children suffering from cyanotic congenital heart disease with aspirine and persantine has been advocated, however should only be carried out in collaboration with a competent hamostasiological laboratory.
Adolescent↗
Synthesis and evaluation as platelet aggregation inhibitors of 6-phenyl-2,4-substituted-3(2H)-pyridazinones and their rigid analogues benzo[h]cinnolin-3,5-diones.
A series of 5-acyl-6-phenyl-2,4-substituted-3(2H)-pyridazinones and analogous benzo[h]cinnolin-3,5-diones with reduced flexibility has been prepared and evaluated as human platelet aggregation inhibitors. The 4-methylsulfoxide 13b was the most potent compound of the series (IC50 = 1.2 microM). SAR studies have shown the primary importance of an electronegative substituent at position 4 and an acetyl group at position 5 of the pyridazine system for potent platelet aggregation inhibitory activity. Biological tests performed on a group of representative compounds showed these products have not effects on prostaglandins, thromboxanes and nitric oxide biosynthetic pathways. Some of synthesized compounds produced a moderate increase of cAMP level in platets which does not depend on the adenylate-cyclase stimulation. Tests performed on human platelet PDE III have shown that these compounds are not inhibitors of this enzyme.
Blood Platelets↗
Phospholipase A(2) with platelet aggregation inhibitor activity from Austrelaps superbus venom: protein purification and cDNA cloning.
Four phospholipase A(2) (PLA(2)) enzymes (Superbins a, b, c, and d) with varying platelet aggregation inhibitor activities have been purified from Austrelaps superbus by a combination of gel filtration, ion-exchange, and reversed-phase high-pressure liquid chromatography. Purity and homogeneity of the superbins have been confirmed by high-performance capillary zone electrophoresis and mass spectrometry. The electron spray ionization mass spectrometry data showed that their molecular masses range from 13,140 to 13,236 Da. Each of the proteins has been found to be basic and exhibit varying degrees of PLA(2) activity. They also displayed different platelet aggregation inhibitory activities. Superbin a was found to possess the most potent inhibitory activity with an IC(50) of 9.0 nM, whereas Superbin d was found to be least effective with an IC(50) of 3.0 microM. Superbins b and c were moderately effective with IC(50) values of 0.05 and 0.5 microM, respectively. The amino-terminal sequencing confirmed the identity of these superbins. cDNA cloning resulted in the identification of 17 more PLA(2) isoforms in A. superbus venom. It has also provided complete information on the precursor PLA(2). The precursor PLA(2) contained a 27-amino-acid signal peptide and 117- to 125-amino-acid PLA(2) (molecular mass ranging from 13,000 to 14,000 Da). Two of these PLA(2) enzymes resembled more closely (87%) Superbin a in structure. Two unique PLA(2) enzymes containing an extra pancreatic loop also have been identified among the isoforms.
Agkistrodon↗
Pyridazines. Part 28: 5-alkylidene-6-phenyl-3(2H)-pyridazinones, a new family of platelet aggregation inhibitors.
The synthesis and anti-platelet activity of several 5-alkylidene-6-phenyl-3(2H)-pyridazinones are described. The most active compounds are those that contain oxygenated functions (COOR, COMe) on the alkylidene fragment (6a, 6b and 6c).
Platelet Aggregation Inhibitors↗
A platelet aggregation inhibitor--ticlopidine--in diabetic nephropathy: a randomized double blind study.
A randomized double blind trial was performed to investigate the effect of the platelet aggregation inhibitor ticlopidine on the rate of decline in renal function in diabetic nephropathy. Twenty-two patients with insulin dependent diabetes complicated by nephropathy completed the trial--11 on ticlopidine, and 11 on placebo for one year. Ticlopidine effectively reduced platelet aggregation in vitro. Renal clearance of 51Cr-EDTA declined from 39 +/- 10 to 30 +/- 13 ml/min per 1.73 m2 body surface in the ticlopidine group and from 42 +/- 9 to 39 +/- 13 in the placebo group. The difference in decline between the two groups was not significant. In the ticlopidine group renal function expressed as the slope coefficient for 1/S-creatinine per month remained the same as before the trial. It is concluded that although there is much evidence to suggest a role of platelets in the development or progression of diabetic nephropathy treatment with ticlopidine could not prevent this process.
Adult↗
Bleeding in a patient receiving platelet aggregation inhibitors.
IMPLICATIONS: We describe a patient who experienced intraoperative bleeding after being treated with platelet receptor glycoprotein IIb/IIIa antagonist eptifibatide. We used Sonoclot and Thrombelastograph to monitor antiplatelet effects of eptifibatide.
Aged↗