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PubMed1991

Platelet aggregation inhibitors from the seeds of Swietenia mahagoni: inhibition of in vitro and in vivo platelet-activating factor-induced effects of tetranortriterpenoids related to swietenine and swietenolide.

The ether extract from the seeds of Swietenia mahagoni Jacq. (Meliaceae) was found to inhibit platelet-activating factor (PAF)-induced platelet aggregation. Systematic separation of the extract afforded twenty eight tetranortriterpenoids related to swietenine and swietenolide. Among them, several new compounds, named swietemahonin A, D, E, and G and 3-O-acetylswietenolide and 6-O-acetylswietenolide, showed a strong inhibition against PAF-induced aggregation in vitro and in vivo assays.

Animals↗
PubMed2005

C-phycocyanin, a very potent and novel platelet aggregation inhibitor from Spirulina platensis.

The aim of this study was to systematically examine the inhibitory mechanisms of C-phycocyanin (C-PC), one of the major phycobiliproteins of Spirulina platensis (a blue-green alga), in platelet activation. In this study, C-PC concentration-dependently (0.5-10 nM) inhibited platelet aggregation stimulated by agonists. C-PC (4 and 8 nM) inhibited intracellular Ca2+ mobilization and thromboxane A2 formation but not phosphoinositide breakdown stimulated by collagen (1 microg/mL) in human platelets. In addition, C-PC (4 and 8 nM) markedly increased levels of cyclic GMP and cyclic GMP-induced vasodilator-stimulated phosphoprotein (VASP) Ser(157) phosphorylation. Rapid phosphorylation of a platelet protein of Mw 47,000 (P47), a marker of protein kinase C activation, was triggered by phorbol-12,13-dibutyrate (150 nM). This phosphorylation was markedly inhibited by C-PC (4 and 8 nM). In addition, C-PC (4 and 8 nM) markedly reduced the electron spin resonance (ESR) signal intensity of hydroxyl radicals in collagen (1 microg/mL)-activated platelets. The present study reports on a novel and very potent (in nanomolar concentrations) antiplatelet agent, C-PC, which is involved in the following inhibitory pathways: (1) C-phycocyanin increases cyclic GMP/VASP Ser157 phosphorylation and subsequently inhibits protein kinase C activity, resulting in inhibition of both P47 phosphorylation and intracellular Ca2+ mobilization, and (2) C-PC may inhibit free radicals (such as hydroxyl radicals) released from activated platelets, which ultimately inhibits platelet aggregation. These results strongly indicate that C-PC appears to represent a novel and potential antiplatelet agent for treatment of arterial thromboembolism.

Bacterial Proteins↗
PubMedDate not supplied

Treatment program and comparison between anticoagulants and platelet aggregation inhibitors after transient ischemic attack.

Transient cerebral ischemic attacks (TIA) are an important warning symptom of threatening stroke from cerebral infarction (CI). A local treatment program aimed at identifying as many individuals with TIA as possible and treating them in a uniform manner is desirable. Platelet aggregation inhibitors with a combination of acetylsalicylic acid and dipyridamole (ASA + DP) has been compared with anticoagulants (AC). The average length of treatment was 24 months and all patients received the treatment for at least 6 months. Sixty patients received AC and 65 ASA + DP. Four patients in the ASA + DP group (6 percent) and 2 in the AC group (3.3 percent) sustained cerebral infarction. These figures are essentially lower than the expected incidence of 15--20 percent.

Aged↗
PubMed1998

[Intracerebral hemorrhage and treatment with platelet aggregation inhibitors: study of 21 cases].

INTRODUCTION: The place of platelet antiaggregants in the aetiology of intracerebral hemorrhage (IH) has not been extensively studied. OBJECTIVE: To analyze the characteristics of IH in patients treated with platelet antiaggregants and the possible clinical and prognostic differences from other primary IH. PATIENTS AND METHODS: A retrospective study of patients admitted to hospital with primary IH from 1985 to 1997. The cases were IH patients while being treated with platelet antiaggregants. For each case we selected two controls with IH and similar age and IH risk factors. The following data was analyzed: start of clinical condition; type, dose, indication and duration of treatment with antiaggregants; mortality, localization, volume and extension of IH to the ventricles. The last four variables were compared with the control group using the ji squared test (chi 2) and the t student test. RESULTS: 21one patients had a primary IH while being treated with antiaggregants: 20 with salicylates (17 aspirin and 3 riflusal) and one with ticlopidine. The dose of aspirin was 500 mg or less in 90% of the cases. In the group treated with salicylates, this was given for more than 20 months in 90% of the cases. Initially there was no clinical progression in any case. No significant differences were observed between the variable compared, although there was a tendency to greater volume, extension to the ventricles and mortality in the group treated with antiaggregants. CONCLUSIONS: More studies with larger numbers of patients are necessary to be able to confirm the tendencies observed.

Aged↗
PubMedDate not supplied

Platelet aggregation inhibitors from Philippine marine invertebrate samples screened in a new microplate assay.

A new microplate assay for Ca(2+)-induced platelet aggregation as detected by Giemsa dye was used to screen marine invertebrate samples from the Philippines for inhibitors of human platelet aggregation. Out of 261 crude methanol extracts of marine sponges and tunicates, 25 inhibited aggregation at 2 mg/ml. Inhibition of agonist-induced aggregation in an aggregometer was used to confirm results of the microplate assay and to determine the specific mode of inhibition of 2 samples. The marine sponge Xestospongia sp. yielded a xestospongin/araguspongine-type molecule that inhibited collagen-induced aggregation by 87% at 2 micro g/ml, and epinephrine-induced aggregation by 78% at 20 micro g/ml, while the marine sponge Aplysina sp. yielded 5,6-dibromotryptamine, which inhibited epinephrine-induced aggregation by 51% at 20 micro g/ml. In this study we have found that the microplate assay is a simple, inexpensive, yet useful preliminary tool to qualitatively screen a large number of marine samples for antiplatelet aggregation activity.

Adenosine Diphosphate↗
PubMed2000

[Contribution of platelet aggregation inhibitors in the prevention of complications of atherothrombosis].

RECOGNIZED EFFICACY: Platelet antiaggregats have been used with success for more than twenty years in industrialized countries, participating in reducing the number of complications of atherothrombosis. New compounds have appeared on the market over the last 3 years. CLOPIDOGREL: Clopidogrel is a thienopyridine similar to ticlopidine but with less toxicity, particularly hematological toxicity. Compared with aspirin for secondary prevention of atherothrombotic events in high risk patients, clopidogrel provides a significant 8.7% (p < 0.043) reduction in the relative risk of severe complications: myocardial infarction, ischemic stroke, death due to vascular cause. The most remarkable benefit is obtained in patients with atheromatous arteriopathy of the lower limbs: 23.8% reduction in relative risk. STENT AFTER ANGIOPLASTY: A combination regimen using aspirin and ticlopidine the month following stent implantation has allowed a very significant reduction in acute (within 24 hours) and subacute (within 30 days) coronary occlusions. Currently the aspirin-clopidogrel combination tends to be used instead of the aspirin-ticlopidine combination due to the lower hematological risk for a similar effect. GPIIBIIIA INHIBITORS: Injectable GPIIbIIIa inhibitors have changed management of the acute phase of coronary artery disease. Among these compounds, abciximab has the most extensively proven efficacy. It is mainly indicated for severe forms of coronary angioplasty with or without stent insertion. It provides a significant short-term and long-term reduction in severe events (myocardial infarction + death + revascularization). Oral formulations of GPIIbIIIa can be used to maintain and/or amplify the benefits obtained with injectable formulations. They are not currently available on the market. ASPIRIN: Due to its very low cost and low side-effect profile, aspirin plays an essential role in most indications where it remains the most widely used first-line platelet anti aggregate.

Aspirin↗
PubMed1992

Platelet aggregation inhibitors from Populus sieboldii Miquel.

The water extract of Populus sieboldii Miquel (Salicaceae) inhibited arachidonic acid-induced platelet aggregation. Pyrocatechol and salicyl alcohol were isolated as active constituents. Pyrocatechol showed an inhibitory effect on platelet aggregation induced by arachidonic acid with IC100 value of 4 microM, which was 25 times more potent than aspirin.

Drugs, Chinese Herbal↗
PubMed1997

Pyridazines. XIII. Synthesis of 6-aryl-5-oxygenated substituted-3(2H)-pyridazinones and evaluation as platelet aggregation inhibitors.

Several 6-aryl-5-oxygenated substituted pyridazinones have been synthesized and evaluated in vitro for inhibition of platelet aggregation induced by adenosine 5'-diphosphate (ADP), thrombin and collagen. All the tested compounds (except 8 and 9) inhibited platelet aggregation in a dose-dependent manner. The IC50 of the most active substance, compound 2b, was around 60 microM against ADP and collagen as inducers. The inhibition of platelet aggregation caused by test compounds was dependent on the level of oxidation of the function at the 5-position, with the order of IC50 values being R-OH (2a, b, 5) < R-CHO (6, 7) < < R-COOH (8, 9). None of the tested compounds increased the intracellular levels of cAMP, indicating a lack of inhibitory activity on cAMP phosphodiesterase (PDE III) in intact cells. These results suggest that the group present at the 5 position of 6-aryl-5-substituted pyridazinones determines the platelet aggregation-inhibitory activity, and that a mechanism other than PDE inhibition is responsible for this effect.

Adenosine Diphosphate↗
PubMed1996

Total Synthesis of Natural PI-091, a New Platelet Aggregation Inhibitor of Microbial Origin.

The total synthesis of a new platelet aggregation-inhibiting gamma-lactam PI-091 (1) gave a 1:1 diastereomeric mixture at the gamma-ketal carbon. The high-yielding aldol reaction of an appropriately protected 1,3,4-trihydroxy-4-methyldecan-2-one 42, prepared from D-glucose, with the kinetically generated enolate of 3-methyl-2-butanone provided 43. The resulting diastereomeric mixture of the aldol adduct 43 was converted to a 2,4-alkylated furan 45 via an intramolecular ketalization followed by dehydration. The addition of a singlet oxygen to the alpha-trimethylsilylated furan 48derived from 45 under photochemical conditions efficiently provided an alpha,gamma-dialkylated gamma-hydroxy gamma-lactone 47. The transformation of methyl ketal 52 prepared from 47 into gamma-hydroxy gamma-lactam 53 was achieved by exposure to liquid ammonia in MeOH. The total synthesis of 1 was achieved from 52 through the Dess-Martin periodinane oxidation of the secondary hydroxy group in the side chain. The present total synthesis revealed that the stereogenic carbon center in the side chain in natural 1 is S.

Journal Article↗
PubMed1997

Oral platelet aggregation inhibitor Ro 48-3657: determination of the active metabolite and its prodrug in plasma and urine by high-performance liquid chromatography using automated column switching.

A sensitive and highly automated high-performance liquid chromatography (HPLC) column-switching method has been developed for the simultaneous determination of the active metabolite III and its prodrug II, both derivatives of the oral platelet inhibitor Ro 48-3657 (I), in plasma and urine of man and dog. Plasma samples were deproteinated with perchloric acid (0.5 M), while urine samples could be processed directly after dilution with phosphate buffer. The prepared samples were injected onto a pre-column of a HPLC column switching system. Polar plasma or urine components were removed by flushing the precolumn with phosphate buffer (0.1 M, pH 3.5). Retained compounds (including II and III) were backflushed onto the analytical column, separated by gradient elution and detected by means of UV detection at 240 nm. The limit of quantification for both compounds was 1 ng/ml (500 microl of plasma) and 25 ng/ml (50 microl of urine) for plasma and urine, respectively. The practicability of the new method was demonstrated by the analysis of about 6000 plasma and 1300 urine samples from various toxicokinetic studies in dogs and phase 1 studies in man.

Animals↗
PubMed1992

Ticlopidine: a new platelet aggregation inhibitor.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of ticlopidine are reviewed. Ticlopidine appears to inhibit platelet aggregation induced by adenosine diphosphate. Ticlopidine hydrochloride is rapidly absorbed after oral administration, and maximum antiplatelet effects occur one to three hours after the dose. In multicenter, randomized, double-blind trials, ticlopidine was more effective than aspirin or placebo in preventing stroke, myocardial infarction, or death caused by vascular events. Ticlopidine was more effective than aspirin in preventing recurrent transient ischemic attacks after six months of therapy. Ticlopidine has also been used to prevent occlusion and improve patency of aortocoronary bypass grafts, to prevent ischemic ulcers in patients with chronic arterial occlusive disease, and to slow the progression of diabetic microangiopathy. The most serious adverse effect, neutropenia, occurred in about 1% of patients. The most frequently reported adverse effects are diarrhea, nausea, vomiting, and abdominal cramps. Ticlopidine is indicated for reducing the risk of thrombotic stroke in patients who have experienced a minor stroke, transient ischemic attack, or completed thrombotic stroke. The recommended dosage is 500 mg/day in two divided doses taken with food. Ticlopidine is an alternative agent for the primary and secondary prevention of stroke. Because of the risk of neutropenia and agranulocytosis and the high cost of therapy, ticlopidine should be reserved for patients who are intolerant of or lack benefit from aspirin.

Animals↗
PubMed1989

Trifenagrel: a chemically novel platelet aggregation inhibitor.

Trifenagrel.HCl (trifenagrel) (2-[2-(2-dimethylaminoethoxy) phenyl]-4,5-diphenylimidazole monohydrochloride) is a chemically novel, potent inhibitor (IC50 = 0.3-3.0 microM) of arachidonate (AA)- and collagen-induced aggregation of platelets from several animal species and humans. When trifenagrel was administered p.o. to guinea pigs, there was a sustained (greater than 3 hr) inhibition of AA- and collagen-induced platelet aggregation ex vivo (1 hr ED50 = 1.4 and 9.4 mg/kg, respectively). In humans, trifenagrel inhibited the second phase of ADP-induced aggregation ex vivo up to 6 hr after a single dose of 100 to 300 mg p.o. The mechanism of action of trifenagrel appears to be a reversible inhibition of platelet AA cyclooxygenase. Doses of trifenagrel up to 100 mg/kg p.o. in rats and guinea pigs inhibited gastric mucosal AA cyclooxygenase but did not produce the gastric damage associated with the administration of other cyclooxygenase inhibitors such as aspirin and indomethacin. To our knowledge this is the first report of a compound which inhibits gastric mucosal prostaglandin levels but causes little or no gastrointestinal (g.i.) irritation in rodents. Although trifenagrel caused g.i. irritation in dogs and humans, the nature of the damage suggests that the compound may have acted as a local irritant in these species. Furthermore, compared to aspirin trifenagrel produced significantly less gastric irritation and fecal blood loss in humans. The physiochemical properties of trifenagrel may be important for the lack of g.i. irritation in rodents and for the diminished damage relative to aspirin in humans.

Animals↗
PubMed2002

Platelet aggregation inhibitors for use in peripheral vascular interventions: what can we learn from the experience in the coronary arteries?

During the last decade, an enormous amount of information has been gathered about the function of the platelet and its impact on percutaneous vascular interventions. With the discovery of the GP IIb/IIIa receptor, which is responsible for platelet aggregation, new drug antagonists have been developed to prevent platelet aggregation that may result in arterial thrombosis or platelet microembolization. These drugs include the three GP IIb/IIIa receptor antagonists approved by the Food and Drug Administration: abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). These drugs have been used in several large studies to improve the outcome of coronary interventions and in conjunction with plasminogen activators to accelerate thrombolysis. In addition, because no oral GP IIb/IIIa inhibitor exists, other oral regimens have been developed with use of the thienopyridines, ticlopidine (Ticlid) and clopidogrel (Plavix), in combination with aspirin to prevent platelet aggregation and thrombosis. Because the majority of investigations have been performed in patients undergoing coronary interventions, knowledge of these data is necessary to attempt to translate the use of these antiplatelet drugs to peripheral vascular interventions. The goal of this article is to review the use of these agents in the percutaneous treatment of coronary artery disease and give insight to their potential utility in noncoronary interventions.

Coronary Vessels↗