Inhibition Of Blood Platelet Aggregation Research Articles

Genuine and Sequestered Natural Products from the Genus Orobanche (Orobanchaceae, Lamiales).

The present review gives an overview about natural products from the holoparasitic genus Orobanche (Orobanchaceae). We cover both genuine natural products as well as compounds sequestered by Orobanche taxa from their host plants. However, the distinction between these two categories is not always easy. In cases where the respective authors had not indicated the opposite, all compounds detected in Orobanche taxa were regarded as genuine Orobanche natural products. From the about 200 species of Orobanche s.l. (i.e., including Phelipanche) known worldwide, only 26 species have so far been investigated phytochemically (22 Orobanche and four Phelipanche species), from 17 Orobanche and three Phelipanche species defined natural products (and not only natural product classes) have been reported. For two species of Orobanche and one of Phelipanche dedicated studies have been performed to analyze the phenomenon of natural product sequestration by parasitic plants from their host plants. In total, 70 presumably genuine natural products and 19 sequestered natural products have been described from Orobanche s.l.; these form the basis of 140 chemosystematic records (natural product reports per taxon). Bioactivities described for Orobanche s.l. extracts and natural products isolated from Orobanche species include in addition to antioxidative and anti-inflammatory effects, e.g., analgesic, antifungal and antibacterial activities, inhibition of amyloid β aggregation, memory enhancing effects as well as anti-hypertensive effects, inhibition of blood platelet aggregation, and diuretic effects. Moreover, muscle relaxant and anti-spasmodic effects as well as anti-photoaging effects have been described.

Mortality in Individuals Treated With Glucose-Lowering Agents: A Large, Controlled Cohort Study.

Several observational studies and meta-analyses have reported increased mortality of patients taking sulfonylurea and insulin. The impact of patient profiles and concomitant therapies often remains unclear. The objective of the study was to quantify survival of patients after starting glucose-lowering agents (GLAs) and compare it with control subjects, matched for risk profiles and concomitant therapies. This was a retrospective, controlled, cohort study. The study is based on health expenditure records of the largest Belgian health mutual insurer, covering more than 4.4 million people. A total of 115 896 patients starting metformin, sulfonylurea, or insulin (alone or in combination) between January 2003 and December 2007 participated in the study. Control subjects without GLA therapy were matched for age, gender, history of cardiovascular events, and therapy with antihypertensives, statins and blood platelet aggregation inhibitors. There were no interventions. Five-year survival after the start of GLA was measured. Profiles of patients using different GLAs varied, with patients on sulfonylurea being oldest and patients on insulin having more frequently a history of cardiovascular disease. Excess mortality differed across GLA therapies compared with matched controls without GLAs, even after adjusting for observable characteristics. Only metformin monotherapy was not associated with an increased 5-year mortality compared with matched controls, whereas individuals on a combination of sulfonylurea and insulin had the highest mortality risks. Age and concomitant use of statins strongly affect survival. Differences exist in 5-year survival of patients on GLA, at least partly driven by the risk profile of the individuals themselves. Metformin use was associated with lowest 5-year mortality risk and statins dramatically lowered 5-year mortality throughout all cohorts.

Comparative effects of Hirudo, Frankincense and Motherwort on the inhibition of blood platelet aggregation and P-selectin secretion

Blood harmonizing Leonurus japonicus Houtt. (Motherwort), blood activating Boswellia carterii Birdw. (Frankincense), and blood breaking and stasis expelling Whitmania pigra Whitman (Hirudo), which all belong to traditional medicines of activating blood and resolving stasis (ABARS), have been used in the treatment of tumors and tumor metastasis for years. However, their eventual efficacies have never been clearly investigated. This paper described and compared the effects of the water extracts of Hirudo, Frankincenseand Motherwort on human platelet functions including platelet aggregation and protein secretion. It has been demonstrated that Hirudo for “break blood and expel stasis”extremely suppressed platelet activation and adhesion, but Motherwort for “Harmonize the Blood” did not exhibit the same effects on CD41 and CD62p levels, implying that the platelet inhibiting potency of the ABARS drug for “break blood and expel stasis” was indeed stronger than that for “Harmonize the Blood”. The results promoted us to choose a different drug on the basis of the P-selectin level of patients, which will assist clinicians to select drugs rationally. Key words: Hirudo, Motherwort, Frankincense, platelet aggregation, CD41, CD62p.

ChemInform Abstract: New 5H-Pyridazino(4,5-b)indole Derivatives. Synthesis and Studies as Inhibitors of Blood Platelet Aggregation and Inotropics.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

New Purines with Antiplatelet Activity

Four purine-2,6-diamines, 4a, b, 5a, b, nineteen N-(purin-2-yl)benzenecarboxamides 6a-q, 7b, and one N-(purin-2-yl)-2-furanecarboxamide 8 were prepared for the first time and tested for their inhibition of blood platelet aggregation. Six compounds, 6a, b, h, m, o, p, inhibited the platelet aggregation induced by collagen with IC(50 )values between 3 and 10 micromol/L in the Born test. ADP, PAF, and adrenaline were used as specific aggregation inducers to examine the mechanism of the anti-aggregating activity. An astonishing pattern of activities in the nanomolar, with 6m, 7b, 8 and even subnanomolar range, with 6b, was observed. Compound 6b inhibited the platelet aggregation induced by ADP with an IC(50) = 0.45 nM (6m: 3.5 nM; 8: 30 nM). Compound 7b showed an antagonism against the inducer adrenaline with an IC(50) = 1.8 nM (6o: 20 nM; 8: 30 nM). The strongest antagonism against PAF was observed with 7b showing an IC(50) = 1 nM (6b: 35 nM; 8: 74 nM).

The Ideal Synthetic Method Aimed at the Leads for an a2-Blocker, an Inhibitor of Blood Platelet Aggregation, and an Anti-osteoporosis Agent

According to the definition of the ideal synthetic method, an example aimed at the leads for an α 2 -blocker, an inhibitor of platelet aggregation, and an anti-osteoporosis agent is established starting from tryptamine. The originality rate, the intellectual property, and the application potential factors of the method are 71, 54, and 100, respectively. The method employs only conventional reagents and reaction conditions without using any protecting groups.

Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides

Using N -[4-(hexyloxy)phenyl]piperidine-3-carboxamide ( 17c ) as a structural lead, a number of isomers, derivatives, and ring-opened analogs were synthesized and tested for their ability to block the in vitro aggregation of human platelets induced by adenosine 5′-diphosphate (ADP). For the most active compounds, inhibition of the platelet aggregation triggered by arachidonic acid (AA) and ADP-induced intraplatelet calcium mobilization was also demonstrated. Based on quantitative structure–activity relationships (QSARs), we proved the impact of hydrophobicity on antiplatelet activity by a nonlinear (parabolic or bilinear) relationship between pIC 50 and lipophilicity, as assessed by RP-HPLC capacity factors and Clog P (i.e. calculated 1-octanol–water partition coefficients). This study highlighted the following additional SARs: quasi-isolipophilic isomers of 17c (isonipecotanilides and pipecolinanilides) and ring-opened analogs (e.g. anilide of β-alanine) exhibited lower antiplatelet activity; methylation of the piperidine nitrogen of 17c has no effect, whereas alkylation with an n -propyl group decreases the activity by a factor of approximately 2, most likely due to a conformation-dependent decrease in lipophilicity.

Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides.

Using N-[4-(hexyloxy)phenyl]piperidine-3-carboxamide (17c) as a structural lead, a number of isomers, derivatives, and ring-opened analogs were synthesized and tested for their ability to block the in vitro aggregation of human platelets induced by adenosine 5'-diphosphate (ADP). For the most active compounds, inhibition of the platelet aggregation triggered by arachidonic acid (AA) and ADP-induced intraplatelet calcium mobilization was also demonstrated. Based on quantitative structure-activity relationships (QSARs), we proved the impact of hydrophobicity on antiplatelet activity by a nonlinear (parabolic or bilinear) relationship between pIC(50) and lipophilicity, as assessed by RP-HPLC capacity factors and ClogP (i.e. calculated 1-octanol-water partition coefficients). This study highlighted the following additional SARs: quasi-isolipophilic isomers of 17c (isonipecotanilides and pipecolinanilides) and ring-opened analogs (e.g. anilide of beta-alanine) exhibited lower antiplatelet activity; methylation of the piperidine nitrogen of 17c has no effect, whereas alkylation with an n-propyl group decreases the activity by a factor of approximately 2, most likely due to a conformation-dependent decrease in lipophilicity.

Protein disulfide isomerase and sulfhydryl-dependent pathways in platelet activation.

The inhibition of blood platelet aggregation and secretion was studied using covalent thiol reagents, maleimides, or mercuribenzoates, or using inhibitors of protein disulfide isomerase (PDI), bacitracin or antibodies to PDI. As expected, both types of inhibitors were effective against stimulation by normal physiologic stimuli. On the other hand, when stimulation was initiated with the peptide LSARLAF, that specifically activates the integrin alphaIIbbeta3 (the fibrinogen receptor), the PDI inhibitors were without effect. LSARLAF-induced aggregation was, however, inhibited by the sulfhydryl reagents. To further investigate the role of sulfhydryl-containing proteins and alphaIIbbeta3, platelets were labeled with membrane-impermeant sulfhydryl reagents. Nine bands were found labeled on gel electrophoresis. Two of the labeled bands were identified as alphaIIb and beta3. The conclusions are that while PDI is required for platelet aggregation and secretion, an additional sulfhydryl-dependent step or protein is also required. This latter reaction occurs at the level of alphaIIbbeta3. In distinction to most literature reports, at least a subpopulation of alphaIIbbeta3 contains free sulfhydryl groups, consistent with the possibility that it is a substrate for PDI or part of the sulfhydryl-dependent response.

Effect of raw versus boiled aqueous extract of garlic and onion on platelet aggregation

The effects of aqueous extracts of raw and boiled garlic and onions were studied in vitro on the collagen-induced platelet aggregation using rabbit and human platelet-rich plasma. A dose dependant inhibition of rabbit platelet aggregation was observed with garlic. Onion also showed dose-dependent inhibitory effects on the collagen-induced platelet aggregation but this inhibition was of a lesser magnitude compared to garlic when related to dose. The concentration required for 50% inhibition of the platelet aggregation for garlic was calculated to be approximately 6.6 mg ml−1plasma, whereas the concentration for onion was 90 mg ml−1plasma. Boiled garlic and onion extracts showed a reduced inhibitory effect on platelet aggregation. Garlic but not onion significantly inhibits human platelet aggregation in a dose-dependent fashion. The potency of garlic in inhibiting the collagen-induced platelet aggregation is approximately similar to that of rabbit platelets (8.8 mg ml−1produced 50% inhibition of platelet aggregation). The results of this study show that garlic is about 13 times more potent than onion in inhibiting platelet aggregation and suggest that garlic and onion could be more potent inhibitors of blood platelet aggregation if consumed in raw than in cooked or boiled form.

Strength of Onion-induced Human Antiplatelet Activity is Associated with Plant Development

Much of the medicinal activity induced by vegetable Alliums is derived from a suite of organosulfur compounds formed following hydrolysis of the S-alk(en)yl-l-cysteine sulfoxides (ACSOs). One of these medicinal activities is the inhibition of blood platelet aggregation; a factor that may influence cardiovascular health. Concentrations of ACSOs in the onion bulb ebb-and-fl ow during the vegetative phase, suggesting they act as storage forms of sulfur. To examine whether medicinal efficacy paralleled these changes, I tracked bulb, leaf, and inflorescence-induced antiplatelet activity during reproductive growth of four onion genotypes. Levels of bulb-induced antiplatelet activity dropped sharply for the first 8 weeks following the end of vernalization. Leaf-induced antiplatelet activity also dropped rapidly for the first 4 weeks, but rose precipitously by week 6. The rapid loss in leaf-induced antiplatelet efficacy between week 6 and week 8 suggests a recycling of these organosulfur compounds from the leaves to the developing flower stalk and inflorescence, which would be needed for protection against insect pests. Overall, I found a dramatic decrease in bulb-induced antiplatelet activity concomitant with an initially similar decrease and subsequent increase in leaf-induced antiplatelet activity. These were complemented by the presence of high levels of antiplatelet activity induced by the inflorescence. These data indicate development mediates the medicinal activity induced by onion plants. Furthermore, the flux of antiplatelet activity induced by various plant organs suggests that this medicinal trait is serendipitously associated with the storage and cycling of sulfur in onion plants; perhaps in response to insect predation.

ChemInform Abstract: Synthesis of g‐Annelated Phthalazines as Potential Blood Platelet Aggregation Inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

In-vitro and ex-vivo inhibition of blood platelet aggregation by naftazone.

Because of the considerable interest in the role of platelets and antiplatelet therapy in cardiovascular disease, including the aggregation of platelets to each other during arterial thrombosis and atherogenesis, we have studied the effect of naftazone (Etioven), an original vasculotropic drug on platelet aggregation. Rat and human platelets were prepared and incubated in-vitro with different concentrations of naftazone. We found that naftazone inhibited both platelet secretion and aggregation in platelet-rich plasma (PRP) and washed platelets after stimulation with thrombin or ADP. Rats were also treated intraperitoneally for five days with various naftazone doses (0.125-10 mg kg-1) and ex-vivo platelet aggregation compared, at various times after the last injection, with that of control animals. Inhibition by naftazone was dose-dependent in both PRP and isolated platelets. The inhibition was transient, a maximum value (approximately 50%) being obtained about 3-6 h after the last injection, with a return to near-control values after 24 h. Naftazone also facilitated platelet deaggregation after in-vitro stimulation with thrombin or ADP. In another series of experiments, rats were treated intraperitoneally for five days with 10 mg kg-1 of aspirin, ticlopidine, dipyridamole or naftazone. Platelets were prepared and tested for aggregation 90 min after the last injection. Thrombin-induced aggregation in PRP and washed platelets was significantly reduced after in-vivo treatment with ticlopidine and naftazone. Except for dipyridamole, all the drugs inhibited ex-vivo ADP-induced aggregation in PRP. In isolated platelet preparation, only naftazone induced a significant inhibition of ADP- or thrombin-stimulated aggregation. We conclude that naftazone inhibits platelet aggregation in-vitro and ex-vivo.

ChemInform Abstract: New Indole and Pyridazinoindole Analogues ‐ Synthesis and Study as Inhibitors of Phosphodiesterases and as Inhibitors of Blood Platelet Aggregation.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A possible mechanism for the inhibition of blood platelet aggregation by pyridoxal-5'-phosphate

A possible mechanism for the inhibition of blood platelet aggregation by pyridoxal-5'-phosphate

5362879 4?5-diphenyloxazole derivatives as inhibitors of blood platelet aggregation

5362879 4?5-diphenyloxazole derivatives as inhibitors of blood platelet aggregation

New indole and pyridazinoindole analogs--synthesis and study as inhibitors of phosphodiesterases and as inhibitors of blood platelet aggregation.

This paper presents the synthesis of new indole, pyridazino[4,5-b]-indole, and pyridazino[4,5-a]indole analogs as well as a study of their "in vitro" activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro-aggregants, is also included. The selected compounds 8-benzyloxy-3,4-dihydro-1-(3,4,5-trimethoxy)benzylideneaminopyridazin o[4,5- b]indole 14g, and 8-benzyloxy-4-[(3,4-dimethyl)pyrazolyl]pyridazino[4,5-b]indo le 20 present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8-benzyloxy-3,4-dihydro-1-[4-(methyl)piperazino]acetamidopyrida zino[4,5- b]indol-4-one 16c and 8-benzyloxy-3,4-dihydro-1-[4-(2- methoxyphenyl)piperazino]acetamidopyridazino[4,5-b]indol-4-o ne 16f stood out as inhibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade.

ChemInform Abstract: Polycyclic N‐Heterocyclic Compounds. Part 41. Synthesis of 4‐ Substituted 6,7‐Dihydro‐5H‐pyrimido(5,4‐d)(1)benzazepines, 1,2,5,6‐ Tetrahydro‐4H‐imidazo(1′,2′:1,6)pyrimido(5,4‐d)(1)benzazepines and Their Related Compounds as a Series of Potential Blood Platelet Aggregation Inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The Nuclear Magnetic Resonance Solution Structure of Flavoridin, an Antagonist of the Platelet GP IIb-IIIa Receptor

The snake venom protein flavoridin, a polypeptide of 70 amino acid residues, is a potent inhibitor of blood platelet aggregation. It binds to cell-surface integrin receptors such as the fibrinogen receptor glycoprotein IIb/IIIa. The inhibitory properties of flavoridin have been attributed to the tripeptide segment Arg-Gly-Asp (residues 49 to 51). This paper describes the determination of the three-dimensional structure of flavoridin in aqueous solution based on two-dimensional nuclear magnetic resonance spectroscopy. A family of 18 conformers was selected to characterize the solution structure. The molecule comprises two structural domains, an N-terminal unit extending from residues 1 to 25, and a C-terminal unit from residues 26 to 70. Whereas the mutual spatial orientation of these regions is not well defined, each one is well organized within itself. The segment 26 to 70, which is homologous to the sequence of the snake toxins echistatin and eristostatin, shows an average value of 1·0 Å for the root-mean-square deviations of the backbone atoms among the 18 conformers. The structure of flavoridin consists essentially of non-repetitive elements such as tight turns and loops, whose location and conformation are characterized in this paper. With the exception of two short regions of antiparallel β-sheet, no classic element of protein secondary structure is present. The six disulphide bridges, which have been mapped by applying a novel computational strategy (see accompanying paper), are the dominant organizational feature of the polypeptide fold of flavoridin. Two of the bridges are located in the N-terminal domain, three in the C-terminal domain and one connects the two structural units. The mobile RGD recognition sequence for integrins is located peripheral to the core region of the C-terminal domain at the most exposed end of a nine residue loop structure, which is attached to a short β-sheet. The C terminus is close to this loop structure.

Polycyclic N‐hetero compounds. XLIII. Syntheses and properties of 2‐substituted 1‐acetoxy‐6‐acetyl‐5,6‐dihydro‐4H‐imidazo[1′,2′:1,6]‐pyrimido[5,4‐d][1]benzazepines viaN‐(6,7‐dihydro‐5H‐pyrimido[5,4‐d]‐[1]benzazepin‐4‐yl)amino acids and their analogous mesoionic compounds, and their related compounds as a series of potential blood platelet aggregation inhibitors

AbstractA study of the cyclization method by heating of N‐(6,7‐dihydro‐5H‐pyrimido[5,4‐d][1]benzazepin‐4‐yl)amino acids 3a‐h, 6, and 9a,b with excess acetic anhydride for the preparation of 2‐substituted 1‐acetoxy‐6‐acetyl‐5,6‐dihydro‐4H‐imidazo[1,2′:1,6]pyrirnido[5,4‐d][1]benzazepines 4a‐h and tetra‐ and penta‐cyclic mesoionic compounds 7 and 10a,b has been made. In addition, a tetracyclic mesoionic compound having a sulfur atom on the skeleton, 5,6‐dihydro‐4H‐thiazolo[3′,2′:1,6]pyrimido[5,4‐d][1]benzazepiniurn‐1‐one (12) was similarly prepared by treatment of 2‐(6,7‐dihydro‐5H‐pyrimido[5,4‐d][1]benzazepm‐4‐ylthio)acetic acid (11) with excess acetic anhydride. Their inhibitory activities against collagen‐induced aggregation of rabbit blood platelets in vitro were also investigated, and some heterocycles exhibited from a two‐ to a four‐fold more potent activity as compared with aspirin.