Antiplatelet effects of 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in relation to its disposition in rats, rabbits and dogs.

KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) was evaluated for the inhibition of platelet aggregation and prostanoid production in rats, rabbits and dogs, comparing with acetylsalicylic acid (ASA). Correlations between the inhibitory action and plasma concentration of KC-764 were examined in rabbits. KC-764 was 200 times more potent than ASA in inhibiting collagen-induced rabbit platelet aggregation and TXA2 production in vitro. KC-764 exhibited more selective inhibition of TXA2 production over PGI2 production than ASA. The ratio of IC50's of PGI2 production to TXA2 production of KC-764 was 175 in rats, 72 in rabbits and 65 in dogs, respectively. Such a selectivity was also confirmed ex vivo. The depression of plasma TXB2 levels was well correlated with the ex vivo antiaggregatory activity in rabbits at oral doses of KC-764 ranging from 0.02-1.5 mg/kg. The concentrations/in vitro inhibitory activity relationship was expressed by a sigmoid Imax model equation. The ex vivo antiplatelet activity and prostanoid production were reconstructed with Imax model equation using the simulated plasma drug concentrations and in vitro Imax model parameters in all animals. The relationship could be applied for the prediction of the inhibitory activity of KC-764 in humans. These results indicate that KC-764 is a potent, selective and reversible antiplatelet drug, being different from ASA.     

Protective effect of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine on myocardial damage due to coronary occlusion and reperfusion in rabbit.

The effects of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) on infarct size, myeloperoxidase (MPO) activity and plasma prostanoid levels were studied using coronary artery occlusion (1 h)-reperfusion (3 h) model in rabbits, comparing with acetylsalicylic acid (ASA). Myocardial infarct size, MPO activity in the infarcted region and plasma glutamate oxalo-acetate transaminase, lactate dehydrogenase and creatine kinase were significantly suppressed by treatment with KC-764 (2 mg/kg i.v.), but not by ASA (10 mg/kg i.v.). KC-764 completely depressed the increase in plasma TXB2 level during occlusion-reperfusion with a little influence on plasma 6-keto-PGF1 alpha. Thus, the ratio of 6-keto-PGF1 alpha to TXB2 levels was increased by KC-764. On the other hand, ASA treatment depressed both plasma TXB2 and 6-keto-PGF1 alpha levels to the same extent. The in vitro study with guinea-pig neutrophils showed that KC-764 reduced the chemotaxis induced by formyl-methionyl-leucyl- phenylalanine at 3 x 10(7)-3 x 10(-6) mol/l, while ASA did not influence the neutrophil chemotaxis. These results suggest that KC-764 may salvage the damaged ischemic myocardium by the selective inhibition of TXA2 synthesis and the suppression of leukocyte migration.     

Comparison of in vitro and ex vivo antiplatelet effects of 1,2-benzisothiazolin-3-one and its 2-amino derivative

The in vitro and ex vivo antiplatelet effects of 2-amino-1,2-benzisothiazolin-3-one (1) are compared with those of its parent compound 1,2-benzisothiazolin-3-one (2) and with acetylsalicylic acid (ASA) against different agonists. 2-Amino-1,2-benzisothiazolin-3-one inhibits adenosine diphosphate (ADP)-, arachidonic acid (AA)- and collagen-induced human platelet aggregation in vitro, with IC50 values of 8.90 x 10(-5), 1.50 x 10(-6) and 5.11 x 10(-8) mol/l, respectively. The strong inhibitory activity is significant not only for collagen but also for AA-induced aggregation. The same compound inhibits ex vivo collagen- and particularly AA-induced rabbit platelet aggregation at the tested dose of 10 mg/kg i.m. In view of the potential use of 2-amino-1,2-benzisothiazolin-3-one as antithrombotic agent, the log P values for both 1,2-benzisothiazolin-3-one derivatives 1 and 2 are determined, to gain an understanding of the significance of the 2-amino group in the 1,2-benzisothiazolin-3-one moiety with respect to the biological activity under study.     

Effects of novel antifungal azole derivatives on the 5-lipoxygenase and cyclooxygenase pathway

5-Lipoxygenase and cyclooxygenase catalyze the first steps of the conversion of arachidonic acid into leukotrienes and prostanoids, respectively. Leukotrienes are important mediators of inflammation and thromboxanes are mainly involved in platelet functions. The effects of the new antimycotic drugs, itraconazole and fluconazole, on the 5-lipoxygenase pathway in human polymorphonuclear leukocytes (PMNL), on the eicosanoid metabolism in platelets, platelet aggregation and on cyclooxygenase activity were investigated and compared with miconazole and ketoconazole. Itraconazole inhibited the formation of 5-lipoxygenase metabolites in human PMNL (IC50 = 2 x 10(-6) mol/l), while it had no effect on cyclooxygenase and platelet aggregation at concentrations up to 10(-4) mol/l and 10(-5) mol/l, respectively. Fluconazole was ineffective in all assays. Miconazole inhibited thromboxane synthase (IC50 = 1 x 10(-5) mol/l) and platelet aggregation (IC50 = 3 x 10(-5) mol/l). Ketoconazole was less active in this respect (IC50 for platelet aggregation = 2 x 10(-4) mol/l). All compounds did not affect cyclooxygenase activity in concentrations up to 10(-4) mol/l in the pure enzyme assay. These results indicate that among the tested azoles two compounds show remarkable effects. Miconazole inhibits thromboxane synthesis and itraconazole is a potent inhibitor of leukotriene formation which has only minor effects on the cyclooxygenase pathway. This finding is of considerable interest regarding the application of itraconazole during immunosuppressive therapy and suggests further studies of its potential antiphlogistic properties.     

阿司匹林铜的抗血小板聚集作用

目的：研究阿司匹林铜（ＣｕＡｓｐ）对血小板聚集性的影响及其机制，方法；用Ｂｏｒｎ氏法测定ＣｕＡｓｐ对兔血小板聚集性的影响，用荧光光度法和放射免疫法观察ＣｕＡｓｐ对兔血小板５－羟色胺的释放和ＴＸＢ２的产生及血浆中ＴＸＢ２和６－ｋｅｔｏ－ＰＧＦ１α水平的影响，结果：ＣｕＡｓｐ体外呈浓度依赖性抑制花生四烯酸（ＡＡ）诱导的血小板聚集和５－羟色胺的释放（ＩＣ５０分别为１７和１９μｍｏｌ．Ｌ＾－１，９５％可信     

Inhibition of cyclooxygenase activity, platelet aggregation and thromboxane B2 production by two environmental toxicants: m- and o-cresol

Cresol is a well-known environmental pollutant, toluene metabolite, uremic toxicant and accidental poisoning product. Formocresol, a preparation of formalin and cresol, is also used as a root canal medicament and for pulpotomy of primary teeth. However, little is known about its effect on cardiovascular system. In this study, m-cresol inhibited the AA-induced platelet aggregation by 43-97% at concentrations ranging from 0.25 to 1 mM. Collagen-induced platelet aggregation was also inhibited by 0.25-1 mM of m-cresol by 47-98%. Accordingly, o-cresol (0.1-0.5 mM) also inhibited the AA-induced platelet aggregation by 46-96% and the collagen-induced platelet aggregation by 35-88% at concentrations of 0.1-1 mM. AA- and collagen-induced platelet thromboxane B(2) (TXB(2)) production was inhibited by even 0.1 mM of m-cresol with 88 and 54% of inhibition, respectively. The o-cresol (0.1 mM) also inhibited the AA- and collagen-induced platelet TXB(2) production with 91 and 97% respectively. Although m- and o-cresol (<1 mM) showed little effect on thrombin-induced platelet aggregation, they effectively inhibited the thrombin-induced platelet TXB(2) production. The m-cresol (2 and 5 mM) inhibited the COX-1 activity by 55-99%, but showed little effect on COX-2 enzyme activity. Moreover, o-cresol (0.5 and 1 mM) inhibited the COX-1 activity by 40-95%. COX-2 enzyme activity was inhibited by 68% at a concentration of 5 mM o-cresol. These results indicate that acute cresol-poisoning, direct root canal medication with formocresol or long-term occupational exposure to cresol and toluene may potentially suppress blood clot formation and lead to tissue hemorrhage via inhibition of platelet aggregation, TXB(2) production and COX enzyme activity.     

Effect of a new thromboxane A2 antagonist, S-145, on platelet aggregation

The newly synthesized compound S-145, (+/-)-5(Z)-7-(3-endo-phenylsulfonylamino [2.2.1] bicyclohept-2-exo-yl)heptenoic acid, inhibited arachidonic acid (AA)-, 9,11-methanoepoxy-PGH2 (U46619)-, collagen- and ADP-induced human platelet aggregation in vitro with IC50 values of 0.25, 0.34, 0.22, and 0.08 microM, respectively. The inhibiting potency of this compound to AA- or U46619-induced platelet aggregation was about twice that of ONO-3708 and 1/7-1/14 that of SQ29,548 in human platelets, about 7 times that of ONO-3708 and 1/3-1/7 that of SQ29,548 in guinea pig platelets, and 250-800 times that of ONO-3708 and 1-7 times that of SQ29,548 in rabbit platelets. When S-145 was administered orally to guinea pigs at the dose of 0.1 mg/kg, AA-induced platelet aggregation was completely inhibited at 30 and 60 min after the administration, but not at 3 and 6 hr. The minimum effective doses of S-145 (p.o.) to AA- and collagen-induced platelet aggregation at 60 min after the administration were 0.01 mg/kg and 0.03 mg/kg, respectively. The potency of S-145 (p.o.) to inhibit AA- and collagen-induced guinea pig platelet aggregation was 30-300 times that of ONO-3708 or SQ29,548 and 300-1000 times that of aspirin. These results suggest that S-145 is a thromboxane A2 antagonist showing a potent inhibiting effect on platelet aggregation by oral administration.     

Pharmacological studies on proglumetacin maleate, a new non-steroidal anti-inflammatory drug (4). Mode of action on anti-inflammatory activity

The possible mechanism of the anti-inflammatory activity of proglumetacin maleate (PGM), a new indomethacin (IND) derivative interacting with arachidonic acid (AA) metabolism, was investigated to elucidate the contributions of PGM itself and its two major metabolites, desproglumideproglumetacin maleate (DPP) and IND. PGM caused much less inhibition of PGE2 formation by sheep seminal vesicle microsomes (IC50 = 310 microM) and TXB2 formation by a washed rabbit platelet suspension (IC50 = 6.3 microM) than IND. DPP also caused less inhibition of cyclooxygenase than IND. Moreover, PGM had less effect on sodium arachidonate (SAA)-induced rat platelet aggregation ex vivo and AA-induced sudden death in rabbits than IND. These results show that PGM has anti-inflammatory activity after its conversion to the active metabolite IND. However, the inhibitory effects of PGM and DPP were as strong as that of IND on SAA- or collagen-induced rabbit platelet aggregation in vitro. These activities are considered to be associated with platelet membrane interaction. Moreover, unlike IND, PGM (IC50 = 1.5 microM) and DPP (IC50 = 16.3 microM) strongly inhibited 5-HETE formation by the cytosol of guinea pig polymorphonuclear leukocytes. This unique activity of PGM on 5-lipoxygenase may contribute to its anti-inflammatory activity.     

Studies on the inhibitory effect of etafenone hydrochloride on platelet aggregation

The inhibitory effect of etafenone hydrochloride (etafenone) on platelet aggregation in rabbit platelet rich plasma and the involvement of the arachidonic acid (AA) cascade in the inhibitory mechanism for etafenone on platelet aggregation were studied. 1) Etafenone exhibited a dose-dependent inhibitory effect on collagen (15--20 micrograms/ml)-induced platelet aggregation, and its median inhibitory concentration (IC50) was 1.7 X 10(-5)M. 2) In ADP (20 microM)-induced aggregation, etafenone also exhibited a dose-dependent inhibitory effect, but its IC50 was 2.7 X 10(-4)M and was significantly higher than that in the case of collagen. 3) Etafenone inhibited AA (0.3--0.5mM)-induced platelet aggregation dose-dependently. Its IC50 was 2.8 X 10(-5)M. 4) In thromboxane (TX) A2-induced aggregation, etafenone exhibited a dose-dependent inhibition, and the IC50 was 3.2 X 10(-4)M. 5) Trapidil which was reported to inhibit platelet aggregation via phosphodiesterase (PDE) inhibition had a similar IC50 on ADP- and TXA2-induced platelet aggregation to that of etafenone, but in collagen- and AA-induced aggregation, its IC50 was higher than that of etafenone. 6) Etafenone (3 X 10(-6)--3 X 10(-4)M) dose-dependently inhibited the production of TXB2 in PRP induced by collagen. 7) Etafenone scarcely affected TXA2 synthetase activity in rabbit platelet homogenate. 8) The correlation between the inhibitory effect of etafenone on platelet aggregation and inhibition of AA metabolism activation and PDE inhibition was discussed.     

Two new non-glycosidic iridoids from the leaves of Campsis grandiflora

Two new non-glycosidic iridoids, which were named cachinol (1) and 1-O-methyl cachinol (2), were isolated from the methanol extract of the leaves of Campsis grandiflora together with a known iridoid cachineside I (3). The structures of compounds 1 and 2 were determined on the basis of spectroscopic methods including two dimensional NMR and high resolution mass spectrometry. All of the isolated compounds showed mild inhibitory activities on rat platelet aggregation. Compounds 1 and 3 (IC50 : 246 and 219 microM, respectively) showed about 2-fold higher inhibitory effects than acetylsalicylic acid (ASA, IC50: 412 microM) on collagen-induced aggregation. Compounds 1 and 2 (IC50: 43.2 and 38.4 microM, respectively) were about 2-fold more inhibitory than ASA (IC50: 75.2 microM), and about 4-fold more effective than their glycoside 3 (IC50: 189 microM) on AA-induced aggregation.     

Antithrombotic activity of NSP-513, a novel selective phosphodiesterase 3 inhibitor, on femoral arterial thrombosis induced by physical stenosis and electrical current: comparison of antithrombotic and hemodynamic effects

NSP-513, a novel potent and selective phosphodiesterase 3 (PDE 3) inhibitor, and cilostazol, a previously developed PDE 3 inhibitor, were compared with respect to antiplatelet, antithrombotic, and hemodynamic effects. In the in vitro antiplatelet aggregation studies, NSP-513 and cilostazol inhibited collagen-induced canine platelet aggregation with median inhibitory concentration (IC50) values of 0.093 and 3.1 miccroM, respectively, and inhibited adenosine diphosphate (ADP)-induced canine platelet aggregation with IC50 values of 0.15 and 12 microM, respectively. For ADP-induced platelet aggregation, the presence of prostaglandin E1 (PGE1; 3 and 10 nM) further decreased the IC50 values for NSP-513 to 0.11 and 0.032 microM, respectively. In ex vivo antiplatelet aggregation studies, orally administered NSP-513 (0.03-1 mg/kg) and cilostazol (50 mg/kg) inhibited collagen-induced canine platelet aggregation. In an in vivo canine femoral arterial thrombosis model, intraduodenally administered NSP-513 (0.01-0.03 mg/ kg) dose-dependently prevented thrombus formation without any changes in blood pressure, heart rate, or bleeding time. In conscious dogs, NSP-513 at oral doses of > or =0.3 mg/kg produced hemodynamic changes such as decreased blood pressure and increased heart rate and LVdP/dt(max). Thus the minimal hemodynamically effective dose of NSP-513 was 0.3 mg/kg, and the hemodynamic effects of this dose were comparable to those of 50 mg/kg of cilostazol. In conclusion, these data suggest that NSP-513 has in vivo selectivity for antiplatelet and antithrombotic activities over hemodynamic activity, and that the selectivity of NSP-513 is higher than that of cilostazol in dogs.     

Pharmacokinetics of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in laboratory animals.

KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo [1,5-a]pyridine CAS 94457-09-7) and its metabolites in serum and urine were determined after intravenous and oral administration in mice, rats, rabbits and dogs at a dose of 5 mg/kg. KC-764 was rapidly eliminated from serum in all species. The biological half-lives of unchanged KC-764 after intravenous administration in mice, rats, rabbits and dogs were 1.31, 0.29, 1.94 and 1.20 h, respectively. 2-Methyl-3-(1,4,5,6-tetrahydro-6-oxonicotinoyl)pyrazolo-[1,5-a]pyr idine was a common major metabolite in serum of all species, although 6,7-dihydro-6,7-dihydroxy-2-methyl-3-(1,4,5,6- tetrahydro-6-oxonicotinoyl) pyrazolo-[1,5-a]pyridine (M-8) was more abundant in rabbits. Urinary recovery of unchanged KC-764 was as low as 0.4-2.2% in all species. The major urinary metabolite was 2-methyl-3-(1,4,5,6-tetrahydro-6-ureidonicotinoyl)pyrazolo-[1,5-a] pyridine in mice, rats and dogs, but M-8 was in rabbits. KC-764 was rapidly and well absorbed by oral administration, and extensively metabolized in all species tested.     

哒嗪酮类新化合物9612的抗血小板聚集作用

研究了新型哒嗪酮类化合物 96 12对家兔和大鼠血小板聚集的影响 .结果发现 ,96 12在体外能明显抑制花生四烯酸 (AA) ,腺苷二磷酸 (ADP)和凝血酶 (thrombin)诱导的家兔血小板聚集 ,其IC50 分别为 3 2 0 ,9 44和 7 10 μmol/L .96 12 .灌胃给药 (ig) ,能显著抑制AA和ADP诱导的大鼠血小板聚集 ,其作用与同等剂量 (15 0mg/kg)的阿斯匹林 (ASA)相比无明显差异 (P >0 0 5 ) .     

Pharmacological properties of the orally active leukotriene antagonist [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]thio]-1,3,4- thiadiazol-2-yl]thio]acetic acid

The anti-leukotriene effect of [[5-[[3-(4-acetyl-3-hydroxy -2- propylphenoxy)propyl] thio]-1,3,4-thiadiazol-2-yl] thio] acetic acid (YM-16638) was examined. In isolated guinea-pig ileum, YM-16638 antagonized the contractions induced by slow reacting substance of anaphylaxis (SRS-A) and leukotriene D4 (LTD4) with IC50 values of 6.0 x 10(-8) and 1.1 x 10(-7) mol/l, respectively. However, the compound at 10(-5) mol/l did not affect the contractions induced by histamine, acetylcholine, 5-hydroxytryptamine, prostaglandin (PG)E2 and PGF2 alpha. In isolated guinea-pig trachea, YM-16638 inhibited the contractions elicited by LTC4, LTD4 and LTE4 and its IC50 values were 5.7 x 10(-8), 1.6 x 10(-7) and 9.6 x 10(-8) mol/l, respectively. In isolated human bronchi, YM-16638 also antagonized the contractions induced by LTC4, LTD4 and LTE4 and its IC50 values were 6.0 x 10(-8), 1.2 x 10(-7) and 2.1 x 10(-8) mol/l, respectively. YM-16638 at the doses of 3 to 100 mg/kg p.o. inhibited the skin reaction induced by LTD4 in conscious guinea-pigs and its ED50 value was 17.9 mg/kg p.o. Successive oral administration of YM-16638 (50 mg/kg/d) for 10 days did not develop tolerance in its inhibitory effect against LTD4-induced skin reaction. Furthermore, the compound at the doses of 10 and 30 mg/kg p.o. significantly inhibited the antigen-induced bronchoconstriction in conscious guinea-pigs pretreated with mepyramine, propranolol and indomethacin. These results indicate that YM-16638 is a selective, potent and orally active leukotriene antagonist.     

Antiplatelet activity of [5-(2-methoxy-5-chlorophenyl)furan-2-ylcarbonyl]guanidine (KR-32570), a novel sodium/hydrogen exchanger-1 and its mechanism of action

The antiplatelet effects of a novel guanidine derivative, KR-32570 ([5-(2-methoxy-5-chlorophenyl) furan-2-ylcarbonyl]guanidine), were investigated with an emphasis on the mechanisms underlying its inhibition of collagen-induced platelet aggregation. KR-32570 significantly inhibited the aggregation of washed rabbit platelets induced by collagen (10 microg/mL), thrombin (0.05 U/mL), arachidonic acid (100 microM), a thromboxane (TX) A2 mimetic agent U46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F2, 1 microM) and a Ca2+ ATPase inhibitor thapsigargin (0.5 microM) (IC50 values: 13.8 +/- 1.8, 26.3 +/- 1.2, 8.5 +/- 0.9, 4.3 +/- 1.7 and 49.8 +/- 1.4 microM, respectively). KR-32570 inhibited the collagen-induced liberation of [3H]arachidonic acid from the platelets in a concentration dependent manner with complete inhibition being observed at 50 microM. The TXA2 synthase assay showed that KR-32570 also inhibited the conversion of the substrate PGH2 to TXB2 at all concentrations. Furthermore, KR-32570 significantly inhibited the [Ca2+]i mobilization induced by collagen at 50 microM, which is the concentration that completely inhibits platelet aggregation. KR-32570 also decreased the level of collagen (10 microg/mL)-induced secretion of serotonin from the dense-granule contents of platelets, and inhibited the NHE-1-mediated rabbit platelet swelling induced by intracellular acidification. These results suggest that the antiplatelet activity of KR-32570 against collagen-induced platelet aggregation is mediated mainly by inhibiting the release of arachidonic acid, TXA2 synthase, the mobilization of cytosolic Ca2+ and NHE-1.     

Effects of plumbagin on platelet aggregation and platelet-neutrophil interactions

The effects of plumbagin were investigated on platelet aggregation in vitro and ex vivo, on the binding of thrombin-stimulated platelets to neutrophils, and platelet aggregation induced by intact neutrophils and N-formyl-methionyl-leucyl-phenylalanine (fMLP) or platelet activating factor (PAF) activated neutrophils, by use of the methods of Hamburger, McEver and Born, respectively. The results showed that plumbagin in vitro significantly inhibited adenosine diphosphate (ADP)-, arachidonic acid (AA)-, or platelet activating factor (PAF)-induced platelet aggregation, in a concentration-dependent manner. The medium inhibitory concentrations (IC 50 ) were 39.4, 82.7 and 38.1 microM, respectively. Intragastric plumbagin at 10 mg/kg markedly suppressed platelet aggregation induced by ADP, AA, or PAF. Plumbagin decreased the binding between thrombin-stimulated platelets and neutrophils with an IC 50 of 62.9 microM. Plumbagin significantly inhibited washed platelet aggregation stimulated by fMLP- or PAF-activated neutrophils. The IC 50 values were 54.3 and 47.6 microM, respectively. On the other hand, plumbagin and aspirin increased the inhibition of intact neutrophils on AA-induced platelet aggregation. It is suggested that plumbagin inhibited platelet aggregation in vitro and ex vivo, suppressed the binding of activated platelets to neutrophils, inhibited platelet aggregation induced by activated neutrophils, and increased inhibition of intact neutrophils on platelet reactivity. Abbreviations. DMSO:dimethyl sulphoxide fMLP: N-formyl-methionyl-leucyl-phenylalanine ADP:adenosine diphosphate AA:arachidonic acid PAF:platelet activating factor     

Single oral dose study of two isosorbide-based aspirin prodrugs in the dog

The objective of this study was to compare two aspirin prodrugs, isosorbide diaspirinate (ISDA) and a nitroaspirin (ISMNA), with aspirin in terms of effects on dog platelet function after administration of a single oral dose. Groups of six dogs were administered ISDA (2mg kg(-1)), ISMNA (4 mg kg(-1)) or aspirin (2mg kg(-1)). Blood was sampled at 1, 2, 4, 8, 12 and 24 h post-dosing and evaluated for capacity to generate post-clotting thromboxane (TX)B2. The aggregation response to arachidonic acid (AA) (100 microM), ADP (30 microM) or collagen (10 microg mL(-1)) was estimated at each time-point using the whole blood impedance method. Plasma ISMN following oral administration of ISMNA was also measured and compared with plasma ISMN following administration of a physical mixture of ISMN and aspirin. ISDA administration (2 mg kg(-1)) was associated with a significant reduction (P < 0.05) in serum TXB2 at 12 and 24 h (>90%) post-dosing and persistent inhibition of AA-induced platelet aggregation. ISDA administration caused a more marked depression of post-clotting TXB2 levels than aspirin in this study, although its ability to inhibit platelet aggregation was less consistent than that of aspirin. The nitroaspirin ISMNA was least effective at inhibiting platelet aggregation response or TXB2 production. The ISMN AUC(0-24 h) for the ISMNA-treated dogs was 77% of that for the physical mix-treated dogs and the tmax was delayed. This study indicates that the two aspirin esters cause aspirin-like effects on platelet function, probably through aspirin release, when administered orally to dogs.     

Inhibition of prostaglandin biosynthesis in human endotoxin-stimulated peripheral blood monocytes: effects of caffeine

There is an ongoing debate about possible advantages of the coadministration of caffeine with cyclooxygenase (COX) inhibitors in the treatment of pain. There are results suggesting interference by caffeine with COX expression and activity in rat immune cells. In the present study, we have used, therefore, human endotoxin-stimulated monocytes to investigate a possible influence of caffeine on indometacin-induced inhibition of prostaglandin E(2) (PGE(2)) formation. Endotoxin caused a concentration- and time-dependent increase in immunoreactive PGE(2) that was dependent on CD14-mediated mechanisms. In order to investigate pharmacological inhibition of the COX activity, a submaximal concentration of 1 ng/ml endotoxin (4 h exposure time) was used. Indometacin caused a concentration-dependent inhibition of PGE(2) with an apparent IC(50) of 8.9 +/- 1.4 x 10(-9) mol/l and an I(max) of 1 x 10(-7) mol/l. Caffeine (5 x 10(-6) to 1.5 x 10(-4) mol/l) on its own produced no statistically significant effect on endotoxin-induced PGE(2) formation. In the presence of caffeine (5 x 10(-6) to 1.5 x 10(-4) mol/l), inhibition of PGE(2) biosynthesis by indometacin (1 x 10(-8) mol/l) was not significantly altered. These results show that, in human monocytes, caffeine, up to concentrations severalfold higher than those reached in patients, has no significant effect on endotoxin-induced PGE(2) formation nor on its inhibition by indometacin.     

苦豆碱对兔血小板聚集的影响

苦豆碱抑制低浓度花生四烯酸(AA)和胶原诱导的兔血小板聚集,IC_(50)分别为184μg·L~(-1)和38.3mg·L~(-1)提高AA浓度使其抑制作用明显减弱。苦豆碱还抑制兔血小板形成血栓素B_2(TXB_2),此作用可能和其对血小板聚集的抑制有关。