Aspirin protected against endothelial damage induced by LDL： role of endogenous NO synthase inhibitors in rats

AIM: To study the protective effect of aspirin on damages of the endothelium induced by low-density lipoprotein (LDL), and whether the protective effect of aspirin is related to reduction of nitric oxide synthase inhibitor level.METHODS: Vascular endothelial injury was induced by a single injection of native LDL (4 mg/kg) in rats. Vasodilator responses to acetylcholine (ACh) in the isolated aortic rings were determined, and serum concentrations ofasymmetric dimethylarginine (ADMA), malondialdehyde (MDA), tumour necrosis factor-α (TNF-α), and the activity of dimethylaminohydrolase (DDAH) were measured. RESULTS: A single injection of LDL (4 mg/kg)significantly decreased vasodilator responses to ACh, increased the serum level of ADMA, MDA, and TNF-α, anddecreased DDAH activity. Aspirin (30 or 100 mg/kg) markedly reduced the inhibition of vasodilator responses toACh by LDL, and the protective effect of aspirin at the lower dose was greater compared with high-dose aspiringroup. Aspirin inhibited the increased level of MDA and TNF-α induced by LDL. Aspirin at the dose of 30 mg/kg,but not at higher dose (100 mg/kg), significantly reduced the concentration of ADMA and increased the activity ofDDAH. CONCLUSION: Aspirin at the lower dose (30 mg/kg) protects the endothelium against damages elicitedby LDL in vivo, and the protective effect of aspirin on endothelium is related to reduction of ADMA concentrationby increasing DDAH activity.     

Effect of oral aspirin dose on platelet aggregation and vascular prostacyclin (PGI2) synthesis in humans and rabbits

Large doses of oral aspirin inhibit platelet aggregation and vascular synthesis of the antiaggregatory vasodilator prostaglandin I2 (PGI2) by irreversibly acetylating the cyclooxygenase enzyme. In order to determine if one can achieve selective inactivation of platelet cyclooxygenase using oral doses of aspirin, we studied human and rabbit platelet aggregation and rabbit aortic synthesis of PGI2 before and 3 hr after various doses of aspirin. In rabbits, lower doses of aspirin produced a major inhibition of platelet aggregation and a minor inhibition of PGI2 synthesis, while higher doses of aspirin inhibited both platelet aggregation and vascular PGI2 synthesis. In humans, we found that a dose equivalent to approximately 1/4 of one 300 mg aspirin tablet consistently produced a major inhibition of cyclooxygenase-dependent platelet aggregation in a pattern similar to the inhibition of rabbit platelet aggregation where the majority of rabbit PGI2 synthetic capacity was not inhibited. In another rabbit study, we found that it takes the vasculature over 24 hr to return to control PGI2 synthetic capacity following a single, high dose of oral aspirin. In conclusion, we speculate that approximately 1/4 of an aspirin tablet, which inhibits a major portion of cyclooxygenase-dependent human platelet aggregation, may not inhibit a major portion of vascular cyclooxygenase-dependent PGI2 synthesis and may be more efficacious as an antithrombotic agent in man than are higher doses of aspirin.     

Effects of a new antihypertensive agent, SGB-1534, on rat platelet aggregation

The present study was designed to examine the antiplatelet activity of SGB-1534, 3-[2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl]-2,4(1H, 3H)- quinazolinedione monohydrochloride, compared with prazosin, ketanserin and aspirin. The equihypotensive doses of SGB-1534, prazosin and ketanserin were administered orally to rats; and 1 hr later, their effects on collagen-induced platelet aggregation, compared with those of aspirin, were examined under ex vivo conditions. The bleeding time was determined by using the tail transection method. SGB-1534 (10 mg/kg) as well as ketanserin (3 and 10 mg/kg) and aspirin (10 mg/kg) effectively inhibited the platelet aggregation; and in addition, they significantly prolonged bleeding times. Prazosin in doses of 10 and 30 mg/kg did not affect either the aggregation or bleeding times. Whereas 10(-4) M aspirin significantly inhibited the production of malondialdehyde (MDA) in rat platelets, SGB-1534, prazosin and ketanserin even in considerably high concentrations (10(-4) or 10(-3) M) did not affect the MDA production and the cyclic AMP levels in the platelets. In isolated rat femoral arteries, SGB-1534, prazosin and ketanserin antagonized the contractile response to phenylephrine with pA2 values of approximately 10.06, 10.39 and 7.71, respectively. Also, SGB-1534 and ketanserin attenuated the contractile response to 5-hydroxytryptamine (5-HT) with pA2 values of 6.36 and 9.53, respectively, while prazosin had no antagonistic effects on 5-HT-induced contraction.     

Inhibition of platelet function by a controlled release acetylsalicylic acid formulation — Single and chronic dosing studies

Summary The extent to which a controlled release acetylsalicylic acid (ASA) formulation inhibited platelet function has been evaluated in single and chronic dosing studies. In the single dose study, the platelet inhibitory effect of the controlled release formulation was compared with that of an equivalent dose of soluble ASA and an equimolar dose of sodium salicylate (SA). In the chronic dosing study, ASA dose-response curves for platelet function, including cyclooxygenase activity, were determined for various doses (20–1300 mg) of the controlled release (enteric coated pellets) ASA formulation taken by volunteers daily for one week. Platelet function was assessed by the degree of inhibition of aggregation for several aggregating agents, and the degree of inhibition of activity of platelet cyclooxygenase quantified by the estimation of malondialdehyde (MDA) production. Plasma ASA and SA concentrations were also determined in each study. The controlled release product inhibited platelet function to the same extent as an equimolar dose of soluble ASA, but did so with much lower and sometimes undetectable peak systemic plasma ASA concentrations. SA, the direct metabolite of aspirin, did not have any effect on platelet function. The ASA dose-platelet function response curves obtained from chronic dosing with the controlled release formulation appeared to be similar to those reported previously for the soluble product. The inhibition of platelet function appeared to be unrelated to plasma ASA concentrations.     

Captopril augments both basal and frusemide-induced natriuresis in normal man by suppression of circulating angiotensin II.

1. The effect of increasing doses of orally administered aspirin (30-900 mg) on platelet aggregation and ATP release induced by arachidonic acid (AA), collagen and platelet activating factor (PAF) was assessed in 12 normal volunteers. 2. Aspirin ingestion was associated with a significant increase in EC50 for AA (P less than 0.0001) and collagen (P less than 0.0001) but not for PAF (P greater than 0.495) although the normal biphasic aggregation response for the latter was abolished. Maximum ATP release was reduced by aspirin for all three agonists. 3. The mean maximum degrees of inhibition of platelet aggregation induced by aspirin for AA, collagen and PAF were 100%, 48% and 21% of baseline, respectively. The corresponding mean maximum inhibition of ATP release was 100%, 63% and 57%. The minimum cumulative doses of aspirin producing these effects were 240, 240 and 90 mg for AA, collagen and PAF respectively. For collagen alone, there was a significant decrease in the degree of inhibition of aggregation between the last dose on day 1 (150 mg) and the baseline measurement on day 2. 4. Platelets from female subjects were more sensitive to collagen (P less than 0.05) and AA (P less than 0.01) stimulation compared with males. However, prior to aspirin ingestion, PAF produced a greater maximum response in platelets from females (P less than 0.02) while following aspirin ingestion PAF-induced activation was inhibited to a greater degree in females (P less than 0.02). 5. These results indicate that collagen- and PAF-induced platelet activation are only partially dependent on cyclo-oxygenase and for PAF this seems related only to the second phase of aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition by picotamide of thromboxane production in vitro and ex vivo

Summary The effect of picotamide on platelet function has been studied in vitro and ex vivo.Picotamide at micromolar concentrations inhibited platelet aggregation induced by ADP, arachidonic acid and collagen, and it also inhibited the production of thromboxane A₂ (TxA₂). Unlike aspirin, picotamide did not affect the synthesis of prostacyclin by blood vessels.In eight healthy subjects who took picotamide 1200 mg/d platelet aggregation and TxA₂ production were inhibited.Picotamide appears to be an antiplatelet drug that reduces TxA₂ synthesis without affecting cyclooxygenase activity.     

Differential effect of platelet inhibitors in normal and in hypercholesterolaemic subjects.

Dibutyryl cyclic AMP, forskolin, dipyridamole and butyl imidazole inhibited platelet aggregation (induced by ADP or collagen) in washed platelets more than in platelet-rich plasma preparations. Aspirin, indomethacin and epoprostenol (prostacyclin, PGI2) showed no preferential inhibition of these platelet preparations. When platelet-rich plasma from either normal or familial hypercholesterolaemic (FH) subjects was used, aspirin, indomethacin and dipyridamole (but not forskolin) inhibited platelet aggregation in normal subjects more than in FH patients. When low doses of aspirin (75 mg daily for 7 days) or dipyridamole (250 mg, single dose) were administered in vivo, platelet aggregation was inhibited more in the normal subjects in comparison to the patient group.     

Efficacy of different doses of aspirin in decreasing blood levels of inflammatory markers in patients with cardiovascular metabolic syndrome

Objectives Inflammation and platelet aggregation and activation are key processes in the initiation of a cardiovascular event. Patients with metabolic syndrome have a high risk of cardiovascular events. This study determined whether small and medium doses of aspirin have anti‐inflammation and antiplatelet aggregation effects in patients with metabolic syndrome. Methods One hundred and twenty‐one consecutive patients with metabolic syndrome were randomized into three groups, receiving 100 mg/day of aspirin, 300 mg/day of aspirin or a placebo, respectively, for 2 weeks. The blood levels of thromboxane B2 (TXB2), a stable product of the platelet aggregation mediator TXA2, 6‐keto‐prostaglandin F1‐α (6‐keto‐PGF1‐α), a stable product of the endogenous cyclooxygenase metabolite prostaglandin I2, and inflammatory mediators including high‐sensitivity C‐reactive protein (hs‐CRP), tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), were determined by ELISA and radioimmunoassay. Key findings The blood levels of hs‐CRP, TNF‐α, IL‐6 and TXB2 were significantly decreased after 2 weeks of treatment with 300 mg/day of aspirin. Patients who received 100 mg/day of aspirin had decreased blood levels of hs‐CRP and TXB2. The blood level of IL‐6 in the 300 mg/day aspirin group was significantly lower than that in the other two groups after 2 weeks of therapy. Aspirin at either dose did not affect the blood level of 6‐keto‐PGF1‐α. Conclusions Aspirin at all doses suppresses the blood levels of inflammatory markers and the platelet aggregation mediator TXA2 in Chinese patients with metabolic syndrome. Since the suppression induced by 300 mg/day of aspirin was greater than that induced by 100 mg/day of aspirin, these data suggest that 300 mg/day of aspirin may be beneficial in decreasing the risk of cardiovascular events in Chinese patients with metabolic syndrome.     

Diacylglycerol overcomes aspirin inhibition of platelets: evidence for a necessary role for diacylglycerol accumulation in platelet activation

Aspirin, an inhibitor of cyclooxygenase, inhibits platelet aggregation in response to many stimuli. Previous studies suggested an important and necessary role for protein kinase C (PKC) in platelet aggregation and secretion. Therefore, the effects of aspirin on sn-1,2-diacylglycerol (DAG), the endogenous activator of PKC, were investigated. Specifically, we sought to determine whether inhibition of DAG production is critical for aspirin action on platelets. Total DAG mass was measured using the DAG kinase assay. At low doses of gamma-thrombin (4 nM), aspirin (5 mM) completely inhibited secondary aggregation; this inhibition was associated with near-complete inhibition of DAG production. Inhibition of collagen-induced aggregation by aspirin (50 microM) was also associated with complete inhibition of collagen-stimulated DAG production and secondary aggregation. Concomitantly, aspirin reduced phosphorylation of the 40-kDa protein, a specific PKC substrate strongly suggesting inhibition of PKC in response to aspirin. To determine the physiologic significance of the inhibition of DAG production by aspirin, reconstitution studies were conducted with dioctanoylglycerol (diC8), a cell-permeable DAG. Under conditions in which aspirin completely inhibited secondary aggregation induced by gamma-thrombin, collagen, or arachidonic acid, diC8 overcame aspirin inhibition of agonist action and reconstituted secondary aggregation. DiC8 exerted these effects at low concentrations (2-3 microM), which caused minimal aggregation of control platelets. Phorbol 12,13-dibutyrate, a phorbol ester that directly activates PKC, mimicked the effects of diC8 in overcoming aspirin inhibition of collagen-induced platelet activation. However, subthreshold concentrations of the calcium ionophore ionomycin, arachidonic acid, or gamma-thrombin were unable to overcome aspirin inhibition of collagen-induced platelet aggregation, suggesting that the ability to overcome aspirin inhibition is not shared by other second messengers and is not due to nonspecific synergy. These studies constitute evidence that inhibition of DAG production and subsequent PKC activation are crucial to the antiaggregatory effects of aspirin. They also support the hypothesis that DAG production and PKC activation may be the final common pathway for induction of secondary aggregation.     

Morphine sex-dependently induced place conditioning in adult Wistar rats

The present study was conducted to investigate the potential sex-differences in morphine-induced conditioned place preference. A 3-day unbiased conditioning procedure was used to establish conditioned place preference in adult male and female Wistar rats (weighing 200-250 g). The effect of morphine on locomotor activity of subjects was also studied. Naloxone (0.5-2 mg/kg, i.p.), a selective antagonist of mu-opioid receptor or sulpiride (0.5-2 mg/kg, s.c.), a selective antagonist of dopamine D(2) receptor was administered, during conditioning, to indicate the receptor-mediated mechanisms governing upon possible sex-differences to the opioid response. Results show that morphine (0.5-10 mg/kg, s.c.) differently produced a significant place preference in female and male Wistar rats. Although, the opioid maximum response in both sexes was observed at 7.5 mg/kg, but, it was found that female rats acquired conditioned place preference at a lower dose (0.5 mg/kg, s.c.) of morphine compared to male rats. Moreover, the increase in morphine-induced response at higher doses (5-10 mg/kg, s.c.) was more pronounced in females than the males, indicating that female Wistar rats are more sensitive to the place conditioning induced by morphine. Also, the females were more sensitive to locomotor activation induced by morphine at least at one dose (7.5 mg/kg). Animals' body-weight at 10 mg/kg of opioid was increased, the effect that was not dependent to sex. The results also demonstrate that naloxone (1 and 2 mg/kg, i.p.) induced a significant place preference in two sexes with no significant effect on animals' locomotor activity. The antagonist in males but not in females showed a significant effect on animals' body-weight. Naloxone (0.5-2 mg/kg, i.p.) prior-administration to morphine, during conditioning, attenuated the opioid response in two sexes. The attenuation of the morphine response was more pronounced in males than the other sex at the higher dose (2 mg/kg) of the antagonist. In addition, the preadministration of naloxone, during morphine conditioning, both attenuated the drug-induced hyperactivity in females and decreased the animals' body-weight, albeit more effectively in females than the males. Sulpiride injections (1 and 2 mg/kg s.c.), during the conditioning period, induced a significant aversion in males but not in females with no significant effect either on locomotor activity or body-weight in both sexes. When sulpiride (0.5-2 mg/kg, s.c.), during conditioning, was morphine pre-injected, the antagonist at higher doses significantly attenuated the opioid response in males, reflecting the involvement of dopamine D(2) receptor in sex-dependent morphine-conditioned place preference. Prior-injections of sulpiride to morphine produced a significant effect on locomotor activity of females. The effect of the antagonist preinjections on body-weight was also observed in males. Present results indicate sex-differences both in reinforcing and locomotor activity effects of morphine in Wistar rats.     

Antithrombotic effects of KBT-3022, a novel antiplatelet agent,in an arterial thrombosis model in the guinea-pig

We examined the antithrombotic effect of KBT-3022, a novel antiplatelet agent, on photochemically induced arterial thrombosis in the guinea-pig saphenous artery, and compared its effect with that of aspirin and that of ticlopidine. Pretreatment with KBT-3022 [0.1 mg (0.2 μmole), 0.3 mg (0.7 μmole), 1 mg (2.2 μmole) and 3 mg (6.7 μmole)/kg, p.o.] 3 h prior to thrombosis induction prolonged the time required to achieve the thrombotic occlusion and inhibited the collagen (low concentration, 0.2 μg/ml; high concentration, 1 μg/ml)-induced platelet aggregation in whole blood ex vivo, each effect being concentration-dependent. The effects were tested of ticlopidine [30 mg (99.9 μmole), 100 mg (333.1 μmole) and 300 mg (999.2 μmole)/kg, p.o.] and aspirin [10 mg (55.5 μmole), 30 mg (166.5 μmole) and 100 mg (555.1 μmole)/kg, p.o.]. Both drugs prolonged the time to occlusion (but only at their highest concentration), and also inhibited the collagen (low concentration)- induced platelet aggregation in whole blood ex vivo. Aspirin [100 mg (555.1 μmole)/kg, p.o.], but not ticlopidine (at any concentration), inhibited the collagen (high concentration)-induced platelet aggregation. A good correlation was found between the antithrombotic and antiplatelet-aggregating effects of both KBT-3022 and aspirin, but not of ticlopidine. The antithrombotic potency of KBT-3022 was 300 times that of aspirin and 1000 times that of ticlopidine. These observations suggest that KBT-3022 may be clinically effective against platelet-rich thrombosis. Drug Dev. Res. 40:217–222, 1997. © 1997 Wiley-Liss, Inc.     

Effects of antiaggregant and antiinflammatory doses of aspirin on coronary hemodynamics and myocardial reactive hyperemia in conscious dogs

Clinical studies have shown that low doses of aspirin (<300 mg/day) inhibit thromboxane A2 production and platelet aggregation but preserve prostacyclin synthesis. In contrast, high doses of aspirin (>1,000 mg/day) suppress the synthesis of both eicosanoids. Because the consequences of aspirin administration have never been investigated on coronary vasomotor tone in vivo, we investigated the effects of low and high doses of aspirin on systemic and coronary hemodynamics under basal conditions and after myocardial reactive hyperemia in conscious dogs. Dogs were instrumented with a Doppler flow probe and a hydraulic occluder. Coronary blood flow was measured in the conscious state at baseline and during myocardial reactive hyperemia after 10, 20, and 30 s of coronary occlusion. Thromboxane B2 serum concentrations, an index of platelet aggregation, decreased by >90% after long-term i.v. administration of aspirin, 100 mg/day for 7 days (low dose). Neither systemic and coronary hemodynamics nor reactive hyperemia were affected by the drug. After combined administration of this low dose of aspirin and of the nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NNA, 30 mg/kg/day/7 days), reactive hyperemia decreased to the same extent as when L-NNA was administered alone. After administration of a unique high-dose aspirin (1,000 mg, i.v.), myocardial reactive hyperemia was markedly reduced, and this effect was still observed after previous blockade of NOS and cyclooxygenase by L-NNA and diclofenac, respectively. Thus long-term treatment with a low antiaggregant dose of aspirin does not alter the ability of coronary vessels to dilate during myocardial reactive hyperemia in conscious dogs. In contrast, short-term administration of a high antiinflammatory dose of aspirin severely blunts myocardial reactive hyperemia through a mechanism that is independent of both cyclooxygenase and nitric oxide metabolic pathways.     

Inhibitory effect of tiaramide of aggregation in vivo and on electrophoresis of rabbit platelets

Effects of tiaramide, aspirin an indomethacin were studied on rabbit platelet aggregation in vivo and on platelet electrophoretic mobility. When tiaramide (6 mg/kg), aspirin (30 mg/kg) or indomethacin (1.3 mg/kg) was injected into the ear vein of rabbit during 60 sec, tiaramide only inhibited ADP-induced aggregation, 20 min after the injection. All three drugs prevented collagen-induced aggregation 20 and 120 min after the injection. Tiaramide and aspirin prevented aggregation 24 hours later. The inhibitory effects on the aggregation of tiaramide are presumably independent of prostaglandin synthesis, because malondialdehyde (a metabolite of PGG2) production was not influenced. Tiaramide reduced cyclic AMP levels in platelets after 20 min incubation, despite the ability of this agent to inhibit platelet aggregation. Tiaramide, aspirin and indomethacin per se has no effect on platelet electrophoretic mobility, while tiaramide prevented the decrease in the mobility produced by ADP. Tiaramide and aspirin also depressed the decrease in the mobility produced by collagen.     

Effects of 6-[p-(4-phenylacetylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)pyridazinone (CCI 17810) and aspirin on platelet aggregation and adhesiveness.

1. The effects of 6-[p-(4-phenylacetylpiperazin-1-yl)]-4,5-dihydro-3(2H)pyridazinon (CCI 17810) on platelet aggregation and adhesiveness have been investigated and compared with those of aspirin. 2. In vitro, CCI 17810 was a potent inhibitor of the aggregation of human platelets induced by collagen, adenosine 5'-diphosphate (ADP) (primary response), thrombin and arachidonic acid, with EC50 values in the range 0.5 to 10 micrograms/ml. The second phase of the response to adrenaline was blocked by concentrations in the range 15 to 25 micrograms/mg. Platelets from rats, rabbits and dogs were as sensitive as human platelets to the effects of CCI 17810. Aspirin was nearly as effective as CCI 17810 against collagen, and adrenaline but about 10 times less active against arachidonic acid; it did not inhibit the primary response to ADP and was only a weak inhibitor of thrombin-induced aggregation. 3. In mice, single oral doses of CCI 17810 in the range 12.5 to 100 mg/kg inhibited collagen-induced thrombocytopenia. Arachidonic acid-induced mortality was markedly reduced by 10 mg/kg and possibly slightly reduced by 1 mg/kg. Aspirin was considerably less active than CCI 17810 in inhibiting collagen-induced thrombocytopenia but was almost as active as CCI 17810 in reducing arachidonic acid-induced mortality. 4. In vitro, CCI 17810 reduced the adhesiveness of human platelets to glass beads (retention of platelets in glass bead columns). Single oral doses of CCI 17810 in the range 25 to 200 mg/kg reduced mouse platelet adhesiveness; rat platelet adhesiveness was reduced by doses in the range 12.5 to 100 mg/kg. Aspirin (20 or 200 mg/kg) slightly increased mouse platelet adhesiveness.     

Sex differences in discriminative stimulus effects of morphine in the rat

Nine female and ten male rats were trained to discriminate 3.0mg/kg s.c. morphine from saline. The six female rats that acquired and maintained the morphine discrimination did so in significantly fewer sessions than the eight males did (28 +/- 5 vs 51 +/- 9 sessions, respectively), and the ED(50) for morphine substitution was significantly lower in females (0.69 +/- 0.15 vs 1.28 +/- 0.20mg/kg). The time course of morphine substitution was approximately equivalent in females and males. The μ agonist fentanyl completely substituted for morphine in both sexes, with no sex difference in potency to substitute for morphine. The μ agonist buprenorphine partially or completely substituted for morphine in all females and five of six males, but at a lower dose in females (ED(50) 0.009 +/- 0.002 vs 0.019 +/- 0.006mg/kg). The delta agonist BW373U86 partially substituted for morphine in both sexes, with no potency differences; the kappa agonist U69,593 and the non-opioid cocaine did not substitute for morphine in either sex. On a test of spontaneous locomotor activity, morphine increased locomotion to a slightly but not significantly greater extent in males than in females. Morphine also produced significantly greater hotplate antinociception in males than in females. Further drug discrimination training with a lower dose of morphine, 1.0mg/kg, decreased the ED(50) for morphine substitution in females and males to 0.26 +/- 0.06 vs 0.45 +/- 0.11mg/kg, respectively (not significant). In a separate group of age-matched rats, there was no sex difference in brain or plasma levels of morphine measured via HPLC 20min post-injection, the pretreatment time used to examine behavioral effects of morphine. The HPLC results, plus the fact that sex differences were not the same for all behavioral effects of morphine, suggest that sex differences in discriminative stimulus effects of morphine are not due to differential pharmacokinetics. The possibility that sex differences in morphine discrimination reflect sex differences in opioid receptor pharmacology, or differential reinforcement between morphine and saline levers for males but not females, is discussed.     

Effects of two preparations of 75-mg extended-release aspirin on platelet aggregation, prostanoids and nitric oxide production in humans

OBJECTIVE: The lowest dose of aspirin shown to be effective in the secondary prevention of thrombotic accidents is 75 mg/day. Presystemic acetylation of cyclooxygenase and the formation of salicylic acid in the liver are fundamental to ensure optimum antithrombotic effects of aspirin. This study was designed to compare the effects of two forms of extended-release aspirin (at 75 mg/day) on prostanoid and nitric oxide synthesis in healthy volunteers. METHODS: The participants in this single-blind cross-over study (n = 6) were randomly assigned to receive one of three different formulations: plain-formulated aspirin (PF), extended-release aspirin that released acetylsalicylic acid steadily over 5 h (EX5) or an extended-release formulation that released 49% of the drug during the first 2 h after intake (EX2) and the rest of the dose during the subsequent 5 h. Laboratory analyses were done for platelet aggregation and thromboxane B2 (in whole blood), 6-keto-prostaglandin F1alpha (in leucocytes), neutrophil nitric oxide production and plasma nitrite/ nitrate levels. RESULTS: The PF and EX2 formulations inhibited platelet aggregation by 97% with no significant difference in effect between the two. In contrast, maximum inhibition of aggregation by the EX5 formulation was only 30%. Similar effects were found for platelet thromboxane production: PF and EX2 led to 99% inhibition, whereas EX5 led to 76% inhibition (P < 0.05). The inhibition of prostacyclin production differed in all three treatments (63% for PF, 40% for EX2 and 24% for EX5). The increase in leucocyte nitric oxide production also differed in all three treatments (1.01-fold the basal value with PF, 1.4-fold with EX5 and 3.6-fold with EX2). Both extended-release formulations maintained high levels of nitric oxide production 24 h after the last dose, whereas in the PF period nitric oxide concentration had returned to basal values after this time. The changes in plasma nitrite concentrations in each period of treatment were similar to those seen for leucocyte nitric oxide. CONCLUSION: The pharmacodynamic profile of the extended-release formulations was better than that of plain-formulated aspirin in terms of thromboxane/prostacyclin balance and nitric oxide production. However, the EX2 formulation inhibited platelet function more effectively than did the EX5 formulation.     

Sex difference in the effect of aspirin on intracellular Ca2+ mobilization and thromboxane A2 production in rat platelets

The intracellular Ca2+ mobilization in thrombin-stimulated platelets was greater in male rats than in female rats. Thromboxane (TX) B2 production in male platelets was greater than that in female platelets. Aspirin suppressed Ca2+ mobilization in rat platelets, but the inhibitory effect of aspirin was more efficient in males than that in females. Aspirin inhibited TXB2 production, and this inhibitory effect of aspirin was stronger in male platelets than in female platelets. Castration decreased Ca2+ mobilization and TXB2 production and weakened the effect of aspirin on them. It is suggested that the sex difference in the antiplatelet effect of aspirin results from the difference in the inhibition of Ca2+ mobilization via the inhibition of TXA2 production in thrombin-stimulated rat platelets.     

The effect of itazigrel and aspirin on the mucosa of the esophagus, stomach, and duodenum of normal subjects

The effects of aspirin, itazigrel (U-53,059; a new antiplatelet drug), and placebo on the mucosa of the esophagus, stomach, and duodenum were evaluated in this double-blind, randomized, placebo-controlled study. Six normal male subjects were included in each of five treatment groups: aspirin (325 mg each morning for five doses), aspirin (325 mg tid for 12 doses), itazigrel (25 mg each morning for five doses), itazigrel (50 mg tid for 12 doses), and placebo. Aspirin and itazigrel, at all doses investigated, significantly inhibited ex vivo, ionophore (A23187)-stimulated thromboxane B2 synthesis. Collagen-induced platelet aggregation was significantly inhibited on day 3 (P = .021) and day 5 (P = .002) in both aspirin and itazigrel groups as compared with placebo. Upper gastrointestinal endoscopy was performed before the first dose of drug (day 1) and two hours after the last dose (day 5) for each subject. A rating scale was used to score the amount of mucosal damage. The baseline (day 1) endoscopic scores revealed no significant differences between groups. On day 5, neither placebo nor itazigrel treatment groups showed any significant change compared with baseline. On day 5, both aspirin groups had significantly (P less than .001) more mucosal damage than the placebo group and either itazigrel group. It is concluded that in this relatively acute study, at doses that produce comparable inhibition of platelet aggregation and platelet cyclo-oxygenase, itazigrel was superior to aspirin in terms of toxicity to the upper gastrointestinal tract.     

Effects of a new anti-inflammatory imidazole derivative, fenflumizole, on platelet aggregation in the rabbit

The antiplatelet effect of fenflumizole, compared with aspirin or ticlopidine, was examined in in vitro, ex vivo and in vivo situations of the rabbit. Unlike ticlopidine, fenflumizole and aspirin effectively inhibited in vitro the platelet aggregation elicited by arachidonate and collagen. The activity of fenflumizole was 350 times more potent than that of aspirin. Fenflumizole (0.3-3 mg/kg) given p.o. was 4.2 and 8.1 times more potent than aspirin in inhibiting arachidonate- and collagen-induced platelet aggregations, respectively. Ticlopidine (300 mg/kg, p.o.) resulted in only weak effects on the aggregations. Fenflumizole (3 mg/kg) as well as aspirin (10 mg/kg) given p.o., unlike ticlopidine (300 mg/kg), effectively prevented the arachidonate-induced sudden death.     

Acute effect of ethanol administration on platelet function

The acute effect of single dose of ethanol (1.5 g kg) and aspirin (10 mg/kg) alone and in combination, on platelet aggregation time and platelet adhesiveness were studied in rabbits. There was a significant and comparable increase in aggregation time both by aspirin and ethanol. Similarly platelet adhesiveness was decreased by both the agents.