Single Oral Dose Of Aspirin Research Articles

Low dose aspirin like analgesic and anti-inflammatory activities of mono-hydroxybenzoic acids in stressed rodents

AimsTo compare analgesic and anti-inflammatory activities of aspirin and mono-hydroxybenzoic acids after their daily oral doses. Main methodsEfficacies of repeated daily stress response suppressing low oral doses (20mg/kg) of aspirin and 2-, 3-, and 4-hydroxybenzoic acids in mice hot plate test for centrally acting analgesics, and in acetic acid induced writing test were compared. Effects of their same daily doses and treatment regimen in cotton pellet granuloma and carrageenan edema test for anti-inflammatory drugs in stressed rats were compared in a second experiment. Effects of treatments on body weights, basal rectal temperatures, organ weights and plasma glucose, insulin and cortisol levels in stressed animals were compared also. Key findingsAlthough stress response suppressing effects of aspirin and all the three hydroxybenzoic acids in both mice and rats were almost equal, effectiveness of 3- and 4-hydroxybenzoic acids as analgesic and anti-inflammatory agents were lower than those of aspirin or salicylic acid. SignificanceObservations made after single oral doses of aspirin or of mono-hydroxybenzoic acids are not very reliable predictors of their pharmacologically interesting bioactivity profiles and efficacies. Prostaglandin synthesis inhibition is not involved in low dose anti-inflammatory activities of 3- and 4-hydroxybenzoic acids. After their repeated daily low oral doses they are almost as potent stress response desensitizers as aspirin or salicylic acid.

A Possible Role for Gastroprotectives on Aspirin-Induced Gastric Ulcer in Rats

Background: Gastric ulcer is a discontinuity in the gastric mucosa that occurs due to imbalance between gastric mucosal protective factors and aggressive factors. The Aim of the present work was to test and compare the protective effects of an antisecretory H 2 receptor blocker; ranitidine and other recently suggested gastroprotective drugs: L-arginine; a precursor of NO, zinc sulfate; an anti-inflammatory antioxidant agent and pioglitazone; a PPAR-g agonist, on a rat model of aspirin induced gastric ulcer. Methods: Acute gastric lesion was induced in rats by a single oral dose of aspirin 300mg/ kg body weight. L-arginine 200mg / kg b. wt, zinc sulfate 80 mg/ kg b. wt, and pioglitazone 10 mg / kg b. wt. were given alone and in combination with ranitidine 50 mg / kg b. wt for 3 days before induction of gastric lesion. Results: Aspirin induced a significant increase in gastric mucosal lesion score and free and total gastric hydrochloric acid with a significant decrease in gastric nitric oxide and mucin levels as compared to normal group. A significant increase in gastric malondialdhyde and decrease in reduced glutathione as compared to normal group. L-arginine, zinc sulfate, and pioglitazone produced improvement of most of the measured parameters as compared to non-treated group. Combination of L-arginine and ranitidine was superior in prophylaxis against aspirin-induced gastric ulcer when compared to the effects of each drug used individually, and the other studied combinations. Conclusion: The role of HCl and NO seems more important in the pathogenesis of aspirin induced gastric ulcer, as evidenced by the better protective effects of combination of ranitidine and L-arginine in comparison to the ranitidine with either zinc sulfate or pioglitazone.

Vascular Effects of Apelin In Vivo in Man

This study was designed to establish the direct vascular effects of apelin in vivo in man. Apelin is the endogenous ligand for the previously orphaned G-protein-coupled receptor, APJ. This novel pathway is widely expressed in the cardiovascular system and is emerging as an important mediator of cardiovascular homeostasis. In pre-clinical models, apelin causes venous and arterial vasodilation. Vascular effects of apelin were assessed in 24 healthy volunteers. Dorsal hand vein diameter was measured by the Aellig technique during local intravenous infusions (0.1 to 3 nmol/min) of apelin-36, (Pyr(1))apelin-13, and sodium nitroprusside (0.6 nmol/min). Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of apelin-36 and (Pyr(1))apelin-13 (0.1 to 30 nmol/min) and subsequently in the presence or absence of a "nitric oxide clamp" (nitric oxide synthase inhibitor, L-N(G)-monomethylarginine [8 mumol/min], coinfused with nitric oxide donor, sodium nitroprusside [90 to 900 ng/min]), or a single oral dose of aspirin (600 mg) or matched placebo. Although sodium nitroprusside caused venodilation (p < 0.0001), apelin-36 and (Pyr(1))apelin-13 had no effect on dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (Pyr(1))apelin-13-mediated vasodilation was attenuated by the nitric oxide clamp (p = 0.004) but unaffected by aspirin (p = 0.7). Although having no apparent effect on venous tone, apelin causes nitric oxide-dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis.

Abstract 1295: The Vasomotor Effects of Apelin in vivo in Man

BACKGROUND In preclinical models, apelin, the endogenous ligand for the G protein-coupled APJ receptor, lowers systemic venous tone, causes nitric oxide (NO)-mediated arterial vasodilatation and is the most potent inotrope yet studied. We aimed to establish the in vivo vasomotor effects of apelin in man. METHODS Dorsal hand vein diameter was measured by the Aellig technique in 6 subjects during local intravenous infusions (0.1–3 nmol/min) of two apelin agonists, apelin-36 and (Pyr1)apelin-13, and sodium nitroprusside (SNP; 0.6 nmol/min) in the presence and absence of norepinephrine preconstriction. Forearm blood flow (FBF) responses to intrabrachial infusions of apelin-36 and (Pyr1)apelin-13 (0.1–30 nmol/min) were measured by venous occlusion plethysmography in 8 subjects on 4 occasions. In a 2×2 factorial design, a further 8 subjects received an intrabrachial infusion of (Pyr1)apelin-13 (0.3–3 nmol/min) in the presence or absence of the NO clamp (NO synthase inhibitor, L-N-monomethylarginine (8 micromol/min), co-infused with SNP (1–128 ng/min) to maintain basal flow and clamp endogenous NO production), and following a single oral dose of aspirin (600 mg) or matched placebo. RESULTS Although SNP caused venodilatation (P&lt;0.0001), apelin-36 and (Pyr1)apelin-13 had no effect on dorsal hand vein diameter in the presence or absence of norepinephrine (P=0.2). Both apelin-36 and (Pyr1)apelin-13 caused reproducible dose-dependent vasodilatation in forearm resistance vessels (P&lt;0.0001): maximal increase of 198+/−27% and 90+/−7% respectively. Vasodilatation had a rapid onset (within 6 min) and slow offset that remained 36 min post-infusion (P&lt;0.01). Plasma apelin concentrations and non-infused FBF (P&lt;0.05) were increased at doses &gt;3 nmol/min, consistent with systemic spillover. (Pyr1)apelin-13-mediated vasodilatation was attenuated by the NO clamp (AUC reduced by 64%; P=0.004) but was unaffected by aspirin (P=0.7). CONCLUSION Although having no apparent effect on venous tone, apelin causes a rapid onset and sustained NO-dependent arterial vasodilatation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis and its therapeutic potential in heart failure.

Effects of recombinant human erythropoietin on antiplatelet action of aspirin and clopidogrel in healthy subjects: Results of a double-blind, placebo-controlled randomized trial

Recombinant human erythropoietin (rHuEpo) reduces myocardial injury in experimental ischemia and has been proposed as a cardioprotective agent for potential use in acute coronary syndromes. Its safety profile in clinical acute ischemic settings is uncertain because rHuEpo has been reported to increase platelet reactivity and the risk of thromboembolism in some disease populations. Whether prothrombotic effects of rHuEpo mitigate the effects of antiplatelet agents used in acute coronary syndrome patients is unknown. Recombinant human erythropoietin 100, 200, 400 U/kg, or placebo was given intravenously once daily for 3 consecutive days in a double-blind randomized trial in 96 healthy subjects. A single oral dose of aspirin 325 mg or clopidogrel 300 mg was given immediately after the last dose of study drug. Bleeding time and in vitro high shear stress platelet function assays (PFA)-100 were determined before; 5 hours; and 1, 5, and 7 days after aspirin or clopidogrel. Recombinant human erythropoietin at doses of 100 and 200 U/kg did not alter bleeding time or PFA-100 closure times at any time point when compared with placebo. Recombinant human erythropoietin at a dose of 400 U/kg significantly blunted the post-aspirin increase in bleeding time when compared with placebo (P = .03) but did not alter post-clopidogrel bleeding times nor PFA closure times. The 400-U/kg dose did not change hematocrit but did significantly increase the platelet count at 5 days after study drug administration when compared with placebo (P = .014). Short-term rHuEpo at doses up to 200 U/kg did not mitigate the effects of administration of aspirin or clopidogrel on either in vivo or in vitro measures of platelet function in healthy subjects. The 400-U/kg dose attenuated the effects of aspirin on bleeding time and increased the platelet count. Studies of the effects of rHuEpo on platelet function in patients with coronary artery disease are warranted to further characterize dose/safety profile.

Heat shock protein and high-dose aspirin: effects on random skin flap survival in a rat model.

The heat shock response is known to have a protective effect against flap ischemia. It has been shown that heat shock protein (hsp) expression can be augmented in vivo with the administration of high-dose aspirin before heat treatment. The authors hypothesized that administration of aspirin before hsp induction through heat stress would enhance further the protective effects of the heat shock response against skin flap ischemia. They used a random dorsal skin flap model in 32 rats divided into four groups (N = 8 each): control, heat shock, aspirin plus heat shock, and aspirin. Before surgery, rats in the two heat shock groups were placed in a 45 degrees C water bath until core body temperature measured 42 degrees C, and they were maintained at 42 degrees C for 15 minutes. Rats in the two aspirin groups received a single oral dose of aspirin (100 mg per kilogram) 1 hour before heat bath or surgery. Immunohistochemistry confirmed hsp expression in the two heat groups. Skin flap survival was improved significantly (p < 0.05) in the heat shock (55%), aspirin plus heat shock (58%), and aspirin (60%) groups when compared with controls (45%). Contrary to their hypothesis, aspirin combined with hsp induction did not offer greater protection from ischemia than hsp induction alone (p > 0.05). However, high-dose aspirin administration alone did improve skin flap survival when compared with controls. Future studies are needed to investigate further the role of pharmacological therapy combined with hsp induction in improving skin flap survival and to delineate the dose-response relationship between aspirin and hsp.

Role of neutrophils and mucosal blood flow in gastric adaptation to aspirin.

Gastric mucosa adapts to ulcerogenic action of aspirin but the mechanism of this phenomenon is unknown. In this study, acute gastric lesions were produced by single or repeated oral administration of acidified aspirin in rats with intact or deactivated (by capsaicin) sensory nerves and with intact or suppressed synthase of nitric oxide (NO). Single oral dose of aspirin produced a dose-dependent increase in the area of gastric lesions accompanied by a significant increase in blood neutrophils, neutrophil infiltration into the mucosa, leukotriene B4 formation and almost complete suppression of prostaglandin synthesis. After repeated administration of aspirin, the mucosal damage progressively declined and this was accompanied by a significant augmentation in gastric blood flow. In addition, a reduction in blood neutrophil count, mucosal neutrophil infiltration and leukotriene B4 release was observed during this adaptation of the stomach to repeated aspirin insults. Capsaicin denervation of sensory nerves aggravated the damage induced by the first exposure of the stomach to aspirin and caused a significant reduction in gastric blood flow, but with repeated aspirin administration, gastric adaptation to this agent and a rise in gastric blood flow were observed. Pretreatment NG-nitro-L-arginine with (L-NNA), a specific inhibitor of nitric oxide synthase, eliminated the hyperemic response to repeated aspirin insults but failed to affect the adaptation to aspirin. We conclude that the rat stomach adapts readily to repeated aspirin insults despite sustained inhibition of prostaglandin biosynthesis and this adaptation appears to be mediated by a significant increase in gastric blood flow and a reduction in neutrophil activation and leukotriene B4 release.

Effect of single oral dose of aspirin on human platelet functions and plasma plasminogen activator inhibitor-1.

Previous reports documented the inhibitory efficacy of different doses of aspirin on arachidonic acid (AA)-induced platelet aggregation, however, the sensitivity of platelets toward other agonists as well as the effects of aspirin on platelet and plasma plasminogen activator inhibitor-1 (PAI-1) release and levels were not investigated. Hence, the present study was undertaken to investigate the effect and duration of action of a single oral dose (650 mg) of aspirin on human platelet functions (n = 34, normal healthy male and female volunteers) including aggregation, fibrinogen binding and PAI-1 release, and on the plasma level of PAI-1. Aspirin demonstrated a rapid onset of action (at 2 h after ingestion) in specifically inhibiting ex vivo AA-mediated functions including (a) fibrinogen binding to gel-purified platelets, (b) platelet aggregation, and (c) platelet PAI-1 release. A peak reduction of plasma PAI-1 level at 2 h was demonstrated as well. The effect of aspirin on the ex vivo AA-mediated effects (a-c) was shown to last for up to 4 days. However, aspirin treatment resulted in a rebound effect in platelet function (a-c) to other platelet agonists such as adenosine diphosphate or the combination of agonists including adenosine diphosphate, epinephrine, and AA. In conclusion, a single oral dose of aspirin has long-acting effects on AA-induced platelet activation and reduces plasma levels of PAI-1 as well.(ABSTRACT TRUNCATED AT 250 WORDS)

THROMBELASTOGRAPHY AFTER ASPIRIN INGESTION IN PREGNANT AND NON-PREGNANT SUBJECTS

The thrombelastograph (TEG) and bleeding time were performed before and 6 h after a single oral dose of aspirin 600 mg in a group of eight healthy volunteers and 12 pregnant patients. Measured TEG variables (r, k, r+k times and maximum amplitude) were unaltered after aspirin although there was a significant prolongation of the bleeding time in both groups. Although the TEG appeared not to detect aspirin-induced changes in platelet function, the TEG measures all phases of coagulation and the unaltered TEG after aspirin suggested a functioning coagulation system.

Critical Evaluation of Platelet Aggregation in Whole Human Blood

Platelet aggregation studies generally are performed in platelet-rich plasma (PRP) by the turbidometric method. The authors compared this technic with the recently introduced impedance aggregometry in PRP and whole blood (WB). In healthy controls there was a good correlation between the two technics when aggregation was induced by ADP or collagen. As compared with PRP, platelets in WB were more sensitive to the aggregating effect of thrombin, ristocetin, and arachidonic acid. Platelet sensitivity to prostacyclin was increased in WB. The anti-platelet effect of a single oral dose of aspirin could be detected for a longer period in WB than in PRP. Platelet aggregation tests in WB from patients with platelet dysfunctions showed the same response pattern to different aggregating agents as in PRP. In contrast to turbidometry, the impedance method in PRP and WB enabled registration of platelet aggregation in a dose-dependent fashion in a sample from a patient with severe hyperlipoproteinemia. It is concluded that platelet aggregation can be studied conveniently with the impedance method in the more physiologic medium of WB. Providing the same information as the well-established turbidometry, the time-sparing impedance method needs less citrated blood. Moreover, our results show an increased sensitivity of the WB system to some aggregating and anti-platelet agents.

Inhibition by aspirin of human arterial and venous prostacyclin synthesis

Prostacyclin (PGI 2) synthesis by human mesenteric arteries and veins was measured ex vivo in 62 patients who received either no medication or a single oral dose of aspirin 40 mg, 75 mg or 300 mg approximately 24 hrs pre-operatively. Each dose of aspirin caused a significant reduction in both arterial and venous PGI 2 synthesis compared with the untreated group. Arterial PGI 2 synthesis did not differ significantly from venous PGI 2 synthesis whether assessed by sample weight or sample area.

Failure of Salicylate to Reduce Inhibition of Human Venous Prostacyclin in Synthesis by Conventional Dose Aspirin

Ex vivo venous prostacyclin synthesis was measured in 24 patients who received no medication, or a single oral dose of aspirin 300 mg, sodium salicylate, 500 mg, or a combination of sodium salicylate 500 mg followed by aspirin 300 mg 1 1/2 or 3 hr later. Aspirin alone substantially reduced PGI2 synthesis but sodium salicylate alone had no effect. Sodium salicylate administration prior to aspirin did not reverse the inhibitory effect of aspirin on PGI2 synthesis.

Urinary excretion of aspirin.

Six human volunteers were each given single oral doses of aspirin (ASA) ranging from 300-1,500 mg. The unchanged ASA excreted in the urine was proportional to dose and urinary pH. The mean percent (+/- s.d.) of dose excreted was 1.9 +/- 0.67. The clearance for ASA was 1.42 +/- 0.28 1/h. The rate of in vitro hydrolysis of ASA to salicylic acid in urine at 37 degrees C was 4 micrograms/min for an initial ASA concentration of 7.5 mg in 100 ml human urine.

Blood flow reductions in stenosed canine coronary arteries: vasospasm or platelet aggregation?

In 67 dogs with a 60-80% coronary stenosis produced by an external constricting plastic ring, blood flow measured with an electromagnetic flowmeter showed cyclical flow reductions of varying magnitude and duration, and then an abrupt return to control flow. In 45 dogs, heparin did not prevent these flow reductions, but ibuprofen (Motrin) or indomethacin abolished them. With incremental doses of each of these drugs, the cyclical flow reduction and the platelet function in vitro were diminished proportionately. In 10 more dogs, during low flow, pinching or poking the narrowed vessel suddenly restored normal flow. Topical application of papaverine and nitroglycerin proximal to the stenosis did not abolish the cyclic flow reduction, although a transient fall in systemic pressure indicated that they had been absorbed. Seven dogs had the constricting cylinder and flow probe chronically implanted for 4-6 weeks. A single oral dose of aspirin, 20 mg/kg, abolished their cyclic flow reductions for 2-4 days. In five dogs with 70% stenosis in the circumflex coronary artery, coronary arteriography was performed before coronary flow reduction and when coronary blood flow was low. This showed that there was a considerable additional reduction in the size of the mechanically constricted lumen during spontaneous flow reduction. In one dog, a nonopacified mass was dislodged from the area of constriction in 67 msec and this restored the lumen to its control diameter. Similar rapid clearing was filmed in two more dogs. In no case was vasospasm observed. These results suggest that obstruction from platelets aggregated in the narrowed lumen caused the cyclic flow reductions.

Rapid return of cyclo-oxygenase active platelets in dogs after a single oral dose of aspirin

A single dose of oral aspirin in human subjects inhibits the aggregation response of platelets to arachidonate and other agents for approximately one week after ingestion. In the present study we have evaluated the rate at which cyclo-oxygenase active platelets return] to the circulation in human and dogs and compared the response curves obtained to improvements in cyclo-oxygenase activity produced by the aspirin platelets. After a single dose of aspirin, dog platelet function was compromised for several days. Normal responses to arachidonate and other aggregating agents were restored six days after aspirin, and the pattern of recovery was the same for dogs and human subjects. However, cyclo-oxygenase active platelets returned to the circulation in dogs more rapidly than in humans and chemical competence was erstored in both species well before correction of the defective response to aggregating agents. The delay of 1–3 days before return of significant numbers of cyclo-oxygenase active platelets most likely reflects acetylation of bone marrow megakaryocytes by the drug. More rapid return of chemically competent cells in dogs than humans probably relates to the more rapid turnover and shorter life span of canine platelets. The basis for the discrepancy in return of chemical integrity compared to functional activity after aspirin in vivo compared to simultaneous correction of chemistry and function when 10% normal platelets are added to aspirin platelets in vitro remains unresolved.

Salicylate metabolite kinetics after several salicylates.

Single oral doses of aspirin (ASA, 1,500 mg), sodium salicylate (NaSA, 1,500 mg, 1,200 mg), and salicyluric acid (SUA, 500 mg) were given to five subjects. Serial plasma and urine samples were collected for 24 hr (plasma) and up to 48 hr (urine); salicylic acid (SA), SUA, and gentisic acid (GA) were measured by high-pressure liquid chromatography. The plasma concentration/time profiles for SUA after ASA and NaSA were fitted to the empirical equation CpSUA = A-Bt-Ce-alpha t -- (A-C)e-beta t. Michaelis constants (Vm and Km) for the conversion of SA to SUA were calculated from the equation (formula see text), where Cl is the renal clearance of SUA, ke is the rate constant of elimination of SUA, CpSA is the plasma concentration of salicylic acid. The term Cl (formula see text) is the estimated rate of formation of SUA from SA at any time (t). The calculated values (mean +/- SD) of Vm, Km, and Kmf (Km in terms of unbound SA) were 43.4 +/- 10.1 mg SA/hr, 14.3 +/- 3.4 mg SA/l plasma, and 0.75 +/- 0.15 mg unbound SA/l plasma. The Vm values were in accord with those reported, but the value for Km was considerably lower. Renal clearances of SUA and GA were 340 +/- 51 and 65 +/- 10 ml/min.

Possible significance of small numbers of functional platelets in a population of aspirin-treated platelets in vitro and in vivo

Recent evidence has suggested that platelets capable of thromboxane synthesis enter the human circulation at the rate of 10% per day after a single oral dose of aspirin (ASA). We investigated the possible importance of a similar proportion of functional rabbit platelets in vitro and in the circulation of ASA-treated rabbits. Functional platelets obtained from untreated rabbits and ASA-treated rabbits were combined in a ratio of 1:9 respectively. Arachidonate-induced platelet aggregation and serotonin release were measured in vitro. The small proportion of functional platelets fully restored platelet aggregation and partially restored serotonin release in ASA-treated platelets. Untreated rabbits infused with arachidonic acid exhibited profound in vivo platelet aggregation and hypotension. These changes were associated with elevated thromboxane B 2 (TXB 2) levels. Rabbits pretreated with ASA were protected from these effects and the elevation in plasma TXB 2 was blocked. When ASA-treated rabbits were transfused prior to arachidonate infusion with a sufficient number of functional platelets to contribute 10% of the platelet population, the protective effect of ASA was reversed. These results suggest that 10% functional platelets can remove the protective effect of ASA on platelet aggregation both in vitro and in vivo.

Nephrotoxicity of mild analgesics in the Gunn strain of rat.

1 Homozygous members of the Gunn strain of rat, mutant Wistars jaundiced from lack of the enzyme uridine diphosphate glucuronyl transferase, are highly susceptible to analgesic-induced renal papillary necrosis. 2 A single oral dose of aspirin, phenacetin or paracetamol will produce the lesion, a circumstance which does not occur in other strains. 3 The reasons for this susceptibility have not been determined, but the experimental model should prove useful in further studies of the nephrotoxicity of analgesic drugs.

Acute effect of systemic aspirin on gastric mucosa in man.

Aspirin was administered intravenously to study its effect upon gastric mucosa at high blood levels in the therapeutic range for rheumatic diseases. Five healthy volunteers were studied twice each with intravenous aspirin (3 g over 2 hr) and isotonic saline infusion as control. In one study, gastric potential difference was measured; in the other, coded gastric biopsies were taken sequentially prior to infusion, and at the end of infusion. Duplicate biopsies were taken for light and scanning electron microscopy. Mean potential difference at the end of the intravenous aspirin infusions was -47.7 +/- 1.4 mV, compared with saline, -51.1 +/- 2.5 mV (P greater than 0.05). The percentage of cells damaged after 2 hr intravenous infusion of aspirin (3.2 +/- 0.4%) was not significantly different from that after intravenous saline (2.6 +/- 0.3%). In contrast to oral aspirin, acute administration of aspirin parenterally does not produce detectable histological damage in man, nor does it significantly alter gastric mucosal potential difference. We conclude that high blood levels of circulating salicylate do not acutely damage gastric mucosa. Thus, histologic gastric mucosal damage produced acutely after single oral doses of aspirin are due to its topical, rather than systemic, action.

Effect of a single oral dose of aspirin on the platelet aggregation response to arachidonic acid.

1 The platelet aggregation response to arachidonic acid ex vivo was measured in six volunteers daily before and for 10 days after a single oral dose of 600 mg aspirin. 2 Arachidonic acid induced aggregation of platelets from all subjects before aspirin and aggregation occurred after an interval which varied inversely with the concentration of arachidonic acid. No aggregation occurred for 4 days after aspirin; a reduced response, compared with pre-aspirin values, was obtained on the 5th, 6th and 8th day. The values on days 7, 9 and 10 were not consistently different from the pre-aspirin values. In 6 subjects 24 h after aspirin ingestion the addition of 10--25% v/v normal platelets restored the aggregation response. 3 It is concluded that aspirin has an effect on the platelet precursors in the marrow in addition to its effect on circulating platelets.