Single Dose Of Aspirin Research Articles

The differential inhibition of prostaglandin synthesis in platelets and vascular tissue in response to aspirin

Since aspirin inhibits the platelet as well as vascular prostaglandin synthesis it may therefore, paradoxically induce a thrombotic tendency when used as an antithrombotic agent. The in vivo effect of therapeutic doses of aspirin on the prostaglandin synthetic capacity of the rat platelets and vascular tissue was therefore studied to determine the significance of this paradoxical aspirin effect. A single aspirin dose of 5 mg/kg or greater was found to significantly decrease the synthesis of prostaglandin E by rat platelets. Even the normal augmentation of PGE synthesis by N-ethyl maleimide was significantly reduced by this single aspirin dose. In contrast, doses as high as 20 mg/kg of aspirin failed to reduce the production of 6-keto PGFla by aortic slices from rats pretreated with aspirin. These results indicate that the cyclo-oxygenase enzyme (CO) system in the prostaglandin biosynthetic pathway within blood vessel walls has the capacity to recover from this inhibitory effect of aspirin or it is less susceptible to inhibition than the CO in platelets. This relative resistance of CO to the inhibitory effects of aspirin may serve to protect the organism from excessive thrombotic tendencies brought about by the effect of aspirin on the vascular prostaglandin generating system. These results indicate that an aspirin dose of 5–10 mg/kg would be optimal if aspirin were to be used as an antithrombotic agent.

Clinical pharmacokinetics of salicylates: a re-assessment.

1 Aspirin is partly hydrolyzed to salicylic acid during absorption. Absorbed aspirin is rapidly hydrolyzed systemically. Salicylic acid elimination kinetics are dependent on drug concentration due to the limited capacity of two major biotransformation pathways: formation of salicyluric acid and of salicylphenolic glucuronide. 2 The time courses of the various pharmacological effects of single doses of aspirin are not directly coincident with the plasma concentrations of either aspirin or salicylic acid but there is reasonably good evidence that the pharmacological effects are related to the concentration of aspirin, salicylic acid, or both. 3 Steady-state plasma salicylate concentrations increase more than proportionally with increasing daily dose; the time required to reach steady state increases with increasing daily dose. Dosage intervals of 8 or even 12 h are usually sufficient to maintain plasma salicylate concentrations in the anti-inflammatory concentration range. Monitoring of plasma salicylate concentrations in this range is facilitated by the relatively small drug concentration fluctuations during a dosing interval at steady-state. 4 Limited data suggest that the pharmacological activity of salicylate is produced by free (unbound) drug. As the plasma protein binding of salicylic acid is concentration-dependent and subject to pronounced interindividual differences, it is preferable, at least in principle, to monitor free rather than total concentrations of salicylate in plasma. Although salicylate concentration in saliva reflects the free rather than total salicylate concentration in plasma or serum, use of saliva for indirect monitoring of plasma salicylate concentrations seems to be impractical for technical reasons.

The effect of aspirin on vascular prostaglandin I2 formation in rabbits

Vascular prostaglandin I2 (PGI2) is a potent inhibitor of platelet aggregation and keeps the vascular wall non-thrombotic. Since aspirin inhibits the synthesis of both thromboxane A2 and PGI2, the usefulness of this drug in thrombosis prevension is subject for discussion.In this report, we studied first the assay method of PGI2 using platelet aggregation test, and then the effect of aspirin on platelet MDA and vascular PGI2 formation.One hundred mg of aortic rings (approximately 3mg/ring) were indcubated in 100μl of 50mMol. tris-buffer (pH7.5) for 5 minutes at room temperature. The supernate contained platelet aggregation inhibiting activity equivalent to 200ng/ml of PGI2. The activity was stable for 3 hours at 0°C. PGI2 released from each of three equal sized portions of aorta cut into rings each weighing around 2.3, 3.3 or 7.7mg, respectively, were same.Vascular PGI2 formation was almost completely inhibited for at least 12 hours after the administration of aspirin (0.3g), and returned to initial level after 24 hours. But platelet MDA formation was markedly inhibited even 48 hours after the administration of aspirin. This means that the inhibitory effect of a single dose of aspirin lasts longer on platelet than on vascular PG synthesis.From these data, it is suggested that a dose of aspirin which inhibits platelet cyclooxygenase completely with slight inhibition of vascular cyclooxygenase may exist.

The Effects of “Anti-platelet” Drugs on Bleeding Time and Platelet Aggregation in Normal Human Subjects

The effects on hemostasis of several commonly used drugs previously described as inhibiting platelet function were evaluated in a randomized, double-blind study of 54 normal volunteers. The subjects were each given a single dose of aspirin, chlorpromazine, glyceryl guaiacolate, diphenhydramine, indomethacin or lactose placebo. A single dose of aspirin significantly prolonged the template bleeding time and inhibited secondary platelet aggregation two and 24 hours after ingestion. Single doses of indomethacin and chlorpromazine affected aggregation at two hours but had no effect on bleeding time, although multiple doses of indomethacin did prolong bleeding time. Glyceryl guaiacolate inhibited aggregation one hour after ingestion but had no effect on bleeding time. Diphenhydramine did not affect either. These findings suggest that standard doses of many commonly used "anti-platelet" drugs may have little clinical effect on the hemostatic mechanism in normal man. Results of in-vitro platelet-drug incubations may not be directly applicable to in-vivo hemostasis.

Electron microscopic study of the repair of aspirin-induced gastric erosions

To investigate the fine-structural events occurring during repair of aspirin-induced erosions, rats were killed at times from 2 to 48 hrs after a single aspirin dose. Erosions were rapidly covered by a line of flattened cells with little evidence of cytoplasmic specialization. Some of these cells lining early erosions contained a few mucous granules, but none showed features to suggest a derivation from parietal or zymogen cells. By 24-48 hr, considerable differentiation had accurred in the repairing epithelium, with many cells containing mucous granules and with "young" parietal cells being abundant. Some epithelial cells contained erythrocyte fragments, thus demonstrating phagocytic capability. It is concluded that dedifferentiation of surviving gastric epithelial cells occurs rapidly in response to aspirin injury and that the mucoid cells, rather than specialized glandular cells, are the likely source of the initial repair epithelium.

Inhibition of platelet release reaction by acetylsalicylic acid

Summary The inhibitory potency and duration of action of single doses of aspirin B.P., claradin (a low sodium effervescent preparation of acetylsalicylic acid) and aloxiprin (an aluminium co-polymer of acetylsalicylic acid) on platelet release reaction induced by adenosine diphosphate (ADP) were studied in seventeen volunteers. Aspirin B.P. and claradin at 300 mg and 150 mg inhibited release reaction in all subjects within 24 hr; 75 mg was effective only in some subjects. Aloxiprin gave less marked response and a dose of 300 mg was required to inhibit the effect in all volunteers. Where occurring, inhibition of release reaction persisted for three days after treatment with all preparations and restoration to normal occurred in most subjects by the sixth day. A daily dose of 50 mg claradin for 12-15 days in five volunteers produced complete inhibition of release reaction for most of the treatment period. Inhibition of release reaction took up to 3 days to occur. Normal aggregation returned within 3 days of discontinuing treatment in all subjects. A daily dose of 25 mg claradin gave inconsistent results. It is suggested that if a trial of acetylsalicylic acid be undertaken for the prevention of arterial thrombosis based on its ability to inhibit platelet release reaction then a daily dose of 50 mg would be sufficient.

Effect of carbenoxolone sodium on aspirin-induced injury of the rat gastric mucosa.

Investigations were performed in the rat to examine the effect of carbenoxolone sodium on aspirin-induced gastric mucosal injury. Mucosal damage was quantitated histologically in the body of the stomach (corpus) after a single dose of aspirin and after 2 weeks of daily aspirin. Over dosage ranges of 2–30 mg/kg/day of carbenoxolone and 10–120 mg/kg of aspirin, carbenoxolone treatment conferred no protection, despite evidence of a significant carbenoxolone effect on gastric mucus. This contrasts with the known protective action of carbenoxolone against injury by restraint stress and by corticosteroids. Much current evidence suggests that the mechanisms of erosion production by aspirin differ from those by restraint stress and corticosteroids, and it is likely that the present findings reflect such differences in pathogenesis.

Aspirin injury to rat gastric mucosa

Histological and radio-autographic studies with tritiated thymidine were performed on the gastric mucosa of rats following aspirin administration by oesophageal intubation. Following single doses of aspirin, multiple acute erosions were present in the fundic mucosa of all rats. After repeated doses, 3 types of lesions were observed: acute, re-epithelialized and chronic erosions. Administration of daily aspirin for 6 mth resulted in chronic gastric ulcers and atypical proliferatlon of gastric mucosal glands. This experimental model may have a clinical counterpart in patients with habitual ingestion of aspirin and chronic gastric ulcer.

Comparison of gross and microscopic gastric lesions produced in rats after single doses of aspirin and 2-deoxyglucose

Gross and microscopic examination was made of the stomachs from vagotomized or sham-vagotomized rats 4 hours after single doses of (1) 128 mg/kg aspirin po, (2) aspirin and 3 ml of 0.075 n hydrochloric acid po, (3) 256 mg/kg 2-deoxyglucose sc, or (4) 2-deoxyglucose sc and hydrochloric acid po. In the sham-vagotomized rats, aspirin and 2-deoxyglucose both produced 100% incidence of gastric hemorrhage and microscopic erosions. When aspirin was given to vagotomized rats, no gastric hemorrhage was observed grossly, but microscopic erosions were seen in each rat. When hydrochloric acid was given with aspirin in vagotomized rats, the incidence of gastric hemorrhage returned to 100% and microscopic examination showed deeper erosions. The incidence of gastric hemorrhage with 2-deoxyglucose was reduced from 100% to 0 by vagotomy, and on microscopic examination, only one animal was found to have an erosion; no gross or microscopic lesions were found in a group of vagotomized rats given hydrochloric acid with 2-deoxyglucose. Acid in the gastric lumen increased the severity of the erosions produced in vagotomized rats given aspirin but did not influence the production of gastric lesions in 2-deoxyglucose-treated rats.

Platelets in Rheumatoid Arthritis

SummaryPlatelet counts and adhesiveness in vivo were examined in 140 patients with rheumatoid arthritis and in 30 healthy subjects. Increased platelet counts were found in 50% of cases and impaired adhesiveness in vivo in 40%. Thrombocyte counts showed high positive correlation with leukocytosis but none with adhesiveness in vivo and degree of anemia. Ivy bleeding time was prolonged in 15 among 30 examined r.a. cases. Adhesion of normal platelets to purified collagen prepared from tendons of r.a. patients was found to be unimpaired. Aggregation of platelets with connective tissue extracts was delayed in r.a. PRP as compared with normal PRP. Extracts of r.a. synovia was less effective as aggregating agent than extracts of control synovia. It was found that a single dose of aspirin (2 g) does not influence platelet adhesiveness in vivo in healthy persons. On the basis of the presented results and literature data it is suggested that overproduction of platelets is a probable cause of thrombocytosis in r. a. while impairment of in vivo adhesiveness may be due to intrinsic defect of platelet and/or to presence of some inhibitory substances in blood and tissues.