High-dose Acetylsalicylic Acid Research Articles

Pulmonary haemodynamics during exercise after low and high doses of acetylsalicylic acid in sheep.

Despite comparable increases in cardiac output there is a greater reduction in pulmonary vascular resistance (PVR) in sheep during exercise than in dog or man. The mechanism for this marked reduction in PVR in sheep is unknown. To assess the role of arachidonic acid metabolites in producing this low PVR we measured the effect of intravenous acetylsalicylic acid (ASA, 10 mg/kg) on PVR at rest and during exercise in sheep. ASA caused a slight rise in resting PVR (p less than 0.05), but did not affect the exercise-induced decrease in PVR. High-dose ASA (100 mg/kg), presumably sufficient to block the lipoxygenase pathway produced the same responses as low-dose ASA which should only block the cyclo-oxygenase pathway. Products of the cyclo-oxygenase and lipoxygenase pathways which include vasodilator prostaglandins, have only a minor role in maintaining low pulmonary vascular resistance at rest and have no demonstrable role in the reduced PVR that occurs during exercise in sheep.

Effect of a Prostaglandin E1 Derivative (OP-1206) and Acetylsalicylic Acid on Electrically Induced Thrombosis in Guinea-Pig Mesenteric Artery and Its Modification by an Inhibitor of Prostaglandin I2 Synthetase, Tranylcypromine

The antithrombotic effect of a prostaglandin E1 derivative, OP-1206 (17S-20-dimethyl-trans-Δ2-PGE1)⋅α-cyclodextrin clathrate (OP-1206⋅α-CD), was compared with that of acetylsalicylic acid (ASA) in a electrically induced thrombosis model of guinea-pig mesenteric arteries using intact animals and animals subjected to the superfusion of tranylcypromine (TC, 15 mM) over their mesentery. The drug-effect was assessed by the change of the threshold voltage for the thrombus formation. 1) TC (1.5–15 mM) lowered the threshold voltage, and the effect was comparable to its inhibitory effect on PGI2 formation in vitro, investing that PGI2 generated in mesenteric arteries acts to prevent thrombus formation. 2) In intact animals, OP-1206⋅α-CD at doses of 0.01–0.3 mg/kg, p.o. (as OP-1206), significantly and dose-dependently elevated the threshold voltage. ASA 30–1000 mg/kg, p.o.) significantly elevated the threshold voltage, but the effect reached to its maximum at 100 mg/kg and lessened with further Increase of 3) In TC-treated animals, OP-1206⋅α-CD elevated the threshold voltage dose-dependently, but the elevation of threshold voltage by ASA reached to its plateau evel which was significantly lower than that obtained with OP-1206⋅α-CD at 0.3 mg/kg, indicating that the antithrombotic effect of ASA is incomplete in this model. 4) Threshold voltages in TC-treated animals given OP-1206⋅α-CD was significantly lower than those in intact animals at all doses tested, but threshold voltages in TC-treated and intact animals given ASA at 300–1000 mg/kg were not different, suggesting that high doses of ASA inhibits PGI2 formation in vivo. Thus, the antithrombotic effect of ASA was restricted by its inhibitory effect on PGI2 formation and its incomplete inhibition on thrombus formation, while such differences were not observed in OP-1206⋅α-CD.

Intimal thickening in autogenous vein grafts in rabbits: influence of aspirin and dipyridamole.

The effects of three different platelet modifying regimens on the degree of intimal thickening of autogenous vein grafts in rabbits were measured one month after operation. Dipyridamole alone (2 mg/kg/6 h) had little effect on the intimal thickness of these rabbits compared with that of controls (mean (1 SEM) for treated animals: 72.0 (7.9) micron; controls: 63.6 (6.0) micron). High dose acetylsalicylic acid (40 mg/kg/24 h) plus dipyridamole (2 mg/kg/6 h) increased intimal thickening significantly (85.8 (6.0) v 63.6 (6.2) micron; p = 0.05, n = 17). Low dose acetylsalicylic acid (0.5 mg/kg/24 h) plus dipyridamole (2 mg/kg/6 h) also increased intimal thickening (79.0 (6.1) v 63.6 (6.0] micron but not to a significant degree. It has previously been shown in vitro that acetylsalicylic acid increases the area of an exposed subendothelial arterial surface covered by platelets. Such an effect may explain our finding of increased intimal thickening with high dose acetylsalicylic acid plus dipyridamole.

Human Joints and their Artificial Replacements

<h3>Background</h3> Pipeline embolization devices (PEDs) are increasingly used in the treatment of cerebral aneurysms. Yet, major ischemic or hemorrhagic complications after PED treatment associated with antiplatelet regimens are not well-established. <h3>Objective</h3> To investigate the risk of ischemic and hemorrhagic complications associated with common antiplatelet regimens following PED treatment, and to examine whether platelet function testing (PFT) is associated with a lower risk of these complications. <h3>Methods</h3> We searched Medline, Embase, and Cochrane from 2009 to 2017. Twenty-nine studies were included that had reported a uniform antiplatelet regimen protocol and had provided data on major ischemic and hemorrhagic complications following PED treatment. Random-effect meta-analysis was used to pool overall ischemic and hemorrhagic event rates across studies. The rate of these complications with respect to the antithrombotic regimen and PFT was assessed by χ² proportional tests. <h3>Results</h3> Overall, 2002 patients (age 55.9 years, 76% female) were included. A low-dose acetylsalicylic acid (ASA) regimen before and after PED treatment was associated with a higher rate of late ischemic complications than with high-dose ASA therapy (2.62 (95% CI 1.46 to 4.69) and 2.56 (1.41 to 4.64), respectively). Duration of post-procedure clopidogrel therapy &lt;6 months was associated with greater rates of ischemic complications (1.56, 95% CI 1.11 to 2.20) than a clopidogrel regimen of ≥6 months. Performing PFT before PED treatment was not associated with the risk of ischemic complications (1.27, 95% CI 0.77 to 2.10). <h3>Conclusion</h3> High-dose ASA therapy and clopidogrel treatment for at least 6 months were associated with a reduced incidence of ischemic events, without affecting the risk of hemorrhagic events.

Diflunisal, a New-Acting Analgesic and Prostaglandin Inhibitor: Effect of Concomitant Acetylsalicylic Acid Therapy on Ototoxicity and on Disposition of Both Drugs

Intermittent and concomitant acetylsalicylic acid (ASA) therapy was superimposed onto a 21-day regimen with diflunisal 250 mg b.i.d. Low doses of ASA (600 mg single dose or 300 mg q.i.d.) did not influence signficantly diflunisal blood levels whereas a 600 mg q.i.d. dosing caused a small significant drop, especially at trough level. This drop is not expected to be clinically significant. No ototoxicity could be demonstrated with any treatment of diflunisal though four of fourteen subjects reported mild tinnitus during concomitant therapy at the higher doses of ASA. Diflunisal at 375 mg b.i.d. failed to alter the metabolism of a single dose of labelled ASA (600 mg) as judged by plasma levels, urinary excretion and plasma binding. Daily urinary excretion of prostaglandins E1 and E2 major metabolite was decreased by about 70% by diflunisal.

INFLUENCE OF ACETYLSALICYLIC ACID, AN INHIBITOR OF PROSTAGLANDIN SYNTHESIS, ON THE DURATION OF HUMAN GESTATION AND LABOUR

A retrospective survey of 103 patients taking high-dose acetylsalicylic acid for at least the last 6 months of pregnancy has been carried out and comparisons made with control populations. Aspirin administration was associated with a highly significant increase in the average length of gestation, in the frequency of postmaturity, and in the mean duration of spontaneous labour. These observations are compatible with the known capacity of aspirin to inhibit the synthesis of prostaglandins, and suggest that endogenous prostaglandins are important regulators of the duration of human gestation and labour. The possibility is raised that aberrations in prostaglandin metabolism could be responsible for certain instances of postmaturity or prolonged labour.

Analgetika und renale Enzymausscheidung: Harnenzymaktivitäten bei ratten nach verabreichung von hohen dosen acetylosalicylsäure

The model of renal enzyme excretion in rats was used to investigate the influences of acetylsalicylic acid, one of the most widely used analgetic drugs, on the kidneys. The recorded changes in four enzymatic activities in urine (alkaline phosphatase = AP, lactic dehydrogenase = LDH, aspartate aminotransferase = GOT and “leucine aminopeptidase” = LAP) revealed three different actions of the drug, (1) High doses of acetylsalicylic acid exert a nephrotoxic action leading to the increase of renal enzymuria, mainly AP and LDH activity. (2) Acetylosalicylic acid provokes the desquamation of numerous tubular cells; this effect reaches its maximum at the second and third day following the administration of the drug. The appearance of numerous tubular cells is accompanied by highly increased activities of enzymes liberated from renal cells; GOT activity reached highest values during this period. (3) Acetylsalicylic acid inhibits the fibrinolytic system and blocks activation of renal (and urinary) peptidases. This might account for the fact that the LAP activity of urine did not reveal increased values despite the disturbed permeability and despite the appearance of numerous renal cells in urine. In vitro experiments ruled out any influence of acetylosalicylic acid on enzyme determinations in urine. The results are discussed in respect to the value of determinations of urinary enzymes for investigations in clinical pharmacology.