Large Doses Of Aspirin Research Articles

Freedom from complications related to dual ball-and-cage mechanical valve prostheses despite thirty years without anticoagulation

We report a case of a 57-year-old patient with a history of a Starr-Edwards mitral valve prosthesis and DeBakey-Surgitool aortic valve prosthesis implanted 30 years ago who presented with symptoms consistent with class IV heart failure. The patient had been on no anticoagulation for approximately 30 years secondary to recurrent epistaxis occurring two years after starting warfarin therapy postoperatively. Throughout the patient's lifetime he experienced no thromboembolic complications from the lack of anticoagulation, despite developing concomitant atrial fibrillation approximately ten years prior to admission. In place of warfarin the patient had substituted large doses of aspirin. A workup revealed normal function of the mechanical valves for this extensive period.

A Proposal for Evaluation of Platelet Aggregation and Adhesiveness for Clinical Trials with Cyclooxygenase Inhibitors and Nonsteroidal Antiinflammatory Drugs

The concern of the public and the medical profession in response to the recent reports of the serious side effects of Rofecoxib (Vioxx [Merck]) and naproxen prompts this suggestion that platelet aggregation and adhesiveness be evaluatedaspartoftheundertakingofclinicaltrialsofsuch substances. 1 In1977,Ireportedonthevariabilityofplateletfunction inresponsetoaspirin.Inagroupofpatientswithhistoryof gastrointestinal bleeding after ingestion of aspirin, platelet aggregation and adhesiveness significantly decreased in comparison to these measurements in controls. By contrast, in a group of patients with arthritis, platelet function was higher than in healthy individuals and was little affected despite large doses of aspirin. In some patients with arteriosclerotic vascular disease, platelet aggregation and adhesiveness were high and were hardly altered by aspirin, althoughinothers,theresponsewasvariable.Subsequently, others have reported similar variability. 2-4 I recommended that platelet function should be evaluated when patients wereputonlongtermaspirinmedicationtoavoidbleeding complicationinsomeandafalsepresumptionofproviding protectioninotherssusceptibletothromboembolicevents. Ouroldstudyofplateletaggregationandadhesivenesswith aspirin appears to be relevant to the recent revelation of cardiac events and strokes in patients on medication with COX-2 inhibitors and nonsteroidal antiinflammatory drugs, 5 which are widely used for their pain-relieving and cytoprotective effects. It is generally agreed that the complex platelet/ endothelial interaction plays an important role in the pathogenesis of thrombosis and homeostasis. Platelet aggregationandadhesivenessreflectthiscomplexinteraction, which, to variable degrees, is governed by factors such as cyclooxygenase 1 and 2, prostaglandin I 2, the chemical milieu, and operating hemodynamics. It has been established that prostaglandinI2ismainlya product of COX-2 in the endothelial cells and it has vasodilatory and antiplatelet aggregatory effects, and thromboxane A2i sderived from COX-1 and it has a potent aggregatory effect. The balance between these two, with otherfactorssuchasshearstressandavailabilityofNO,will determine the degree of platelet aggregation and adhesiveness. So patients with cardiovascular disease with significant damaged endothelial surface are compromised, not only by inadequate availability of NO locally, but also by insufficientproductionofprostaglandinI2.COX-2inhib

Prinzmetal’s Angina

Prinzmetal's angina, often referred to as "variant" angina, is a temporary increase in coronary vascular tone (vasospasm) causing a marked, but transient reduction in luminal diameter. This coronary vasospastic state is usually focal at a single site and can occur in either a normal or diseased vessel. Patients are predominantly younger women who may not have the classical cardiovascular risk factors (except for cigarette use). PVA has been associated with vasospastic disorders such as Raynaud's phenomenon and migraine headaches. Arrhythmias are common and may be life threatening especially when the effects of vasospasm are seen in those ECG leads that reflect the potential variations of the epicardial surface of the left ventricle. Endothelial dysfunction has been considered as primarily responsible for PVA. The diagnosis is made by observing transient ST-segment elevation during the attack of angina. Since PVA is not a "demand"- induced symptom, but rather a supply (vasospastic) abnormality, exercise treadmill stress testing is of no value in the diagnosis of PVA. The most sensitive and specific test for PVA is the administration of ergonovine intravenously. Fifty micrograms at 5-minute intervals is given until a positive result or a maximum dose of 400 microg has been administered. When positive, the symptoms and associated ST-segment elevation should be present. Nitroglycerin rapidly reverses the effects of ergonovine if refractory spasm occurs. Medical therapy classically employs vasodilator drugs, which include nitrates and calcium channel blockers. The prognosis is good when there is no significant coronary artery stenosis. Treatment of associated coronary atherosclerosis in elderly patients with PVA is advised. When PVA is associated with coronary atherosclerosis, the prognosis is determined by the severity of the underlying disease. beta-Blockers and large doses of aspirin are contraindicated in PVA.

Endogenous cyclo-oxygenase substrates mediate the neuroactivity of evening primrose oil in rats

The role of cyclo-oxygenase and or its substrate(s) on the neuroactivity of evening primrose oil was investigated on the basis that a blockade of cyclo-oxygenase activity using aspirin would inhibit neuroactivity of primrose oil if this effect was mediated by prostanoids. Streptozotocin diabetic rats and controls were all given large doses of aspirin, but only subgroups of them received primrose oil. Saphenous sensory A- and C-fibre, and sciatic motor conduction velocities were measured to assess neuroactivity of primrose oil. Aspirin enhanced the neuroactivity of primrose oil thus indicating that prostanoids are unlikely to mediate this neuroactivity, but also suggesting that substrates of cyclo-oxygenase are neuroactive. It is likely that cyclo-oxygenase antagonises neuroactivity of primrose oil by competing with the process for substrates. Thickly myelinated sensory A-fibres were most affected by primrose oil suggesting that the predominant sensory symptoms in diabetic neuropathy could be due to the sensitivity of sensory nerves to the metabolic aberration in diabetes. Normal nerve function is probably preserved by cyclo-oxygenase during an influx of neuroactive fatty acids from the gut, since inhibition of the enzyme rendered non-diabetic nerves vulnerable to dietary primrose oil.

Gastric mucosal protective effects of the synthetic prostanoid Ro 22‐1327 in rats

AbstractNonsteroidal antiinflammatory drugs (NSAID) and ethanol can produce gastritis and mucosal hemorrhages in man. We report the potent protective effects of a synthetic prostanoid, Ro 22‐1327, on experimental models of NSAID and ethanol‐induced gastric mucosal injury. Rats were orally administered aspirin (200 mg/kg in 150 mM HCl), indomethacin (80 mg/kg), or absolute ethanol (1 ml) after pretreatment with vehicle or Ro 22‐1327. Oral administration of 10 μg/kg and 100 μg/kg of Ro 22‐1327 significantly (P ≤ ·05) protected the gastric mucosa from the corrosive effects of aspirin and ethanol; Ro 22‐1327 protected against indomethacin at a dose of 100 μg/kg. The duration of the protective effect was 90 and 180 min for aspirin and ethanol, respectively. Topical (dermal) application of 100 μg/kg and intraperitoneal injection of 1 μg/kg and 100 μg/kg of Ro 22‐1327 produced significant (P ≤ ·01) inhibition of the formation of ethanol‐induced lesions. Orally administered Ro 22‐1327 produced a significant (P ≤ ·001) dose‐related (25 μg/kg–225 μg/kg) increase (40–90%) in mean thickness of mucus covering the gastric mucosa. PGE2 was less effective than Ro 22‐1327. Ro 22‐1327 produced diarrhea only when administered orally at doses that were 100‐fold greater than the dose required for mucosal protection. The results suggest that this new prostanoid may be useful as adjunctive therapy in rheumatoid arthritic patients susceptible to gastritis and mucosal injury caused by large doses of aspirin or other NSAID.

Lack of evidence for aspirin use and prevention of cataracts.

A population-based cross-sectional survey of 838 men aged 30 years and over was conducted to examine the effect of aspirin, and other potential risk factors, on the prevalence of cataracts. Lens opacities were graded on clinical examination for location (cortical, nuclear, and posterior or subcapsular) and severity. The results do not support the claim that large doses of aspirin, or frequent use of aspirin, protects against or retards the growth of lens opacities.

Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man.

Acetylsalicylic acid (aspirin) inhibits prostanoid synthesis by irreversible acetylation of fatty acid cyclooxygenase (EC 1.14.99.1). It thereby inhibits synthesis of pro-aggregatory thromboxane A2 (TXA2) by platelets and is widely used in the treatment and prophylaxis of vascular disease. Its efficacy, however, may be reduced since it also inhibits formation of prostacyclin (PGI2) which is a vasodilator and anti-aggregatory agent. There is uncertainty over the optimum dose regimen for aspirin since although it inhibits platelet thromboxane production for many days, the magnitude and duration of its effect on PGI2 production by vascular endothelium in vivo is unknown. Resting plasma concentrations of PGI2 (measured as the stable hydrolysis product 6-oxo-PGF1 alpha) are at or below the limit of sensitivity of the most sensitive assays and cannot therefore be used to demonstrate a reduction in production. Bradykinin stimulates PGI2 synthesis by cultured human vascular endothelial cells and we have shown that it stimulates PGI2 production by man in vivo. We report here that an oral dose of aspirin (600 mg) causes rapid and substantial inhibition of bradykinin-stimulated PGI2 production, but recovery occurs within 6 hours; this implies that endothelial PGI2 synthesis would be spared most of the time during dosing once daily with even this relatively large dose of aspirin.

Aspirin and the Prevention of Experimental Arterial Thrombosis: Difficulty in Establishing Unequivocal Effectiveness

A trial of the efficacy of aspirin in the prevention of thrombotic occlusion of an "aortic loop" in rats was made simultaneously by two experimental surgeons. A relatively large dose of aspirin (80-100 mg/kg/day) was used, starting two days before operation. It appeared that aspirin was of limited benefit, reducing thrombotic occlusions by about 17% seven days after the insertion of the loop into the abdominal aorta. Although the average occlusion time was prolonged by about 17% in aspirin-treated animals, the separate trials gave no conclusive result. When the data from both operators were pooled, a statistically significant protection by aspirin was apparent (p = 0.02), by a two-tailed Student's t test. However, on using the powerful non-parametric randomization test, the occlusion times in control and aspirin-treated groups appeared not statistically different (p = 0.07). No significant difference was also found between control and treated groups when data were analyzed by X2 test. Independently of the statistical analysis, these data are quite similar to those obtained from aspirin trials in men surviving myocardial infarction. This finding points to the usefulness of the aorta loop as an animal model for arterial thrombosis.

Prostacyclin (PGI 2) and thromboxane A 2 interaction in vivo. Regulation by aspirin and relationship with anti-thrombotic therapy

The interaction between prostacyclin (PGI 2) and thromboxane A 2 (TXA 2) during intravenous infusions of arachidonate into cats or rabbits was studied using a technique for continuous measurement of platelet aggregation in whole blood. Arachidonate infused directly into the blood superfusing a strip obtained from an Achilles tendon induced platelet aggregation, presumably due to the conversion into TXA 2 by the platelets. However, when infused intravenously into the animals arachidonate had no effect or induced a little and reversible decrease in tendon weight due to platelet dis-aggregation consequent to conversion into prostacyclin by the vascular tissues. The dis-aggregating effect of intravenous infusion of arachidonate was potentiated by treating the animals with a small dose of aspirin but it was blocked after a large dose of aspirin. The manipulation of the PGI 2/TXA 2 ratio by using different doses of aspirin, suggests that the final pro- or dis-aggregating effect observed depends upon a balance between these two compounds.

Unstable metabolites of arachidonic acid aspirin and the formation of the haemostatic plug

Aspirin has a biphasic effect on cutaneous bleeding time of anaesthetized rabbits. In small doses it significantly prolongs the bleeding time. However, after a large dose this effect is not present. Intravenous infusion of arachidonate increased the bleeding time of control rabbits. This effect is enhanced by a small dose of aspirin and blocked by the large dose of aspirin. The effects of different doses of aspirin on the basal bleeding time and on the bleeding time modified by arachidonate seem to be the result of selective blockade of thromboxane A 2 (TXA 2) by the small dose and the blockade of both TXA 2 and prostacyclin (PGI 2) by the large dose. The balance of TXA 2/PGI 2 is important for the formation of the haemostatic plug.

Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiency.

People with the variants of glucose-6-phosphate dehydrogenase (GPD) deficiency common in the southern Chinese (Canton, B(-)Chinese, and Hong Kong-Pokfulam) have a moderate shortening of red-cell survival but no anaemia when they are in the steady state. With a cross-transfusion technique, primaquine, nitrofurantoin, and large doses of aspirin were found to aggravate the haemolysis while sulphamethoxazole did so only in some people. Individual differences in drug metabolism may be the reason for this. Many commonly used drugs reported to accentuate haemolysis in GPD deficiency did not shorten red-cell survival.

Analgesic Abuse and Kidney Disease

The analgesic syndrome, comprising renal disease, hypertension, peptic ulcer, anaemia and recurrent headache, accounts for wide-spread morbidity and mortality especially in Queensland and New South Wales. Epidemiological and clinical evidence gathered from many Western societies implicates unsupervised consumption of compound analgesic preparations, particularly those containing phenacetin, in the causation of the majority of cases. Laboratory experiments so far have failed to produce an entirely satisfactory model of clinical analgesic nephropathy. In small animals, papillary necrosis results from prolonged feeding with large doses of aspirin and a number of other anti-inflammatory agents more readily than when phenacetin, paracetamol or phenazone is given alone. The apparently conflicting deductive and experimental data may be reconciled if, as indicated by preliminary observations, salicylates enhance the toxicity of phenacetin derivatives. In planning a programme of prevention for the analgesic syndrome, the central aetiological role of non-narcotic drug dependency must be recognized. As the analgesics to which addiction commonly occurs are the compound powders and tablets, or those containing a stimulant, these preparations should be available only in circumstances where their use can be monitored. Suspected unsupervised and unwarranted consumption of analgesics should be checked by urinary testing for drug metabolites. Because the underlying problem of analgesic dependency is behavioural and environmental in origin rather than medical, the physician must combine forces with the social engineer to devise a definitive solution for this condition.

Effect of intravenous salicylates on the gastric mucosal barrier in man.

A high incidence of gastric ulceration is reported in patients with rheumatoid arthritis and in addicts taking large doses of aspirin. In rheumatoid arthritis a serum salicylate level of 15 mg% is considered to be therapeutic. We studied gastric mucosal permeability to ions in 9 healthy subjects given 3 g aspirin intravenously over 2 hours (mean serum salicylate, 17 mg%). Atropine was injected intravenously to reduce acid secretion which masks H+ loss. H+ and Na+ fluxes during aspirin infusion were not significantly different from those during intravenous saline infusion. Thus, high blood levels of salicylates did not impair the gastric mucosal barrier. Intragastric salicylic acid following intravenous aspirin infusion increased gastric mucosal permeability to H+ and Na+ ions. Under the conditions of these studies the effect was more marked in males. Gastric absorption of salicylic acid was similar in males and females, and the amount absorbed was unaffected by the presence of high blood levels of salicylates. Absorption of salicylic acid was significantly greater in the first period of salicylic acid instillation (mean, 28%) than in the second (mean, 21%) and third (mean, 16%) periods. Percentage absorption of undissociated salicylic acid was at least three times greater than that of H+ ions.

Simultaneous Metabolism of Aspirin and Acetaminophen in Man

Aspirin, administered orally in a single dose (2.9 g.) 1hr. before 650mg. acetaminophen, had no effect on the formation of the glucuronide and sulfate of acetaminophen. When aspirin was administered on a multiple-dose regimen of 2.6g. daily for 3 days, followed by a 650-mg. dose of acetaminophen on the 4th day, there was likewise no effect on the formation of acetaminophen metabolites. Since large doses of aspirin have no apparent effect on acetaminophen metabolism, it appears these two drugs may be metabolized by different enzyme systems.

ANTACID AND ANTIULCER PROPERTIES OF THE POLYSACCHARIDE CHITOSAN IN THE RAT.

ConclusionsChitosan, a polymer glucosamine obtained from the chitin of lobsters and crabs, affords a moderate, but definite protection to pylorus ligated rats against peptic ulceration of the rumin. This anti-ulcer activity has been shown to be due to a moderate capacity to bind free gastric acid and to a significant ability to act as a demulcent. Gastric demulcent activity was also observed in unligated dogs given a large dose of aspirin. Antipeptic activity was not observed with chitosan, but was with an aluminum hydroxide coprecipitate of chito-san. This latter material was almost equal to carrageenin in inhibiting proteolytic activity of gastric secretions but was not as effective as the sulfated galactosan in preventing peptic ulceration. A possible explanation of the lesser antiulcer potency of chitosan-AlOH is discussed.

RENEWED INTEREST IN ASPIRIN AS A HYPOGLYCEMIC AGENT

The blood-sugar-lowering effect of aspirin in diabetic patients was demonstrated by Ebstein (1876) and Bartels (1878) in Germany, and by Williamson in England (1901). Its use was abandoned because of its failure in advanced cases and because of the frequent development of salicylism when large doses of aspirin were used. Recently interest in this subject has been renewed, stimulated perhaps by the introduction of other, more widely known, oral hypoglycemic agents. To 12 diabetic and 13 non-diabetic patients from the wards and clinics of Kings County Hospital in Brooklyn, Hecht and Goldner¹administered minimal daily doses of 4.8 gm. of standard aspirin tablets for from 1 to 3 weeks. Marked hypoglycemic effects were obtained in both groups of patients, and the higher the glycosuria the more marked was the response to the action of aspirin. Two patients, whose fasting blood sugar levels initially were 62 and 86 mg.%, respectively,

The effect of aspirin upon the glycosuria of partially depancreatized rats in the presence and absence of the adrenal glands.

SALICYLATES and related compounds are capable of activating the adrenal cortices via the anterior pituitary (Cronheim, King and Hyder, 1952). Hailman (1952) has summarized the evidence that the therapeutic and biologic effects of these compounds are mediated by the increased secretory activity of the adrenal cortices. We have considered the possibility that aspirin can cause a state of hypercorticalism in the laboratory rat. If this were true, it would be expected that aspirin would exacerbate the diabetes of the partially depancreatized rat since corticotropin and the 11-oxygenated steroids of the adrenal cortex are diabetogenic (Ingle, 1948). On the contrary, large doses of aspirin suppress the glycosuria and hyperglycemia of diabetic patients and animals (see Gross and Greenberg, 1948, for review). In the present study it is shown that large doses of aspirin ameliorate the diabetes of partially depancreatized rats in both the presence and absence of the adrenal glands.

A case of aspirin poisoning.

From time to time accounts have appeared of recoveries and of deaths following the ingestion of large doses of aspirin. A further case is here reported.

UNUSUAL IDIOSYNCRASY TO ASPIRIN

The following case is reported because it seems unusual, and because of the violent reaction to an extremely small dose of aspirin. Judging from reports in the literature, poisoning from large doses of aspirin is relatively more frequent than that from small doses, which alone can show a distinct idiosyncrasy to the drug. History. —On June 20, 1910, the patient, a woman aged 40, on complaining of slight frontal headache, was given, at 10 a. m., 5 grains of aspirin and 1/60 grain strychnin sulphate, with instructions to take a similar amount of each at the end of one hour, if the headache persisted. Symptoms of Poisoning. —Fifty minutes later I was called and found the patient very nervous, excited and frightened. She complained of feeling queer and dizzy. The headache was worse and pain in the inner corner of the right eye was intense. Both eyes were puffy and