Plasma Aspirin Research Articles

Thrombotic Microangiopathy of the Miscellaneous Secondary Type Responding to Plasma Exchange in a Liver Transplant Recipient

A thrombotic microangiopathy syndrome, clinically and pathologically similar to thrombotic thrombocytopenic purpura (TTP) has been reported in recipients of tissue transplants, including renal and bone marrow allografts. The diagnosis is made only after other causes of microangiopathic hemolytic anemia have been excluded. In this case report we present the outcome of the combination of plasma exchange, dipyridamole and aspirin in the management of a TTP-like syndrome that complicated the post-operative course of liver transplantation.

The Evolution of Non-Steroidal Anti-Inflammatory Drugs and their Mechanisms of Action

The pro-inflammatory effects of prostaglandins have been clearly demonstrated with the use of various animal models of inflammation. Furthermore, the anti-inflammatory effects and some of the side effects of aspirin and other non-steroidal anti-inflammatory agents have been shown to depend on their ability to inhibit cyclo-oxygenase. These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane. They do not affect leukotriene production and there is no firm evidence to suggest that they alleviate inflammation through any other mechanism. In contrast, the corticosteroids facilitate the release of lipocortin which, through inhibition of phospholipase A2 reduces arachidonic acid release. These drugs possess potent anti-inflammatory properties and attempts have been made to develop non-steroidal drugs, such as BW755C, that display similar anti-inflammatory activity through inhibition of the 2 main pathways of the arachidonic acid cascade. Administration of low dose aspirin 40 mg/day selectively inhibits production of thromboxane A2 without affecting prostacyclin. This may be because, firstly, about 60% of an administered dose of aspirin is deacylated to salicylate during first-pass metabolism and, secondly, platelets cannot regenerate cyclo-oxygenase. Thus, absorbed aspirin irreversibly affects platelet thromboxane production in the pre-systemic circulation, but the systemic plasma aspirin concentration is likely to be too low to affect prostacyclin synthesis. Studies in experimental inflammation have shown that after the administration of aspirin, the concentration of salicylate in inflammatory exudate is considerably higher than that of aspirin. In addition, a comparison of prostaglandin synthesis inhibitory potencies shows that the concentration of salicylate, but not of aspirin, at the inflammatory site is high enough to substantially inhibit prostaglandin synthesis.

Determination of plasma aspirin and salicylic acid concentrations after low aspirin doses by high-performance liquid chromatography with post-column hydrolysis and fluorescence detection

Determination of plasma aspirin and salicylic acid concentrations after low aspirin doses by high-performance liquid chromatography with post-column hydrolysis and fluorescence detection

Plasma esterase activity in patients with aspirin-sensitive asthma or urticaria.

Plasma aspirin esterase activity and cholinesterase activity were reduced in patients with aspirin sensitive asthma and aspirin sensitive urticaria compared to asthmatic and dermatological controls. Phenylacetate (non specific) esterase activities, were however unaltered in these patients. The reason for the lower activity is uncertain but it does not appear to be due to genetically determined lower cholinesterase or due to the avoidance of aspirin by sensitive patients. A low aspirin esterase activity may be a contributory factor in precipitating these aspirin sensitive reactions.

A New Formulation of Aspirin: Bioavailability and Analgesic Efficacy in Migraine Attacks

Plasma aspirin and salicylate concentrations were followed after 600 mg of a new palatable glycinated preparation of aspirin was given to six healthy male volunteers in an attempt to investigate whether pre-gastric absorption of aspirin could occur. In each subject the drug was administered by three different routes, viz. (i) swallowed with water, (ii) dissolved sublingually and retained in the mouth, and (iii) allowed to disperse on the tongue, and then swallowed without water intake. Using the latter route of administration and the same aspirin formulation, plasma aspirin and salicylate concentrations were also followed in 10 patients during acute migraine attacks. These results were compared with those from another 10 migraineurs given 600 mg of soluble aspirin swallowed with water during attacks. Aspirin and salicylate pharmacokinetic parameters (Cmax, tmax, t1/2, Kabs and AUC) in the normal volunteers were not significantly different (p greater than 0.05) whether glycinated aspirin was swallowed with water or swallowed without water after dispersion in the mouth. However, negligible aspirin was absorbed when the glycinated preparation was retained in the mouth. In migraine patients, there was no significant difference (p greater than 0.05) between the bioavailabilities of soluble aspirin swallowed with water (AUC = 5.7 +/- 2.3 mg h/l) and glycinated aspirin swallowed without water (AUC = 4.4 +/- 1.6 mg h/l). There also was no significant difference (p greater than 0.05) when the time courses of pain relief were compared, both treatments being associated with a significant (p less than 0.01) analgesic effect. The glycinated aspirin was thus bioequivalent to swallowed aspirin but has no advantages for migraineurs over soluble aspirin if water is readily available for self-administration.

Peripheral Venous Plasma Aspirin Concentrations and Platelet Aggregation Inhibition Produced by Enteric-Coated Aspirin Formulations

In a random cross-over design, six healthy consenting adult volunteers were given on separate occasions single doses of 300-650 mg of 3 different formulations of enteric-coated aspirin. Over various intervals for 48-54 h following dosage, plasma aspirin and salicylate concentrations were measured together with percentage inhibition of platelet aggregation activated by threshold concentrations of sodium arachidonate alone and combined with ADP and collagen. In all subjects each formulation delivered measurable quantities of aspirin to the peripheral circulation, the unchanged drug being detected at various times up to and including 28 h after dosage. Moreover, low aspirin concentrations were found to co-exist with unimpaired platelet aggregation. All 3 formulations yielded statistically significant (P less than 0.01) inhibition of platelet aggregation activated both by arachidonate and by the combination of aggregants when tested 24-29 and 48-54 h after dosage; there were no significant differences (P greater than 0.05) between the 3 formulations in this regard. Two different patterns of delivery of unchanged aspirin to the systemic circulation from these enteric-coated formulations were apparent. These patterns may be important when considering which aspirin formulation might be most appropriate in chronic use for an antiplatelet effect. None of the enteric-coated formulations used in this study may be optimal in this regard.

A sensitive liquid chromatographic assay for plasma aspirin and salicylate concentrations after low doses of aspirin.

An original, highly sensitive and specific high performance liquid chromatographic method has been developed for the measurement of aspirin and salicylate in plasma. Minimum concentrations of 10 micrograms/L (aspirin) and 0.5 mg/L (salicylate) can be measured using 1 ml of plasma. After collection, plasma is first treated with physostigmine sulfate to inhibit enzymatic hydrolysis of aspirin to salicylate. Maximal recovery is achieved using an acid extraction into anhydrous diethyl ether with a subsequent drying-down step in an iced water bath. Aspirin and salicylate are separated by elution with a mixture of methanol, 1-butanol, orthophosphoric acid, and water on a reversed-phase octadecyl silane column at 47 degrees C and detected at 234 nm by ultraviolet absorption. Quantitation is achieved using the peak height ratio of aspirin and salicylate to internal standard (m-anisic acid). The assay has been used for the study of simultaneous aspirin and salicylate pharmacokinetics after a single oral dose of 100 mg soluble glycinated aspirin for platelet antiaggregatory therapy in six subjects, one of whom was also studied after receiving a 600 mg dose.

Attenuation of aspirin analgesia by calcium loading in healthy subjects.

To clarify the mechanism of aspirin analgesia, the relationship among analgesic and hypocalcemic effects and pharmacokinetics of aspirin was investigated in 20 healthy subjects at 20-23 years old. Four experimental groups were made, that is, (1) aspirin 1.0 g, (2) aspirin 1.0 g + calcium gluconate 1.5 g X 2, (3) calcium gluconate 1.5 g X 2, (4) control (placebo). Calcium gluconate was administered orally twice, that is, 30 and 90 min after oral administration of aspirin. The experiments were carried out under a double blind method. As an analgesic test, the ultrasonic method was used. Aspirin (1.0 g) caused a significant analgesia, the effect reaching the maximum at 90 min and prolonging for about 3 h. Simultaneously, plasma calcium level significantly decreased and kept going down, at least, until 180 min after administration of aspirin. However, when calcium gluconate was loaded at 30 and 90 min after administration of aspirin, both the analgesic and hypocalcemic effects of aspirin were significantly inhibited. The plasma aspirin concentration reached a maximum 30-60 min after administration of aspirin in both groups: aspirin alone and aspirin with calcium gluconate. On the other hand, plasma salicylic acid concentration kept increasing up to 180 min after administration of aspirin in either group. The plasma aspirin and salicylic acid levels in both groups were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase.

When aspirin is administered by mouth in low doses, poor systemic bioavailability may contribute to its apparent dose-related "selective inhibition" of thromboxane A2 formation. Systemic bioavailability of orally administered aspirin is necessary to inhibit prostacyclin synthesis by systemic vascular endothelium, whereas cumulative inhibition of thromboxane A2 formation by platelets may occur in the presystemic (portal) circulation. We simultaneously administered unlabeled aspirin orally and deuterium-labeled aspirin intravenously in five healthy volunteers. This permitted an estimation of the bioavailability of an oral dose from the ratio of plasma drug concentration-time curves for the labeled and the unlabeled species. Systemic bioavailability ranged from 46 to 51 per cent of single oral doses of 20, 40, 325, and 1300 mg of aspirin. Bioavailability was similar after single-dose and long-term oral administration of 325 mg. Thromboxane B2 formation in serum ex vivo after oral administration of 20 mg of unlabeled aspirin was reduced 39 per cent before aspirin was detected in the systemic circulation. Furthermore, incubation of simulated peak plasma aspirin concentrations in whole blood in vitro underestimated the inhibition of thromboxane B2 ex vivo after oral administration of 20 or 40 mg of unlabeled aspirin. These data are consistent with presystemic inhibition of platelets by aspirin and suggest that biochemical "selectivity" might be enhanced by slow administration of very low doses of aspirin, thereby optimizing conditions for cumulative, presystemic acetylation of platelet cyclooxygenase and inhibition of thromboxane formation.

Kinetics of Aspirin Absorption Following Oral Administration of Six Aqueous Solutions with Different Buffer Capacities

Fifteen volunteers each received two of six aspirin solutions in a balanced incomplete block design. The solutions contained 0, 3, 6, 10, 16, and 34mEq of sodium bicarbonate-citric acid buffer and 650mg of aspirin. Plasma aspirin levels were measured in blood samples collected frequently during the first 2.5h, and the accumulation of aspirin, salicylic acid, and salicyluric acid were measured over 2 and 24h. The most rapid absorption rates occurred with solutions which contained small quantities of the antacid buffer. The 3- and 6-mEq antacid buffers had mean maximal aspirin concentrations of 17.3 and 17.8μg/mL, respectively. In the absence of the buffering agent, the 650mg of aspirin failed to dissolve completely and gave a mean maximal plasma concentration of 13.4μg/mL. With 34mEq of a buffering agent, a delay in the onset of absorption occurred and the presystemic hydrolysis increased. This was probably because more aspirin was emptied into and absorbed from the small intestine with higher concentrations of the buffering agent.

Comparative Aspirin Absorption Kinetics after Administration of Sodium- and Potassium-Containing Buffered Solutions

Twelve fasting normal volunteers received three aspirin dosage forms in a single 325-mg dose in a complete crossover study; the plasma aspirin and salicylic acid levels and the urine salicylic acid and salicyluric acid levels were measured over 10h. The three dosage forms included an unbuffered tablet and two effervescent solutions, one with sodium bicarbonate-citrate buffer and the other with potassium bicarbonate-citrate buffer. A significantly faster absorption rate was observed with the sodium bicarbonate-citrate buffer, when compared with the potassium bicarbonate-citrate buffer and the unbuffered tablets, which were equivalent. These differences were attributed primarily to gastric emptying rate differences. Urine pH and salicylate renal clearance were significantly affected by the single dose of antacid buffer. The area under the curve and urine accumulation comparisons suggested that ∼25% more aspirin reaches the general circulation intact after administration of the unbuffered tablet than the two solutions, but that the total salicylate absorbed is equivalent for all three dosage forms. This difference in aspirin bioavailability is probably due to the fact that the two buffered solutions are predominantly absorbed through the intestine, in which presystemic hydrolysis occurs, whereas a significant portion of the tablet dose is absorbed through the gastric mucosa.

Pharmacokinetics of aspirin and salicylate in elderly subjects and in patients with alcoholic liver disease.

Plasma aspirin, salicylate and salicyluric acid concentrations were monitored in young, elderly and alcoholic subjects after ingestion of a single 1.2 g dose of soluble aspirin. The plasma aspirin, salicylate and unbound salicylate concentration-time profiles varied considerably between individual subjects. Most of the pharmacokinetic parameters derived from these profiles were not significantly different between young subjects, elderly subjects and subjects with alcoholic liver disease. Individual plasma albumin concentrations provided a better index of the unbound plasma salicylate clearances and salicylate plasma protein binding than the age of the subject or the presence of alcoholic liver disease. Highest unbound plasma salicylate concentrations were found in subjects with the lowest plasma albumin concentrations.

Plasma aspirin levels and platelet antiaggregatory effect in oral administration

It is known that aspirin acts as one of platelet antiaggregatory agents and also inhibits production of prostacyclin which has antiagrregatory effect. Thus administration of small dose of aspirin is recommended. In this point of view, we determined plasma aspirin levels and platelet antiaggregatory effects after administration of small dose of aspirin. Our experimentation includes eight old persons. Aggregation of plateletes was evaluated by Born's method and plasma aspirin and salicylate levels by high pressure liquid chromatography. In five cases with maximum level of aspirin above 1.30μg/ml, excellent antiaggregatory effect was seen. But in three cases, maximum aspirin levels less than 1.01μg/ml revealed no effect. According to our data, it is suggested that a fixed aspirin plasma level is necessary for platelet antiaggregatory effect, but minimum dose for oral administration differs person to person.

Relevance to redesigning aspirin therapeutic regimens

The quantitative relationship between the plasma aspirin (ASA) concentrations and the various responses have not been established in man. Nevertheless, available information would suggest that the pharmacodynamic Emax model adequately describes both the inhibition of TxB 2 production by ASA and the competitive role of salicylic acid (SA) in the reaction. Available pharmacokinetic data can be used to predict plasma ASA and SA levels following different ASA dosing regimen. Such information can be useful in designing prospective studies and managing patients who receive ASA.

Aspirin treatment of migraine attacks: plasma drug level data.

Plasma aspirin and salicylate levels were measured at intervals over a two hour period during migraine attacks in 10 subjects given 900 mg oral aspirin alone, in 10 subjects given 900 mg oral aspirin plus 10 mg oral metoclopramide, and in 10 subjects given 900 mg oral aspirin plus an intramuscular injection of 10 mg metoclopramide. Higher peak aspirin and salicylate levels occurred in patients given aspirin with metoclopramide. Aspirin tended to appear in plasma earlier in patients given aspirin with oral metoclopramide than in patients given aspirin alone, or aspirin with intramuscular metoclopramide. Patients given aspirin with oral metoclopramide tended to obtain better early pain relief than the other two treatment groups, though by one hour from dosage use of injected metoclopramide was also associated with better pain relief.

Plasma aspirin esterases in normal individuals, patients with alcoholic liver disease and rheumatoid arthritis: characterization and the importance of the enzymic components.

Abstract. Two enzymes in human plasma capable of hydrolysing aspirin (‘aspirin esterases’) were isolated (by ion exchange and gel chromatography) and characterized, since their activity has been reported to be important in certain disease/therapeutic situations. The optimum pH and calcium concentration for plasma aspirin esterases were 80 and 5 mmol/1 respectively.The main enzymic activity (enzyme ‘C’) was associated with plasma cholinesterases. This component had a Km of 6‐5 mmol/1 for aspirin and a Kmax of 0–27 /imol salicylate/mg protein/min at pH 80 (Ca2+ present). It was not acetylated by aspirin but was inhibited by anti‐cholinesterase agents (eserine, echothiophate) and the neuromuscular blocking agent, decameth‐onium. The other enzymic component in plasma was albumin esterase.The sex difference in aspirin esterase activity in normal individuals previously reported by Menguy and co‐workers [1] was re‐investigated since it appeared that they had employed non‐optimal assay conditions. No significant differences were observed between the sexes in either normal individuals or patients with rheumatoid arthritis when the enzyme was assayed at either pH 7‐4 or the optimal pH of 80 (with Ca2+ added). The plasma albumin esterase activity was, however, markedly depressed in patients with alcoholic liver cirrhosis when assayed at pH 7‐4 and 80. Plasma aspirin esterases were elevated in nine rheumatoid arthritic patients receiving gold salt or D(‐)penicil‐lamine. Aspirin esterase 'C activity was negatively correlated with pain score in the plasma of female but not male rheumatoid arthritics. Also the percentage activation by calcium of aspirin esterase was correlated with the concentration of plasma calcium indicating that small changes in plasma calcium concentration may markedly affect enzymic activity.These results suggest that certain drugs (anti‐cholinesterase agents), disease states (e.g. alcoholic liver cirrhosis) or genetic deficiences (e.g. inactive pseudo‐cholinesterase) may be potentially important in the pharmacological and iatrogenic activities of aspirin.

Prediction of fetal drug concentrations

Equations are derived for the fetal concentrations of a drug [F(t)] during and after the slow release of the drug into the maternal circulation. To solve these equations it is necessary to know the placental drug clearance (Cp), the clearance of the drug from the fetal circulation by the fetal tissues (Cf), and the volume of distribution of the drug in the fetal compartment (V). With these values for acetylsalicylic acid (aspirin) it can be shown that the maximum fetal aspirin concentration will be much less than the maximum maternal concentration and that after the release of aspirin has stopped, some drug is trapped in the fetal circulation. Therefore, there will be a period of time when the fetal plasma aspirin concentration is greater than maternal plasma aspirin concentration.

Influence of Food and Fluid Ingestion on Aspirin Bioavailability

The influence of test meals and accompanying fluid volume on aspirin bioavailability from commercial tablets was determined following single oral doses to healthy male volunteers. Plasma aspirin and salicylate levels were determined simultaneously using a GLC end-point. Area analysis indicated that approximately 5–8% of absorbed drug entered the systemic circulation as unchanged aspirin in nonfasted subjects compared to 16–18% in fasted individuals. Food tended to reduce the appearance rate of aspirin into the circulation, resulting in lower and somewhat more sustained levels than with fasting. Plasma salicylate levels were not influenced markedly by the various treatments, although levels were higher in fasted than in nonfasted subjects during the 1st hr after dosing. After this time, fat pretreatment tended to produce higher levels than other treatments.

Comparative Antidotal Effectiveness of Activated Charcoal, Arizona Montmorillonite, and Evaporated Milk

Activated charcoal, Arizona montmorillonite, and evaporated milk were compared for their ability to reduce gastrointestinal absorption of three potential poisons. Time-course drug-concentration studies were performed on kerosene- and aspirin-treated animals. Activated charcoal and Arizona montmorillonite reduced blood kerosene level at all time periods studied, whereas evaporated milk was effective only during the early time periods. Activated charcoal reduced plasma aspirin level at all time periods studied, whereas Arizona montmorillonite was slightly effective only during the late time periods and evaporated milk was effective only during the initial few hours. Activated charcoal, Arizona montmorillonite, and evaporated milk reduced liver concentration of strychnine, which was analyzed only at the 5-min. time period, by approximately 80–90%. These antidotes also significantly elevated the median lethal dose (LD50) of strychnine. Although activated charcoal appears to have the greatest adsorptive spectrum, Arizona montmorillonite and evaporated milk should be investigated further as possible antidotes.