Thesis (Ph. D.)--University of Wisconsin--Madison, 1984. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 253-257).

Observations that some samples of commercial acetylsalicylic acid had different dissolution rates were followed by reports that acetylsalicylic acid exists in more than one polymorphic form. The evidence for polymorphism has been questioned by a number of authors and the effects of such factors as crystal habit, particle size, crystal imperfection, the presence of salicylic acid and spherulites of acetylsalicylic acid have been discussed in an attempt to explain the anomalous behaviour. This work attempts to resolve the conflicting points of view. Acetylsalicylic acid was recrystallized from ethanol in a crystallizer which permitted control of the degree of supersaturation and, therefore, growth rate. In addition, a number of other recrystallization techniques and solvents were used to produce acetylsalicylic acid crystals with a wide variety of habits and varying amounts of salicylic acid. The crystals were compressed into discs both with and without prior size reduction and sieving. Intrinsic dissolution rates, measured using a rotating disc technique showed that the rates were independent of crystal growth rate, crystal size and habit, the content of salicylic acid (up to 3.8% w/w) and the presence of spherulites of acetylsalicylic acid. X-ray diffraction patterns revealed no differences between the various crystals and the original commercial material. Melting points, however, were dependent on the method of measurement and the crystal size and habit. Using the hot-stage method and heating at a rate of 0.2°per minute from a starting temperature of 2° below the approximate melting point (previously determined), acetylsalicylic acid melted, with decomposition, in the range of 128.3 to 132.7°, (excluding spherulites). When heating was started at 100° the melting range became very broad with small unaggregated particles starting to melt at temperatures between 103° and 112°. Analysis of the melt showed that the proportion of salicylic acid increased with decrease in particle size of the original acetylsalicylic acid crystals. Hence, the depression of the melting point of individual crystals is related to the increased susceptibility of small particles to thermal decomposition with the formation of salicylic acid. Evidence for the existence of metastable polymorphs of acetylsalicylic acid rests on the reported properties of needle-like crystals recrystallized from n-hexane and spherulites grown in thin films from saturated alcoholic solution. The needle-like crystals melted over the range 123.9° to 130.1° using a heating rate of 0.2° per minute from a starting temperature 2° below the approximate melting point. The wide melting range is probably due to decomposition of the fine needles and the formation of salicylic acid as discussed above. Spherulites of acetylsalicylic acid underwent a thermal transformation over the range 104° to 128° to form elongated prisms and a solution phase transformation into well defined prisms when in contact with a saturated solution of acetylsalicylic acid in various alcohols. The intrinsic dissolution rates of compressed discs prepared from the needle-like crystals and spherulites were the same as the other acetylsalicylic acid crystals. Moreover, X-ray diffraction patterns of the needle-like crystals, the spherulites and the crystals formed from the spherulites after thermal and solution phase transformation were identical with each other and the original aspirin. Hence, the needle-like crystals and spherulites are not metastable polymorphic forms of acetylsalicylic acid. It is suggested that both the thermal and solution phase transformation are growth processes. / Pharmaceutical Sciences, Faculty of / Graduate

Aspirin is the most commonly used antiplatelet drug in the secondary prevention of cardiovascular events. Many patients experience thromboembolic events despite daily aspirin therapy. On the basis of clinical and laboratory findings, an issue of concern has emerged, frequently referred to as “aspirin resistance”. The aim of this thesis was to establish the prevalence of laboratory aspirin resistance in patient populations and to elucidate the reasons for aspirin failure. The thesis comprises two independent studies in which I assessed a range of clinical and laboratory measures in patients with peripheral arterial disease (PAD) and patients with acute ischaemic stroke. The effect of in-hospital aspirin administration on platelet response was determined in acute stroke patients. Laboratory tests for platelet and aspirin response were compared with the current gold standard assay of optical platelet aggregometry with arachidonic acid. A cut-off value for definition of incomplete response to aspirin was determined. The current literature is reviewed and discussed. Incomplete aspirin response was found in 18% of aspirin-treated patients with PAD. There were no significant differences in any of the measured markers nor in clinical parameters between responders and incomplete responders. The prevalence of incomplete aspirin response in acute ischaemic stroke or TIA was 43%. However, after observed aspirin administration in hospital, this percentage decreased to 29%, suggesting incomplete compliance in some patients. On admission, platelets from patients with incomplete response were significantly more sensitive to adenosine diphosphate (ADP) when compared with those from responders. There were no other differences that characterised the incomplete responders to aspirin. The data support the growing body of opinion that true biochemical resistance to aspirin is uncommon. Incomplete adherence to therapy was found to be a major cause of incomplete response to aspirin and therefore amenable to intervention. The problem remains of which laboratory methods should be employed as no single test has emerged as clinically informative.

BACKGROUND: Preeclampsia is one of the leading causes of maternal and perinatal morbidity and mortality, affecting 2-8% of pregnancies worldwide. It is estimated that 76,000 women and 500,000 babies die from this disease each year globally. Preeclampsia is characterized as hypertension associated with the onset of proteinuria, maternal organ dysfunction or uteroplacental dysfunction occurring at or after 20 weeks of gestation. In addition to its effects on pregnancy, preeclampsia may also have long-term adverse effects on women who experience the disorder and their children later on in life. Currently, the only cure for preeclampsia is delivery, which is often associated with preterm birth, increasing the risk of neonatal death. Daily low-dose aspirin (81mg) has been shown to have a preventive effect on preeclampsia in women at high risk of developing the disorder. OBJECTIVE: To analyze patient data collected at Boston Medical Center to determine the effects of prescribed low dose prenatal aspirin (81 mg) on pregnancy outcomes. METHODS: There were 2648 obstetric deliveries at Boston Medical Center in the two-year span of 2017-2018. Using R, statistical analyses were performed to determine the difference in birth outcomes between the prenatal aspirin prescribed group and the non-aspirin prescribed group as well as the effect of prenatal aspirin on pregnancy outcomes. Logarithmic and linear models as well as basic statistical methods were employed for the analyses. RESULTS: The prenatal aspirin prescribed population had higher major and moderate risk factors as well as worse birth outcomes, Apgar scores and birthweight as compared with the non-prescribed population. However, prenatal aspirin may reduce the adverse effects of both major and moderate risk factors on birth outcomes. CONCLUSIONS: Prenatal aspirin may have beneficial effects on birth outcomes, and the pregnant population at Boston Medical Center may benefit from taking low-dose aspirin. This study was carried out retrospectively with a cohort that was not randomized, so this conclusion needs to be verified by future studies.

Thesis--Aarhus. / Summary in English and Danish. Bibliography: p. [139]-145.

Thesis--Aarhus. / Summary in English and Danish. Bibliography: p. [139]-145.

Aspirin resistance (AR) commonly refers to the concept of reduced aspirin efficacy in preventing cardiovascular disease and platelet inhibition. Obesity increases the risk of heart disease three- to four-fold and has been associated with AR. Aspirin is used as a tool for both primary and secondary prevention, but recent studies suggest that its lack of efficacy for primary prevention is partly attributable to obesity. Several mechanisms have been described that contribute to AR in obese patients using pharmacokinetics and pharmacodynamics. AR may be attenuated through weight loss, alternative dosing regimens, and different drug formulations. With the global rise of obesity, it is imperative to find preventive therapies that adequately address atherosclerotic cardiovascular disease (ASCVD) risk in this population.

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The metabolism of aspirin has been investigated in man following a therapeutic (600 mg) dose and after overdose. The major urinary metabolite in volunteers after the therapeutic dose was salicyluric acid and a sex-related difference in its excretion and that of salicylic acid was observed. Capacity limited formation of salicyluric acid has been demonstrated for the first time in a substantial number of paients with aspirin overdose. Urinary excretion of gentisic acid, salicylic acid and salicyl phenolic glucuronide was higher in overdose patients compared with the volunteers. In addition, the urinary excretion rates of aspirin metabolites and in particular salicyluric acid and salicyl phenolic glucuronide in individual patients varied with time after admission and the maximum observed rates were often greatly in excess of those previously reported in the literature. Depletion of plasma glycine also occurred after aspirin overdose. The in vivo plasma glycine pool was enriched by oral administration of glycine or N-glycylglycine. Glycine and N-glycylglycine treatments were as effective as the standard urine alkalinisation regimen in enhancing renal excretion of total salicylate after overdose but the mechanism of this action is unclear. Thus exogenous glycine may be of therapeutic value in salicylate overdose. The metabolism of 14c-aspirin was also studied in rats over a ten fold dose range and was found to be dose dependent. The principal urinary metabolite after each dose was salicylic acid and salicyluric acid formation was capacity limited. Oral administration of glycine concurrently with aspirin increases the urinary excretion of salicyluric acid. Gentisuric acid and salicyluric phenolic glucuronide have also been quantified in man and rat urine. Metabolism of aspirin was found to be similar in man and rat, although there were quantitative differences; thus rat may serve as a useful experimental model to study man.