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Monitoring acetylsalicylic acid effects with the platelet function analyzer PFA-100.

The efficacy of acetylsalicylic acid (ASA) to prevent thrombotic or embolic events in patients with atherosclerosis was demonstrated in many large trials. Despite this fact, a subpopulation of patients experiences acute myocardial infarction or cerebrovascular ischemia indicating a nonresponsiveness to ASA. These patients would be candidates for an alternative or additional antiplatelet therapy, if they could be reliably identified. The aim of the monitoring of ASA therapy should be the identification of nonresponders to prevent a long-term intake of the drug without adequate benefit, to justify a dose escalation, or to initiate an alternative antiplatelet drug therapy. Considerable progress has been made in the measurement of platelet function. One of the novel devices employed is the platelet function analyzer PFA-100, which was already tested in several studies involving patients with atherothrombosis to detect nonresponsiveness to ASA. Many of these investigations indicate that the PFA-100 could be used for routine identification of nonresponders to ASA and--probably also--for tailoring antiplatelet therapy. The aim of this article is to summarize the data obtained from the studies focusing on the monitoring of ASA therapy by the PFA-100.

Aspirin↗

Intravenous acetylsalicylic acid, magnesium and their combination in experimental arterial thrombosis in rats.

Intravenous acetylsalicylic acid (ASA) and magnesium (Mg) both possess antiplatelet properties and are thus potential inhibitors of the formation of arterial thrombi. Their effect on the dynamic aspects of arterial thrombus formation was investigated following intravenous administration of both substances alone and in combination. A blinded, placebo-controlled, in-vivo study was performed in 71 rats. Thrombus formation was induced by a standardized arteriotomy in the right femoral artery with inversion of the vessel wall during subsequent closure. Thrombus formation was recorded on video tapes and analysed off-line for 30 min. Animals were randomly assigned to one of four groups: 20 mg bolus of ASA followed by 0.3 mmol/h Mg (ASA/Mg group); NaCl followed by 0.3 mmol/h Mg (Mg group); 20 mg bolus of ASA followed by NaCl (ASA group); or NaCl throughout the experiment (control group). In the ASA-treated groups, serum levels of thromboxane B2 were reduced significantly, and the Mg-treated groups reached a serum level of Mg just above 2.0 mmol/l. No significant differences were observed in initial or maximum thrombus area or in mean thrombus area during the study period. In the ASA/Mg group, a trend towards reduced thrombus formation was observed (P = 0.06). In the same group, seven of 22 animals developed an occlusive thrombus (P < 0.01), an unexpected adverse event possibly related to the combined administration of ASA and Mg.

Animals↗

Effects of microencapsulated vs. enteric-coated acetylsalicylic acid on gastric and duodenal mucosa: an endoscopic study.

Two preparations of acetylsalicylic acid (ASA) were tested for their effects on gastroduodenal mucosa in a randomized crossover double-blind study that involved 12 healthy volunteers. Medication M (Monobeltin) consisted of 1,050 mg ASA provided with an enteric coat and medication C (Colfarit) consisted of 1,000 mg of a microencapsulated ASA preparation. Both drugs were taken for 6 consecutive days each. Upper gastrointestinal endoscopy was performed before and 2 and 6 days after each medication. An interval of 10 days elapsed between one treatment and the other. Gastric lesions occurred in 10 of 12 subjects taking medication M and in 11 of 12 subjects taking medication C after 2 days and were present in all subject after 6 days. Duodenal lesions were seen only in subjects taking medication C. The degree of gastric mucosal lesions based on two grading scales was not significantly different between the two treatments. Neither of the two pharmaceutical formulations of ASA provided sufficient protection for the gastric mucosa.

Adult↗

Sunflower (Helianthus annuus L.) Pathogenesis-Related Proteins (Induction by Aspirin (Acetylsalicylic Acid) and Characterization).

Sunflower leaf discs floated on a solution containing aspirin (acetylsalicylic acid) produced a set of new proteins extractable at pH 5.2 and excreted into the intercellular space. More than 80% of the proteins found in the intercellular fluids of induced leaf discs have been identified as pathogenesis-related (PR) proteins by their immunological relationship with tobacco PR proteins. Members of the four major classes of PR proteins have been characterized. Sunflower PR proteins of type 1 (PR1) and of type 3 (PR3) were found to have acidic isoelectric points, whereas the induced PR protein of type 2 (PR2) had a basic isoelectric point. Members of the type 5 PR proteins (PR5), known in tobacco as thaumatin-like proteins, showed a more complex pattern. Multiple sunflower PR5 isomers of similar molecular weight but of different isoelectric points were excreted from the cells in response to the aspirin treatment. PR2 and PR3 proteins were found at very low basal levels in untreated leaves, whereas PR1 and PR5 proteins could not be detected at all in the same extracts. Glucanase and chitinase activities were always associated with PR2 and PR3 proteins in partially purified sunflower extracts. All of these data indicate that, in response to aspirin treatment, sunflower plants produce a complete set of PR proteins characterized by an apparently exclusively extracellular localization.

Journal Article↗

Hydrolysis and stability of acetylsalicylic acid in stearylamine-containing liposomes.

The hydrolysis and the stabilization of acetylsalicylic acid (ASA) in liposomes at 30 degrees C were studied. The liposomes consisted of dimyristoylphosphatidylcholine (DMPC) and stearylamine. At pH 4.0 and 8.0, the pseudo-first-order rate constants (kobs) in DMPC: stearylamine (2: 1 mole ratio) liposomes were approximately 60% of the values in control solutions (kB) if ASA was incorporated via the organic phase. In contrast, when ASA was added via the aqueous phase, kobs = kB at pH 4.0 but kobs < kB at pH 8.0 and kobs increased with the fraction of stearylamine in the liposomes. However, when ASA was added via the organic phase, reactions occurred which resulted in the loss of ASA as a function of the time period between phase admixture and the point of film hydration. A product of the reactions was determined by IR and TLC to be N-stearylacetamide. Both the initial loss of ASA and the increase in stability decreased as the DMPC: stearylamine mole ratio increased. A mechanism of aminolysis occurring in the organic solvent and at liposome surfaces between ASA and stearylamine or DMPC at pH 8.0 has been suggested. It is concluded that the orientation of ASA and the ordered structural environment of the bilayers minimizes the aminolytic and hydrolytic reactions.

Amines↗

Efficacy of 1,000 mg effervescent acetylsalicylic acid and sumatriptan in treating associated migraine symptoms.

Recently a new effervescent acetylsalicylic acid (ASA) tablet with high buffering capacity has been developed. In this double-blind, 3-arm, multicenter, parallel-group study, 433 patients were treated either with 1,000 mg effervescent ASA or 50 mg encapsulated sumatriptan or placebo. The primary endpoint was the percentage of patients with complete remission of the 3 accompanying symptoms nausea, photophobia and phonophobia within 2 h after intake of the study drug. 43.8% of patients treated with ASA, 43.7% of patients treated with sumatriptan and 30.9% of patients treated with placebo showed complete remission of all 3 accompanying symptoms (p < 0.05 for ASA and sumatriptan vs. placebo). Both active treatments were superior to placebo regarding the individual symptoms photophobia and phonophobia, but not for nausea. The percentage of patients with reduction in headache severity from moderate or severe to mild or no pain (secondary objective) was 49.3% for ASA, 48.8% for sumatriptan and 32.9% for placebo. All active treatments were superior to placebo (p < 0.05). 25.3, 24.4 and 14.5% of patients treated with ASA, sumatriptan or placebo were pain free at 2 h. Drug-related adverse events were reported in 3.9, 4.7 and 6.7% of patients treated with placebo, ASA or sumatriptan. The study showed that administration of effervescent ASA leads to remission of the migraine symptoms nausea, photophobia and phonophobia, reduces migraine headache and is comparable to sumatriptan.

Adolescent↗

Acetylsalicylic acid inhibits cell proliferation by involving transforming growth factor-beta.

BACKGROUND: Acetylsalicylic acid (ASA) inhibits cell proliferation. This may be mediated by transforming growth factor-beta (TGF-beta). TGF-beta directly stops cell proliferation, restrains cells in G(0), and inhibits the uptake of platelet-derived growth factor and insulin-like growth factor. These effects are identical to those observed with ASA treatment. METHODS AND RESULTS: We cultured rat thoracic aorta vascular smooth muscle cells and measured cytotoxicity, cell proliferation, cell cycle, transcription of TGF-beta1, and concentration of TGF-beta1 in supernatant medium. ASA dose-dependently restrained cells in G(0) phase with no cytotoxic effect and inhibited cell proliferation by 30.86%. Anti-TGF-beta1 reversed this inhibition by 30.21%. However, ASA treatment decreased TGF-beta1 transcription and had no significant effect on TGF-beta1 concentration. CONCLUSIONS: TGF-beta seems to play an important role in ASA-mediated inhibition of cell proliferation. Therefore, treatment with ASA prevents coronary disease not only by means of its antiplatelet properties but also by an important inhibition of plaque growth. This relationship between ASA and TGF-beta explains many other effects, such as cancer chemoprevention, immunomodulation, and wound healing. The aim of this study was to demonstrate this link.

Animals↗

Influence of maternal drug metabolism on the fetal toxicity induced by acetylsalicylic acid.

Investigations were performed to explore changes in fetal toxicity induced by acetylsalicylic acid (ASA) in pregnant animals treated by various means for maternal alterations. The fetotoxicity induced by ASA (500 mg/kg s.c.) was higher in rats than in mice. In mice with low enzyme activity, those displaying a longer sleeping time in pentobarbital-induced sleep, the ASA-fetotoxicity was higher than that of mice with shorter sleeping time. In rats pretreated with phenobarbital (0.05%), Zn (10 mg/l) and Cu (10 mg/l) in tap water and cysteine (200 mg/kg s.c.), fetal toxicity of ASA was reduced, whereas it was enhanced in rats pretreated with SKF-525A (200 mg/kg s.c.) and alpha-naphthyl acetic acid (200 mg/kg p.o.) and in nephrectomized rats. The UDPGT activity in hepatic 9000 x g supernate was higher in mice than in rats and the activity of mice was increased by phenobarbital and Cu. This study indicates that ASA-induced fetotoxicity can be positively modified by alterations in drug metabolizing activity.

Animals↗

The use of nimesulide in patients with acetylsalicylic acid and nonsteroidal anti-inflammatory drug intolerance.

Intolerance or idiosyncrasy to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem because these drugs are frequently used in medical treatment. In this study, we tested whether nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, might be a valid alternative for patients with histories of adverse reaction to ASA or NSAIDs. A single-blind, placebo-controlled oral challenge procedure was applied to 60 adult patients (19 male, 41 female; with a mean age of 40.31 +/- 10.44 years, range 20-68 years) with a reliable history of ASA/NSAIDs-intolerance. According to history, the clinical presentations of intolerance were urticaria/angioedema in 32 patients, anaphylactoid reaction in 2 patients, respiratory reaction in 19 patients, and respiratory and cutaneous reaction in 7 patients. Atopy was confirmed by means of skin prick test with inhalant allergens. Oral challenge protocol was started with 25 mg of nimesulide and the remaining 75 mg was given 1 hr later. During the challenge procedure, blood pressure, pulse, nasoocular, pulmonary, and cutaneous symptoms were monitored. Of the 60 patients tested, 55 (91.7%) tolerated the drug with no adverse reaction. Only five (8.3%) patients demonstrated a positive response to oral challenge. The clinical presentations of intolerance to nimesulide were urticaria/angioedema in three patients, mild rhinitis in one patient, and mild dyspnea in one patient. The atopy prevalence was higher, with a ratio of 41.7%, in patients with ASA/NSAIDs intolerance than that of the healthy adult population in Turkey (p < 0.05). We believe that nimesulide can be used as an alternative drug for patients with ASA/NSAIDs intolerance.

Administration, Oral↗

[Gastrointestinal tolerance of 30 mg versus 300 mg acetylsalicylic acid daily. An endoscopically controlled double-blind study of healthy subjects].

Acetylsalicylic acid (ASS) is increasingly used in the prevention of cardiovascular diseases. In recent years daily ASS-doses (100 to 300 mg) have been given for this indication. Studies with still lower ASS-doses (f. i. 30 mg daily) are the focus of ongoing clinical trials. In a randomized double-blind study we have evaluated the gastroduodenal tolerability of 30 mg ASS and 300 mg ASS daily in 20 healthy volunteers using upper GI-endoscopy. Both ASS-dosages have been taken for a period of four weeks. Endoscopic controls were performed at entry and repeated after seven, 14 and 28 days of treatment. 30 mg ASS daily did not induce significant gastroduodenal damages during the whole treatment period in contrast to 300 mg ASS daily (p less than 0.05). The lesions score under 300 mg ASS on day 7 and 28 was almost identical. Our data suggest that extremely low doses of ASS are almost harmless to the human gastroduodenal mucosa. No adaptive phenomena occur during a 28 days treatment with 300 mg ASS daily.

Adult↗

[Asthma improved by acetylsalicylic acid].

It is known that in some asthmatic subjects the administration of acetylsalicylic acid (ASA) and non-steroid anti-inflammatory drugs (NSAID) results in bronchodilatation. We have administered 750 mg of ASA intravenously to 100 asthmatic patients who were without history of ASA intolerance. Functional assessment (FEV) was performed under basal conditions and after 5, 10, 15, 30, 60, 90, 120, 150 and 180 minutes after the administration of ASA. 64 patients had no functional variations, 14 showed a percentage variation of less than 20% in FEV and 14 had a doubtful bronchodilatation (FEV 15-20%). The test was repeated after an interval of 1 week in those patients who showed an increase of 20% in FEV and only 2 confirmed the bronchodilatation. The pathogenesis of asthma that is improved by ASA is not entirely clear, but it is an extremely interesting model for study of the role of different mediators in the asthma syndrome.

Adolescent↗

Our experience with acetylsalicylic acid hypersensitivity.

Results of a study carried out in 21 patients with acetylsalicylic acid (Aspirin), hypersensitivity, 17 females and 4 males, aged 16 to 69 years (mean 45.7) are presented. Some patients suffered from several types of allergic symptoms - 11 from Asthma, 3 Rhinitis, 3 Quinke edema, 5 Urticaria and 2 Anaphylactic Shock. Concomitant drug allergies, route of administration and composition of the ingested drug, familiar complaints of drug allergy, nasopharyngeal examination and lung function by spirometry and Acetylcholine tests were evaluated. Blood, sputum and nasal mucous eosinophil count, as well as secretory IgA and its secretory piece identification in saliva and nasal mucous, serotonin and histaminopexic power of serum and immunoelectrophoresis of serum proteins were performed in all patients. Human basophil degranulation test to Aspirin were evaluated in 12 patients. Skin prick tests with one standard range of 21 common allergens were done in all patients and intradermal skin tests with 1 lysine acetyl-salicylate (1/100 and 1/1000) were performed in all patients as well as in a selected control group of 12 healthy subjects.

Adolescent↗

Double-blind comparative trial of indoprofen and acetylsalicylic acid in osteoarthritis.

The effectiveness, safety and acceptability of indoprofen (IP) and acetylsalicylic acid (ASA) were assessed in patients with osteoarthritis, in a double-blind comparative trial. Each patient received IP 600 mg/day or ASA 2100 mg/day for a four-week period; after a one-week wash-out period, the same drug was given at a higher dosage (IP 800 or ASA 2800 mg/day) for another four weeks. Seventeen patients on indoprofen and 14 on SAS completed the trial. A significant improvement was obtained with indoprofen in the different parameters measuring pain, from the first treatment period; results were similar at the end of the second period. Results with ASA, at both dosages, appeared less impressive. Two patients on indoprofen and five on ASA complained of side effects.

Adult↗

Measurement of serum acetylsalicylic acid in a porcine model of aspirin overdose.

Although the pharmacokinetics of acetylsalicylic acid (ASA) absorption and metabolism in therapeutic doses are well described, there is little information for overdose. A porcine model was developed to study ASA pharmacokinetics in overdose and to establish the feasibility of using area-under-the-curve (AUC) for serum ASA vs time rather than salicylate vs time as an indirect method of quantifying total drug absorption. Such a model could be useful in comparing the effectiveness of different methods of gastrointestinal decontamination in poisoning. The hydrolysis of ASA to salicylate, known to be a first-order process in therapeutic doses, was confirmed to remain first-order at high serum concentrations using iv aspirin in 2 pigs. Five simulated overdoses were then carried out in 4 pigs using 500 mg ASA/kg administered enterally as intact tablets. Serial determinations of both serum ASA and salicylate concentration were carried out over 72 h. Plots of ASA concentration vs time for each of the trials revealed delayed, multiple and erratic peaks consistent with a bolus effect from sudden dissolution of aspirin concretions, suggesting our model accurately simulates human overdose. Despite the variable peaks, the AUC of ASA concentration vs time for the 5 trials revealed a coefficient of variation of only 13%, compared with 27% for salicylate concentration vs time AUC. This suggests that serial measurements of serum ASA in a porcine ASA overdose model can be used to measure total drug absorption and thereby compare the effectiveness of different methods of gastrointestinal decontamination.

Administration, Oral↗

Effect of acetylsalicylic acid on nitric oxide production in infarcted heart in situ.

The effect of Acetylsalicylic Acid (ASA, Aspirin) on the myocardial production of the inducible form of nitric oxide synthase (iNOS) and the oxidation products of nitric oxide (nitrite, NO-2 and nitrate, NO-3: NOx) were studied in the rabbit heart two days after ligation of a branch of the left circumflex coronary artery. ASA was administered intravenously as AspisolR, DL-Lysinmono(acetylsalicylate) which is soluble in water. Animals received a total dose of 250, 375, or 500 mg/kg of ASA in five divided doses intravenously. Significant inhibition of iNOS was noted in the infarcted portion of the myocardium at 375 and 500 mg/kg of ASA. The reduction in myocardial nitric oxide (NO) production was paralleled by a diminution in coronary arterial-venous difference of NOx, demonstrating that ASA inhibition extended also to the oxidation products of NO. ASA is an inhibitor of cyclooxygenase (COX). The inhibition of iNOS by ASA demonstrates the close relationship between COX and iNOS activity in the heart in situ. Whether activity of the infarcted heart is influenced by the diminution in the production of NO by ASA is not known.

Animals↗

Acetylsalicylic acid metabolites in blood and urine after plain and enteric-coated tablets.

Acetylsalicylic acid (ASA) was administered orally as a single dose to 7 healthy male volunteers as plain or enteric-coated (Entrophen) tablets using a crossover design. Blood and urine samples were collected and analysed for ASA metabolites by high performance liquid chromatography. Labile and stable glucuronide conjugates of salicylic acid (SA) were measured in urine after differential hydrolysis with glucuronidase. Plasma kinetic parameters for the ASA metabolites SA and salicyluric acid were not different for the 2 formulations, apart from the delayed appearance after the enteric-coated tablets. Total urinary recovery, and recovery of salicyluric acid and the two SA glucuronides were not different, thus confirming the equivalent bioavailability and metabolite profile of the 2 ASA formulations.

Adult↗

Effects of acetylsalicylic acid and naproxen on bone resorption and formation in rats.

The influence of acetylsalicylic acid (ASA) (150 mg/kg/12 h) and naproxen (20 mg/kg/12 h) on bone metabolism in young male rats has been studied. The doses were chosen to provide serum concentrations comparable with ordinary anti-inflammatory steady-state levels in humans. After the rats had been prelabeled with collagen- and mineral-tracing radioisotopes the rats received the drugs by gavage twice a day for 9 and 18 days. Bone resorption was measured as loss of carbon-labeled hydroxyproline (collagen) and strontium-85 (minerals). At 9 days ASA had retarded both collagen and mineral resorption in the femur by about 10% compared with controls. The resorption of both collagen and minerals was inhibited. After 18 days' treatment there were no differences regarding bone resorption, but bone formation had decreased by about 10% in the ASA-treated animals, as measured by net increases of collagen and calcium in the femur. Naproxen did not influence bone resorption or formation significantly. The results indicate an inhibitory effect of ASA on bone resorption and formation in growing rats, whereas the effect of naproxen seems negligible.

Animals↗