Mechanism Of Aspirin Research Articles

Mechanisms of aspirin increasing the susceptibility of Helicobacter pylori to clarithromycin

Mechanisms of aspirin increasing the susceptibility of Helicobacter pylori to clarithromycin

W15-P-007 Influence of aspirin on expression and function of scavenger receptor-BI within primary human macrophages: A new atheroprotective mechanism of aspirin?

W15-P-007 Influence of aspirin on expression and function of scavenger receptor-BI within primary human macrophages: A new atheroprotective mechanism of aspirin?

Electrochemical oxidation of drug residues in water by the example of tetracycline, gentamicine and aspirin®

Electro-chemical oxidation as a method to destroy drug residues like aspirin, tetracycline or gentamicine in water was investigated with C-anodes (modified by manganese oxides) and Pt anodes. The mechanism of aspirin and tetracycline oxidation and the influence of the biocide effect was observed using GC-MS and three different microbiological tests. In general, the biological availability increases with progressive oxidation of the antibiotics.

The antithrombotic profile of aspirin. Aspirin resistance, or simply failure?

The antithrombotic profile of aspirin. Aspirin resistance, or simply failure?

Possible mechanisms of aspirin resistance.

Data regarding possible mechanisms of aspirin (ASA) resistance in patients with recurrent myocardial infarction (MI) or vascular ischemia are limited. Five major possible mechanisms of ASA resistance are documented in the primary literature and are discussed in this paper. These mechanisms include: (1) inadequate blockade of erythrocyte-induced platelet activation; (2) biosynthesis of F2-isoprostane 8-iso-prostaglandin (PGF2alpha), a bioactive product of arachidonic acid peroxidation; (3) stimulation of platelet aggregation by cigarette smoking; (4) ASA resistant platelet aggregability by increased levels of norepinephrine, as seen during excessive exercise or periods of mental stress; and (5) increased platelet sensitivity to collagen. Recognizing mechanisms of platelet activation and identifying reversible risk factors such as smoking and mental stress may help decrease the occurrence of ASA resistance and possibly improve patient outcomes. Until more definitive data become available, when prescribing and dosing ASA for the prevention of MI or vascular ischemia, clinicians should identify possible risk factors for ASA resistance. Whether or not patients at risk for ASA resistance are candidates for additive antiplatelet therapy remains to be determined.

History as a tool in identifying "new" old drugs.

To trace the history of a natural product and its use, it is necessary to identify to correct plant among around a half-million species. One must also know how and when harvest the plant and the morphology of location and extraction. Within the same species plant chemistry varies, depending upon climatic and soil conditions, stage of maturity and even diurnal factors. To all of these variations must be added the diagnostic ability of physicians and native healers (to distinguish between Hippocratically-trained Western physicians and whose knowledge is less formally taught). Seldom was a disease identified as we Know it today, but the constellations of symptoms described, when studied carefully within the framework historical setting of the culture, can be related to modern medicine. It is essential to study the historical contemporary usage data in the language in which those accounts were writTen. Translators are often philologists who are not sensitive to medical nuances. Modern readers of translated historical documents often are unaware of the precision the authors delivered in describing medical afflictions and their treatments. Natural product drugs are truly products of human knowledge. Because so many modern pharmaceuticals are manufactured synthetically we forget that once either the compound or its affinity had a home in a natural product. Over 2,500 years ago man first used a drug obtained from white willow bark, which was aspirin or acetylsalicylic acid. Today's scientists continue to be bewildered by just what aspirin's mechanisms of action are, discovering new modes of action, and how they relate to medical diagnostics. Whatever the science of aspirin, an intelligent person today takes it just as our ancestors did fo millennia. Throughout time, explanations continue to vary just as purpose of administration do as well. Nevertheless, aspirin is perceived as being beneficial. Historical in-use data can also be a factor in judging a drug's safety, since the records of its use provide observations made by intelligent persons over generations of employment Many historical "drugs" have crossed the line from drug to food. A number of them are now common items on our tables: coffee, tea, sugar, lemon, chocolate, pepper, to name a few The example of coffee affords useful insight. It was first employed as a drug (like tobacco), its botany and chemistry are well known, it has been in widespread use for centuries with diverse ethnic populations in a variety of preparations and amounts consumed. Still we are unsure about coffee's effect on health, the latest assertion being that the caffeine it contains may delay the onset of Alzheimer's. In contrast, the mercury drugs were in widespread use for a long period of time by many populations and that fact indicates that the toxic tolerance in humans is probably higher than as currently proscribed. The past contains important data for the scientific investigator. Like any field of research, historical investigation requires specialized knowledge, but much of that knowledge is readily accessible and employable. Rediscovery through examination of historical contemporaneous use data can be efficient and relatively easy compared to the travails of original research in pursuit of a discovery only to learn later that our ancestors had already made that discovery through trial and error in human usage. If we had started a search from the clues provided by history, presumably our discoveries would have been earlier, and we would have benefitted. As it is. we learn history but not science or else we learn science, not history. Both taken together the learning can be enhanced.

Ａｓｐｉｒｉｎの週１〜２回間けつ投与法

The efficacy of platelet inhibition with aspirin for the prevention of secondary and primary events in patients with cardiovascular and cerebrovascular diseases is established. Aspirin irreversibly acetylates platelet cyclooxygenese (COX) and permanently inhibits thromboxane A2 production. Platelets do not re-synthesize COX because platelets do not have nucleus. Therefore, active enzyme returns with a time course reflecting platelet turnover (life span 7-10 days). According to the above pharmacological mechanisms of aspirin, an intermittent administration (1-2 times a week) of aspirin is sufficient to obtain the antiplatelet effect.Eight healthy subjects (3 males: 30-42 years, 5 females: 21-42 years) ingested 81 mg of buffered aspirin. Platelet aggregation was measured before aspirin ingestion and at 90 minutes, 3 days, 5 days, and 7 days after aspirin ingestion of a single 81 mg aspirin . The mean inhibition rate of platelet aggregation was 79.7±7.1% at 90 minutes (p=0.00002), 69.4±15.6% at 3 days (p=0.0002), 44.4±30.0% at 5 days (p=0.003), and 22.1 ±34.8% at 7 days (p=0.048). The inhibition of platelet aggregation of aspirin persisted for five to seven days.The ratio of small, medium and large-sized aggregates was determined simultaneously. The ratio of small, medium and large was 38: 26: 36 (%) before ingestion respectively, 82: 8.6: 9.4 at 90 minutes, 71: 14: 16 at 3 days, 56: 18: 26 at 5 days, and 47: 21: 32 at 7 days after ingestion of a single 81 mg aspirin. Aspirin mainly inhibited the formation of large-sized platelet aggregates.The inhibitory effect of platelet aggregation appeared within 5 minutes and the mean inhibition rate (n=5) was 27.1±28.1% at 5 minutes (p=0.06), 57.1±20.4% at 10 minutes (p=0.004), 72.1±13.5% at 15 minutes (p=0.0007), 78.9 ±9% at 20 minutes (p=0.0002), 85.3±9.5% at 25 minutes (p=0.00006), and 84.1±3.9% at 30 minutes (p= 0.00004) after a single 81 mg aspirin ingestion. The data indicated that aspirin is a quick-working medicine. The ratio of large-sized aggregates decreased from 42% to 19.8% in 10 minutes and to only 5.4% in 30 minutes after ingestion.The present study showed that the inhibitory effect of platelet aggregation of aspirin persisted for at least 5 days or more and that aspirin is a considerably quick working medicine. Thus, it is thought that an intermittent administration of aspirin should be recommended for the secondary and primary prevention of arteriosclerotic diseases.

Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirin-sensitive and aspirin-tolerant patients.

The mechanism of aspirin (acetylsalicylic acid [ASA]) sensitivity associated with severe asthma and chronic rhinosinusitis with nasal polyps ("aspirin triad") has been attributed to arachidonic metabolism alternations, although the putative biochemical defects have not been elucidated. The aim of this study was assessment of the hypothesis that local production of eicosanoids in the respiratory epithelium in patients with ASA-sensitive asthma/rhinosinusitis (ASARS) differs from that of ASA-tolerant patients with rhinosinusitis (ATRS). Nasal polyps were obtained from 10 patients with ASARS and 15 with ATRS during routine polypectomies, and epithelial cells (ECs) were cultured on bovine collagen type I matrix (Vitrogen 100), in medium supplemented with growth factors. The generation of eicosanoids in supernatants of confluent ECs (6 to 8 d of culture; purity > 98%) was quantified by immunoassays. Unstimulated ECs from ASARS patients generated significantly less prostaglandin E(2)(PGE(2)) compared with ATRS (0.8 +/- 0.3 versus 2. 4 +/- 0.5 ng/microg double-stranded deoxyribonucleic acid [dsDNA], respectively), although a similar relative increase in response to calcium ionophore and inhibition with ASA was observed in both groups. Basal levels of 15-hydroxyeicosatetraenoic acid (15-HETE) were not different between groups, and calcium ionophore enhanced its production to a similar extent. However, cells incubation with 200 microM ASA for 60 min resulted in a significant increase (mean +359%) in 15-HETE generation only in ASARS patients, whereas no effect of ASA on 15-HETE generation in ATRS patients was observed. PGF(2alpha) generation was similar in both groups, and no significant generation of PGD(2) or leukotriene C(4) (LTC(4)) was observed in epithelial cell cultures from either group. Our results indicate that nasal polyps ECs from ASA-sensitive patients have significant abnormality in basal and ASA-induced generation of eicosanoids which may be causally related to the mechanism of ASA sensitivity.

Effect of aspirin on platelet desaggregation induced by SR121566, a potent GP-IIb/IIIa antagonist

Since results of recent clinical trial, performed in patients suffering from acute coronary syndromes, suggested that aspirin improved the efficacy of an anti-GP-IIb/IIIa therapy, this work was set to study the mechanism underlying such a mechanism of aspirin. SR121566 (3mg/kg, i.v.), a new selective antagonist of the GP-IIb/IIIa complex inhibited thrombus formation which occurred following electrical stimulation of the carotid artery of rabbits. On rabbits pre-treated with aspirin (10 mg/kg, i.v.), a bolus injection of SR121566 produced a strong reversal of thrombosis compared with the effect obtained on rabbits treated with SR121566 alone. In vitro , the addition of SR121566 to human platelets during the ADP-induced aggregation process resulted in a reversal of the aggregation which was nearly complete when it was added 30s after the induction of aggregation, but progressively decreased when SR121566 was added at later times. ADP-induced platelet aggregation in the presence of aspirin (1 mM) was comparable to that obtained in control platelet-rich plasma, but the addition of SR121566 at all time points of the aggregation process was followed by a complete reversal of the aggregation even at later time points (>120s). Histological examination of the platelet aggregates showed a clear-cut difference in the platelet content between control and aspirin-treated platelets which contained much more dense granules. Inhibition of the release of thrombospondin by aspirin may account for a significant part of its pro-desaggregating activity as demonstrated by the effect of the tetrapeptide VTCG, an inhibitor of the binding of thrombospondin to its receptor, which strongly potentiated the activity of SR121566 as a desaggregating agent. Therefore, our study shows that aspirin pretreatment promotes a 'thrombolytic' activity of GP-IIb/IIIa inhibitors and, in particular, of SR121566, a potent and selective member of this new class of compounds. This effect is mainly due to an inhibition of the release of the platelet granule content and in particular to thrombospondin. This observation may contribute to a greater efficacy of GP-IIb/IIIa inhibitors for the treatment of thrombosis in atherosclerotic patients.

The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.

NF-kappaB comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response. NF-kappaB is sequestered in the cytoplasm by inhibitory proteins, I(kappa)B, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-alpha and IKK-beta, which phosphorylate I(kappa)B, leading to its degradation and translocation of NF-kappaB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-alpha or by overexpression of the cellular kinases MEKK1 and NIK. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-beta to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappaB of genes involved in the pathogenesis of the inflammatory response.

Vascular smooth muscle, endothelial regulation and effects of aspirin in hypertension.

Dysfunction of vascular smooth muscle (VSM) is at the center of occlusive disorders of the cardiovascular system such as hypertension, atherosclerosis, coronary artery disease and hypoxia. In addition to circulating biogenic amines and various neurotransmitters originating from the central nervous system and endocrine system, various autocoids of arachidonic acid metabolism in the blood as well as in the endothelium play an important regulatory role in the maintenance of the tone and the contractile function of VSM. A monolayer of endothelial cells lining the heart and large blood vessels is responsible for producing and releasing both endocrine and paracrine substances such as endothelins, nitric oxide, prostaglandins and prostacyclins. Aspirin, (acetylsalicylic acid/ASA) an ancient remedy against fever and pain, is emerging as an effective drug not only against occlusive disorders but also against various cancers and the AIDs virus. During pregnancy induced hypertension (PIH) and in occlusive disorders, aspirin provides relief through inhibition of cyclooxygenase, an enzyme required for the metabolism of arachidonic acid to produce prostaglandins and prostacyclins in platelets and in endothelial cells. Because of its unique molecular constitution, synergistic ability and solubility in the lipidic environment, various mechanisms of aspirin's actions are being currently investigated. In this review, the effect of aspirin on the regulation of VSM in the presence and absence of endothelium are discussed.

History of drugs for thrombotic disease. Discovery, development, and directions for the future.

The history of the antithrombotic agents--aspirin, heparin, warfarin, and the thrombolytics--is a rich and lively odyssey of serendipity, perseverance, vision, and conflict involving a number of striking personalities. The history of aspirin spans ages and continents from Hippocrates' analgesic for women in labor to the rediscovery of the white willow bark by English country scholar Reverend Edward Stone. Bayer chemist Felix Hoffmann reinvented aspirin for his ailing father; suburban physician L.L. Craven pioneered the prophylactic antithrombotic uses of aspirin; and Sir John Vane elucidated aspirin's mechanism of action as the inhibition of prostaglandin synthetase. Heparin was discovered by McLean, working as a medical student in 1915 in search of a pure procoagulant in dog liver. His original impure material differed somewhat from today's heparin, but purified heparin was rapidly accepted for a myriad of clinical uses; to this day, diverse new properties of this complex glycosaminoglycan continue to be elucidated. The oral anticoagulants emerged from veterinary research in the 1920s on a hemorrhagic disorder afflicting cattle that consumed spoiled sweet clover hay. Several chance encounters led Karl Link and his University of Wisconsin team to the identification of dicumarol as the offending agent in 1939 and its widespread therapeutic use by Wright and others in the 1940s. Link later developed warfarin as a rodenticide, but its use in humans soon followed in the 1950s. Vitamin K was discovered in the 1930s; its involvement in the mechanism of the anticoagulant agents was not delineated until the 1970s. The intrinsic ability of clotted blood to liquify and the fibrinolytic properties of normal urine were noted in the 1800s. Tillett and Sherry's group stumbled on the fibrinolytic properties of streptokinase in the 1930s and pioneered the therapeutic use of streptokinase in the 1940s and of urokinase in the 1960s. Several teams found tissue-type plasminogen activator in various body sites beginning in the 1940s, leading to its cloning and widespread use in the 1980s; anisoylated plasminogen-streptokinase activator complex is an example of rational drug design. The discoverers of these diverse agents have not only provided physicians with a potent armamentarium of antithrombotic drugs but also helped elucidate much basic science and vividly demonstrated the merits of perseverance, independent thought, and adherance to the scientific method.

Use of Scavenging Oxygen‐Derived Free Radicals to Protect the Rat Against Aspirin‐ and Ethanol‐Induced Erosive Gastritis

AbstractOxygen-derived free radicals are cytotoxic and produce tissue damage. The effect of the radical scavengers allopurinol and dimethyl sulfoxide (DMSO) on aspirin‐ and ethanol‐induced acute gastric mucosal injury was studied in the rat. Orogastric instillation of aspirin at 200 mg/kg produced, after 4 h, gastric mucosal injury in 30% of rats without pyloric ligation [score, 3.1 ± 0.8mm2, mean ± standard error of the mean (SEM); n = 10] and in 80% of rats with this ligation (score, 10.4 ± 1.2mm2, mean ± SEM; n = 10). Gavage with 1mL of 2 or 5% allopurinol or DMSO at 24h before and again just before aspirin administration completely protected rats with or without pyloric ligation against injury. Orogastric instillation of ethanol (1mL of a 40% solution) produced, after 1 h, gastric mucosal injury in all rats with or without pyloric ligation (24.1 ± 1.7 and 14.1 ± 1.3mm2, respectively, mean ± SEM; n = 10). Gavage with 1mL of 5% allopurinol or DMSO at 24h before and again just before ethanol administration completely protected rats with or without pyloric ligation against injury. Protection against the aspirin‐ and ethanol‐induced injury was not associated with any significant effect on the H+ output. The results suggest that oxygen‐derived free radicals are directly implicated in the mechanism of aspirin‐ and ethanol‐induced acute gastric mucosal injury and that scavenging these free radicals protects against injury by maintaining the integrit of the gastric mucosa.

Aspirin and prevention of myocardial infarction

Determining the cardioprotective effects of aspirin (acetylsalicylic acid) remains a focus for both basic science and clinical investigation. Although other contributors are probably present, the favorable prostacyclin-to-thromboxane ratio induced by low-dose aspirin appears beneficial for reducing cardiovascular mortality associated with unstable angina and myocardial infarction. The precise dosage, frequency and timing of aspirin's administration to reduce the incidence of vaso-occlusive events remains to be determined. This article reviews aspirin's mechanism of action and use for the prevention of myocardial infarction. aspirin / unstable angina / myocardial infarction.

Effects of platelet-modifying drugs on arterial thromboembolism in baboons. Aspirin potentiates the antithrombotic actions of dipyridamole and sulfinpyrazone by mechanism(s) independent of platelet cyclooxygenase inhibition.

To resolve questions of drug actions, efficacy, and interactions for platelet-modifying agents used clinically, we have compared the relative capacities and mechanisms of aspirin, dipyridamole, sulfinpyrazone, and dazoxiben to prevent arterial thromboembolism in a baboon model. In 136 studies the agents were given twice daily by oral administration both singly and in combination. The antithrombotic efficacy of a given therapy was determined by its capacity to interrupt steady-state platelet utilization induced by thrombogenic arteriovenous cannulae. When given alone, dipyridamole and sulfinpyrazone reduced the rate at which platelets were utilized by thrombus formation in a dose-dependent manner with essentially complete interruption by dipyridamole at 10 mg/kg per d. In contrast, neither aspirin (2-100 mg/kg per d) nor dazoxiben (20-100 mg/kg per d) decreased cannula platelet consumption detectably despite the striking reduction in the capacity of platelets to produce thromboxane B2. However, aspirin, but not dazoxiben, potentiated the antithrombotic effects of dipyridamole and sulfinpyrazone in a dose-dependent fashion without changing the pharmacokinetics for any of the agents. Complete potentiation required aspirin at 20 mg/kg per d to be given with each dose of dipyridamole. Because dazoxiben's blockade of platelet thromboxane A2 production was not associated with antithrombotic potentiation, and because complete potentiation by aspirin required a dose that fully inhibited vascular production of prostaglandin I2 (PGI2), we conclude that aspirin's potentiating effect on dipyridamole is independent of PGI2 production or inhibition of thromboxane A2 formation. In addition, because frequent repeated and synchronous dosing of aspirin was necessary, aspirin's potentiating effects appear to be produced by mechanism(s) unrelated to its potent, irreversible inhibition of platelet cyclooxygenase.

Antiplatelet Drugs in Arterial Thrombosis: A Review

The thrombotic process, basic mechanisms of action of antiplatelet drugs, and clinical trials with platelet inhibitors are reviewed. The role of prostaglandins in platelet reactions and the mechanisms of aspirin's, dipyridamole's and sulfinpyrazone's inhibition of platelet function are discussed. Clinical studies of the use of these three drugs, alone or in combination with each other or with anticoagulants, for the treatment of thrombotic disorders associated with valvular heart disease, prosthetic heart valves, cerebral vascular disease (e.g., transient ischemic attacks), coronary artery diseases (including myocardial infarction), peripheral vascular disease, renal disease and renal allograft rejection are reviewed and evaluated. Clinical evidence suggests that antiplatelet drugs are useful in preventing thromboembolism associated with coronary and cerebral vascular disorders. In peripheral vascular and renal diseases and in renal allografts, their benefits have not been proved. Further controlled clinical studies of the preventive use of these drugs for arterial thrombosis are needed.