Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The action of lipoprotein lipase on chylomicrons (CM) and very low density lipoproteins (VLDL) produces remnant lipoproteins (RLP) which are rich in triglycerides, cholesterol and apolipoprotein E (apo E). Apo E serves as a ligand for uptake of RLP by macrophages, platelets, endothelial cells and other cells expressing the LDL-receptor or the remnant receptor, thus having a major role in the clearance of plasma cholesterol and triglycerides, but at the same time, uptake of apo E-bearing RLP can profoundly alter the physiology of these cells and promote atherosclerosis. Like RLP, blood platelets also have roles in atherosclerosis and thrombosis, hence it is likely that RLP influence platelet activity as well. RLP derived from normal human plasma VLDL and CM were prepared using two monoclonal antibodies, anti-apo B-100 (JI-H) and anti-apo A-I (H-12) coupled to Sepharose 4B gel to form an immunoaffinity column. Lipoproteins containing apo B-100 including VLDL and LDL adsorb to (JI-H)-gel, while CM and HDL with apo A-I adsorb to (H-12)-gel. The particles in the unbound fraction (RLP) are rich in apo B-48, apo E and apo B-100 containing particles with multiple molecules of apo E. The RLP fraction with a total triglyceride of 14+/-3.2 mg/ml; cholesterol, 0.39+/-0.1 mg/ml and protein, 0.78+/-0.24 mg/ml (n=19) was added to aliquots of blood of man, rabbits, guinea pigs, mice, and rats at protein equivalents of 0.98 to 78 microg/ml blood and agitated gently at 37 degrees C for 40 sec. Platelet aggregation was measured as a fall in single platelet count. RLP induced aggregation of platelets in man (p<0.005) rabbit (p<0.0005), guinea pig (p<0.002) and mouse (p<0.0001), but no RLP induced platelet aggregation was observed in the rat blood. Scanning electron microscopy revealed that in the presence of RLP, platelets had adhered to and formed aggregates on red cells. The platelet response to RLP was inhibited by apyrase known to scavenge ADP, by 5 microM 2-chloroadenosine, a platelet ADP receptor antagonist and by 3.4 microM cilostazol, a phosphodiesterase type III inhibitor known to raise cyclic AMP level in platelets. It is thought that RLP cause leakage of ADP from red cells which then mediates platelet aggregation.
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PMID:Adenosine 5'-diphosphate as a factor in platelet aggregation induced by human plasma remnant lipoproteins. 974 29

Clopidogrel, a new platelet ADP receptor antagonist, is more effective than aspirin in reducing the risk of subsequent vascular ischemic events in patients with a broad spectrum of symptomatic atherosclerosis (recent ischemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease). In CAPRIE (clopidogrel versus aspirin in patients at risk of ischemic events), a randomized, blinded, active control trial in 19,185 high-risk patients, clopidogrel reduced the combined risk of ischemic stroke, myocardial infarction or vascular death by 8.7% compared with aspirin (p = 0.043). The CAPRIE cohort had a mean age of 62.5 years, which was reflected in the high proportion of patients who had medical conditions other than symptomatic atherosclerosis, and in the extensive use of concurrent therapies, including commonly used cardiovascular drugs. For all concomitant medications analysed, there was no evidence of statistically or clinically significant interactions with clopidogrel. The CAPRIE data confirm the findings of earlier clinical studies, which suggested that clinically significant drug interactions with clopidogrel are rare, that it can safely be prescribed with a range of other drugs (including phenobarbital, cimetidine, estrogen, digoxin, theophylline, atenolol, nifedipine, or nifedipine-atenolol in combination), and that the clinically proven dose of 75 mg once daily is suitable for all age groups studied. Moreover, CAPRIE demonstrated that there is no need for an adjustment of clopidogrel dose on the basis of gender, weight or race, and that there is no need for routine hematological monitoring. Additional clinical pharmacology studies have shown that the absorption of clopidogrel is unaffected by food or antacids, and that no dose adjustment is necessary in patients with renal impairment or with mild-to-moderate hepatic impairment. Due to pharmacologic considerations and limited clinical data, clopidogrel should be used cautiously with heparin, warfarin or non-steroidal anti-inflammatory drugs. With a simple regimen of 75 mg once daily indicated for all patients, clopidogrel combines a favorable risk/benefit ratio with ease of use in clinical practice.
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PMID:Clinical aspects of the use of clopidogrel, a new antiplatelet agent. 1044 Apr 29

Platelets play an important role in atherothrombotic disease, as well as in the pathogenesis of atherosclerosis and in complications. Antiplatelet therapy with clopidogrel represents at present an important treatment of coronary artery disease (CAD), especially in and after acute coronary syndromes (ACS), and after coronary interventions when stents are used. Clopidogrel is a potent and specific inhibitor of platelet ADP receptor (P2Y(12) receptor) with high antithrombotic activity. Emerging data suggest that a significant percentage of individuals treated with clopidogrel do not receive the expected therapeutic benefit because of a decreased responsiveness of their platelets, which is caused by several extrinsic and/or intrinsic mechanisms. As long as clopidogrel is the "gold standard" in combination with aspirin in the treatment of patients undergoing percutaneous coronary intervention and stent implantation, the overall challenge is to develop a fast "point-of-care" assay to detect clopidogrel resistance early and to enable alternative antithrombotic strategies in non-responders or low-responders. This test should be easily performed (bedside) and reproducible, with a standardized definition of response, which is known to correlate with clinical outcomes. Unfortunately, such a test does not exist at present. As an alternative, new ADP receptor antagonists with better bioavailability and improved pharmacokinetics, e.g. intestinal reabsorption as an active drug or 1:1 conversion into an active metabolite thus reducing individual variations, are in development and have already found their way into clinical use in phase-3 trials. Prasugrel is one of the incoming new drugs with high expectations, but other agents might follow in the near future.
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PMID:Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. 1733 5