Antiplatelet and Antiinflammatory Drug Treatment in
Atherosclerosis May Promote Plaque Instability
Ralph G. DePalma MD, Washington, DC meta-analysis of randomized trials published in atheromas in Figure 2. Similar deeply stained cores and A the Journal of the American Medical Association more severe lesions as compared with controls appeared in 2001 raised cautionary flags about the effects of in plaques sampled from the femoral, inferior mesen- cyclooxygenase-2 (COX-2) inhibitors Vioxx and teric, and spermatic arteries and the infrarenal aorta.
Celecoxib, which increased the relative risk of cardio- Clearly, dipyridamole differs in its action from the vascular events and sudden or unexplained death and current COX-2 inhibitors and other NSAIDs by its significantly increased the annual rates of myocardial action as a coronary vasodilator. It acts on platelets as infarction for patients receiving these agents.1 In the a phosphodiesterase inhibitor and antiaggregant. Was interval following this report, over 120 publications it this action that related to the development of accel- appeared concerning these unexpected problems,2 par- erated atherosclerosis in our model? Would different ticularly as nonsteroidal antiinflammatory drugs doses of either aspirin or dipyridamole have made a (NSAIDs) had been prescribed in patient cohorts where atherosclerosis was likely to be prevalent.3 The results This single study, though labor intensive, did not of randomized trials and observational studies led to answer these questions. I was surprised at the time, the withdrawal of Vioxx from the market in September however, that these observations did not attract more attention and interest, but let the matter drop. I now This communication revisits effects of high-dose believe that the issue needs to be revisited for these aspirin _(13.5 mg/kg) and dipyridamole (15 mg/kg) in classes of drug combinations. In cynomolgus monkeys, two animal models4,5 using equivalent doses of these Hollander, long past, noted that the addition of aspirin- agents prescribed for man for stroke prevention and dipyridamole to a regression diet did not improve the treatment during the 1980s. Direct observations of arter- course of disease in their model,7 but they did not impute ies showed two unexpected effects: in arterial trauma, inhibition of reendothelization after injury with thicker At a time when some believe that all clinical scien- intimal lesions after healing; and, in subhuman primates tific truth can be derived solely from randomized clinical with atherosclerosis, progression of more severe plaques trials, and given the expense, risks, and equivocations with unstable cores and thrombosis of arteries not before of some current trials, I suggest that COX-2 inhibitors for pain and other antiinflammatory/antiplatelet agents In rabbits, after a standard arterial injury that caused should be tested by preliminary observations on estab- aortic endothelialization, described by Bomberger and lished atherosclerotic disease using animal models.
colleagues,4 endothelial regrowth was inhibited by 66% Subhuman primates exhibit similar atherogenic at 4 days, 22% at 7 days, and 28% at 14 days in ani- responses to human disease: results will become evi- mals receiving this drug combination. Sample results dent by 12 months. Studies in affected subhuman primates could provide dose-related data and suggest Later studies showed that the retarded healing caused guidelines before antiplatelet and antiinflammatory by the aspirin-dipyridamole combination caused thicker drugs are widely and publicly marketed to human beings intimal lesions.6 We recommended at that time that antiplatelet drugs should be used cautiously in our ath-erosclerotic patients.
In a study using 10 atherosclerotic rhesus monkeys 1. Mukherjee D, Nissen SE, Topol EJ. Risk of in whom disease had developed after 58 months, we cardiovascular events associated with selective measured disease severity by angiography and arterial COX-2 inhibitors. JAMA 2001;286:_954-9.
biopsies and then treated seven individuals with aspirin- 2. Drazen JM. COX-2 inhibitors-A lesson in unex- dipyridamole for 12 months in equivalent daily doses pected problems. N Engl J Med 2005;352:1131-2.
suggested for humans at that time (four regular aspirin 3. Hippisley-Cox J, Coupland C. Risk of myocardial and eight dipyridamole tablets). The results proved dra- infarction in patients taking cyclooxygenase-2 matic and unexpected. Despite comparable serum inhibitors or conventional non-steroidal anti-inflam- cholesterol levels during the treatment period, ranging matory drugs: population based nested case- 309 to 668 mg/dL (average 501 experimental; 525 con- control analysis. BMJ 2005;330:1366.
trol), atherosclerotic plaques progressed much more 4. Bomberger RA, DePalma RG, Ambrose TA, rapidly in the ensuing 12 months in animals receiving Manalo P. Aspirin and dipyridamole inhibit the antiplatelet combination as measured by angio- endothelial healing. Arch Surg 1982;117:1459-64.
graphic and morphometric grading. One animal on drug 5. DePalma RG, Bellon EM, Manalo PM, Bomberger treatment developed thrombosis on a plaque of the left RA. Failure of antiplatelet treatment in dietary ath- subclavian artery, its origin. Most significantly, plaques erosclerosis: a serial intervention study. In: Gallo in the treated animals all exhibited deeply staining LL, editor. Cardiovascular disease. Washington, potentially unstable cores shown in representative carotid DC: Plenum Publishing; 1987. p. 407-26.
6. Bomberger RA, Wilburn J, DePalma RG. Aspirin and dipyridamole increase intimal thickening after 7. Hollander W, Kirkpatrick B, Paddock J, et al. Studies on the progression and regression of coronary and peripheral atherosclerosis in thecynomolgus monkey. I. Effects of dipyridamoleand aspirin. Exp Mol Path 1979;30:55-73.



International Journal of Systematic and Evolutionary Microbiology (2011), 61, 2338–2341Glaciecola arctica sp. nov., isolated from Arcticmarine sedimentYan-Jiao Zhang,1 Xi-Ying Zhang,1 Zi-Hao Mi,1 Chun-Xiao Chen,1Zhao-Ming Gao,1 Xiu-Lan Chen,1 Yong Yu,2 Bo Chen21The State Key Laboratory of Microbial Technology, Marine Biotechnology Research Center,Shandong University, Jinan 250100, PR China2

Svarbiausios pastarųjų metų publikacijos 1. Borutaite V., Morkuniene R., Valincius G. Beta-amyloid oligomers: recent developments. BioMolecular Concepts. 2011, 2(3): 211–222. 2. Barauskaite J, Grybauskiene R, Morkuniene R, Borutaite V, Brown GC. 3. Cizas P, Budvytyte R, Morkuniene R, Moldovan R, Broccio M, Lösche M, Niaura G, Valincius G, Borutaite V. Size-dependent neurotoxicity of

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