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1.
Figure 6

Figure 6. From: Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.

Discordant dose-response relationships for inhibition of platelet COX-1 (A) and vascular COX-2 (B). Derived from data reported in ref. 28.

Tilo Grosser, et al. J Clin Invest. 2006 January 4;116(1):4-15.
2.
Figure 8

Figure 8. From: Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.

Duration of use of tNSAIDs and individual tNSAIDs among current users (use within a month) and risk of myocardial infarction. Redrawn with permission from BMC Medicine (106). CI, confidence interval; nonuse, reference group with relative risk of 1.00.

Tilo Grosser, et al. J Clin Invest. 2006 January 4;116(1):4-15.
3.
Figure 7

Figure 7. From: Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.

Clinical implications of differences in the dose-response relationships for COX-1 and COX-2 of low-dose aspirin (A), a selective inhibitor of COX-2 (B), and a tNSAID (C). The area between the dose-response curves would correspond to benefit (A) and hazard (B and C) and to the size of these effects.

Tilo Grosser, et al. J Clin Invest. 2006 January 4;116(1):4-15.
4.
Figure 3

Figure 3. From: Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.

Roles of the COX isozymes in cardiovascular (A and C) and renal (B) biology. ACE, angiotensin-converting enzyme; ADP, adenosine diphosphate; aPC, activated protein C; BK, bradykinin; ecNOS, endothelial cell NOS; MBF, medullary blood flow; RAS, renin-angiotensin system; TM, thrombomodulin.

Tilo Grosser, et al. J Clin Invest. 2006 January 4;116(1):4-15.
5.
Figure 4

Figure 4. From: Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.

Illustration of the expected interaction of baseline cardiovascular and thrombotic risk with components of drug exposure including dose, duration of action, and duration of treatment with a selective inhibitor of COX-2. The approximate relationship of cardiovascular hazard detected in controlled studies within this interaction are indicated (not to scale). APC study, ref. 81; APPROVe study, ref. 72; CABG studies, parecoxib/valdecoxib after bypass surgery, refs. 77, 78; VIGOR study, ref. 62.

Tilo Grosser, et al. J Clin Invest. 2006 January 4;116(1):4-15.
6.
Figure 1

Figure 1. From: Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.

Schematic depiction of the structural differences between the substrate-binding channels of COX-1 and COX-2 that allowed the design of selective inhibitors. The amino acid residues Val434, Arg513, and Val523 form a side pocket in COX-2 that is absent in COX-1. (A) Nonselective inhibitors have access to the binding channels of both isoforms. (B) The more voluminous residues in COX-1, Ile434, His513, and Ile532, obstruct access of the bulky side chains of COX-2 inhibitors. Figure modified with permission from Nature from protein structures reported in refs. 18 and 20.

Tilo Grosser, et al. J Clin Invest. 2006 January 4;116(1):4-15.
7.
Figure 2

Figure 2. From: Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.

Expression of COX-2 mRNA in the endothelium (arrows) of human (A) and COX-2 protein in murine (BE) arteries. (A) In situ detection of COX-2 mRNA in the endothelium of a human umbilical artery. Image kindly provided by James N. Topper, Frazier Healthcare Ventures, Palo Alto, California, USA. (BE) Immunostaining shows COX-2 upregulation 4 weeks after left common carotid artery ligation in mice. Scale bars: 50 μm. Baseline COX-2 expression (brown staining) is evident in the intima in cross sections of the right common, unligated carotid artery, which served as a control. Magnification, ×20 (B); ×40 (C). Flow reduction induced further COX-2 expression in the intimal layer and marked endothelial expression as shown in D and E. Magnification, ×20 (D); ×40 (E). LC, left common carotid artery; RC, right common carotid artery. BE are reproduced here with permission from Circulation Research (55).

Tilo Grosser, et al. J Clin Invest. 2006 January 4;116(1):4-15.
8.
Figure 5

Figure 5. From: Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.

The spectrum of selectivity for COX inhibition. (A) The relative affinities of tNSAIDs and coxibs (open circles) for COX-1 and COX-2. The concentrations required to inhibit COX-1 and COX-2 by 50% (IC50) have been measured using whole-blood assays of COX-1 and COX-2 activity in vitro. The diagonal line indicates equivalent COX-1 and COX-2 inhibition. Drugs plotted below the line (orange) are more potent inhibitors of COX-2 than drugs plotted above the line (green). The distance to the line is a measure of selectivity. Note the log scale. For example, lumiracoxib is the compound with the highest degree of selectivity for COX-2 as its distance to the line is the largest. Celecoxib and diclofenac have similar degrees of selectivity for COX-2, as their distances to the line are similar; however, diclofenac is active at lower concentrations and thus located more to the left. Figure modified with permission from The New England Journal of Medicine (28). (B) Implication of the relative degrees of selectivity. Increasing degrees of selectivity for COX-2 are associated with augmented cardiovascular risk while increasing degrees of selectivity for COX-1 are associated with augmented GI risk. The relative size of the circles indicates approximately the variation in sample sizes among the trials.

Tilo Grosser, et al. J Clin Invest. 2006 January 4;116(1):4-15.

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