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- Wan, Y., et al.
(author)
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Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist
- 2004
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In: J Med Chem. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:24, s. 5995-6008
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Journal article (peer-reviewed)abstract
- The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.
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- Gavard, JA, et al.
(author)
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Prognostic significance of elevated creatine kinase MB after coronary bypass surgery and after an acute coronary syndrome: Results from the GUARDIAN trial
- 2003
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In: Journal of Thoracic and Cardiovascular Surgery. - 1097-685X. ; 126:3, s. 807-813
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Journal article (peer-reviewed)abstract
- Objective: To determine if the correlation between magnitude of creatine kinase-myocardial band release after coronary artery bypass surgery and 6-month mortality is comparable to that of patients admitted with an acute coronary syndrome. Methods: The GUARDIAN trial tested the efficacy of cariporide, an Na+/H+ exchange inhibitor, on reduction of myocardial ischemia or death in high-risk patients. We compared 6-month survival in a cohort of 2332 GUARDIAN patients scheduled for coronary artery bypass surgery at entry with 4233 acute coronary syndrome patients stratified by level of creatine kinase-myocardial band release. Cumulative 6-month survival by creatine kinase-myocardial band categories was performed using life table analysis, adjusting for variables known to impact prognosis using Cox regression. Results: The 6-month mortality rates for coronary artery bypass surgery patients with peak creatine kinase-myocardial band ratios of < 1, greater than or equal to1 and <5, greater than or equal to5 and < 10, and ! 10 upper limits of normal (ULN) were 5.8, 2.8, 5.9, and 12.0%, respectively (P < .0001). The 6-month mortality rates for acute coronary syndrome patients with peak creatine kinase-myocardial band ratios of < 1, greater than or equal to 1 and <5, greater than or equal to 5 and < 10, and greater than or equal to10 ULN were 6.3, 9.8, 10.0, and 12.3%, respectively (P < .0001). Patients with coronary artery bypass surgery or acute coronary syndrome had similar adjusted 6-month survival estimates at normal creatine kinase-myocardial band levels and when the creatine kinase-myocardial band level was greater than or equal to 10 ULN. Patients with coronary artery bypass surgery had significantly better survival at intermediate enzyme levels ( ! I and < 10 ULN; P < .001). Conclusions: Modest elevations of creatine kinase-myocardial band release (greater than or equal to 1 and <10 ULN) after coronary artery bypass surgery are not associated with adverse 6-month survival, in contrast to that seen in acute coronary syndrome patients. Routine creatine kinase-myocardial band sampling should be considered in all higher-risk patients undergoing coronary artery bypass surgery procedures to identify the sizable cohort of patients with creatine kinase-myocardial band release ! 10 ULN; these patients may benefit from postoperative angiotensin-converting enzyme inhibitor and beta-blocker therapy. Newer cardioprotective agents that reduce the number of patients with marked creatine kinase-myocardial band release are currently being tested in large randomized controlled clinical trials.
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