Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The continued widespread prevalence of breast cancer supports placing a high priority on research aimed at its primary prevention, particularly among women who are at increased risk for developing this disease. The suggestion of potential agents for the primary chemoprevention of breast cancer evolved out of the treatment setting. Extensive experience with tamoxifen, a first-generation selective estrogen receptor modulator (SERM) showing efficacy, first, in the treatment of advanced breast cancer and, subsequently, as adjuvant therapy for early stage disease established the safety of this agent. Cumulative data from multiple adjuvant studies documented the efficacy of tamoxifen in reducing second primary breast cancers in the contralateral breast, supporting its potential as a chemopreventive agent for breast cancer. The safety and second primary data on tamoxifen, together with extensive information on its pharmacokinetics, metabolism, and antitumor effects, as well as its potentially beneficial effects on lipid metabolism and osteoporosis, led the National Surgical Adjuvant Breast and Bowel Project (NSABP) to select tamoxifen for testing in the first prospective randomized phase III trial of the efficacy of a chemopreventive agent for preventing breast cancer in women at increased risk of the disease. Accordingly, in 1992 the NSABP started the Breast Cancer Prevention Trial (P-1) in which 13,388 women > or = 35 years of age who were at increased risk of breast cancer according to Gail model risk factors [family history, age, and personal history (i.e., age at first birth, age at menarche, previous breast biopsies)] were randomized to tamoxifen 20 mg/day or placebo for 5 years. Through 69 months of follow-up tamoxifen reduced the risk of invasive breast cancer, primarily estrogen receptor-positive tumors, by 49% (two-sided p < 0.00001). Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided p < 0.002). In addition, tamoxifen reduced fractures of the hip, radius, and spine, but it had no effect on the rate of ischemic heart disease. As previously shown, the rates of endometrial cancer and vascular events increased with tamoxifen. With the P-1 results establishing tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high-risk women, concern over the side effects of tamoxifen has prompted a continuing search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene, a second-generation SERM approved for the prevention of osteoporosis in postmenopausal women, displays antiestrogenic properties in the breast and possibly the endometrium, and estrogenic effects in the bone and on the lipid profile, suggesting it as a candidate for comparison with the chemopreventive standard, tamoxifen. Raloxifene will be compared to tamoxifen in an equivalency trial, the Study of Tamoxifen and Raloxifene (STAR) NSABP P-2, which began in July 1999 at almost 500 centers in North America. The plan is to randomize 22,000 postmenopausal women > or = 35 years of age at increased risk of breast cancer by Gail criteria to tamoxifen 20 mg/day or raloxifene 60 mg/day for 5 years. Study endpoints include invasive and noninvasive breast cancer, cardiovascular disease, endometrial cancer, bone fractures, and vascular events.
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PMID:From adjuvant therapy to breast cancer prevention: BCPT and STAR. 1146 26

The purpose of this study is to examine whether raloxifene, one of the selective estrogen receptor modulators, could improve myocardial ischemia and to assess the mechanisms involved. In open-chest beagle dogs anesthetized by intravenous infusion of sodium pentobarbital, the left anterior descending coronary artery (LAD) was perfused from the left carotid artery through an extracorporeal bypass tube. Raloxifene was infused into the LAD through the bypass tube under either ischemic or non-ischemic conditions. In the non-ischemic heart, raloxifene had no effect on coronary blood flow, fractional shortening, and myocardial metabolism. However, raloxifene caused an acute increase in both coronary blood flow and fractional shortening, and also improved myocardial anaerobic metabolism in the ischemic heart. These effects were partially attenuated by pretreatment with either L-NAME or wortmannin and were completely abolished by ICI182780 (an estrogen receptor antagonist) or L-NAME plus charybdotoxin (a blocker of Ca-activated K channels). Raloxifene also increased both Akt activity and the NO level, with these changes being completely abrogated by pretreatment with wortmannin. These results demonstrated that raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism by release of NO and opening of Ca-activated K channels in the ischemic heart, and that NO production is mediated by the phosphatidylinositol 3-kinase/Akt pathway.
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PMID:Raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart: role of phosphatidylinositol 3-kinase/Akt pathway. 1516 76

In the Study of Tamoxifen and Raloxifene (STAR) trial, postmenopausal women at increased risk of breast cancer received either oral tamoxifen (20 mg/day) or raloxifene (60 mg/day) over 5 years. There were an equal number of cases of invasive breast cancer in women assigned to tamoxifen and raloxifene. There were fewer cases of noninvasive breast cancer in the tamoxifen group than in the raloxifene group (risk ratio [RR]: 1.40; 95% confidence interval [CI]: 0.98-2.02). There were more cases of uterine cancer with tamoxifen than with raloxifene (RR: 0.62; 95% CI: 0.35-1.08). Thromboembolic events occurred less often in the raloxifene group (RR: 0.70; 95% CI: 0.54-0.91) and there were fewer cataracts and cataract surgeries in the women taking raloxifene (RR: 0.79; 95% CI: 0.68-0.92). The STAR trial has shown that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of adverse events but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease and stroke is similar for both drugs.
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PMID:The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. 1910 6