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• W2080405489 abstract "Procarboxypeptidase U (proCPU, EC 3.4.17.20), also known as thrombin‐activatable fibrinolysis inhibitor (TAFI), is considered to be a link between coagulation and fibrinolysis [1Wang W. Boffa M.B. Bajzar L. Walker J.B. Nesheim M.E. A study of the mechanism of inhibition of fibrinolysis by activated thrombin‐activatable fibrinolysis inhibitor.J Biol Chem. 1998; 273: 27176-81Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. During coagulation and fibrinolysis the active enzyme, carboxypeptidase U (CPU), can be generated from proCPU. CPU exerts its antifibrinolytic effect by removing C‐terminal lysine residues from partially degraded fibrin [1Wang W. Boffa M.B. Bajzar L. Walker J.B. Nesheim M.E. A study of the mechanism of inhibition of fibrinolysis by activated thrombin‐activatable fibrinolysis inhibitor.J Biol Chem. 1998; 273: 27176-81Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], thereby decreasing the enhanced plasminogen activation and preventing an acceleration of fibrinolysis. Elevated levels of proCPU have been found to be a mild risk factor for venous thrombosis (odds ratio 1.7; 95% confidence interval 1.1–25) [2Van Tilburg N.H. Rosendaal F.R. Bertina R.M. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis.Blood. 2000; 95: 2855-9Crossref PubMed Google Scholar] and were observed in patients with angina pectoris and ischemic stroke. From cross‐sectional studies it is known that proCPU concentrations increase with age in women not receiving postmenopausal hormone therapy (HT) [2Van Tilburg N.H. Rosendaal F.R. Bertina R.M. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis.Blood. 2000; 95: 2855-9Crossref PubMed Google Scholar, 3Juhan‐Vague I. Renucci J.F. Grimaux M. Morange P.E. Gouvernet J. Gourmelin Y. Alessi M.C. Thrombin‐activatable fibrinolysis inhibitor antigen levels and cardiovascular risk factors.Arterioscler Thromb Vasc Biol. 2000; 20: 2156-61Crossref PubMed Google Scholar]. Significantly lower values have been observed in postmenopausal women using HT, compared with non‐users [3Juhan‐Vague I. Renucci J.F. Grimaux M. Morange P.E. Gouvernet J. Gourmelin Y. Alessi M.C. Thrombin‐activatable fibrinolysis inhibitor antigen levels and cardiovascular risk factors.Arterioscler Thromb Vasc Biol. 2000; 20: 2156-61Crossref PubMed Google Scholar], whereas other studies did not confirm these findings. Raloxifene is a second‐generation selective estrogen receptor modulator (SERM) that has estrogen‐like effects on bone and cardiovascular risk factors, and estrogen receptor antagonistic effects on the breast and uterus. Several studies have reported beneficial effects of raloxifene on various cardiovascular risk markers [4Walsh B.W. Kuller L.H. Wild R.A. Paul S. Farmer M. Lawrence J.B. Shah A.S. Anderson P.W. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women.JAMA. 1998; 279: 1445-51Crossref PubMed Scopus (665) Google Scholar, 5Vogelvang T.E. Leurs J.R. Van Der Mooren M.J. Mijatovic V. Hendriks D.F. Neele S.J.M. Netelenbos J.C. Kenemans P. Raloxifene reduces procarboxypeptidase U, an antifibrinolytic marker. A 2‐year randomized, placebo‐controlled study in healthy early postmenopausal women.Menopause. 2004; 11: 110-5Crossref PubMed Scopus (0) Google Scholar, 6Vogelvang T.E. Mijatovic V. Kenemans P. Teerlink T. Van Der Mooren M.J. HMR 3339, a novel selective estrogen receptor modulator, reduces total cholesterol, low‐density lipoprotein cholesterol, and homocysteine in healthy postmenopausal women.Fertil Steril. 2004; 82: 1540-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 7Vogelvang T.E. Mijatovic V. Kenemans P. Schalkwijk C.G. Van Der Mooren M.J. Effect of HMR 3339, a novel selective estrogen receptor modulator, on C‐reactive protein levels in healthy postmenopausal women.Am J Cardiol. 2004; 94: 1205-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Raloxifene has been reported to reduce the risk of cardiovascular events in osteoporotic postmenopausal women at high cardiovascular risk [8Barrett‐Connor E. Grady D. Sashegyi A. Anderson P.W. Cox D.A. Hoszowski K. Rautaharju P. Harper K.D. Raloxifene and cardiovascular events in osteoporotic postmenopausal women. four‐year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial.JAMA. 2002; 287: 847-57Crossref PubMed Google Scholar]. However, like oral HT, raloxifene increases the risk of venous thromboembolic disease [9Cummings S.R. Eckert S. Krueger K.A. Grady D. Powles T.J. Cauley J.A. Norton L. Nickelsen T. Bjarnason N.H. Morrow M. Lippman M.E. Black D. Glusman J.E. Costa A. Jordan V.C. The effect of raloxifene on risk of breast cancer in postmenopausal women—results from the MORE randomized trial.JAMA. 1999; 281: 2189-97Crossref PubMed Scopus (0) Google Scholar]. Recently, we reported a randomized, controlled trial in which raloxifene reduced proCPU plasma concentrations in healthy postmenopausal women during a 2‐year study period suggesting a possible preventive effect on atherothrombotic disease [5Vogelvang T.E. Leurs J.R. Van Der Mooren M.J. Mijatovic V. Hendriks D.F. Neele S.J.M. Netelenbos J.C. Kenemans P. Raloxifene reduces procarboxypeptidase U, an antifibrinolytic marker. A 2‐year randomized, placebo‐controlled study in healthy early postmenopausal women.Menopause. 2004; 11: 110-5Crossref PubMed Scopus (0) Google Scholar]. HMR 3339 (4‐chloro‐11β‐(4‐(2‐(diethylamino)ethoxy)phenyl)‐estra‐1,3,5(10)‐triene‐3, 17β‐diol) is a newly developed SERM for the prevention of postmenopausal osteoporosis, that binds to the human recombinant estrogen receptor and shows tissue‐specific agonistic and antagonistic activity in in‐vitro and in‐vivo models. Preliminary data suggest a favorable effect on menopausal symptoms and the cardiovascular system, as well as beneficial activity on bone and a favorable safety profile on the breast and uterus. Recently, we reported that HMR 3339 therapy was associated with an anti‐atherogenic lipid profile [6Vogelvang T.E. Mijatovic V. Kenemans P. Teerlink T. Van Der Mooren M.J. HMR 3339, a novel selective estrogen receptor modulator, reduces total cholesterol, low‐density lipoprotein cholesterol, and homocysteine in healthy postmenopausal women.Fertil Steril. 2004; 82: 1540-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] and with reduced C‐reactive protein levels [7Vogelvang T.E. Mijatovic V. Kenemans P. Schalkwijk C.G. Van Der Mooren M.J. Effect of HMR 3339, a novel selective estrogen receptor modulator, on C‐reactive protein levels in healthy postmenopausal women.Am J Cardiol. 2004; 94: 1205-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. In the present study we investigated the short‐term effects of three doses of HMR 3339 on plasma proCPU concentrations and compared the effects with raloxifene. For this study, patient selection and inclusion procedures have been reported previously [6Vogelvang T.E. Mijatovic V. Kenemans P. Teerlink T. Van Der Mooren M.J. HMR 3339, a novel selective estrogen receptor modulator, reduces total cholesterol, low‐density lipoprotein cholesterol, and homocysteine in healthy postmenopausal women.Fertil Steril. 2004; 82: 1540-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. In short, 118 healthy, non‐hysterectomized postmenopausal women were included in this 12‐week multicenter, randomized, placebo‐controlled, double‐blind, phase II study. The investigation conformed to the principles outlined in the Declaration of Helsinki. The Institutional Review Boards of all participating centers approved the protocol. Written informed consent was obtained from each participant before entry into the study. Women were assigned randomly to either placebo (n = 22), HMR 3339 2.5 mg day−1 (HMR 2.5 group; n = 25, Hoechst Marion Roussel R&D, Romainville, France), HMR 3339 10 mg day−1 (HMR 10 group; n = 24), HMR 3339 50 mg day−1 (HMR 50 group; n = 24), or raloxifene 60 mg day−1 (Rlx 60 group; n = 23, Eli Lilly and Company, Indianapolis, IN, USA). At baseline and after 4 and 12 weeks of treatment, venous blood samples were collected and stored at −80 °C until analysis. Plasma proCPU concentrations were determined by converting the zymogen to its active form and subsequently measuring the carboxypeptidase activity with a colorimetric assay [10Schatteman K.A. Goossens F.J. Leurs J.R. Kasahara Y. Scharpe S.S. Hendriks D.F. Fast homogeneous assay for plasma procarboxypeptidase U.Clin Chem Lab Med. 2001; 39: 806-10Crossref PubMed Scopus (0) Google Scholar]. The intra‐assay coefficient of variation had a mean of 3.7%. Statistical analysis was performed using the Statistical Package for the Social Sciences 9.0 (SPSS Inc., Chicago, IL, USA). We compared baseline measurements and means of the individual percentage changes from baseline between groups using standard parametric tests. Analysis of covariance (ancova) for repeated measurements with the baseline value of proCPU as a constant covariate was used for comparisons among and between the groups. A two‐tailed P < 0.05 was considered statistically significant. At baseline, no significant differences were found between the groups in either demographic characteristics or in proCPU concentrations. Compared with placebo, ancova with the baseline value of proCPU as a constant covariate, showed a decrease in proCPU concentrations after 12 weeks in the HMR 2.5 group (P = 0.102), HMR 10 group (P = 0.005), HMR 50 group (P < 0.001), and in the Rlx group (P = 0.005). The mean percentage reduction from baseline vs. placebo after 12 weeks of treatment was 5.8% (P = 0.099) in the HMR 2.5 group, 7.0% (P = 0.039) in the HMR 10 group, 10.9% (P = 0.003) in the HMR 50 group and 10.5% (P = 0.002) in the Rlx group (Fig. 1). Post‐hoc analyses revealed no significant differences in the percentage change from baseline after 4 or 12 weeks between the four treatment groups. Until now, three randomized controlled trials have been published that investigated the effect of HT or raloxifene on proCPU concentrations [5Vogelvang T.E. Leurs J.R. Van Der Mooren M.J. Mijatovic V. Hendriks D.F. Neele S.J.M. Netelenbos J.C. Kenemans P. Raloxifene reduces procarboxypeptidase U, an antifibrinolytic marker. A 2‐year randomized, placebo‐controlled study in healthy early postmenopausal women.Menopause. 2004; 11: 110-5Crossref PubMed Scopus (0) Google Scholar, 11Post M.S. Hendriks D.F. Van Der Mooren M.J. Van Baal W.M. Leurs J.R. Emeis J.J. Kenemans P. Stehouwer C.D.A. Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized placebo‐controlled 12‐week study in early postmenopausal women.J Intern Med. 2002; 251: 245-51Crossref PubMed Scopus (0) Google Scholar, 12Bladbjerg E.M. Madsen J.S. Kristensen S.R. Abrahamsen B. Brixen K. Mosekilde L. Jespersen J. Effect of long‐term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: a randomized controlled study.J Thromb Haemost. 2003; 1: 1208-14Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Post et al. described unchanged proCPU levels after 12 weeks in women treated with unopposed oral estradiol 2 mg or oral estradiol 2 mg combined with dydrogesterone 10 mg [11Post M.S. Hendriks D.F. Van Der Mooren M.J. Van Baal W.M. Leurs J.R. Emeis J.J. Kenemans P. Stehouwer C.D.A. Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized placebo‐controlled 12‐week study in early postmenopausal women.J Intern Med. 2002; 251: 245-51Crossref PubMed Scopus (0) Google Scholar]. However, these authors found a reduction compared to placebo of 5.9% in women treated with oral estradiol 2 mg combined with trimegestone 0.5 mg [11Post M.S. Hendriks D.F. Van Der Mooren M.J. Van Baal W.M. Leurs J.R. Emeis J.J. Kenemans P. Stehouwer C.D.A. Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized placebo‐controlled 12‐week study in early postmenopausal women.J Intern Med. 2002; 251: 245-51Crossref PubMed Scopus (0) Google Scholar]. Bladbjerg et al. reported that HT during 5–6 years had no overall effect on proCPU concentrations [12Bladbjerg E.M. Madsen J.S. Kristensen S.R. Abrahamsen B. Brixen K. Mosekilde L. Jespersen J. Effect of long‐term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: a randomized controlled study.J Thromb Haemost. 2003; 1: 1208-14Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Recently, we reported a randomized controlled trial in which proCPU vs. placebo was reduced with 4.3% by raloxifene 60 mg and with 4.0% by raloxifene 150 mg after 24 months, but no significant changes were found in the oral HT group (conjugated equine estrogens 0.625 mg combined continuously with medroxyprogesterone acetate 2.5 mg) [5Vogelvang T.E. Leurs J.R. Van Der Mooren M.J. Mijatovic V. Hendriks D.F. Neele S.J.M. Netelenbos J.C. Kenemans P. Raloxifene reduces procarboxypeptidase U, an antifibrinolytic marker. A 2‐year randomized, placebo‐controlled study in healthy early postmenopausal women.Menopause. 2004; 11: 110-5Crossref PubMed Scopus (0) Google Scholar]. Our present findings with HMR 3339 and raloxifene are in line with the reductions found for raloxifene previously [5Vogelvang T.E. Leurs J.R. Van Der Mooren M.J. Mijatovic V. Hendriks D.F. Neele S.J.M. Netelenbos J.C. Kenemans P. Raloxifene reduces procarboxypeptidase U, an antifibrinolytic marker. A 2‐year randomized, placebo‐controlled study in healthy early postmenopausal women.Menopause. 2004; 11: 110-5Crossref PubMed Scopus (0) Google Scholar]. High proCPU concentrations are associated with an increased risk for a thrombotic event [2Van Tilburg N.H. Rosendaal F.R. Bertina R.M. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis.Blood. 2000; 95: 2855-9Crossref PubMed Google Scholar] and for recurrent venous thromboembolism. It has been suggested that this is caused by a reduced fibrinolytic capacity [2Van Tilburg N.H. Rosendaal F.R. Bertina R.M. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis.Blood. 2000; 95: 2855-9Crossref PubMed Google Scholar]. Data about the role of proCPU in arterial thrombosis are conflicting. Some studies reported an association between arterial thrombotic events and elevated plasma proCPU levels, whereas others reported an association between low proCPU levels and coronary disease. These contradictory results may be explained by the different enzyme‐linked immunosorbent assays (ELISAs) used, which do not all recognize the same polymorphisms [13Gils A. Alessi M.C. Brouwers E. Peeters M. Marx P. Leurs J.R. Bouma B. Hendriks D.F. Juhan‐Vague I. Declerck P.J. Development of a genotype 325‐specific proCPU/TAFI ELISA.Arterioscler Thromb Vasc Biol. 2003; 23: 1122-7Crossref PubMed Scopus (0) Google Scholar]. When we compare HMR 3339 and raloxifene it can be concluded that HMR 3339 acts as raloxifene with regard to plasma proCPU concentrations, as well as for the lipid profile [6Vogelvang T.E. Mijatovic V. Kenemans P. Teerlink T. Van Der Mooren M.J. HMR 3339, a novel selective estrogen receptor modulator, reduces total cholesterol, low‐density lipoprotein cholesterol, and homocysteine in healthy postmenopausal women.Fertil Steril. 2004; 82: 1540-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Because raloxifene has been found to have cardioprotective effects in osteoporotic postmenopausal women at high cardiovascular risk [8Barrett‐Connor E. Grady D. Sashegyi A. Anderson P.W. Cox D.A. Hoszowski K. Rautaharju P. Harper K.D. Raloxifene and cardiovascular events in osteoporotic postmenopausal women. four‐year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial.JAMA. 2002; 287: 847-57Crossref PubMed Google Scholar], but also increases the risk of venous thromboembolic disease [9Cummings S.R. Eckert S. Krueger K.A. Grady D. Powles T.J. Cauley J.A. Norton L. Nickelsen T. Bjarnason N.H. Morrow M. Lippman M.E. Black D. Glusman J.E. Costa A. Jordan V.C. The effect of raloxifene on risk of breast cancer in postmenopausal women—results from the MORE randomized trial.JAMA. 1999; 281: 2189-97Crossref PubMed Scopus (0) Google Scholar], the same cardiovascular profile may also be applicable to HMR 3339. However, randomized controlled trials with hard clinical endpoints are needed to confirm this hypothesis. We thank Mrs M. S. Post MD, and G. A. van Unnik MD for logistic assistance (VU University Medical Center, Amsterdam) and Mrs Y. Sim for technical assistance (University of Wilrijk, Antwerp). Hoechst Marion Roussel financially supported this research through a grant to the Biocare Foundation (grant no. 99–315). Mrs J. R. Leurs and J. Willemse are research assistants of the Fund for Scientific Research Flanders (FWO‐Vlaanderen). Professor Dr P. Kenemans and Professor D. F. Hendriks were involved in scientific review of protocol and manuscript, and Professor D. F. Hendriks was also responsible for laboratory analysis." @default.
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• W2080405489 title "HMR 3339, a novel selective estrogen receptor modulator, reduces concentrations of procarboxypeptidase U, an inhibitor of fibrinolysis. A randomized, placebo‐controlled study in postmenopausal women" @default.
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