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1.
Safety and clinical outcome of tamoxifen in Duchenne muscular dystrophy.
Tsabari, R, Simchovitz, E, Lavi, E, Eliav, O, Avrahami, R, Ben-Sasson, S, Dor, T
Neuromuscular disorders : NMD. 2021;(9):803-813
Abstract
Patients having Duchenne muscular dystrophy (DMD) are currently being treated with corticosteroids, which slow down disease progression at the expense of serious adverse effects. Tamoxifen is a pro-drug some of whose metabolites interact with the nuclear estrogen receptor, leading to anti-fibrotic and muscle-protective effects as has been demonstrated in a murine model of DMD. Here we report the results from a monocentric single arm prospective study in 13 ambulant boys aged 6-14 years with genetically confirmed DMD, aimed to assess the safety of tamoxifen and its impact on disease progression. Boys were treated for up to 3 years with 20 mg/day of oral tamoxifen, in addition to their ongoing corticosteroid treatment. For 8 of these patients, outcome was compared to an age- and performance-matched 12-month natural history dataset. The primary end point was the 6-minute walk test. Secondary end points were the NorthStar assessment, timed function tests, pulmonary function, the biomarker creatine phosphokinase and adverse effects. No adverse effects were noticed other than mild gynecomastia in 4 boys. Tamoxifen-treated patients retained motor and respiratory function, compared with a significant deterioration of age-matched historical control patients receiving corticosteroids only. These encouraging findings warrant a larger clinical trial to substantiate the use of tamoxifen in Duchenne muscular dystrophy.
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Estrogen receptor genotypes, menopausal status, and the effects of tamoxifen on lipid levels: revised and updated results.
Hayes, DF, Skaar, TC, Rae, JM, Henry, NL, Nguyen, AT, Stearns, V, Li, L, Philips, S, Desta, Z, Flockhart, DA, et al
Clinical pharmacology and therapeutics. 2010;(5):626-9
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Abstract
We previously reported that the ESR1 XbaI genotypes were associated with baseline and tamoxifen-induced serum lipid profiles. The analysis in that study was carried out by PCR followed by restriction-enzyme digestion. After reanalysis using more robust TaqMan assays, the findings related to ~10% of the genotypes for the ESR1 XbaI single-nucleotide polymorphism (SNP) were revised. For the other genotypes (i.e., ESR1 PvuII, ESR2, and CYP2D6), the results were nearly identical to those in the previous study. Upon reanalysis, previously reported associations between the ESR1 Xba1 genotypes and baseline triglyceride and low-density lipoprotein (LDL) cholesterol levels were no longer observed. Previously reported associations between the ESR1 XbaI genotypes and tamoxifen-induced changes in levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were also no longer observed. However, the following observations from the original report did not change: (i) the levels of circulating lipids are lower in women taking tamoxifen; (ii) there is an association between the ESR2-02 genotypes and changes in triglyceride levels; and (iii) neither ESR1 PvuII nor CYP2D6 is associated with any changes in serum lipid concentrations in patients receiving treatment with tamoxifen.
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Effects of tamoxifen therapy on plasma lipid profile in patients of breast cancer.
Gupta, S, Tandon, VR, Kapoor, B, Gupta, A, Gupta, GD, Khajuria, V
The Journal of the Association of Physicians of India. 2006;:183-6
Abstract
AIM: To evaluate the effects of tamoxifen therapy on plasma lipid profile in patients of breast cancer. METHOD A total of 55 postoperative patients of breast cancer were given tablet tamoxifen 20mg orally daily for 6 months. Estimation of plasma lipid by standard method was carried out in both pre-menopausal and postmenopausal new patients of early stage breast cancer at 0 day, 3rd month and 6th months of therapy. RESULTS Suggested that in pre-menopausal and postmenopausal patient's TC and LDL-c levels were reduced significantly, whereas, TG, VLDL-c and HDL-c were not altered. Comparison of the effects of tamoxifen in pre-menopausal and postmenopausal patients on lipid profile revealed that fall in TC and LDL-c was significantly higher at both 3 and 6 months in postmenopausal patients. CONCLUSION The study demonstrates that tamoxifen to favorably alter the markers of cardiovascular risk in both pre-menopausal and postmenopausal patients of breast cancer.
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Effect of raloxifene on bone mineral density in premenopausal women at increased risk of breast cancer.
Eng-Wong, J, Reynolds, JC, Venzon, D, Liewehr, D, Gantz, S, Danforth, D, Liu, ET, Chow, C, Zujewski, J
The Journal of clinical endocrinology and metabolism. 2006;(10):3941-6
Abstract
CONTEXT Raloxifene is a promising breast cancer prevention agent in postmenopausal women at increased risk for breast cancer. The effects of raloxifene in premenopausal women are unknown. OBJECTIVE We evaluated the effect of raloxifene in premenopausal women at increased risk for breast cancer on bone mineral density (BMD). DESIGN This was a phase II clinical trial. SETTING This study was conducted at an academic medical center. PARTICIPANTS Thirty-seven premenopausal women at increased risk for breast cancer enrolled in the trial. Thirty subjects began treatment and 27 were evaluable. INTERVENTION Raloxifene (60 mg daily) and elemental calcium (500 mg daily) were given for 2 yr. Subjects were followed up off medications for 1 yr. MAIN OUTCOME MEASURE The primary end point was the intrasubject percent change in BMD at 1 yr measured by dual-energy x-ray absorptiometry. RESULTS The mean baseline lumbar spine density was 1.027 g/cm(2). Lumbar spine density decreased 2.3% at 1 yr (P < 0.00001) and 3.5% at 2 yr (P < .00001). Percent change from yr 2 to 3 was +1.4%. The mean baseline total hip bone density was 0.905 g/cm(2). Total hip density decreased 0.3% at 1 yr and 1.0% at 2 yr (P = 0.033). Percent change from yr 2 to 3 was +1.7%. CONCLUSIONS Raloxifene use is associated with a decrease in BMD in premenopausal women at increased risk for breast cancer. The clinical significance of this decrease is unknown and is attenuated with stopping raloxifene.
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Association of bone metabolism related genes polymorphisms with the effect of raloxifene hydrochloride on bone mineral density and bone turnover markers in postmenopausal women with osteoporosis.
Zhang, ZL, He, JW, Qin, YJ, Huang, QR, Liu, YJ, Hu, YQ, Li, M
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2006;(2):129-33
Abstract
OBJECTIVE To investigate the association of bone metabolism related genes polymorphisms with the effect of raloxifene hydrochloride(RLX) on bone mineral density (BMD) and bone turnover markers in postmenopausal women with osteoporosis. METHODS A total of 68 unrelated postmenopausal women with osteoporosis of Han ethnicity aged 47-74 years were randomly divided into 2 groups of 34 women: RLX group (60 mg were given daily for 12 months) and placebo group. BMD and bone turnover markers were measured at baseline, 6 and 12 months after treatment. The polymorphisms of Xba I and Pvu II sites in estrogen receptor 1 gene(ESR1), Ras I site in ESR2 gene, and start codon (Fok I) and CDX2 binding sites in vitamin D receptor gene (VDR) were analyzed. RESULTS A total of 58 patients completed 12 months of study period. By the end of study, the increased percentage of BMD in lumbar spine 2-4 (L2-4), total hip, and trochanter were found significantly different between RLX group and placebo group(P<0.05), and the decreased percentage of C-telopeptide and osteocalcin were significantly different between the two groups (P<0.01). The BMD of total hip and trochanter of women with FF genotypes of VDR Fok I site were decreased by 1.98%+/-4.86% and 2.26%+/-4.73% respectively in the RLX group, but those of women with Ff/ff genotypes were increased by 2.52%+/-2.75% and 2.74 %+/-2.97%, respectively(P<0.05). Moreover, the total hip BMD of women with PP/Pp genotypes of ESR1 Pvu II site was increased by 2.12%+/-2.78%, and of women with pp genotype it was decreased by 1.34%+/-3.73%(P<0.05). However, no significant association was observed of the polymorphisms of five sites with the changes of BMD and bone turnover markers in the placebo group. CONCLUSION The effect of RLX on BMD in postmenopausal women with osteoporosis is regulated by the polymorphisms of Fok I of VDR gene and Pvu II of ESR1 gene. The study is valuable to select this drug according to genotype of patients in clinical.
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Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women.
Komi, J, Lankinen, KS, Härkönen, P, DeGregorio, MW, Voipio, S, Kivinen, S, Tuimala, R, Vihtamäki, T, Vihko, K, Ylikorkala, O, et al
Menopause (New York, N.Y.). 2005;(2):202-9
Abstract
OBJECTIVE To compare ospemifene and raloxifene regarding their effects on hormones, lipids, genital tract, and tolerability in postmenopausal women. DESIGN A randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) of ospemifene or 60 mg (n = 29) of raloxifene for 3 months. RESULTS There were no significant differences in the baseline characteristics between study groups. In comparison with raloxifene, follicle-stimulating hormone levels decreased significantly more in the 90-mg ospemifene group and sex hormone-binding globulin levels increased more in all ospemifene groups. Total cholesterol and low-density lipoprotein cholesterol levels decreased more in raloxifene than in ospemifene groups, although the difference in low-density lipoprotein cholesterol between 90-mg ospemifene and raloxifene was not significant. Endometrial thickness did not change in any study group and endometrial biopsies showed atrophy in the majority of subjects at 3 months. All ospemifene groups demonstrated a clear estrogenic effect on the vaginal epithelium, as seen in Pap smears. This was in sharp contrast to the raloxifene group, which had no effect on the vaginal epithelium. Kupperman index decreased in all study groups during treatment. The adverse events were mild, mainly single cases, and no clustering of events was observed. There were no clinically significant abnormal findings in laboratory safety parameters. CONCLUSIONS Ospemifene, at the dose of 90 mg/day, was more estrogenic than raloxifene, as shown by changes in serum follicle-stimulating hormone and sex hormone-binding globulin levels. Neither agent stimulated endometrium, but in contrast to raloxifene, ospemifene had a clear estrogenic effect in the vagina. Further studies with ospemifene are needed in subjects with vaginal atrophy.
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[Effects of raloxifene on bone biomarkers in postmenopausal women on maintenance haemodialysis].
Matsuo, K, Fujinaga, M, Tsuchiya, K, Nakamoto, M, Yasunaga, C
Clinical calcium. 2005;:92-6; discussion 96-7
Abstract
Postmenopausal women on maintenance haemodialysis (MHD) has considerably higher risk of bone fracture than general population with combination of postmenopausal osteoporosis and renal osteodystrophy. However, the treatment of osteoporosis on MHD has not been established. Evidence indicates raloxifene (RLX), a selective estrogen receptor modulator, is effective for a protection of bone fracture without increasing of breast cancer and endometrial cancer. We hereby report short-term use experience of RLX for the postmenopausal MHD patients. Fifteen postmenopausal MHD patients with less than 80% of YAM bone density in DEXA administrated 60 mg RLX on every HD days (3 days/week). Serum NTX level significantly decreased after 6 months (180 +/- 18 vs. 95 +/- 12 nmol/BCE/L, p< 0.05), however, i-PTH did not have the significant difference. (115 +/- 23 vs. 157 +/- 29 pg/mL). RLX is effective for bone biomarker improvement in postmenopausal MHD patients. Further evaluation for the effectiveness and safety of RLX is necessary in the long term.
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Effect of raloxifene on serum triglycerides in women with a history of hypertriglyceridemia while on oral estrogen therapy.
Carr, MC, Knopp, RH, Brunzell, JD, Wheeler, BS, Zhu, X, Lakshmanan, M, Rosen, AS, Anderson, PW
Diabetes care. 2005;(7):1555-61
Abstract
OBJECTIVE Raloxifene hydrochloride is a selective estrogen receptor modulator that to date has not been shown to cause hypertriglyceridemia in normal, diabetic, or hypertriglyceridemic women. This study was designed to assess the effect of raloxifene on serum triglycerides in postmenopausal women who have a history of increased hypertriglyceridemia with oral estrogen therapy. RESEARCH DESIGN AND METHODS This was a single-center, uncontrolled, open-label study investigating the effects of 8 weeks of raloxifene (60 mg/day) therapy on plasma lipids. The study subjects were 12 postmenopausal women, ages 49-73 years, with a documented history of oral estrogen-induced hypertriglyceridemia (serum triglycerides > or =3.39 mmol/l [> or =300 mg/dl]). RESULTS At week 2 of the study, three (25%) of the subjects withdrew from the trial because they developed marked hypertriglyceridemia (>or =11.3 mmol/l [> or =1,000 mg/dl]) during raloxifene therapy. These three women had higher baseline triglyceride and glucose levels, were not being treated with lipid-lowering agents, and were more likely to have diabetes than the other study subjects. The remaining nine patients (75%) completed the 8-week trial and experienced a nonsignificant increase in mean triglyceride levels from baseline to end point. Raloxifene treatment also resulted in a significant 16% decrease in hepatic lipase activity and a 26% increase in HDL(2) levels (P = 0.013 and 0.03, respectively). CONCLUSIONS Patients with a previous history of hypertriglyceridemia on oral estrogen therapy should have serum triglyceride levels monitored closely after beginning raloxifene therapy and may even require fibrate therapy before beginning raloxifene.
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Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene.
Duvernoy, CS, Kulkarni, PM, Dowsett, SA, Keech, CA
Menopause (New York, N.Y.). 2005;(4):444-52
Abstract
OBJECTIVE To determine the incidence of arterial and venous thromboembolic (VTE) events, to determine the effect of raloxifene on the incidence of combined vascular (arterial and VTE) events, and to identify patient characteristics associated with these vascular events, in women participating in the MORE trial. DESIGN In a post hoc analysis using MORE data, arterial, VTE, and combined vascular event rates were compared between participants receiving placebo (n = 2,576) and those receiving 60 mg/d of raloxifene (n = 2,557). Baseline characteristics were compared between those who did and did not experience an arterial event. The same analysis was performed for VTE events. RESULTS Overall, during a mean follow-up time of 41 months, 178 women experienced an arterial event and 40 experienced a VTE event. In the placebo group, the incidence of arterial events exceeded VTE events by at least sevenfold. Raloxifene had no significant effect on the incidence of combined vascular events in the overall cohort (hazard ratio 0.95, 95% CI, 0.73-1.24). In a subset of women retrospectively determined to be at increased cardiovascular risk, raloxifene was associated with a lower incidence of combined vascular events (hazard ratio 0.63, 95% CI, 0.40-0.97). Baseline characteristics differed between those who did and those who did not experience an arterial event, but this was generally not the case for VTE events. CONCLUSIONS Arterial events were more common than VTE events. The characteristics of women experiencing an arterial event differed from those experiencing a VTE event. Raloxifene had a neutral effect on the risk of combined vascular events in the overall population, and was associated with a reduced combined vascular event rate in women at increased cardiovascular risk. Additional studies are needed to confirm the effect of raloxifene on overall vascular outcomes.
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Effectiveness and safety of raloxifene in post-menopausal females.
Abdullah, KN, Raoof, A, Raoof, M
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2005;(5):266-9
Abstract
OBJECTIVE To determine effects of raloxifene on lipid profile, breast tissue and endometrial thickness in post-menopausal women. DESIGN A longitudinal cohort study. PLACE AND DURATION OF STUDY The study was conducted at Department of Gynaecology and Obstetrics, PNS Shifa Hospital, Karachi over a period of one year. PATIENTS AND METHODS Fifty cases of postmenopausal women, aged 45-60 years, who had last menstrual period 2-8 years back, visiting Gynea OPD at PNS Shifa Hospital, Karachi, were included in the study. The subject received raloxifene (Evista) 60 mg once daily. The tests done at the start of study as baseline were serum lipid profile (HDL, LDL, total triglyceride and cholesterol levels), TVS (trans vaginal sonography) for endometrial thickness and mammography. The above tests were again done at the end of study after 12 months. The adverse effects were recorded. RESULTS Fifty women were enrolled for study out of which 48 completed the study that is 96%. Mean age was 54 years, SD = 3.95. The mean value of LDL, total triglyceride and cholesterol decreased by 15.2%, 1.2% and 10.2 % respectively. The change was statistically significant. (p < 0.001) HDL change was 0.665% and was not statistically significant. TVS, for endometrial thickness, and mammography for breast density showed no change. Adverse effects reported were hot flushes, leg cramps and vaginal symptoms in few cases. CONCLUSION Raloxifene therapy significantly decreases cardiovascular risk markers LDL, total triglyceride and cholesterol. No abnormal change in breast density and in endometrial thickness indicate good safety profile of this agent.