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Effects of high dose raloxifene in selected patients with advanced breast carcinoma.

Gradishar W, Glusman J, Lu Y, Vogel C, Cohen FJ, Sledge GW Jr.

Northwestern University, Chicago, Illinois, USA.

BACKGROUND: An earlier trial of raloxifene, conducted in women with metastatic breast carcinoma who initially had responded to tamoxifen and subsequently developed disease progression, suggested no antitumor activity for raloxifene in tamoxifen-refractory disease. However, preclinical studies and preliminary clinical data in healthy women suggest that raloxifene antagonizes growth of estrogen-dependent neoplasia. METHODS: Raloxifene HCl 150 mg twice daily was given to 22 postmenopausal women with metastatic (American Joint Committee on Cancer Stage IV) or locoregionally recurrent, initially estrogen receptor positive breast carcinoma. Prior systemic treatment of metastatic disease was not allowed. Prior adjuvant chemotherapy or hormonal therapy was required to have been completed at least 1 year before study entry. Tumor response was evaluated every other month either radiographically or by physical examination. Evaluable disease was defined as bidimensionally measurable lesions. RESULTS: Twenty-one patients were eligible for efficacy analysis; 6 had been treated previously with tamoxifen. There were no complete tumor responses. Four patients (19%; 95% confidence interval [95% CI], 2.2%, 36%) had partial tumor responses lasting 6.3, 17.5, 23.9, and 28.1 months, respectively. Prolonged stable disease (i.e., tumor size stable for > or = 6 months) was observed in 3 patients (14%; 95% CI, 0.0%, 29%) and lasted 7.9, 12.2, and 25.1 months, respectively. Combining partial responses and prolonged stable disease yielded an overall clinical benefit rate of 33% (95% CI, 13%, 53%). Adverse events generally were consistent with the disease state; there were no serious adverse events or laboratory changes believed to be therapy-related. CONCLUSIONS: Raloxifene HCl, 150 mg, administered twice daily was safe, well tolerated, and modestly effective in highly selected postmenopausal women with advanced breast carcinoma. Further study of high dose raloxifene as monotherapy for advanced breast carcinoma most likely is unwarranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10813716&dopt=Abstract raloxifene Evista



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The effect of raloxifene on the uterine weight response in immature mice exposed to 17beta-estradiol, 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane, and methoxychlor.

Al-Jamal JH, Dubin NH.

Department of Gynecology and Obstetrics, Union Memorial Hospital, Baltimore, MD, USA.

OBJECTIVE: The purpose of this study was to determine the effects of raloxifene on the uterine responses to both estradiol and the environmental estrogens 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane and methoxychlor in immature mice.Study Design: Immature female mice received the following compounds alone or in combination: sesame oil (control), 17beta-estradiol 1 mg/kg body weight, tamoxifen 1 mg/kg body weight, raloxifene 5 mg/kg body weight, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane 10 mg/kg body weight, and methoxychlor 10 mg/kg body weight. The animals were treated subcutaneously once a day for 5 consecutive days with the compound or compounds of interest in 0.1 mL sesame oil. Approximately 24 hours after the final treatment the animals were killed and the uteri were excised, stripped of remaining fat and mesentery, and weighed. Groups were analyzed with analysis of variance. RESULTS: Estradiol increased the mean (+/-SE) weight from 20 +/- 6.4 mg (as measured in the control group) to 77 +/- 6.2 mg. Tamoxifen increased uterine weight to 60 +/- 6.2 mg; however, raloxifene had no effect on uterine weight. Both 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane and methoxychlor increased uterine weight significantly, to 82 +/- 2.4 mg and 35 +/- 6.0 mg respectively. When raloxifene was coadministered with 17beta-estradiol it did not block the increase in uterine weight; however, when raloxifene was coadministered with 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane or methoxychlor, it completely blocked the uterine weight gain induced by either xenoestrogen. CONCLUSION: Raloxifene blocked the xenoestrogens 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane and methoxychlor but did not block 17beta-estradiol in the mouse model described. These results suggest that the xenoestrogens exert their estrogenic activities through a different site on the estrogen receptor or through a different mechanism than 17beta-estradiol.

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Clinically favorable effects of raloxifene on bone mineral density and serum lipids: population assessment via bivariate analysis.

Shah A, Iversen P, Mitlak B.

Introduction: Raloxifene is a nonsteroidal benzothiophene derivative that is classified as a selective estrogen receptor modulator (SERM). It has clinical promise because of its actions as an estrogen-agonist on bone and serum lipids and an estrogen-antagonist on the breast and uterus.Objectives: To determine the percentage of women who respond to raloxifene therapy with regard to bone mineral density (BMD) and serum low density lipoprotein cholesterol (LDL-C) concentration in a large population of healthy postmenopausal women.Methods: Pooled 24-month interim data from two multicenter, placebo-controlled, double-blind phase III studies were used in this analysis. The study population included 1145 healthy women, 45-60 years of age and 2-8 years postmenopausal, randomized to receive either placebo, raloxifene (RLX) 30 mg/day, RLX 60 mg/day, or RLX 150 mg/day. Changes in BMD, measured by dual x-ray absorptiometry, and serum LDL-C concentration, measured by enzymatic assay, were analyzed simultaneously by plotting the median percentage change (baseline to endpoint) in BMD of the lumbar spine and total hip on the y-axis against the corresponding median percentage change in serum LDL-C on the x-axis for each subject in the placebo group and each of the raloxifene groups. The data localized to one of four quadrants on the plot, the upper-left quadrant representing clinically favorable shifts (increased BMD and decreased LDL-C) and the lower-right quadrant representing clinically unfavorable shifts (decreased BMD and increased LDL-C). The bivariate mean, 50th and 95th percentile ellipses, and the percentage of patients improving in one, both, or neither of the measured parameters are displayed.Results: At the end of 24 months, the bivariate mean and the 50th and 95th percentile ellipses of the placebo group for lumbar spine BMD and LDL-C were shifted to the clinically unfavorable quadrant of the plot, reflecting a decrease in BMD and an increase in LDL-C. In contrast, the bivariate mean for all raloxifene groups had shifted to the clinically favorable quadrant of the plot, reflecting an increase in BMD and a decrease in LDL-C. There was a statistically significant difference (Hotelling-Lawley test, P <.001) in the bivariate mean for all doses of raloxifene compared to placebo. Only 19.1% of subjects in the placebo group exhibited improvement in both lumbar spine BMD and LDL-C, whereas 43.5%, 47.4%, and 49.8% of subjects in the RLX 30, RLX 60, and RLX 150 group, respectively, exhibited improvement in both of these variables. Furthermore, 35.9% of subjects in the placebo group exhibited no improvement in either lumbar spine BMD or LDL-C, whereas only 13.7%, 10.1%, and 11.6% of subjects in the RLX 30, RLX 60, and RLX 150 groups, respectively, exhibited no improvement in either of these variables. Similar results were obtained comparing total hip BMD and LDL-C.Conclusions: Compared with placebo, raloxifene has beneficial effects on BMD and LDL-C in a large sample of healthy postmenopausal women. Thus, insofar as these intermediate endpoints predict disease outcomes, long-term therapy with raloxifene may be beneficial in the prevention of osteoporosis and cardiovascular diseases.

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Raloxifene effects on vasomotor and other climacteric symptoms in postmenopausal women.

Glusman JE, Huster WJ, Paul S.

Introduction and Objectives: Raloxifene, a novel selective estrogen receptor modulator (SERM), is under investigation for the prevention of osteoporosis in postmenopausal women. Like traditional estrogen replacement therapy, raloxifene has beneficial effects on bone and on serum lipids whereas, in contrast to estrogen's adverse effects in the breast and uterus, raloxifene is an estrogen antagonist in the breast and is nonstimulatory in the uterus. This study examines the effects of raloxifene 60 mg/day compared with placebo on: 1) the incidence of vasomotor symptoms: hot flashes (flushing) and sweating (including night sweats), 2) the severity and time course of hot flashes, and 3) the relation of hot flashes to baseline subject characteristics and study discontinuations. Additionally, the study explores the effects of raloxifene 60 mg/day compared with placebo on other climacteric symptoms that affect the quality of life of postmenopausal women, such as depression, insomnia, mood lability and genitourinary complaints.Methods: Integrated data from five randomized, placebo-controlled studies involving 1,165 healthy, postmenopausal women, with up to 30 months of study drug exposure, were analyzed. The incidence and severity of hot flashes and other climacteric symptoms were compared in patients treated with placebo or raloxifene (60 mg/day) via open-ended, non-directed subject self-assessment questionnaires. Data were analyzed for subgroup-by-therapy interactions using many baseline subject characteristics such as age, body mass index, smoking, alcohol, and years post-menopause, as well as preexisting conditions such as hot flashes, sweating, insomnia, depression, and history of hysterectomy. The overall incidence of other climacteric symptoms were reported as adverse events.Results: The increase in overall incidence of hot flashes in raloxifene-treated (24.6%) and placebo-treated (18.3%) subjects was modest, but statistically significant. However, this difference was significant only during the first 6 months of therapy, raloxifene (20.1%) compared with placebo (14.4%). After 6 months of treatment, there was no statistically significant difference in the incidence of hot flashes between the two treatment groups. The majority of hot flashes in raloxifene-treated subjects were subject-assessed as "mild-to-moderate" in severity (89%). The incidence of hot flashes reported as "severe" did not differ significantly in raloxifene- or placebo-treated subjects. Subgroup analyses revealed the overall incidence of hot flashes to be highest for both raloxifene and placebo-treated subjects, in younger (age < 55 years) women (P =.004), in women who had previously experienced hot flashes (P =.031), and in women having had hysterectomies (P <.001). Within each of these subgroups, there was no statistical difference in the incidence of hot flashes between the raloxifene and placebo groups. Between the two treatment groups, there was no difference in the overall incidence of subject discontinuations from study due to hot flashes. The occurrence of the other common vasomotor symptom, sweating (which includes night sweats), was not statistically different for the raloxifene- or placebo-treated subjects.Genitourinary complaints are often symptoms related to vaginal dryness, such as dyspareunia and decreased libido, as well as other symptoms of vaginitis and leukorrhea. No statistically significant differences occurred for raloxifene- or placebo-treated subjects in reports of these genitourinary symptoms. Similarly, for the other common climacteric symptoms; depression, insomnia, and mood lability, no significant differences in incidence between the raloxifene and placebo treatment groups were observed.Conclusions: Raloxifene (60 mg/day) treatment modestly increased the incidence of hot flashes compared with placebo, however, this difference was only statistically significant during the first 6 months of treatment. There were no differences in the severity of hot flashes between treatment groups, and this symptom did not adversely affect subjects' study participation. In both the raloxifene and placebo treatment groups, young postmenopausal women (age < 55), those with baseline hot flashes, and those with histories of hysterectomy were most likely to experience hot flashes. Raloxifene therapy did not affect the occurrence of other climacteric symptoms commonly affecting the quality of life of women after menopause.

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Raloxifene HCl is not stimulatory in the endometrium as assessed by the blaustein criteria and an estrogenicity scoring system.

Shah AS, Scheele WH, Glant MD, Fugere P.

Hopital Saint-Luc, Department of Obstetrics and Gynecology, PQ, Montreal, Canada

Introduction: Raloxifene, a selective estrogen receptor modulator (SERM), acts as an estrogen agonist in the bone and on serum lipids and an estrogen antagonist in breast tissue. The effect of raloxifene on the endometrium of postmenopausal women is a key factor in determining its clinical application.Objectives: The objectives are to determine and compare the histologic outcomes of endometrial samples from healthy postmenopausal women receiving either a high dose of raloxifene or hormone replacement therapy (HRT).Design: The current study is a 24-month, multicenter, double-blind, randomized study of 136 healthy postmenopausal women randomized to receive either raloxifene 150 mg/day (RLX) or continuous combined HRT (Premarin(R) 0.625 mg/day and Provera(R) 2.5 mg/day).Materials and Methods: Endometrial samples obtained by Pipelle biopsy at baseline and endpoint were evaluated using Blaustein's criteria (Kurman RJ, editor Blaustein's pathology of the female genital tract. 1994), which is composed of descriptive diagnostic categories and a newly developed estrogenicity scoring system to quantify subtle morphologic changes in the postmenopausal endometrium (Boss et al. Am J Obstet Gynecol, in press). All subjects with adequate baseline and post-baseline endometrial samples were included in the analyses. The results from the 12-month interim analyses are reported and the Blaustein's criteria and the estrogenicity scoring system are compared.Results: Overall, 95.2% of the baseline biopsies were normal. At endpoint 30.6% of the subjects in the HRT group with normal baseline biopsies developed proliferative endometrium and 2.8% developed a polyp, while none in the RLX group developed either. Histological evaluation of stromal and glandular features revealed substantially lower estrogenicity scores in the RLX group. As shown in the table, a high degree of agreement was observed between the estrogen effect grades and the Blaustein's descriptive diagnostic categories at endpoint as shown by a Spearman correlation coefficient of 0.75 and a Kappa coefficient of 0.91.Conclusion: Results from the 12-month interim analyses reveal that, in contrast to HRT, raloxifene does not have stimulatory effects on the endometrium. Also, there is high degree of agreement between Blaustein's criteria and the estrogenicity scoring system used to evaluate endometrial histology.

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Luteinizing hormone secretion elicited in a ligand-independent activation of progesterone receptor manner at pituitary level in the rat: differential effect of two selective estrogen receptor modulators.

Gonzalez D, Bellido C, Aguilar R, Garrido-Gracia JC, Hernandez G, Alonso R, Sanchez-Criado JE.

Department of Cell Biology, Physiology and Immunology, University of Cordoba School of Medicine, Cordoba, Spain.

In the absence of progesterone, RU486 reduced basal and luteinizing hormone-releasing hormone (LHRH)-stimulated LH secretion in pituitaries from proestrous rats, a fact which evidences a ligand-independent activation of progesterone receptors (LIAPR) at pituitary level. This was also observed in pituitaries from rats treated with tamoxifen, and absent in glands from either ovariectomized or raloxifene-treated animals. Both ovariectomy or raloxifene treatment reduced the stimulatory effect of LHRH on LH secretion, while tamoxifen induced an even higher response. Prolactin (PRL) secretion was unaffected by either RU486 or LHRH, nor it was influenced by ovariectomy or raloxifene treatment. However, treatment with tamoxifen elevated PRL in all groups. These findings indicate that LIAPR is an estrogen-dependent phenomenon at the anterior pituitary of the female rat, and that tamoxifen and raloxifene present agonist and antagonist estrogen activity, respectively, at this level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10904132&dopt=Abstract raloxifene Evista