Evista
The selective estrogen receptor modulator, raloxifene: reproductive assessments in adult male rats.

Hoyt JA, Fisher LF, Swisher DK, Byrd RA, Francis PC.

Toxicology and Drug Disposition, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140, USA. J.A.Hoyt Lilly.com

Raloxifene HCl is a nonsteroidal, selective estrogen receptor modulator developed for postmenopausal osteoporosis. Reproductive toxicity of raloxifene was examined in adult male CD rats after the oral administration of doses of 0, 10, 30, or 100 mg/kg/d. In the first study, males (12/group) were treated for 2 weeks followed by 2 weeks without treatment. After dose administration on Day 13, 6 males/group were cohabited with untreated females (1:2) for up to 7 d. Males were killed on Day 14 or 28 (6/group each day). Sperm were collected from the right cauda epididymis and evaluated for relative concentration, motion characteristics, and breakage. The kinetics of spermatogenesis were examined by DNA flow cytometry. The left testis and epididymis were preserved for histopathologic evaluation. Females were examined for reproductive status on Gestation Day 13. In a second study, males (20/group) were treated for 7 weeks (4 weeks prior to cohabitation during a 2-week cohabitation period, and for 1 additional week). Treated males were cohabited with untreated females (1:1). On Gestation Day 20, untreated females were examined for reproductive status and fetuses were examined for viability, weight, gender, and morphology. At necropsy, male reproductive tissues were collected, weighed, and preserved for histopathologic evaluation. In both studies, male body weight gain and food consumption were depressed at all dose levels. There was no indication in either study that raloxifene caused important changes in sperm production, sperm quality, or male reproductive performance at doses as high as 100 mg/kg/d.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9628547&dopt=Abstract raloxifene Evista



Evista
The selective estrogen receptor modulator, raloxifene: reproductive assessments following premating exposure in female rats.

Hoyt JA, Fisher LF, Buelke-Sam JL, Francis PC.

Toxicology and Drug Disposition, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140, USA. J.A.Hoyt Lilly.com

Raloxifene HCl is a nonsteroidal, selective estrogen receptor modulator developed as a therapeutic agent for postmenopausal osteoporosis. Two studies were conducted that examined the effects of premating exposure to raloxifene HCl. In the first study, adult female CD rats (20/group) were given diets containing 0, 0.01, or 0.1% raloxifene (providing an average of 0, 6, or 63 mg/kg/d, respectively) for 2 weeks, after which the treated diets were replaced with control diet. Following a 2-week period without treatment, each female that had displayed at least three conversions in vaginal cytology from cornified cells to leukocytes was cohabited for 1 to 2 d with an untreated male as she entered proestrus. Females were killed at midgestation and examined for evidence of pregnancy. In the second study, adult female CD rats (40/group) were given oral gavage doses of raloxifene (0, 0.1, 1, or 10 mg/kg/d) for 4 weeks. Immediately or following a 2-week period without treatment, 20 females/group were cohabited with untreated males (1:1) for up to 3 weeks. The females were allowed to deliver and rear their offspring until Postpartum Day 21. Progeny survival, growth, and development were evaluated. Maternal body weight, body weight gain, and food consumption were depressed in all raloxifene treatment groups. Doses > or =1 mg/kg caused disruptions in estrous cycles. In Study 1, 90% of the females treated with raloxifene resumed normal cycling, and fertility was not significantly affected. Although there were no statistically significant differences in time-to-mating, fertility, or liveborn indices in Study 2, females in the 10-mg/kg immediate-cohabitation group had slightly increased gestation lengths and smaller litter sizes. Progeny from these litters were larger on Postpartum Day 1 and had advanced incisor eruption and eye opening. In addition, slight delays were seen in physical landmark appearance in the 0.1- and 1-mg/kg immediate-cohabitation groups and in the 1- and 10-mg/kg delayed-cohabitation groups. Progeny viability, growth, and negative geotactic performance were not adversely affected. In these studies of maternal premating exposure to raloxifene, findings were consistent with established pharmacologic activity of the test chemical. Reproductive effects (disrupted estrous cycles and decreased litter size) occurred at doses > or =1 mg/kg and were generally reversible. Effects on offspring were seen at doses > or =0.1 mg/kg, were of minor importance, and were resolved during the lactation period.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9628548&dopt=Abstract raloxifene Evista



Evista
The selective estrogen receptor modulator, raloxifene: reproductive assessments following preimplantation exposure in mated female rats.

Clarke DO, Griffey KI, Buelke-Sam J, Francis PC.

Toxicology and Drug Disposition, Lilly Research Laboratories (a Division of Eli Lilly and Company), Greenfield, Indiana 46140, USA. doclarke lilly.com

Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed for postmenopausal osteoporosis. As part of an integrated reproductive toxicity assessment, two studies were conducted in which raloxifene was administered orally to CD rats during Gestation Days (GD) 0 through 5. In each study, animals received daily raloxifene doses of 0, 0.1, 1, or 10 mg/kg. In Study 1, GD 20 evaluations of maternal reproductive parameters identified dose-related increases in pre- and postimplantation loss, reductions in the numbers of corpora lutea and live conceptuses, and reduced fetal weight. The low fetal weights were consistent with an extent of morphologic development that corresponded to developmental ages up to 8 d younger than GD 20. Study 2 characterized the potential impact of this disrupted and apparently delayed implantation on gestation length, parturition, and progeny viability. Dams were allowed to deliver and rear their offspring through Postpartum Day 21. Gestation lengths were extended up to 1 week, and litter sizes were reduced in a dose-dependent manner. Nevertheless, parturition occurred normally and pup morphology, survival, and physical and behavioral development were unaffected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9628549&dopt=Abstract raloxifene Evista



Evista
The selective estrogen receptor modulator, raloxifene: segment II studies in rats and rabbits.

Byrd RA, Francis PC.

Toxicology Research Laboratories, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140, USA. rab lilly.com

Raloxifene is a nonsteroidal, selective estrogen receptor modulator developed by Eli Lilly and Company primarily as a therapeutic agent for postmenopausal osteoporosis. Two Segment II studies were conducted that examined maternal reproductive parameters and fetal outcome following gestational exposure to raloxifene. Pregnant CD rats (25/group) and New Zealand white rabbits (20/group) were dosed once daily by oral gavage with 0, 0.1, 1, or 10 mg/kg on Gestation Days (GD) 6 through 17 and 7 through 19, respectively. Maternal body weight and food consumption were monitored throughout pregnancy. Caesarean sections were performed on GD 20 and GD 28 for rats and rabbits, respectively, to evaluate fetal viability, weight, and morphology. In rats, maternal body weight, body weight gain, and food consumption were reduced in all raloxifene treatment groups. Fetal viability was depressed in the 10-mg/kg group and was often associated with signs of hemorrhaging from the vagina. Fetal growth retardation was indicated in the 1- and/or 10-mg/kg groups by increased incidences of fetal runts and the developmental deviations, wavy ribs and kidney cavitation. There was no evidence of treatment-related malformations in rat fetuses. In rabbits, depressions in body weight gain and food consumption occurred in the 10-mg/kg group, and a single abortion occurred in the 1-mg/kg group. Fetal viability and weights were not affected in any of the raloxifene treatment groups. The overall proportions of fetuses with malformations, deviations, or variations were not affected by treatment with raloxifene; however, one fetus each from the 0.1-, 1-, and 10-mg/kg groups had incomplete closure of the interventricular septum. Therefore, maternal and fetal no-effect levels were not obtained in this study of raloxifene.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9628550&dopt=Abstract raloxifene Evista



Evista
The selective estrogen receptor modulator, raloxifene: a segment II/III delivery study in rats.

Buelke-Sam J, Cohen IR, Wierda D, Griffey KI, Fisher LF, Francis PC.

Toxicology Research Laboratories, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140, USA. jb_s lilly.com

Raloxifene is a nonsteroidal, selective estrogen receptor modulator developed by Eli Lilly and Company as a therapeutic agent for postmenopausal osteoporosis. Raloxifene was administered orally by gavage at doses of 0, 0.1, 1, or 10 mg/kg/d to female CD rats (25/group) on Gestation Day 6 (GD 6) through Postpartum Day 20 (PD 20). Females were allowed to deliver and maintain their progeny until PD 21. All dead pups and pups culled on PD 1 were given internal and external examinations. One pup/sex/litter was assigned to each of the following assessment groups: 1) the primary pair for the F1 generation study, in which survival, growth, development, behavior, indicators of sexual maturation, and reproductive performance were evaluated; 2) terminal necropsy evaluations at PD 21; 3) terminal necropsy evaluations at 60 d of age; and 4) assessments of immune function at 5 to 6 weeks of age. At termination on PD 21, 60, or approximately 140, a necropsy was performed; crown rump and tibia lengths were measured; pituitary weights were taken; and a portion of the anterior pituitary was retained for growth hormone, luteinizing hormone, and prolactin content determinations (control and 10-mg/kg groups only). The remainder of the pituitary and reproductive tissues were retained for histologic evaluations. Dose-related depressions in maternal body weight and food consumption occurred during gestation. Mean gestation length was increased at 1 and 10 mg/kg. Delayed, extended, and/or disrupted parturition occurred in dams given 10 mg/kg, which resulted in a high incidence of maternal morbidity and/or death, increased numbers of dead pups, and the survival of only 66% of live pups to PD 21. Progeny body weights were not decreased at birth, but were depressed progressively in a dose-related manner during the 3-week lactation period. Negative geotaxis and incisor eruption were apparently accelerated in the 1- and 10-mg/kg groups, but eye opening was delayed at 10 mg/kg. Postweaning activity levels, auditory startle, and passive avoidance performance were not affected in the raloxifene groups. Dose-related decreases in spleen cellularity and thymus weights occurred in both sexes, but immune system function, as measured by splenic natural killer cell activity and antibody response to sheep red blood cells, was not affected. Postweaning body weights and growth parameters, as well as pituitary hormone content, were affected in both an age- and sex-specific manner. Preputial separation was not affected, but vaginal patency occurred ca 2 d earlier than controls in females from the 10-mg/kg group. Estrous cycles of the F1 females were not affected during the first two weeks after vaginal opening, but were disrupted at 12 to 14 weeks of age in the 10-mg/kg group. These females showed poorer mating and fertility indices, and litter size was reduced in the two females that were pregnant. Histologically, reproductive organs were not affected in males at any age or in females at PD 21. At PD 60, vaginal mucification occurred in females from the 0.1- and 1-mg/kg groups. At PD 140, the only finding was a high rate of uterine hypoplasia in the 10-mg/kg group, and this finding occurred in the absence of any concomitant ovarian or vaginal changes. These reproductive and developmental findings are consistent with estrogen antagonist activity of raloxifene.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9628551&dopt=Abstract raloxifene Evista



Evista
Growth response of colon cancer cell lines to selective estrogen receptor modulators.

Picariello L, Fiorelli G, Martineti V, Tognarini I, Pampaloni B, Tonelli F, Brandi ML.

Department of Clinical Physiopathology, University of Florence, Florence, Italy.

BACKGROUND: The purpose of this study was to compare the "in vitro" effects of the selective estrogen receptor modulators, tamoxifen and raloxifene, on two human colon cancer cell lines. MATERIALS AND METHODS: Serial concentrations (0.1, 1, 5 and 10 microM) of tamoxifen and raloxifene were used and evaluated for cell proliferation, viability and apoptosis in HCT8 and HCT116 cells. RESULTS: Micromolar doses of raloxifene significantly reduced HCT116 and HCT8 cell proliferation. Tamoxifen (5 microM) strongly reduced HCT8 cell growth with minor effects on HCT116 cells. Raloxifene (10 microM) was lethal on both cell lines, while 10 microM tamoxifen caused lethality only in HCT8 cells. Five microM raloxifene reduced cell viability in HCT8 and HCT116 cells, while 5 microM tamoxifen halved only HCT8 cell viability. Raloxifene and tamoxifen did not induce apoptosis in the two cell lines. CONCLUSION: Tamoxifen, and even more raloxifene, were effective in reducing HCT8 and HCT116 cell proliferation and viability, suggesting their potential application in the prevention and therapy of colorectal cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12894523&dopt=Abstract raloxifene Evista