Pre‐ and postnatal development studies of lasofoxifene, a selective estrogen receptor modulator (SERM), in Sprague–Dawley rats

Weisenburger, Walter P.; Hagler, A.; Tassinari, Melissa S.

doi:10.1002/bdrb.20013

Cited by 13 publications

(8 citation statements)

References 29 publications

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“…These observations are consistent with those in another study using a similar treatment period (GD 6-17) in which red vaginal discharge was observed with doses as low 0.1 and 0.03 mg/kg lasofoxifene (Weisenburger et al, 2004). Similarly, presumptive vaginal bleeding between GD 18-20 was reported in rats treated with idoxifene (Treinen et al, 1998) and raloxifene (Buelke-Sam et al, 1998;Byrd and Francis, 1998).…”

Section: Discussionsupporting

confidence: 89%

“…Importantly, increased systemic levels of somatostatin have been implicated in altered feeding behavior (reviewed in Aponte et al, 1984), altered taste preferences in rats (Scalera and Tarozzi, 1998), and decreased food consumption in rodents and primates (Lotter et al, 1981). Alternate explanations for the lasofoxifene-mediated hypophagy have also been proposed , Terry et al, 2004, Weisenburger et al, 2004. Of note, no clinical signs indicative of frank toxicity were observed in general toxicity studies conducted with similar doses of lasofoxifene (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits

Ozolins̆

Gupta²

2004

Birth Defects Research Pt B

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In general, both maternal and fetal effects of lasofoxifene were similar to those reported with other SERMs. Although the incidence or severity of these effects was, in some instances, greater in the rat than in the rabbit, the doses and the resultant maternal and fetal exposures were many orders of magnitude higher in the rat, suggesting the rabbit to be more sensitive to the toxicological effects of lasofoxifene.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits

Ozolins̆

Gupta²

2004

Birth Defects Research Pt B

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“…Results from the present study support this conclusion and suggest that in some developmental parameters, the lasofoxifene-exposed pups are developmentally 1 week older than controls. Interestingly, no change in age of incisor eruption was reported in the preand post-natal development study with lasofoxifene (Weisenburger et al, 2004). In that study, however, early eye opening was reported and was also interpreted as an artifact of delayed parturition (Weisenburger et al, 2004).…”

Section: Discussionmentioning

confidence: 74%

“…In the implantation study, doses were 0.01, 0.03, and 0.1 mg/kg/day based on findings from two exploratory parturition studies in pregnant rats. The highest dose level in the implantation study was set at 0.1 mg/kg based on pup mortality at a higher doses (Weisenburger et al, 2004). In both the cyclicity and the implantation studies, a constant dose volume of 10 mL/kg was used.…”

Section: Test Article and Treatment Regimenmentioning

confidence: 99%

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats

Terry

Cappon

Hurtt

et al. 2004

Birth Defects Research Pt B

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BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM). With high affinity to the a and b human estrogen receptors and greater potency than other SERMs, lasofoxifene is potentially a superior treatment for postmenopausal osteoporosis. In light of the known effects of estrogen-modulating compounds on female reproductive indices, two studies were conducted to evaluate the effects of lasofoxifene on female rat cyclicity, reproduction, and parturition. METHODS: One study evaluated effects of lasofoxifene on estrous cyclicity, and the second study assessed effects on implantation and parturition. In the cyclicity study, lasofoxifene was administered to female rats at doses of 0.1, 0.3, and 1.0 mg/kg/day for 14 consecutive days. After treatment, there was a 3-week reversibility phase followed by a mating phase. In the implantation study, lasofoxifene was administered to pregnant female rats at doses of 0.01, 0.03, and 0.1 mg/kg/day for 7 consecutive days (gestation day [GD] 0-6). Some animals were euthanized on GD 21, and the remainder of the group was allowed to deliver the F 1 generation. Several developmental indices were evaluated in the F 1 pups through post-natal day (PND) 21. RESULTS: In the cyclicity study, all lasofoxifenetreated females were anestrous by Study Day 7 (1.0 mg/kg) or 9 (0.3 and 0.1 mg/kg). The reversibility phase resulted in restoration of normal estrous cycles by the end of 1 (0.1 mg/kg) or 2 weeks (0.3 and 1.0 mg/kg). During the mating phase, no adverse effects occurred in pregnancy success or reproductive parameters. In the implantation study, all doses of lasofoxifene increased pre-and post-implantation losses, increased gestation length, and reduced litter size. None of the developmental parameters measured on the

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“…Restoration of normal estrous cycle was achieved one to two weeks after the suspension of therapy 70. As part of an International Conference on Harmonization guideline on reproductive and developmental toxicity testing for new pharmaceuticals [http://www.fda.gov/cder/guidances5a.pdf], a pre- and post-natal study in pregnant and lactating female rats was designed 71. Lasofoxifene at oral doses of 0.01, 0.03, and 1 mg/kg decreased maternal body weight, increased dose-dependently the length of gestation and induced dystocia.…”

Section: Summary Of Pharmacology and Preclinical Evidencementioning

confidence: 99%

Lasofoxifene: Evidence of its therapeutic value in osteoporosis

Gennari

Merlotti

Paola

et al. 2009

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Introduction:Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain.Aims:The purpose of this article is to review the clinical trials of lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis. The medical literature was reviewed for appropriate articles containing the terms “lasofoxifene” and SERMs”.Evidence review:There are three (phase II or phase III) clinical trials that clearly demonstrate efficacy and safety of this new SERM in the suppression of bone loss and the prevention of vertebral and nonvertebral fractures. Moreover, lasofoxifene treatment also reduced breast cancer risk and the occurrence of vaginal atrophy.Place in therapy:With its increased potency and efficacy on the prevention of nonvertebral fractures lasofoxifene may be an alternative and cost-effective therapy for osteoporosis in postmenopausal women.

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Pre‐ and postnatal development studies of lasofoxifene, a selective estrogen receptor modulator (SERM), in Sprague–Dawley rats

Cited by 13 publications

References 29 publications

Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits

Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats

Lasofoxifene: Evidence of its therapeutic value in osteoporosis

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