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

Ozolins̆, Terence R.S.; Gupta, U

doi:10.1002/bdrb.20010

Cited by 9 publications

(3 citation statements)

References 46 publications

(54 reference statements)

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“…One hypothesis that has been proposed is that estrogenic compounds inhibit expression of melaninconcentration hormone, a neuropeptide produced by neurons within the hypothalamus, and that those changes lead to reduced food and water intake (Murray et al, 2000). Several additional hypotheses have been proposed for the reduced food consumption and body weights reported after administration of SERMs to adult animals, including involvement of the neuropeptide, neurotensin (Terry et al, 2004) or somatostatin and growth hormone (Ozolins and Gupta, 2004). Regardless of the mechanism responsible, estrogens and estrogenic compounds, including lasofoxifene, clearly affect food and water intake, with the effects possibly mediated via the estrogen receptor; either directly or indirectly.…”

Section: Discussionmentioning

confidence: 99%

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

Weisenburger

Hagler

Tassinari

2004

Birth Defects Research Pt B

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The maternal findings in this study were related to the pharmacologic activity of lasofoxifene. Inhibition of growth of the F1 offspring after perinatal exposure to lasofoxifene was observed, but there were no significant effects on the sensory, behavioral, or functional measures, including learning and memory. There were no effects on the F2 generation. The findings are consistent with those reported for at least one other SERM. The findings of this study do not suggest increased risk for the primary indication of use in postmenopausal women.

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Section: Discussionmentioning

confidence: 99%

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

Weisenburger

Hagler

Tassinari

2004

Birth Defects Research Pt B

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“…These are listed in Table 4, and include the antioxidants BHA (Kawashima et al, 1990) and diphenyl diselenide (Favero et al, 2005), insulin (Ohura and Takayama, 1985;Ohura et al, 1986a,b), the selective estrogen receptor modulators raloxifene (Byrd and Francis, 1998) and lasofoxifene (Ozolins and Gupta, 2004), the anthelmintic bromofenofos (Yoshimura and Delatour, 1986), the anticonvulsant valproic acid (Vorhees, 1987), the antidepressant lithium chloride (Marathe and Thomas, 1986), the glucocorticoid dexamethasone (LaBorde et al, 1992), the neurotoxicant methylmercuric chloride (Fuyata et al, 1978), the nitrile b-aminoproprionitrile Joneja, 1976, 1978), the anti psoriasis drug tretinoin (Chahoud et al, 1991), the solvents glycerol formal (Aliverti et al, 1980) and diethylene glycol monomethyl ether (Hardin et al, 1986), and the sugar replacement Isomalt (WaalkensBerendsen et al, 1989). Table 4 lists those studies that reported a nonsignificant or very low increase in the incidence of wavy ribs that are likely to be incidental to the general effects of these agents.…”

Section: Possible Modes Of Action By Various Agentsmentioning

confidence: 99%

Interpretation of skeletal variations for human risk assessment: delayed ossification and wavy ribs

Carney

Kimmel²

2007

Birth Defects Research Pt B

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Delayed (or incomplete) ossification of developing fetal bones and wavy ribs are some of the most common skeletal variations encountered in regulatory guideline developmental toxicity studies. Although they tend to be regarded as minor effects, they can be quite sensitive and consequently may influence the study lowest-observed-adverse-effect levels (LOAELs), and thus, impact classification, labeling, and risk assessment. In this study, we review the underlying mechanisms of these skeletal variations, evaluate different scenarios in which they have been observed, offer guidance for their interpretation, and comment on their use for risk assessment. Both minor delays in ossification and wavy ribs seem to be readily repairable via postnatal skeletal remodeling, are not mechanistically linked to malformation, and often are seen in the presence of maternal or fetal toxicity. As such, these minor variations would not generally be considered adverse in and of themselves but should be interpreted in the context of other maternal and fetal findings, information available on normal skeletogenesis patterns, mode of action of the test agent, and historical control incidence using a weight of evidence approach. Birth Defects Res 80: 473-496, 2007. r 2007

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“…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. Higher doses (10 or 100 mg/kg) induced teratologic effects 72. Concentrations in maternal plasma were similar to those in milk, and increased with increasing dose, remaining consistent over a 10 day period 71.…”

Section: Summary Of Pharmacology and Preclinical Evidencementioning

confidence: 73%

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

Cited by 9 publications

References 46 publications

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

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

Interpretation of skeletal variations for human risk assessment: delayed ossification and wavy ribs

Lasofoxifene: Evidence of its therapeutic value in osteoporosis

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