Raloxifene hydrochloride:pharmacology, pharmacodynamics and cardiovascular effects

Introduction

Raloxifene hydrochloride(Figure 1) is a selective estrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women. Because raloxifene has estrogen agonist-like effects on bone and on cholesterol metabolism and antagonist-like effects on the endometrium and breasts, it has the potential to produce some of the beneficial effects of estrogen without the possible adverse effects. There is still much to be learned about SERMs and their mechanism of action.[1]

Chemistry

Raloxifene hydrochloride is a benzothiophene nonsteroidal derivative that binds to the estrogen receptor. It is classified as a selective estrogen-receptor modulator. The chemical name is [6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl] hydrochloride.[1]

General pharmacology

The term selective estrogen receptor modulator (SERM) has been applied to compounds such as raloxifene that have tissue-specific estrogen agonist
antagonist properties. Raloxifene hydrochloride, for example, acts as an estrogen antagonist, on the breast and the uterus, but displays estrogen-agonistic activities on bone mass and lipids. Raloxifene hydrochloride is a nonsteroidal benzothiophene compound. Several modifications to the 2-arylbenzothiophene core have shown that the 6-hydroxy substituents of raloxifeneare important for estrogen receptor binding and for mimicking the corresponding 3- and 17-hydroxy groups of 17-estradiol. An estrogen antagonistic region of raloxifeneis characterized by a piperidine side chain. The orthogonal orientation of the basic side chain may contribute to raloxifene’s lack of uterotrophic effects. Replacement of the 6-hydroxy substituent with various functional groups leads to a reduction in cholesterol-lowering effects and an antiproliferative action, whereas substitution of the 4’-hydroxy group with small electronegative substituents does not not change the in vivo activity profile. Substitution of a larger group at the 4 position, however, resulted in increased uterine stimulation. Several raloxifene analogs are under investigation for their potential use in a variety of diseases in which estrogen is thought to play a pathogenic role such as uterine leiomyoma and endometriosis.[2]

Several recent studies have provided insight into the differences between the modes of action of estrogens and SERMs. Both, 17-estradiol and raloxifene, bind to the same ligand-binding domain of the estrogen receptor. The receptor-binding affinity of raloxifene, its binding mechanism, and the structural alterations to the estrogen receptor, that it induces, differ from those of 17-estradiol . Because of structural differences among the various ligands that bind to the estrogen receptor, different patterns of estrogen-induced responses can result. In the 17-estradiol-estrogen receptor complex, for example, helix 12 of the estrogen receptor ligand-binding domain overlies the ligand binding cavity, enabling the AF-2 domain to interact with coactivators. In the raloxifene estrogen receptor complex helix 12 does not overlie the cavity and this may prevent coactivator recruitment to the estrogen receptor ligand-binding domain. Thus differences among ligands produce subtle conformational differences in the resulting ligand-receptor complexes, which ultimately modulate downstream transcriptional effects.[2]

Pharmacodynamics

In three randomized, placebo-controlled trials in Europe, postmenopausal women receiving raloxifene hydrochloride at variable doses of 30 to 150 mg daily demonstrated significant increases in bone mineral density in the lumbar spine, total hip, femoral neck and total body compared to placebo.[3] In the MORE and RUTH trials, there were fewer incidences of vertebral fractures in postmeopausal women receiving raloxifene hydrochloride compared to placebo.[4] In a eight-week study evaluating short-term effects of raloxifene hydrochloride in healthy postmenopausal women, there was a decrease in the bone turnover markers, such as serum alkaline phosphatase level, serum osteocalcin level and urinary calcium excretion.[3] Raloxifene was shown to inhibit estrogen-dependent proliferation of human breast cancer cells in vitro and development of induced mammary tumors in rats in vivo. In adult female rats, raloxifene hydrochloride produced a greater regression of the mammary gland than tamoxifen. The MORE trial was a multicenter, randomized, double-blind clinical trial that investigated the long-term effects of the drug therapy in European and American postmenopausal women receiving raloxifene hydrochloride for 40 months. Additionally, a reduction in the incidence of invasive breast cancer was also demonstrates in the CORE and RUTH trials.[4] Study findings demonstrated that compared to placebo, the risk of invasive breast cancer was decreased by 76% among postmenopausal women with osteoporosis. There was a decrease in the risk of estrogen receptor-positive breast cancer by 90% but there was no increase in the risk of endometrial cancer. Unlike hormone replacement therapy, raloxifene does not mediate proliferative or stimulatory effects on endometrial tissue. Findings from both animal and human studies demonstrated no significant changes in the histologic appearance of the endometrium.[3] Raloxifene hydrochloride promotes estrogen-like effects on lipid metabolism. In a European trial that evaluated lipid profiles following raloxifene therapy over the 24-month period, there were significant decreases in the serum concentrations of total and low-density lipoprotein (LDL) cholesterol over a 24-month period of raloxifene therapy Raloxifene hydrochloride is not associated with causing alterations in the serum levels of HDL cholesterol or triglycerides. As the HDL choesterol level is considered a strong inverse predictor of cardiovascular disease in women, the cardioprotective effects of raloxifene hydrochloride were questioned. Due to limited data on the long-term trials, it is not possible to determine whether the small lipid effects produced by raloxifene correlate with a smaller degree of cardioprotective activity compared with hormone replacement therapy.[3]

Cardiovascular effects of raloxifene hydrochloride

Recent preclinical and clinical findings suggest that raloxifene hydrochloride also possesses beneficial effects on the cardiovascular system. These findings indicated that raloxifene hydrochloride may have cardioprotective properties without an increased risk of cancer or other side effects. Raloxifene hydrochloride has been shown to reduce total and low-density lipoprotein cholesterol concentrations in plasma, an effect similar to that produced by estrogens. Unlike estrogens, however, raloxifene hydrochloride does not increase high-density lipoprotein cholesterol and triglyceride levels in plasma. Endothelium is thought to play an important role in the genesis of atherosclerosis. Several lines of evidence suggest that an intervention with endothelial function might influence the progression of coronary disease and the incidence of cardiovascular events. Raloxifene hydrochloride increases the nitric oxide/endothelin-1 ratio, and improves endothelium-dependent vasomotion in post-menopausal women to the same extent as estrogens. Furthermore, in two randomized trials on post-menopausal women raloxifene hydrochloride reduced homocysteine levels, another independent risk factor for the development of cardiovascular disease. Although estrogens remain the drugs of choice in the hormonal therapy of most postmenopausal women, raloxifene hydrochloride may represent and alternative in women who are at risk of coronary artery disease.[2]

References

[1] Itabashi A. Nihon Rinsho. 2004;62 Suppl 2:528-535.

[2] Saitta A, Morabito N, Frisina N, et al. Cardiovascular effects of raloxifene hydrochloride. Cardiovasc Drug Rev. 2001;19(1):57-74. doi:10.1111/j.1527-3466.2001.tb00183.x

[3] Scott JA, Da Camara CC, Early JE: Raloxifene: a selective estrogen receptor modulator. Am Fam Physician. 1999 Sep 15;60(4):1131-9.

[4] Moen MD, Keating GM: Raloxifene: a review of its use in the prevention of invasive breast cancer. Drugs. 2008;68(14):2059-83. 

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