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American Journal of Health-system... Sep 2000The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and therapeutic role of raloxifene hydrochloride are reviewed. Raloxifene is a selective... (Review)
Review
The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and therapeutic role of raloxifene hydrochloride are reviewed. Raloxifene is a selective estrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women. A SERM interacts with estrogen receptors, functioning as an agonist in some tissues and an antagonist in other tissues. Because of their unique pharmacologic properties, these agents can achieve the desired effects of estrogen without the possible stimulatory effects on the breasts or uterus. Raloxifene is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass glucuronidation. Approximately 60% of a dose is absorbed; however, absolute bioavailability is only 2%. The volume of distribution is 2348 L/kg for a single oral dose of 30-150 mg, and the elimination half-life averages 32.5 hours. In clinical trials in postmenopausal women, raloxifene had an estrogen-like effect on bone turnover and increased bone mineral density. It reduced the risk of fractures in women with osteoporosis. Raloxifene also seemed to reduce the risk of breast cancer and positively influenced blood lipid markers of cardiovascular disease. Raloxifene is generally well tolerated; the most common adverse effects are hot flashes and leg cramps. A serious adverse effect is venous thromboembolism. The recommended dosage is 60 mg/day orally without regard to meals. Ultimately, it will be information on cardiovascular or breast cancer benefits that will determine the future role of raloxifene. Raloxifene is an alternative to traditional hormone replacement therapy for the prevention and treatment of osteoporosis in selected postmenopausal women. More study is needed to verify possible benefits related to heart disease and breast cancer.
Topics: Administration, Oral; Aged; Biological Availability; Bone and Bones; Female; Half-Life; Humans; Intestinal Absorption; Osteoporosis, Postmenopausal; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tissue Distribution
PubMed: 11006795
DOI: No ID Found -
Cardiovascular Drug Reviews 2001Raloxifene hydrochloride binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen... (Review)
Review
Raloxifene hydrochloride binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen receptor modulators (SERMs). Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen-agonist effects on bone and lipids and estrogen antagonist effects on the breast and uterus. In addition to its well established effects on osteoporosis, recent preclinical and clinical findings suggest that raloxifene also possesses beneficial effects on the cardiovascular system. These findings indicated that raloxifene may have cardioprotective properties without an increased risk of cancer or other side effects. Raloxifene 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 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 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 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 may represent and alternative in women who are at risk of coronary artery disease.
Topics: Animals; Bone and Bones; Brain; Breast Neoplasms; Cardiovascular System; Endothelium, Vascular; Female; Genitalia, Female; Humans; Lipids; Osteoporosis, Postmenopausal; Pituitary Gland; Postmenopause; Raloxifene Hydrochloride; Receptors, Estrogen; Selective Estrogen Receptor Modulators
PubMed: 11314601
DOI: 10.1111/j.1527-3466.2001.tb00183.x -
Journal of Bone and Mineral Metabolism 2001Raloxifene is a selective estrogen receptor modulator, a compound that has estrogen agonist activity at some sites and antagonist activity at others. In investigations... (Review)
Review
Raloxifene is a selective estrogen receptor modulator, a compound that has estrogen agonist activity at some sites and antagonist activity at others. In investigations in animals and in rigorously conducted trials in humans, raloxifene treatment is associated with a 30%-40% reduction in risk of one or more spine fractures using the 60 mg dose. This reduction in risk is found in women with or without baseline fractures, in women with bone mineral density (BMD) in the lower, middle, or upper third of the low range (all had BMD reduced by more than 2.5 SD) and in women aged less than 65 years, between 65-70 years, and greater than 70 years. A reduction in ankle fractures, but not hip or wrist fractures, was found. Raloxifene treatment also is associated with a 60%-70% reduction in risk for breast cancer and is associated with reduced total and LDL cholesterol, lower fibrinogen, and no rise in triglyceride. Reduced aortic wall cholesterol content is reported in animal studies. These are surrogate endpoints of cardioprotection. There is no evidence that raloxifene reduces the incidence of myocardial or cerebrovascular events. Raloxifene does not induce breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer, but may be associated with an increased risk of thromboembolic disease (1/1000 cases per year), leg cramps in 2%-4% of cases and hot flushes in 4%-6% of cases, usually in first 6 months.
Topics: Animals; Estrogen Antagonists; Humans; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators
PubMed: 11281162
DOI: 10.1007/s007740170043 -
Nihon Yakurigaku Zasshi. Folia... Jan 2005
Review
Topics: Animals; Bone Density; Bone Remodeling; Bone Resorption; Bone and Bones; Breast Neoplasms; Controlled Clinical Trials as Topic; Coronary Disease; Female; Fractures, Bone; Humans; Osteoporosis, Postmenopausal; Raloxifene Hydrochloride; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Stroke; Transcription Factors
PubMed: 15738620
DOI: 10.1254/fpj.125.37 -
Current Drug Targets Dec 2001Efforts to interfere with the initiation and promotion of breast and other cancers by endocrine manipulation are not new. It is of obvious benefit to cancer patients to... (Review)
Review
Efforts to interfere with the initiation and promotion of breast and other cancers by endocrine manipulation are not new. It is of obvious benefit to cancer patients to administer substances that combine minimal general toxicity with maximal oestrogen inhibition. Raloxifene is a relatively recent addition to a group of compounds loosely designated as antioestrogens, which implies their ability to antagonize oestrogen effects via competitive binding to the various receptors. This is a reductionist simplification, since their effect varies and ranges from interaction with lipid transduction cascades, covalent binding to proteins and DNA, regulation of growth factors, erbB2, mdr1 and probably p53 expression, complexing with E-cadherin/catenin to active induction of apoptosis and many other effects on the genome. Also, the action of most antioestrogens is not solely antagonistic and different compounds do exert some agonistic effects in various tissues. Apart from some "pure" antioestrogens, the benzothiophene derivative Raloxifene has been found to combine a high degree of selective oestrogen suppression with several other desirable characteristics, such as reduction of bone demineralisation and antiatherogenic effects without endometrial stimulation. It is well tolerated, has been successfully tested as a chemopreventive agent for breast cancer in certain groups of the population and does not prevent ovulation in women with normal menstrual cycles. Certainly, Raloxifene is only another forerunner of upcoming "designer" oestrogen modulators, but it represents a welcome addition to the therapeutic choices available for the control of some menopausal problems as well as for the prevention and treatment of breast cancer, as outlined in the following brief review.
Topics: Breast Neoplasms; Clinical Trials as Topic; Drugs, Investigational; Endometrium; Female; Humans; Lipoproteins; Osteoporosis; Ovulation; Raloxifene Hydrochloride; Receptors, Estrogen; Selective Estrogen Receptor Modulators
PubMed: 11732640
DOI: 10.2174/1389450013348263 -
Therapeutic Delivery Jul 2021The present study focused on the development of a dry emulsion tablet of raloxifene hydrochloride (RXF) using a solid carrier adsorption technique to enhance oral...
The present study focused on the development of a dry emulsion tablet of raloxifene hydrochloride (RXF) using a solid carrier adsorption technique to enhance oral bioavailability. An oil-in-water emulsion was formulated and converted into dry powder using HPMC K4M plus Aerosil 200, then compressed into tablets. The prepared emulsion was evaluated for globule size, drug content and zeta potential. release study revealed significantly higher release from emulsion. The prepared tablets possessed acceptable hardness, friability, weight variation, disintegration time, thickness, etc. pharmacokinetic studies indicated a more than sevenfold increase in oral bioavailability. Stability studies indicated good physical and chemical stability of the developed formulation. The authors successfully formulated dry emulsion tablets with enhanced oral bioavailability.
Topics: Adsorption; Biological Availability; Emulsions; Raloxifene Hydrochloride; Solubility; Tablets
PubMed: 34165001
DOI: 10.4155/tde-2021-0025 -
Drug Development Research May 2020Breast cancer is one of the leading causes of mortality specifically for the women. The existing therapy is not sufficient due to the lack of target specificity and drug... (Comparative Study)
Comparative Study
Breast cancer is one of the leading causes of mortality specifically for the women. The existing therapy is not sufficient due to the lack of target specificity and drug resistance. Carbon nanotubes (CNTs) are one of the promising formulation approaches that show a promising effect to target specifically the cancer cells, with better cellular internalization. CNTs were prepared based on the modified Staudenmaier process, where temperature and stirring speed were found to be the most influencing factor for particle size and entrapment of the drug raloxifene hydrochloride (RLX). The optimized formulation was produced with drug loading of about 74.2 ± 4.67% and the average particle size of 234.2 ± 1.7 nm. The surface of the CNTs was functionalized by folic acid (FA), which helps to deliver the drug on the site of the cancer cells only in a target-specific manner. in vitro drug-release studies indicated that the drug release was dependent on the pH of the system. Cytotoxicity study clearly indicated the efficacy of the FA physically conjugated CNTs with affectivity induces apoptosis in the cancer cell line with the IC50 value of 43.57305 μg/ml. The fluorescence imagining study showed higher cellular internalization of the RLX compared with the pure drug and the RLX-CNT formulation.
Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Delivery Systems; Drug Liberation; Estrogen Antagonists; Female; Folic Acid; Humans; Inhibitory Concentration 50; Nanotubes, Carbon; Particle Size; Raloxifene Hydrochloride; Temperature
PubMed: 31782825
DOI: 10.1002/ddr.21620 -
Current Medical Research and Opinion Sep 2011Due to the chronic nature of osteoporosis and the risk of invasive breast cancer, raloxifene 60 mg/day (raloxifene) is intended to be used for long-term treatment... (Review)
Review
BACKGROUND
Due to the chronic nature of osteoporosis and the risk of invasive breast cancer, raloxifene 60 mg/day (raloxifene) is intended to be used for long-term treatment (treatment >3 years).
SCOPE
We review available information concerning long-term use of raloxifene, present several new analyses, and report new data from patients who underwent iliac crest bone biopsies after 8 years of raloxifene therapy. The most important studies were the Multiple Outcomes of Raloxifene Evaluation (MORE) followed by the Continued Outcomes of Raloxifene Evaluation (CORE).
FINDINGS
The primary endpoint in MORE was incidence of vertebral fracture, and the difference between the raloxifene and placebo groups for this endpoint widened during 4 years of therapy, with the relative risk reduction during the fourth year of the study being similar to the relative risk reduction during years 0 to 3 of the study. Continued raloxifene treatment is necessary to preserve bone mineral density (BMD). In MORE, raloxifene lowered markers of bone turnover to a premenopausal reference interval. Biopsies from three patients treated with raloxifene for 8 years showed normal bone and bone cells and double label in all specimens. Invasive breast cancer risk is a clinical consideration in postmenopausal women with osteoporosis, and invasive breast cancer risk reduction was the primary endpoint in CORE. In MORE and CORE, the benefit of raloxifene versus placebo in incidence of invasive breast cancer increased with greater duration of therapy up to 8 years.
CONCLUSIONS
The long-term use of raloxifene has been evaluated through changes in fracture risk reduction, BMD, markers of bone turnover, iliac crest bone biopsies, and invasive breast cancer risk reduction.
Topics: Bone Density Conservation Agents; Female; Humans; Osteoporosis, Postmenopausal; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Time Factors
PubMed: 21787127
DOI: 10.1185/03007995.2011.606312 -
Mini Reviews in Medicinal Chemistry Aug 2007Ovarian hormone deficiency status is associated with increased cardiovascular morbidity and mortality, suggesting that estrogen might exhibit a favorable cardiovascular... (Review)
Review
Ovarian hormone deficiency status is associated with increased cardiovascular morbidity and mortality, suggesting that estrogen might exhibit a favorable cardiovascular effect. Estrogen has a multitude of beneficial biological effects on surrogate markers of cardiovascular disease that may account for this hypothesis. However, none of the randomized trials already conducted with hormone replacement therapy showed overall benefit by means of reducing clinical ischemic cardiovascular events and/or suppressing atherogenesis. Moreover, the Women's Health Initiative study (WHI) has suggested a possible detrimental effect for hormone replacement therapy including increased cardiovascular morbidity, ovarian and breast cancer. Hence, any beneficial effect of estrogen must be carefully weighed against its carcinogenic properties together with its side effects. The need for a more efficient and specific molecule led to the development of the selective estrogen receptor modulators (SERMs). This new generation of drugs mimic the effect of estrogen in some tissues while antagonize several estrogen effects in other tissues. These unique properties offer the possibility to attain the beneficial effects of estrogen while avoiding its carcinogenic effect and the accompanying adverse reactions. Here we review the different effects of raloxifene- a protype second generation SERM on the cardiovascular system. We discuss raloxifene's role at different levels of the atherothrombotic cascade addressing each level separately; trying to clarify the net effect of raloxifene in modulating thrombosis in the arterial tree.
Topics: Cardiovascular Diseases; Cardiovascular System; Female; Humans; Raloxifene Hydrochloride; Risk Factors; Selective Estrogen Receptor Modulators
PubMed: 17692049
DOI: 10.2174/138955707781387911 -
International Journal of Nanomedicine 2014Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability...
Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon(®) 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a homogeneous distribution and low polydispersity index (0.08). They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 μg/cm(2)/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser scanning microscopy proved an enhanced permeation of coumarin-6-loaded transfersomes, to a depth of approximately160 μM, as compared with rigid liposomes. These ex vivo findings proved that a raloxifene hydrochloride-loaded transfersome formulation could be a superior alternative to oral delivery of the drug.
Topics: Administration, Cutaneous; Animals; Drug Carriers; Models, Biological; Nanostructures; Particle Size; Phospholipids; Raloxifene Hydrochloride; Rats; Rats, Wistar; Reproducibility of Results; Research Design; Skin; Skin Absorption; Surface-Active Agents
PubMed: 25246789
DOI: 10.2147/IJN.S65408