Second-generation Selective Estrogen Receptor Modulator Research Articles

Novel Advances in the Role of Selective Estrogen Receptor Modulators in Hormonal Replacement Therapy: A Paradigm Shift.

Estrogen is a key regulatory hormone in the functioning of a female reproductive system. Estrogen hormone regulates many complex physiological processes, which has its role in reproduction and skeletal and cardiovascular systems by acting on estrogen receptors alpha (ERα) and beta (ERβ), which are nuclear transcription factors. Selective estrogen receptor modulators (SERMs) are now being used to treat bone loss, breast carcinoma, and menopausal symptoms, metabolic neurodegenerativebecause of their characteristics that allow them to function as both estrogen agonists and antagonists,depending on the target tissue. First-generation SERMs, such as Tamoxifen, are used in the management protocol for breast cancer, which is estrogen receptor (ER-positive). Raloxifene is a second-generation SERM that is a valuable adjunct used to treat and prevent osteoporosis in postmenopausal women and prevent compression fractures of the vertebral column. Novel SERM molecules are on the horizon, proven more potent and efficacious in preventing and treating osteoporosis. These include Ospemifene, lasofoxifene, bazedoxifene and arzoxifene. The benefits of Raloxifene versus that of Bazedoxifene are under trial. Despite their therapeutic benefits and actions, these medications are not without adverse effects, such as thromboembolic disorders. Increased risk of uterine cancer has been linked to Tamoxifen. This article delves into the world of SERMs, including their development and discovery. The newer SERMs in late development, ospemifene, lasofoxifene, bazedoxifene, and arzoxifene, are described in detail.

Formulation Development for Transdermal Delivery of Raloxifene, a Chemoprophylactic Agent against Breast Cancer

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator approved for the prevention of invasive breast cancer in women. Oral therapy of RLX requires daily intake and is associated with side effects that may lead to low adherence. We developed a weekly transdermal delivery system (TDS) for the sustained delivery of RLX to enhance the therapeutic effectiveness, increase adherence, and reduce side effects. We evaluated the weekly transdermal administration of RLX using passive permeation, chemical enhancers, physical enhancement techniques, and matrix- and reservoir-type systems, including polymeric gels. In vitro permeation studies were conducted using vertical Franz diffusion cells across dermatomed human skin or human epidermis. Oleic acid was selected as a chemical enhancer based on yielding the highest drug delivery amongst the various enhancers screened and was incorporated in the formulation of TDSs and polymeric gels. Based on in vitro results, both Eudragit- and colloidal silicon dioxide-based transdermal gels of RLX exceeded the target flux of 24 μg/cm2/day for 7 days. An infinite dose of these gels delivered 326.23 ± 107.58 µg/ cm2 and 498.81 ± 14.26 µg/ cm2 of RLX in 7 days, respectively, successfully exceeding the required target flux. These in vitro results confirm the potential of reservoir-based polymeric gels as a TDS for the weekly administration of RLX.

Raloxifene-loaded SLNs with enhanced biopharmaceutical potential: QbD-steered development, in vitro evaluation, in vivo pharmacokinetics, and IVIVC.

Raloxifene hydrochloride, a second-generation selective estrogen receptor modulator, has been approved for the management of breast cancer. However, it is known to exhibit poor (~ 2%) and inconsistent oral bioavailability in humans, primarily ascribable to its low aqueous solubility, extensive first-pass metabolism, P-gp efflux, and presystemic glucuronide conjugation. The present research work entails the systematic development and evaluation of SLNs of RLX for its enhanced biopharmaceutical performance against breast cancer. Factor screening studies were conducted using Taguchi design, followed by optimization studies employing Box-Behnken design. Preparation of SLNs was carried out using glyceryl monostearate and Compritol® 888 ATO (i.e., lipid), Phospholipid S-100 (i.e., co-surfactant), and TPGS-1000 (i.e., surfactant) employing solvent diffusion method. The optimized formulation was evaluated for zeta potential, average particle size, field emission scanning electron microscope, transmission electron microscopy, and in vitro release study. Further, MCF-7 cells (cell cytotoxicity assay, apoptosis assay, and reactive oxygen species assay) and Caco-2 cells (cell uptake studies and P-gp efflux assay) were employed to evaluate the in vitro anticancer potential of the developed optimized formulation. In vivo pharmacokinetic studies were conducted in Sprague-Dawley rats to evaluate the therapeutic profile of the developed formulation. The optimized SLN formulations exhibited a mean particle size of 109.7nm, PDI 0.289 with a zeta potential of - 13.7mV. In vitro drug dissolution studies showed Fickian release, with release exponent of 0.137. Cell cytotoxicity assay, apoptosis assay, and cellular uptake indicated 6.40-, 5.40-, and 3.18-fold improvement in the efficacy of RLX-SLNs vis-à-vis pure RLX. Besides, the pharmacokinetic studies indicated quite significantly improved biopharmaceutical performance of RLX-SLNs vis-à-vis pure drug, with 4.06-fold improvement in Cmax, 4.40-fold in AUC(0-72h), 4.56-fold in AUC(0-∞), 1.53-fold in Ka, 2.12-fold in t1/2, and 1.22-fold in Tmax. Further, for RLX-SLNs and pure drug, high degree of level A linear correlation was established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) at the corresponding time-points. Stability studies indicated the robustness of RLX-SLNs when stored at for 3months. Results obtained from the different studies construe promising the anticancer potential of the developed RLX-SLNs, thereby ratifying the lipidic nanocarriers as an efficient drug delivery strategy for improving the biopharmaceutical attributes of RLX.

Bioadhesive polymer/lipid hybrid nanoparticles as oral delivery system of raloxifene with enhancive intestinal retention and bioavailability

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator used to treat osteoporosis in postmenopausal women. RLX fails to be developed into injectable dosage forms due to poor solubility. Although oral formulations are clinically available, the lower bioavailability (<2%) embarrasses the pharmaceutists. This work reported a bioadhesive nanosystem intended for oral delivery of RLX to enhance its oral bioavailability and address the formulation challenge. The bioadhesive nanosystem refers to polymer–lipid hybrid nanoparticles made up of Carbopol 940, glyceryl distearate, and TGPS. RLX was solidly encapsulated into bioadhesive nanoparticles (bNPs) through a nanoprecipitation technique along with synchronous desalting of RLX·HCl. The resultant RLX-loaded bNPs (RLX-bNPs) were characterized by particle size, ζ potential, morphology, and entrapment efficiency. The in vitro release and in vivo oral bioavailability of RLX-bNPs in rats were comparatively investigated with RLX-loaded common lipid nanoparticles (RLX-cNPs). The preferred formulation possesses a particle size of 150 nm around with a polydispersity index (PDI) of 0.282. RLX-bNPs exhibited slower drug release than RLX-cNPs owing to the presence of an adhesive layer. After oral administration, RLX-bNPs resulted in significant enhancement in the bioavailability of RLX, up to 556.9% relative to RLX suspensions, while it was merely 244.7% for RLX-cNPs. Cellular testing and ex vivo transport imaging demonstrated that bNPs were endowed with excellent intestinal epithelial affinity and absorbability. Our study affords an alternative option for designing a suitable oral delivery system specific to amphiphobic drugs like RLX·HCl.

Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment.

PurposeIn the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy.MethodsRaloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model.ResultsThe mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat.ConclusionWe prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These trans-dermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat.

Raloxifene Ameliorates Liver Fibrosis of Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is higher in men than in women, but according to some epidemiological studies, this gender difference disappears after menopause. Estrogen therapy protects against NAFLD and nonalcoholic steatohepatitis (NASH) after menopause. We investigated the therapeutic effect of raloxifene, a second-generation selective estrogen-receptor modulator, on NASH induced by a choline-deficient high-fat (CDHF) diet in female ovariectomized (OVX) mice. Seven-week-old female C57BL/6J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + raloxifene (intraperitoneal injection, 3 mg/kg body weight/day; OVX + RLX group). These three groups of mice were fed a CDHF diet for 8 weeks; choline-sufficient high-fat (CSHF) diet was used as control diet. Serum biochemical indicators of hepatic function and liver histological changes were evaluated. Compared with CSHF diet, ovariectomy enhances liver injury and fibrosis in CDHF diet-fed mice. Serum alanine aminotransferase (ALT) levels were significantly lower in the OVX + RLX group than in the OVX group. The OVX group developed extensive steatosis with inflammation and fibrosis. Lobular inflammatory scores and fibrosis staging in the OVX + RLX group were significantly lower than in the OVX group. Furthermore, the OVX + RLX group exhibited significantly higher expression of hepatic estrogen receptor-α, which was significantly lower in the OVX group than in the SHAM group. Raloxifene may ameliorate progression of liver fibrosis of NASH induced by CDHF diet in ovariectomized female mice, and up-regulation of estrogen receptor-α may play an important role in the beneficial effects of raloxifene on NASH.

Formulation, development and optimization of raloxifene-loaded chitosan nanoparticles for treatment of osteoporosis

Context: Osteoporosis (OP) is a disease of skeletal system and is associated with fragility fracture at the hip, spine and wrist. Various drugs have been used to treat OP. One of them is raloxifene hydrochloride (RLX), a second-generation selective estrogen receptor modulator (SERM) approved by the USFDA. RLX possesses only 2% absolute bioavailability (BA) by oral route due to its extensive first-pass metabolism.Objective: The purpose of the current research work was to develop and evaluate RLX-loaded chitosan nanoparticles (CS-NPs) for treatment of OP with enhanced BA.Materials and methods: The RLX-loaded CS-NPs were prepared by gelation of CS with tripolyphosphate (TPP) by ionic cross-linking. Formulation was optimized and in vitro drug release and in vivo study were performed.Results and discussions: CS-NPs were formed by the ionic gelation method. The particle size, entrapment efficiency and loading efficiency varied from 216.65 to 1890 nm, 32.84 to 97.78% and 23.89 to 62.46%, respectively. Release kinetics showed diffusion-controlled and Fickian release pattern. In vivo study indicated higher plasma drug concentration with NPs administered intranasally as compared to drug suspension administered through oral route (p < 0.05). A significantly higher drug concentration in plasma was achieved in 10 min after nasal administration with respect to oral administration.Conclusion: The results suggest that RLX-loaded CS-NPs have better BA and would be a promising approach for intranasal (i.n.) delivery of RLX for the treatment of OP.

Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo

Raloxifene is a second-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4'-glucuronide (ral-4'-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (Ptrend = 0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4'-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4'-Gluc comprising ~70% of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-4'-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene.

Raloxifene Upregulated Mesangial Cell MMP-2 Activity via ER-β Through Transcriptional Regulation

Raloxifene, a second-generation selective estrogen receptor modulator, exerts estrogen-like effects in specific tissues. In this present study, we examined the effect of raloxifene on mesangial cell matrix metalloproteinase-2 (MMP-2) activity in streptozotocin-induced diabetic mice. Raloxifene increased the MMP-2 level in a dose-dependent and receptor-mediated manner. An antibody against estrogen receptor-β (ER-β) blocked the effect of raloxifene on MMP-2 expression, suggesting that the effect of raloxifene on MMP-2 activity was mediated by ER-β. In addition, the transcription factor AP-2, that plays an important role in MMP-2 gene transcription, was overexpressed under raloxifene simulation. The effect of MMP-2 was blocked by a selective inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway, PD98059. Our results suggested that raloxifene-induced MMP-2 activity increases function through ERK/MAPK signaling via AP-2. In addition, we also found that the effect of raloxifene on MMP-2 expression was mediated via its binding to ER-β. However, at this stage of our investigation, (i) we could only show that both the binding to ER-β and the activation of the ERK/MAPK pathway impacted MMP-2 expression and (ii) we were unable to establish a relationship between ER-β binding and ERK/MAPK pathway activation.

Formulation and characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery system.

Background:Raloxifene, a second-generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women is administered orally in the form of a tablet. The absolute bioavailability of the drug is only 2% because of extensive hepatic first-pass metabolism. Lipid-based formulations are reported to reduce the first-pass metabolism by promoting its lymphatic uptake.Materials and Methods:In the present investigation, microemulsion and Self-Microemulsifying Drug Delivery System (SMEDDS) formulations of Raloxifene were prepared. The prepared formulations were characterized for drug loading, size, transparency, zeta potential, Transmission Electron Microscopy (TEM) and in vitro intestinal permeability.Results:The results indicated that high drug loading, optimum size and desired zeta potential and transparency could be achieved with both SMEDDS and microemulsion. The TEM studies indicated the absence of aggregation with both the systems. The in vitro intestinal permeability results showed that the permeation of the drug from the microemulsion and SMEDDs was significantly higher than that obtained from the drug dispersion and marketed formulation.Conclusion:Lipid based formulations such as microemulsion and Self Microemulsifying drug delivery systems are expected to increase the oral bioavailability as evidenced by the increased intestinal permeation.

Therapeutically Relevant Concentrations of Raloxifene Dilate Pressurized Rat Resistance Arteries via Calcium-Dependent Endothelial Nitric Oxide Synthase Activation

Selective estrogen receptor modulators (SERMs) inhibit constriction of mammalian conduit arteries. However, it is unknown whether SERMs at therapeutically achievable concentrations could reduce vascular tone in resistance arteries. The present study aimed to examine roles of Ca(2+) influx in endothelium and endothelial nitric oxide synthase (eNOS) activation in dilatations induced by raloxifene, a second-generation SERM in myogenically active arteries. Small mesenteric arteries from Sprague-Dawley rats were isolated and mounted in a pressure myograph for measurement of changes in vessel diameter. [Ca(2+)](i) images on native endothelial cells of intact arteries were determined by the fluorescence imaging technique, and phosphorylation of eNOS was assayed by Western blotting. Raloxifene (0.3 to 10 nmol/L) produced dilatations on established steady myogenic constriction. Female rat arteries dilated significantly more in response to raloxifene than male arteries. Raloxifene-induced dilatations of female arteries were blunted by N(G)-nitro-l-arginine methyl ester but unaffected by 1400W, charybdotoxin plus apamin, wortmannin, or LY294002. Raloxifene (3 nmol/L) triggered rises in endothelial cell [Ca(2+)](i) and increased eNOS phosphorylation at Ser1177. Both effects were greater in arteries from female rats than in arteries from male rats. Increases in endothelial cell [Ca(2+)](i) and in eNOS phosphorylation were prevented by removal of extracellular Ca(2+) ions. Finally, ICI 182,780 did not affect the raloxifene-stimulated rise in endothelial cell [Ca(2+)](i), eNOS phosphorylation, and vasodilatations. Chronic raloxifene treatment reduced myogenic constriction in arteries from female but not male rats. Raloxifene at therapeutically relevant concentrations inhibits myogenic constriction by an NO-dependent mechanism that causally involves the elevated [Ca(2+)](i) in endothelial cells and subsequent eNOS activation. Raloxifene dilates resistance arteries more effectively in female rats, indicating its significant gender-related action on endothelial cells in microcirculation.

Recent Advances in Selective Estrogen Receptor Modulators for Breast Cancer

Estrogen has important physiological effects on the growth and function of hormone-dependent tissues, and the link between estrogen and breast cancer has been deciphered at the end of the 20(th) century. Tamoxifen, one of the first generation selective estrogen receptor modulators (SERMs), has been the gold standard of first-line therapeutic drugs for all stages of estrogen-dependent breast cancer and has been found to reduce the incidence of breast cancer in high-risk pre- and postmenopausal women. Raloxifene, a second-generation SERM, was recently approved by FDA to decrease the risk of invasive breast cancer in postmenopausal women. During these years, many other novel types of SERAMs are being studied. This review highlights their recent advances. The discovery of selective estrogen receptor alpha modulators (SERAMs) and the latest information about their clinical and preclinical trials will be introduced intensively.

Raloxifene

Raloxifene (Evista) is a second-generation selective estrogen receptor modulator (SERM) that functions as an estrogen antagonist on breast and uterine tissues, and an estrogen agonist on bone. It is available in many countries worldwide for the treatment and prevention of osteoporosis in postmenopausal women, and has also been approved in the US for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis or postmenopausal women at increased risk of invasive breast cancer.Raloxifene reduces the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer and in postmenopausal women with osteoporosis. In addition, it is a well established agent for the prevention and treatment of osteoporosis. There was no significant difference between raloxifene and tamoxifen in the reduction in the risk of invasive breast cancer achieved in postmenopausal women at high risk of such cancer. Raloxifene was associated with an increased, albeit rare, risk of venous thromboembolism across several placebo-controlled trials and an increased risk of fatal stroke in one placebo-controlled trial in postmenopausal woman at increased risk for major coronary events. However, raloxifene was associated with a lower risk of venous thromboembolic events and cataracts than tamoxifen in a head-to-head trial. The choice of chemoprevention agent must consider a risk-benefit assessment for each individual patient. In this context, raloxifene is a valuable option for the prevention of invasive breast cancer in postmenopausal women with osteoporosis or at high risk of invasive breast cancer.

Pharmacokinetics and tolerability of exemestane in combination with raloxifene in postmenopausal women with a history of breast cancer

Raloxifene is a second-generation selective estrogen receptor modulator that reduces the incidence of breast cancer in postmenopausal women. Exemestane, a steroidal aromatase inhibitor, decreases contralateral new breast cancers in postmenopausal women when taken in the adjuvant setting. Preclinical evidence suggests a rationale for coadministration of these agents to achieve complete estrogen blockade. We tested the safety and tolerability of combination exemestane and raloxifene in 11 postmenopausal women with a history of hormone receptor-negative breast cancer. Patients were randomized to either raloxifene (60 mg PO daily) or exemestane (25 mg PO daily) for 2 weeks. Patients then initiated combination therapy at the same dose levels for a minimum of 1 year. Pharmacokinetic and pharmacodynamic data for plasma estrogens, raloxifene, exemestane, and their metabolites were collected at the end of single-agent therapy and during combination therapy. Plasma concentration-time profiles for each drug were unchanged with monotherapy versus combination therapy. Raloxifene did not affect plasma estrogen levels. Plasma estrogen concentrations were suppressed below the lower limit of detection by exemestane as monotherapy and when administered in combination with raloxifene. The most common adverse events of any grade included arthralgias, hot flashes, vaginal dryness and myalgias. In this small study, coadministration of raloxifene and exemestane did not affect the pharmacokinetics or pharmacodynamics of either agent to a significant degree in postmenopausal women. The combination of estrogen receptor blockade and suppression of estrogen synthesis is well tolerated and warrants further investigation.

Drug Insight: breast cancer prevention and tissue-targeted hormone replacement therapy

The first-generation selective estrogen receptor modulator (SERM) tamoxifen has been the mainstream hormone therapy in breast cancer. Tamoxifen benefits all stages of the disease, but its use increases the risk of uterine cancer and thromboembolic events and it can only be administered for 5 years. Aromatase inhibitors are superior to tamoxifen at advanced stages of disease and as adjuvants; however, because they increase fractures, aromatase inhibitors are unlikely to be used to prevent disease. Raloxifene, a second-generation SERM, leads, like tamoxifen, to approximately 50% fewer cases of invasive breast cancer in high risk women, with a lower incidence of thromboembolic events. Several other SERMs are in development to improve tissue specificity, efficacy and tolerance. Raloxifene shows protection against vertebral fractures similar to bisphosphonates; however, no significant effect has been observed on nonvertebral fractures. Many SERMs are in development for prevention and treatment of osteoporosis. As breast cancer metastasizes early and advanced disease cannot be cured, prevention is essential. To avoid the concerns about the use of traditional hormone replacement therapy, dehydroepiandrosterone--a tissue-targeted precursor of sex steroid formation--offers hope of a physiological tissue-targeted hormone replacement that, combined with a SERM, would simultaneously prevent breast and uterine cancer.

Raloxifene Modulates Pulmonary Vascular Reactivity in Spontaneously Hypertensive Rats

Selective estrogen receptor modulators (SERMs) reduce vascular tone in the systemic circulation. Their effects on the pulmonary circulation are unknown. The present study examined the effect of oral treatment with raloxifene (a second-generation SERM) on vasomotor reactivity in pulmonary arteries from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Pulmonary arterial rings were suspended in a multi-channel myograph, and changes in isometric tension were measured. WKY rings constricted less to U46619 than SHR rings, and the difference was eliminated after chronic treatment with raloxifene. More contraction to U46619 was obtained after inhibition of nitric oxide synthase (NOS) by L-NAME (as an index of basal NO release) in raloxifene-treated than in control SHR rings. Less U46619-induced contraction after raloxifene treatment occurred only in SHR rings with endothelium, and this effect was abolished upon removal of the endothelium. Raloxifene treatment did not enhance the contribution of basal NO to U46619-induced constriction in WKY rings. Raloxifene treatment did not modify endothelium-dependent relaxation to acetylcholine and endothelium-independent relaxation to nifedipine. The reduced relaxing sensitivity to sodium nitroprusside (SNP) in SHR rings was normalized by raloxifene treatment. Raloxifene treatment reduced CaCl2-induced tone in SHR but not in WKY rings. The results show that chronic treatment with raloxifene could improve pulmonary vascular function in hypertensive animals by (1) increasing basal NO release, (2) reducing vascular smooth muscle tone, and (3) improving the effect of NO on vascular smooth muscle in SHR. In contrast, raloxifene has little effect on vascular reactivity in pulmonary arteries from normotensive WKY rats.

Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial

The selective estrogen receptor modulator (SERM) tamoxifen has long been used to treat both early and advanced breast cancer. Raloxifene is a second-generation SERM that, in addition to combatting osteoporosis, may also lessen the risk of invasive breast cancer in postmenopausal women; The National Surgical Adjuvant Breast and Bowel Project (NSABP) Study of Tamoxifen and Raloxifene (STAR) is a prospective, randomized, double-blind trial conducted at nearly 200 clinical centers throughout North America. Participating were 19,747 postmenopausal women whose mean age was 58.5 years and whose 5-year breast cancer risk was increased at 4.03%. The minimal 5-year risk for entering the trial was 1.66%. The women received either 20 mg tamoxifen or 60 mg raloxifene daily for 5 years. During a mean follow up of 3.9 years, there were 163 cases of invasive breast cancer in women assigned to receive tamoxifen and 268 in those assigned to raloxifene, for respective incidence rates of 4.3 and 4.4 per 1000 and a risk ratio (RR) of 1.02 (95% confidence interval [CI], 0.82-1.28). Noninvasive breast cancers were less numerous in the tamoxifen group (RR, 1.40; 95% CI, 0.98-2.00), but uterine cancers were more frequent in this group (RR, 0.62; 95% CI, 0.35-1.08). No group differences were documented for invasive cancer at other sites, ischemic heart disease events, or strokes. Thromboembolic events were less frequent in raloxifene-treated women. Women in the 2 treatment groups had similar numbers of osteoporotic fractures. Those taking raloxifene had fewer cataracts and underwent fewer cataract surgeries. There was no difference in total deaths, and causes of death were similarly distributed in the 2 groups.

Chemoprevention of Breast Cancer: Tamoxifen, Raloxifene, and Beyond

Breast cancer is the most common cancer and the second most common cause of cancer death among women in the United States. While nonrandomized studies have reported that prophylactic mastectomy or oophorectomy can significantly reduce the risk of breast cancer, these approaches are unacceptable to the majority of women. Chemoprevention, which is defined as the prevention of cancer by pharmacological agents that inhibit or reverse the process of carcinogenesis, has thus increasingly become the focus of breast cancer prevention efforts. The first-generation selective estrogen receptor modulator (SERM) tamoxifen is the only US Food and Drug Administration- approved drug for breast cancer prevention and reduces the risk of breast cancer by as much as 50% in high-risk women. Raloxifene, a second-generation SERM, also has demonstrated efficacy for breast cancer prevention and is being compared with tamoxifen in a large randomized trial that has recently completed accrual. The aromatase inhibitors (AIs) decrease the incidence of contralateral breast cancer when used in the adjuvant setting and are being evaluated in ongoing primary prevention studies. In addition, a number of novel agents, including antiinflammatory drugs and retinoid derivatives, which appear to be of promise based on preclinical and epidemiological data, are under investigation. Several important challenges remain, including determination of the appropriate dose and duration of treatment when used in the primary prevention setting and development of new research models using surrogate end points for breast cancer incidence and mortality to permit more rapid clinical application of promising new agents.

Lasofoxitene: A new type of selective estrogen receptor modulator for the treatment of osteoporosis

Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen agonists and antagonists. Thus far SERMs have proven to be a highly versatile group and are being evaluated primarily for conditions associated with aging, including hormone-responsive cancer and osteoporosis. Tamoxifen and toremifene are currently used to treat advanced breast cancer and also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene is the only SERM compound actually approved worldwide for the prevention and treatment of postmenopausal osteoporosis and fragility fractures. Unfortunately, although these SERMs possess many benefits, they are also responsible for some very serious side effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These contraindications represent a major concern for the type of long-term, chronic therapy that is required to prevent osteoporosis. Moreover, both preclinical and clinical reports suggest that these SERMs are considerably less potent than estrogen, probably due to their reduced bioavailability. Lasofoxifene (CP 336,156) is a naphthalene-derivative, third-generation SERM, structurally distinct from the first- and second-generation SERMs. This compound selectively binds to both estrogen receptor subtypes (estrogen receptor-alpha or -beta) with high affinity. It has a half-inhibition concentration similar to that seen with estradiol and thus at least 10-fold higher than those reported for raloxifene and tamoxifen. Moreover, due to increased resistance to intestinal wall glucuronidation, lasofoxifene has a remarkably improved oral bioavailability with respect to other SERMs. In both preclinical and short-term clinical studies lasofoxifene has shown a proven efficacy in preventing bone loss and lowering cholesterol levels. Dose modeling from phase II studies allowed the selection of lasofoxifene 0.25 mg/day as the lowest fully effective dose. The compound shows a favorable safety profile and is currently in phase III development for the prevention and treatment of osteoporosis in postmenopausal women.

Emerging Selective Estrogen Receptor Modulators

Menopause, regardless of age at onset, is associated with a marked increase in coronary heart disease (CHD) risk. On the basis of epidemiological studies that demonstrated mainly positive effects of postmenopausal hormone therapy on CHD as well as on risk markers of CHD, it has been suggested that CHD could be prevented in postmenopausal women with long-term hormone therapy. However, since the publications of the Heart and Estrogen/progestin Replacement Study and the Women's Health Initiative trial, prescription of hormone therapy for the prevention of CHD has become controversial. Major efforts have been made to identify alternatives for hormone therapy. Compounds suggested have included selective estrogen receptor modulators (SERMs), which represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This pharmacological profile may offer the opportunity to dissociate favourable estrogenic effects on the bone and cardiovascular system from unfavourable stimulatory effects on the breast and endometrium. Two SERMs presently on the market are tamoxifen and raloxifene. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. These trials found fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a second-generation SERM that has been shown to prevent osteoporotic fractures, is safe for the endometrium and holds high promise for the prevention of breast cancer. The effect of raloxifene on CHD is still uncertain. On the basis of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, raloxifene may offer some protection to women with CHD or to those who are at high risk of CHD. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Next-generation SERMs taken into clinical development include idoxifene, droloxifene, ospemifene, arzoxifene, acolbifene/EM-800, levormeloxifene, lasofoxifene, bazedoxifene and HMR 3339. The aim is to find a compound with the ideal profile, that is, alleviation of climacteric symptoms and prevention of osteoporotic fractures, but without an adverse effect on the breast and endometrium, and no negative effect or even a beneficial effect on the cardiovascular system and the brain. Currently, limited data are available with regard to these next-generation SERMs and CHD. Nevertheless, some of these novel agents provide arguments for continuing the search for an ideal SERM.