Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This article reviews lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women.
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PMID:Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene. 2016 39

Lasofoxifene, a new selective estrogen receptor modulator (SERM), was investigated to assess its efficacy and safety in the management of postmenopausal osteoporosis. A dose of 0.5 mg/day of lasofoxifene, given to postmenopausal women with osteoporosis, induced a reduction in vertebral fracture rates after 3 years and a reduction, after 5 years, of nonvertebral fractures, estrogen receptor-positive and invasive breast cancers, major coronary heart diseases and strokes. However, this dose was associated with significant side effects including venous thromboembolisms, pulmonary embolisms, leg cramps, hot flushes, uterine polyps, endometrial hypertrophy, arthralgia and vaginal candidiasis. Since no effect was evidenced on hip fractures, the risk-benefit ratio of this new medication, compared with previously marketed SERMs is, at best, uncertain.
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PMID:Interest of lasofoxifene in the treatment of osteoporosis. Evaluation of "Lasofoxifene in postmenopausal women with osteoporosis". N Engl J Med 2010;362:686-96. 2018 70

Selective estrogen receptor modulators (SERMs) interact with estrogen receptors as agonists or antagonists depending on the target tissue. Currently available SERMs are used to treat and prevent breast cancer and osteoporosis, to treat ovulatory dysfunction in women, and for contraception. Because current therapies do not adequately treat menopausal symptoms, the search continues for the optimal SERM for postmenopausal women, which would relieve hot flushes, treat vaginal atrophy, and prevent fractures, while protecting the endometrium, breast, and cardiovascular system. Future use of SERMs may also include their use in a tissue selective estrogen complex (TSEC), a therapy that combines a SERM with estrogen(s), designed to deliver the efficacy of each component with improved overall tolerability for the treatment of postmenopausal women. The future of SERMs may also include their use in men for the treatment of osteoporosis and various syndromes associated with secondary hypogonadism and possibly prostate cancer. Continued research should allow the full potential of SERMs to be uncovered.
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PMID:SERMs: progress and future perspectives. 2058 May 2

Menopause has been associated with vasomotor symptoms, vulvar-vaginal atrophy and osteoporosis. One of the goals in exploring the potential of selective estrogen receptor modulators (SERMs) was to determine if they could prevent fractures, reduce menopausal symptoms and treat vaginal atrophy, while being neutral or protective on the uterus, breast and cardiovascular system. However, no SERM to date has achieved this goal. More recently, the idea of pairing a SERM with estrogen(s), known as a tissue-selective estrogen complex (TSEC), has been studied in postmenopausal women. A TSEC combines the complementary tissue-selective activities of a SERM and estrogen(s), in an attempt to gain the benefits of each with better overall tolerability. The Selective estrogen Menopause And Response to Therapy (SMART) trials were multicentre, randomized, double-blind, placebo- and active-controlled phase 3 studies evaluating the safety and efficacy of the SERM, bazedoxifene (BZA) paired with conjugated estrogens (CEs) in healthy postmenopausal women. In the first SMART trial, BZA/CE protected the endometrium from estrogenic stimulation, relieved hot flushes and maintained bone mass, with rates of amenorrhea, breast pain and overall adverse events similar to those with placebo in more than 3400 women over two years. BZA 20 mg was the lowest effective dose of BZA in BZA/CE to protect the endometrium and maintain bone mass when paired with CE 0.625 mg and CE 0.45 mg. In SMART-2, these BZA/CE doses significantly reduced the frequency and severity of hot flushes over 12 weeks. Collectively, these data support the TSEC containing BZA/CE as a new paradigm for treating menopausal symptoms and preventing osteoporosis while protecting the endometrium from unopposed estrogenic stimulation.
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PMID:Tissue-selective agents: selective estrogen receptor modulators and the tissue-selective estrogen complex. 2095 88

Hormone therapy classically consists of an estrogen with an added progestin; however, concerns have been raised about the potential negative effects of progestin. The recent realization that estrogen agonist-antagonists or selective estrogen receptor modulators might be paired with estrogens instead of a progestin has led to the development of a novel form of menopausal therapy called tissue selective estrogen complex (TSEC). A TSEC is the pairing of a selective estrogen receptor modulator (SERM) with estrogen(s). The TSEC containing conjugated estrogens (CE) and the SERM, bazedoxifene (BZA), has reached clinical development. This short review outlines the effects of this particular TSEC, which maintains or increases bone mass in women at high risk for osteoporosis, and has clinical qualities of a promising new menopausal therapy. Randomized, double-blind, placebo-controlled phase 3 trials in postmenopausal women showed that, in addition to bone preservation, BZA/CE was shown to relieve hot flushes and treat vulvar-vaginal atrophy and its symptoms, with a good safety and tolerability profile.
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PMID:Preventing osteoporosis with a tissue selective estrogen complex (TSEC) containing bazedoxifene/conjugated estrogens (BZA/CE). 2106 94

Tamoxifen is used as an adjuvant therapy to reduce breast cancer recurrence among women with estrogen receptor positive tumors. Antidepressants are also commonly used in such women, to treat depression or to manage hot flushes, a frequent tamoxifen secondary effect. Some antidepressants could potentially inhibit cytochrome P450 2D6, required to activate tamoxifen, interfering with its action. Although there is not a clear cut directive on the subject, it is nowadays recommended to treat women with antidepressants with the lower cytochrome P450 2D6 inhibition potential to avoid a possible antagonism that may reduce tamoxifen s prevention of breast cancer recurrence at least in some patients with CYP2D6 genetic variation. The recommended antidepressants are desvenlafaxine, milnacipran, venlafaxin, escitalopram and citalopram.
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PMID:[Antagonism of tamoxifen and antidepressants among women with breast cancer]. 2152 23

Vasomotor symptoms and vulvar-vaginal atrophy are common consequences of menopause, and the only treatment approved by the US Food and Drug Administration is hormone therapy. Because both physicians and women are concerned with the tolerability and safety profile of estrogen and estrogen plus progestin treatments, alternative menopause therapies are needed. An ideal menopause treatment modality would relieve menopausal vasomotor and vulvar-vaginal symptoms, maintain bone mass, and have neutral or beneficial cardiovascular effects, without stimulating the breast or endometrium. The novel tissue-selective estrogen complex (TSEC) agent was paired with a selective estrogen receptor modulator (SERM) with estrogen(s) in an attempt to achieve a more favorable clinical profile based on the blended tissue activities of its components. This article reviews the published reports from Phase III trials of TSEC, which paired bazedoxifene (BZA) and conjugated estrogens (CEs). BZA/CE alleviated menopausal symptoms and prevented postmenopausal bone loss, had an overall good safety profile with an incidence of amenorrhea and breast pain similar to that with placebo, and did not stimulate the endometrium. The largest (N = 3397) and longest (2 years) study of this TSEC containing BZA/CE demonstrated endometrial hyperplasia rates similar to that with placebo and changes in lumbar spine bone mineral density that were significantly better than that with placebo, when a minimum dose of 20 mg of BZA was used with 0.625 or 0.45 mg of CE. Subsequent smaller studies showed that BZA/CE effectively reduced the incidence and frequency of hot flushes and significantly improved signs and symptoms of vaginal atrophy. Longer term safety with regard to cardiovascular and breast effects have not been established. Given the efficacy and safety reported in these Phase III trials, the TSEC of BZA/CE may be a promising new option for the treatment of menopause.
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PMID:Treating menopausal symptoms with a tissue-selective estrogen complex. 2153 25

The pharmacological management of disease should involve consideration of the balance between the beneficial effects of treatment on outcome and the probability of adverse effects. The aim of this review is to explore the risk of adverse drug reactions and drug-drug interactions with treatments for postmenopausal osteoporosis. We reviewed evidence for adverse reactions from regulatory documents, randomized controlled trials, pharmacovigilance surveys, and case series. Bisphosphonates are associated with gastrointestinal effects, musculoskeletal pain, and acute-phase reactions, as well as, very rarely, atrial fibrillation, atypical fracture, delayed fracture healing, osteonecrosis of the jaw, hypersensitivity reactions, and renal impairment. Cutaneous effects and osteonecrosis of the jaw are of concern for denosumab (both very rare), though there are no pharmacovigilance data for this agent yet. The selective estrogen receptor modulators are associated with hot flushes, leg cramps, and, very rarely, venous thromboembolism and stroke. Strontium ranelate has been linked to hypersensitivity reactions and venous thromboembolism (both very rare) and teriparatide with headache, nausea, dizziness, and limb pain. The solidity of the evidence base depends on the frequency of the reaction, and causality is not always easy to establish for the very rare adverse reactions. Drug-drug interactions are rare. Osteoporosis treatments are generally safe and well tolerated, though they are associated with a few very rare serious adverse reactions. While these are a cause for concern, the risk should be weighed against the benefits of treatment itself, i.e., the prevention of osteoporotic fracture.
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PMID:Adverse reactions and drug-drug interactions in the management of women with postmenopausal osteoporosis. 2163 97

The results of hormone therapy (HT) studies have changed the perception of HT benefits and risks. Selective estrogen receptor modulators (SERMs) represent drugs with a tissue-specific estrogen receptor agonist/antagonist activity and they are an alternative to HT. Each SERM stimulates and blocks different genes with different biological responses. Established SERMs or second generation are tamoxifen and raloxifene. Both SERMs have positive effects on breast, bone and lipids, but with an increased risk for venous thromboembolism and hot flushes. None of these SERMs has shown a preventive effect on non-vertebral fractures. At present, there is a new generation of SERMs (third generation: bazedoxifene, lasofoxifene and ospemifene) which has completed phase III clinical trials and has been submitted to the Health Regulatory Authorities for approval. A new concept, tissue selective estrogen complex (TSEC), has the potential to demonstrate the benefits of SERMs along with the additional benefits of estrogens. A long road to the ideal SERM still remains, but new SERMs represent an attractive new menopause treatment.
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PMID:Selective estrogen receptor modulators: the future in menopausal treatment. 2165 12

Bazedoxifene, a novel selective estrogen receptor modulator, has been developed to have favorable effects on bone and the lipid profile while minimizing stimulation of uterine or breast tissues. Two large Phase III clinical trials showed that bazedoxifene, as well as raloxifene, increased bone mineral density, decreased levels of bone turnover markers, and significantly reduced the risk of new vertebral fractures in postmenopausal women compared with placebo. Although the incidence of nonvertebral fractures with bazedoxifene or raloxifene did not differ significantly from that with placebo, a post hoc analysis of a subgroup of women at higher fracture risk revealed that bazedoxifene significantly reduced the nonvertebral fracture risk relative to placebo and raloxifene. Bazedoxifene also improved the lipid profile by reducing the serum concentrations of total cholesterol and low-density lipoprotein cholesterol, with an increase in the serum level of high-density lipoprotein cholesterol. The incidences of vasodilatation (hot flushes), leg cramps, and venous thromboembolic events were significantly higher with bazedoxifene and raloxifene compared with placebo. There was no evidence of endometrial and breast stimulation with bazedoxifene. Taking advantage of the favorable effects of bazedoxifene on the breast and endometrium, the pairing of bazedoxifene with conjugated estrogens is under investigation for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. A Phase III trial showed that combination therapy of bazedoxifene and conjugated estrogens significantly increased bone mineral density and decreased bone turnover markers, with relief of hot flushes and improvement of vaginal atrophy. This article reviews the clinical efficacy and safety of bazedoxifene in the treatment of postmenopausal osteoporosis.
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PMID:Efficacy and safety of bazedoxifene for postmenopausal osteoporosis. 2175 70


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