Advanced searches left 3/3
Search only database of 7.4 mil and more summaries

Levormeloxifene

Summarized by PlexPage
Last Updated: 12 December 2020

* If you want to update the article please login/register

General | Latest Info

Levormeloxifene

Chemical and physical data
3D model ( JSmol )Interactive image
FormulaC 30 H 35 N O 3
Molar mass457.614 gmol 1
Clinical data
Other namesLevomeloxifene; 6720-CDRI; NNC-460020
Identifiers
CAS Number31477-60-8 N
ChEMBLChEMBL301327 Y
ChemSpider32935 Y
CompTox Dashboard ( EPA )DTXSID6046844
PubChem CID35805
UNII9512UKZ352

ESTROGEN replacement therapy is effective in preventing postmenopausal bone loss and osteoporotic fracture and in alleviating climacteric complaints, such as hot flushes and vaginal dryness. Furthermore, HRT seems to reduce the risk of coronary heart disease by changing lipoprotein subfractions in a favorable way. However, due to side-effects such as vaginal bleeding and breast tenderness, compliance with long-term use of HRT is poor. Compliance is also affected by apprehensions regarding the risk of breast cancer. In the search for drug that possess beneficial actions of ESTROGEN on bone mass and cardiovascular system, but not its undesirable effects, number of compounds with both estrogenic and antiestrogenic effects have been evaluated over the last few years. Centchroman, ESTROGEN antagonist widely used in India since 1980 as an anti-fertility agent, has been shown to prevent bone loss in animal studies. As Centchroman is a racemic mixture, investigations were undertaken to examine whether the bone-preserving effect was confined to one of the enantiomers. It was found to reside in l-enantiomer of compound, named Levormeloxifene. Furthermore, Centchroman is being developed for the treatment of advanced breast cancer. The chemical name of Levormeloxifene is-3 4-trans-7methoxy-2 2-dimethyl-3phenyl-4 {4-phenyl} Chromane. Like raloxifene, Levormeloxifene is a selective ESTROGEN receptor modulator. Raloxifene is approved for the prevention and treatment of osteoporosis. Without stimulating endometrium, raloxifene increases bone density in postmenopausal women, decreases bone turnover, lowers serum total and low density lipoprotein cholesterol, and reduces the incidence of fracture and breast cancer in osteoporotic women. According to nonclinical pharmacology, Levormeloxifene seems to possess the same desire estrogenic effect on the skeleton and cardiovascular system without inducing endometrial hyperplasia. We present here results of Phase II, 12-month interim analysis of a 2-yr multicenter, double-blind, placebocontrolled study of the effect of Levormeloxifene on bone mineral density, biochemical bone markers, lipid profile, and endometrial safety in 301 postmenopausal women. Three hundred and one healthy women between 45 and 65 yr of age and at least 1 yr postmenopausal were randomly assigned to 12-month double-blind therapy with Levormeloxifene, low dose continuous combine HORMONE replacement therapy, or placebo. All of the women were also given daily supplement of calcium. Serum CrossLaps decreased by about 50 % in the Levormeloxifene groups, with no dose-response effect. The group receiving HRT decreased more, and the placebo group decreased by about 10 %. The pattern was similar for bone alkaline phosphatase, except that decreases were smaller, about 30 % for the Levormeloxifene groups and 50 % for the HRT group. Serum osteocalcin also showed highly significant decreases, of the same magnitude in Levormeloxifene and HRT groups. Spinal bone mineral density decreased by less than 1 % in the placebo group and increased by about 2 % in the Levormeloxifene groups and by almost 5 % in the HRT group. BMD of total hip and total body change in the same direction, although differences between groups were not as pronounced as those for BMD spine.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Subjects and Methods

Here, we report the effects of estrogen and selective estrogen receptor modulator levormeloxifene on adrenocortical measures in ovariectomized female cynomolgus monkeys. Animals were randomized into one of five treatment groups, each containing 23 to 26 animals: placebo, 0. 016 mg / kg 17-estradiol, 0. 5 mg / kg levormeloxifene, 1. 0 mg / kg levormeloxifene, and 5. 0 mg / kg levormeloxifene. Treatments were administered orally each day for 18 mo. All doses of levormeloxifene result in adrenal weights at least 50 % greater than placebo. The Target dose of levormeloxifene results in higher serum concentrations of cortisol, dehydroepiandrosterone-sulfate, and androstenedione compared with the placebo group. In contrast, E 2 results in no significant differences in adrenal weight or adrenocortical steroids. Oral E 2 and all SERM doses result in similar reductions in serum gonadotropins and at least threefold greater uterine weight versus placebo. Results indicate that SERM levormeloxifene, in contrast to E 2, may have robust stimulatory effects on adrenocortical hormones in postmenopausal model. These findings warrant further investigation into long-term SERM effects on adrenocortical function. Adrenocortical hormones influence a variety of chronic diseases in postmenopausal women. For example, age-associate declines in adrenal-derive androgens have been associated with increased risk of osteoporosis, loss of muscle mass and libido, depression, and cognitive decline, while elevated concentrations of circulating cortisol have been implicated in decreased cognitive function and metabolic dysfunction, including insulin resistance and type 2 diabetes. Despite these observations, determinants of adrenocortical hormone production in postmenopausal women are poorly understood. Selective estrogen receptor modulators are nonsteroidal agents that bind estrogen receptors and elicit tissue-specific estrogen agonist and antagonist effects. This versatile class of compounds includes tamoxifen and raloxifene, which are important endocrine therapies and preventive agents for ER-positive breast cancers. Raloxifene and newer generation SERMs also have ER agonist activity in the bone and are widely used clinically for prevention of osteoporosis in postmenopausal women. Apart from these beneficial applications, SERMs elicit a range of secondary, nontarget effects, including modulation of endocrine hormones. Long-term effects of SERMs on adrenocortical activity are unclear, however, particularly in postmenopausal women. Levormeloxifene is a benzopyran SERM previously under development for prevention and treatment of postmenopausal osteoporosis but discontinued because of high incidence of adverse events in the reproductive tract. Endocrine-related effects of levormeloxifene are poorly document. The primary goal of this study was to evaluate adrenocortical effects of this SERM in comparison to oral micronized estradiol in postmenopausal primate model.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Discussion

The Beneficial effect of estrogen and HT on bone turnover and serum lipids is well established 34-36. However, several recent largescale randomized trials have failed to show beneficial effect of HT on cardiovascular risk 36 37. Longterm HT furthermore increases the risk of breast cancer 37. There is therefore still request for development of pharmaceutical agents that retain the desired effects of estrogens, but have no inherent undesired estrogenic side effects. Levormeloxifene was developed by Danish pharmaceutical company Novo Nordisk. Initial clinical trials were promising and showed that levormeloxifene had a considerable greater effect on bone turnover and serum lipids than raloxifene 1 13. In addition, other studies had shown that women with the greatest effect on BMD also revealed the most beneficial effects on lipid metabolism 38. Development of levormeloxifene was, however, discontinued in September 1999 due to increased incidence of adverse events related to endometrium 14 17. The present review of previous study results indicates that occurrence of gynecologic adverse events late in development of levormeloxifene was not unexpected. The minimum effective dose for prevention of bone loss was never established before taking the drug in phase III trials 10 12. In the phase II trial, lasting only 3 months, doseresponse relationship was observed in bone markers at dose 0. 25-1. 25 mg / day, whereas no doserelated effect on bone loss was observed for higher doses 9. Levormeloxifene 0. 5 and 1. 25 mg / day was thus chosen for the phase III trial in hope that doserelated effect in bone turnover markers reflect similar pattern in terms of prevention of bone loss. There was a stimulatory effect on the uterus in all preclinical trials, which should have infer specific focus on the genital system in clinical trials. However, detailed baseline evaluation and followup measurements of the female reproductive system in all participants were unfortunately not performed uniformly throughout study and followup periods, hampering evaluation of gynecologic adverse effects 14 17 39. The relationship between increased uterine weight, increased frequency of uterine prolapse, and urinary incontinence is thus plausible. However, study weaknesses preclude conclusion on causal associations between these side effects. It is furthermore unclear whether treatment groups were comparable at baseline in terms of confounding factors such as parity, obesity, cigarette smoking, and other risk factors for pelvic organ prolapse. There were no systematic diagnostic criteria for diagnosis of uterine prolapse, which introduced the possibility of discrepancy in assessment of pelvic organ prolapse at baseline and during study. Kinetic studies of levormeloxifene have shown slow elimination of the drug-up to 8 days in postmenopausal women-indicating significant accumulation of drug during daily administration, especially in uterus 40 41. Results suggest possible appearance of longterm side effects in this organ and also suggest why adverse events related to uterus were not detected in shortterm phase I trials that only lasted up to 8 weeks 9.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Anti-catabolic Bone Agents

SERMs are a specific type of ER-binding estrogen that has selective effects on target tissues. Present studies support that SERMs have more consistent beneficial effect on bone tissue, and therefore some have been approved for treatment of osteoporosis, such as lasofoxifene and bazedoxifene in Europe and the USA. Subsequent studies have found that SERMs also have a beneficial role in other joint tissues, thus maintaining joint health as a whole. Compared with the controversial effects of estrogen administration on OA, SERMs have more stable and favorable effects on OA. Basic research has shown that SERMs inhibit destruction of articular cartilage and subchondral bone, delaying OA progression. Meanwhile, SERMs have anti-inflammatory effect and prevent OA-like joint degeneration as a whole. Intraarticular administration of tamoxifen was shown to reduce cartilage damage and antagonize chondrodestructive effects of high-dose estradiol in different rabbit OA models. Tamoxifen played a protective effect on articular cartilage in intact male rabbits, suggesting that its therapeutic effect might not only be associated with its anti-estrogenic role. Furthermore, both levormeloxifene and cis-3 4-7hydroxy-3phenyl-4chromane suppress OVX-induced acceleration of bone and cartilage turnover and ameliorated destruction of cartilage in female rats. Andersson et al. Find recently that anti-osteoporotic drugs lasofoxifene and bazedoxifene ameliorate cartilage and bone lesions and histologic grade of synovitis, indicating that they are potent inhibitors of joint inflammation and destruction of cartilage and bone in experimental Arthritis. Similarly, Saito et al. Find that bazedoxifene inhibits OVX-induced deterioration of structural properties of vertebral cancellous bone in monkeys and improves bone strength. The Consistent effect of SERMs in vivo indicates a protective effect on chondrocytes. Kavas et al. Report that 1 M of raloxifene reduced expression of OA-relate genes, apoptosis, and extracellular matrix-degrading enzymes, and increased extracellular matrix deposition and improved mechanical properties in rat articular chondrocytes with OA-like degeneration. However, these effects were reversed with increased dose, demonstrating that low-dose raloxifene has potential to cease or decrease cartilage degeneration in OA. In cultured human chondrocytes, when raloxifene and IL-1 were coincubated in culture medium, proteoglycans were significantly and dose-dependently augment, and matrix metalloproteinase-3 and nitric oxide levels were significantly decrease, demonstrating that raloxifene antagonize IL-1induced OA-like chondrocyte changes. In another study, natural SERM genistein antagonize lipopolysaccharide-induced OA-like chondrocyte changes with a significant decrease of COX-2 protein and NO level in supernatant of cultured human chondrocytes, indicating that genistein may maintain joint health through anti-inflammatory effect. SERMs appear to have protective effects on joint tissues. SERMs regulate metabolism of articular cartilage and subchondral bone, maintain their normal biomechanical structure and performance, and possibly delay disease progression of OA. In addition, SERMs may have a potential analgesic effect on OA. Moreover, SERMs may play protective roles on synovium and other joint tissues, maintaining joint health as a whole. In Health, Aging and Body Composition Study cohort, raloxifene significantly reduced subchondral bone attrition, bone marrow edema-like abnormalities, and knee pain according to Western Ontario and McMaster Universities Arthritis Index scores when compared with the control group.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Synopsis

There are currently 2 main chemical classes of SERMS approved for clinical use: first-generation triphenylethylene derivatives, tamoxifen and toremifene, which are used in treatment and in case of tamoxifen in prevention of breast cancer; and Raloxifene, second-generation benzothiopene derivative indicated for treatment and prevention of Osteoporosis and reduction of breast cancer incidence in high risk post-menopausal women. All 3 compounds also have beneficial effects on serum lipids, but are still associated with adverse effects such as hot flushes and increase in risk of venous thromboembolism. Raloxifene is the only SERM compound approved worldwide for prevention and treatment of postmenopausal Osteoporosis and fragility fractures. The Pivotal registration MORE trial was a multicentered, randomize, blind, placebo-control trial that included 7705 women aged 31-80 years from 25 countries. Results of the trial show significantly reduced vertebral fractures in the Raloxifene group. Raloxifene does not significantly reduce nonvertebral fractures at either 60 or 120 mg / day. BMD increased by 0. 4 to 1. 20 % at lumbar spine; these effects have been documented for at least 7 years in the CORE trial. All participants receive 500 mg of calcium and 400-600 IU of vitamin D each day, in addition to study treatments. It is also important to stress that continuous treatment with Raloxifene effectively controls the development of breast cancer. Raloxifene lacks estrogenic activity in the uterus and has not demonstrated tamoxifen-like effects on the uterus either histopathologically or ultrasonographically, but it has been associated with adverse effects such as VTE and vasomotor symptoms, including hot flushes. In addition, both preclinical and clinical reports suggest that these ER agonists are considerably less potent than Estrogen for treatment of Osteoporosis. The goal, therefore, is to create Designer Estrogen and enhance the value of new multifunctional medicines. Newer generation SERMS being investigated for prevention and treatment of Osteoporosis in postmenopausal women include ospemifene, lasofoxifene, bazedoxifene, and Arzoxifene which are in Phase III clinical trials or have undergone regulatory review. Other SERMS have had clinical trials suspended prematurely: levormeloxifene, for causing urinary incontinence and uterine prolapse, and idoxifene, for producing increased endometrial thickness on ultrasonography but without significant histologic abnormalities. The Four SERMS we will consider in detail have all achieved significant clinical evaluation. Some have moved forward to be approved in some countries, others have not been advance. It is, however, important from a drug development perspective to state the idea for each structure was improvement on the original discovery of CORE structure, in some cases, 50 years ago. Links with original pharmacologic discoveries are illustrated in Fig., But the goal is to find the ideal SERM. Ospemifene is direct result of discovery of weak anti-estrogenic Metabolite of tamoxifen Metabolite Y, formed by demethylation, and deamination to glycol side chain. An analogous metabolite was found for toremifene and became ospemifene. Unlike tamoxifen, toremifine is not rat hepatocarcinogen so ospemifene would be safer SERM.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

a. Arzoxifene

A wide variety of molecules interact with estrogen receptors. The central conceptual difference between these agents and 17-estradiol is that these agents may replicate estradiol action, to greater or lesser degree in some tissues while, to greater or lesser degree, having no effect or even blocking estrogen action in other tissues. This chapter reviews data on these agents, focusing on those agents that are currently considered to have effect on the skeletal system. We first review mechanism of action of selective estrogen receptor modulators and phytoestrogens, followed by discussion of indications, benefits, and risks of individual agents. The most potent and mechanistically best understood of these compounds are SERMS developed by pharmaceutical companies in recent years. These compounds have been primarily selected for their beneficial effects in postmenopausal osteoporosis and breast cancer; however, some data support their use in prostate cancer. Compounds currently available for clinical use include raloxifene, tamoxifen, and toremifene, although others, such as bazedoxifene and arzoxifene, are in development. Although there are some similarities in compounds, there are significant biological differences, some of which are clinically significant as demonstrated by the fact that some SERMS developed for osteoporosis may have adverse effects on the pelvic floor, and thus be unsuitable for human use. Such concerns result in levormeloxifene research being discontinued in phase III clinical trials. Although there is a long history of development of effective pharmaceuticals from plant products, including such important compounds as digoxin, atropine, cocaine, morphine, and salicylic acid, promise of effective plant-derive estrogenic molecules for treatment of disorders of skeleton has not been realize. Nevertheless, there are a substantial number of studies of phytoestrogen effects on bone and mineral systems, including cellular studies and in vivo studies in animals and both observational studies and control clinical trials in humans. Thus, subject still merits discussion.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

logo

Plex.page is an Online Knowledge, where all the summarized are written by a machine. We aim to collect all the knowledge the World Wide Web has to offer.

Partners:
Nvidia inception logo
jooble logo

© All rights reserved
2021 made by Algoritmi Vision Inc.

If your domain is listed as one of the sources on any summary, you can consider participating in the "Online Knowledge" program, if you want to proceed, please follow these instructions to apply.
However, if you still want us to remove all links leading to your domain from Plex.page and never use your website as a source, please follow these instructions.