- Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity. [Journal Article]
- FPFront Pharmacol 2016; 7:503
- Selective estrogen receptor modulators (SERMs) are used to treat estrogen receptor (ER)-positive breast cancer and osteoporosis. Interestingly, tamoxifen and newer classes of SERMs also exhibit cytot...
Selective estrogen receptor modulators (SERMs) are used to treat estrogen receptor (ER)-positive breast cancer and osteoporosis. Interestingly, tamoxifen and newer classes of SERMs also exhibit cytotoxic effects in cancers devoid of ERs, indicating a non-estrogenic mechanism of action. Indicative of a potential ER-independent target, reports demonstrate that tamoxifen binds to cannabinoid receptors (CBRs) with affinity in the low μM range and acts as an inverse agonist. To identify cannabinoids with improved pharmacological properties relative to tamoxifen, and further investigate the use of different SERM scaffolds for future cannabinoid drug development, this study characterized the affinity and activity of SERMs in newer structural classes at CBRs. Fourteen SERMs from five structurally distinct classes were screened for binding to human CBRs. Compounds from four of five SERM classes examined bound to CBRs. Subsequent studies fully characterized CBR affinity and activity of one compound from each class. Ospemifine (a triphenylethylene) selectively bound to CB1Rs, while bazedoxifine (an indole) bound to CB2Rs with highest affinity. Nafoxidine (a tetrahydronaphthalene) and raloxifene (RAL; a benzothiaphene) bound to CB1 and CB2Rs non-selectively. All four compounds acted as inverse agonists at CB1 and CB2Rs, reducing basal G-protein activity with IC50 values in the nM to low μM range. Ospemifine, bazedoxifene and RAL also acted as inverse agonists to elevate basal intracellular cAMP levels in intact CHO-hCB2 cells. The four SERMs examined also acted as CB1 and CB2R antagonists in the cAMP assay, producing rightward shifts in the concentration-effect curve of the CBR agonist CP-55,940. In conclusion, newer classes of SERMs exhibit improved pharmacological characteristics (e.g., in CBR affinity and selectivity) relative to initial studies with tamoxifen, and thus suggest that different SERM scaffolds may be useful for development of safe and selective drugs acting via CBRs.
- Data of aromatase inhibitors alone and in combination with raloxifene on microarchitecture of lumbar vertebrae and strength test in femoral diaphysis of VCD treated ovotoxic mice. [Journal Article]
- DBData Brief 2017; 10:444-448
- Currently, the third generation aromatase inhibitors are the drugs of choice for treatment of early and advanced breast cancer in postmenopausal women. The negative impact of these drugs on bone heal...
Currently, the third generation aromatase inhibitors are the drugs of choice for treatment of early and advanced breast cancer in postmenopausal women. The negative impact of these drugs on bone health is the significant limiting factor during this therapy. Here we report the effect of two aromatase inhibitors viz. letrozole and exemestane alone and in combination with raloxifene on lumbar vertebrae and femoral diaphysis after one month of treatment but no discernible effects were observed on bone when tested by micro CT and strength test except in trabecular number which was reduced in lumbar vertebrae following letrozole and exemestane. Further studies with letrozole and exemestane should be done at higher doses for longer duration of time to check whether effects are observed in other parameters as well. The data is an extension of our published work in Mol. Cell Endocrinology (A. Kalam, S. Talegaonkar, D. Vohora, 2017)  describing letrozole-induced bone loss on femoral epiphysis and its reversal by raloxifene.
- Variability of Zaleplon 5-Oxidase Activity in Mice and Humans, and Inhibition by Raloxifene. [Journal Article]
- DMDrug Metab Lett 2016 Dec 27
- Zaleplon (ZAL) is a sedative-hypnotic agent, which is mainly metabolized to inactive 5-oxidized zaleplon (5-oxo-ZAL) and N-des-ethylated ZAL (des-ethyl-ZAL) in mice and humans. The former reaction is...
Zaleplon (ZAL) is a sedative-hypnotic agent, which is mainly metabolized to inactive 5-oxidized zaleplon (5-oxo-ZAL) and N-des-ethylated ZAL (des-ethyl-ZAL) in mice and humans. The former reaction is considered to be catalyzed by aldehyde oxidase present in liver cytosol. Here, we examined sex and strain differences of ZAL metabolism to 5-oxo-ZAL among four strains of mice, as well as the inter-individual variation in humans, in order to evaluate the variability of 5-oxo-ZAL-forming activity and its relationship with aldehyde oxidase activity. In mice, the activity in C57BL/6J strain was the highest, followed by C3H/He and BALB/c. The activity in DBA/2J was the lowest, being 2.3-fold lower than that of C57BL/6J mice. The activity of male mice was higher than that of female mice. Large inter-individual variations were observed among humans, with a range of 10-fold. Raloxifene, an inhibitor of aldehyde oxidase, markedly decreased the formation of 5-oxo-ZAL by liver cytosol of mice and humans. Further, the plasma level of 5-oxo-ZAL in mice was decreased when raloxifene was co-administered with ZAL. Our results indicate that the formation of 5-oxo-ZAL from ZAL is mainly catalyzed by aldehyde oxidase in mice and humans, and the variability of 5-oxo-ZAL formation is due primarily to differences of aldehyde oxidase activity. High inter-individual variability of ZAL 5-oxidase activity and potential for interaction of ZAL with other medicines that are inhibitors of aldehyde oxidase should be taken into consideration in clinical usage of ZAL.
- Real-world evidence of raloxifene versus alendronate in preventing non-vertebral fractures in Japanese women with osteoporosis: retrospective analysis of a hospital claims database. [Journal Article]
- JBJ Bone Miner Metab 2016 Dec 27
- We conducted a retrospective cohort study using a de-identified hospital administrative claims database to assess the risk of non-vertebral fracture in Japanese women with osteoporosis treated with r...
We conducted a retrospective cohort study using a de-identified hospital administrative claims database to assess the risk of non-vertebral fracture in Japanese women with osteoporosis treated with raloxifene compared with alendronate. The study included Japanese women ≥50 years of age with newly initiated alendronate or raloxifene treatment between July 2008 and March 2013 (index date was defined as the day of first prescription for alendronate or raloxifene), and had any claim with an osteoporosis definition during the study period. A total of 37,056 patients in the database initiated treatment, and there were 4802 and 1250 patients included in the alendronate and raloxifene analysis groups, respectively. The mean observation period in the alendronate group (529.2 days) was significantly longer than that for the raloxifene group (473.5 days, P < 0.001). Non-vertebral fractures accumulated linearly, at a similar rate, for both study drugs: incidence at 1 year was 2.83 and 2.64% for the alendronate and raloxifene groups, respectively. For the relative risk of non-vertebral fracture within 1 year, the adjusted hazard ratio was 0.933 for raloxifene versus alendronate, indicating that the relative risk of non-vertebral fracture was similar for the two drugs. The effectiveness of raloxifene in preventing non-vertebral fractures in Japanese women with osteoporosis was similar to that of alendronate. Therefore, raloxifene may be worthy of consideration as an alternative treatment.
- A case report of desmoid tumour-a forgotten aspect of FAP? [Journal Article]
- IJInt J Surg Case Rep 2016 Dec 01; 30:122-125
- CONCLUSIONS: FAP is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli (APC) gene. Gardner's syndrome is also caused by a mutation in the APC gene, and is now considered a different phenotypic presentation of FAP. Desmoid tumours are initially kept under observation while their size remains stable. Treatment options for enlarging desmoids tumours include surgery (first-line), radiotherapy, and systemic therapy with non-cytotoxic and cytotoxic therapy.FAP patients should be examined regularly post-panprocotocolectomy, since desmoid tumours may arise. The presence of epidermal cysts in this FAP patient suggests a diagnosis of Gardner's syndrome.
- The Selective Estrogen Receptor Modulator Raloxifene Inhibits Neutrophil Extracellular Trap Formation. [Journal Article]
- FIFront Immunol 2016; 7:566
- Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory...
Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effects on human neutrophils, the primary phagocytic leukocytes of the immune system, remain poorly understood. Here, through a screen of pharmacologically active small molecules, we find that raloxifene prevents neutrophil cell death in response to the classical activator phorbol 12-myristate 13-acetate (PMA), a compound known to induce formation of DNA-based neutrophil extracellular traps (NETs). Inhibition of PMA-induced NET production by raloxifene was confirmed using quantitative and imaging-based assays. Human neutrophils from both male and female donors express the nuclear estrogen receptors ERα and ERβ, known targets of raloxifene. Similar to raloxifene, selective antagonists of these receptors inhibit PMA-induced NET production. Furthermore, raloxifene inhibited PMA-induced ERK phosphorylation, but not reactive oxygen species production, pathways known to be key modulators of NET production. Finally, we found that raloxifene inhibited PMA-induced, NET-based killing of the leading human bacterial pathogen, methicillin-resistant Staphylococcus aureus. Our results reveal that raloxifene is a potent modulator of neutrophil function and NET production.
- Effects of Raloxifene on the Proliferation and Apoptosis of Human Aortic Valve Interstitial Cells. [Journal Article]
- BRBiomed Res Int 2016; 2016:5473204
- We aimed to explore the effects of raloxifene (RAL) on the proliferation and apoptosis of human aortic valve interstitial cells (AVICs). Different concentrations of RAL were used to act on AVICs. MTS...
We aimed to explore the effects of raloxifene (RAL) on the proliferation and apoptosis of human aortic valve interstitial cells (AVICs). Different concentrations of RAL were used to act on AVICs. MTS kit is used to test the effects of different concentrations of RAL on the proliferation of AVICs. Cell cycle and apoptosis test used flow cytometry after seven-day treatment. The relative expression levels of caspase-3 and caspase-8 are tested with RT-qPCR and Western blot. The results of MTS testing revealed that the absorbance value (OD value) of the cells in the concentration groups of 10 and 100 nmol/L RAL at a wavelength of 490 nm at five, seven, and nine days significantly decreased compared with that in the control group. Meanwhile, the results of flow cytometry of the cells collected after seven days showed that the ratio of the S stage and the cell apoptosis rate of AVICs can be significantly reduced by RAL in the concentration groups of 10 and 100 nmol/L. The mRNA and protein expressions of caspase-3 and caspase-8 were significantly decreased compared with those in the control group. This study laid the foundation for further treatment of aortic valve disease by using RAL.
- Raloxifene microsphere-embedded collagen/chitosan/β-tricalcium phosphate scaffold for effective bone tissue engineering. [Journal Article]
- IJInt J Pharm 2016 Dec 14; 518(1-2):80-85
- Engineering novel scaffolds that can mimic the functional extracellular matrix (ECM) would be a great achievement in bone tissue engineering. This paper reports the fabrication of novel collagen/chit...
Engineering novel scaffolds that can mimic the functional extracellular matrix (ECM) would be a great achievement in bone tissue engineering. This paper reports the fabrication of novel collagen/chitosan/β-tricalcium phosphate (CCTP) based tissue engineering scaffold. In order to improve the regeneration ability of scaffold, we have embedded raloxifene (RLX)-loaded PLGA microsphere in the CCTP scaffold. The average pore of scaffold was in the range of 150-200μm with ideal mechanical strength and swelling/degradation characteristics. The release rate of RLX from the microsphere (MS) embedded scaffold was gradual and controlled. Also a significantly enhanced cell proliferation was observed in RLX-MS exposed cell group suggesting that microsphere/scaffold could be an ideal biomaterial for bone tissue engineering. Specifically, RLX-MS showed a significantly higher Alizarin red staining indicating the higher mineralization capacity of this group. Furthermore, a high alkaline phosphatase (ALP) activity for RLX-MS exposed group after 15days incubation indicates the bone regeneration capacity of MC3T3-E1 cells. Overall, present study showed that RLX-loaded microsphere embedded scaffold has the promising potential for bone tissue engineering applications.
- Selective estrogen receptor modulators and the vitamin D analogue eldecalcitol block bone loss in male osteoporosis. [Journal Article]
- BBBiochem Biophys Res Commun 2016 Dec 11
- Rapid increases in the number of elderly people have dramatically increased the number of female and male osteoporosis patients. Osteoporosis often causes bone fragility fractures, and males exhibit ...
Rapid increases in the number of elderly people have dramatically increased the number of female and male osteoporosis patients. Osteoporosis often causes bone fragility fractures, and males exhibit particularly poor prognosis after these fractures, indicating that control of osteoporosis is crucial to maintain quality of men's lives. However, osteoporosis therapies available for men have lagged behind advances available for women. Here, we show that three selective estrogen receptor modulators (SERMs), namely, raloxifene, bazedoxifene, and tamoxifen, plus the vitamin D analogue ED71, also called eldecalcitol, completely block orchiectomy-induced, testosterone-depleted bone loss in male mice in vivo. Patients treated with hormone deprivation therapy for prostate cancer also exhibit male osteoporosis, and bone management is critical for these patients. Given that androgen replacement therapy is not an option for these patients, our results represent a novel approach potentially useful to control male osteoporosis.
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- Treatment of menopausal symptoms. New era with new options or new options for menopausal symptoms after 15 years of WHI study. [Journal Article]
- MGMinerva Ginecol 2016 Dec 14
- Menopausal symptoms include vasomotor symptoms (VMS), vulvar-vaginal atrophy, and loss of bone mass associated with an increased risk of fracture. Treatment of VMS consists of lifestyle changes, horm...
Menopausal symptoms include vasomotor symptoms (VMS), vulvar-vaginal atrophy, and loss of bone mass associated with an increased risk of fracture. Treatment of VMS consists of lifestyle changes, hormone treatment (estrogens with and without progestogens, tissue selective estrogens complex or conjugated estrogens and bazedoxifene [CE/BZA], progestogens, and tibolone), and nonhormonal treatments. Genitourinary symptoms due to vulvar-vaginal atrophy are treated with systemic and local hormones, moisturizer creams and gels, CE/BZA, and a selective estrogen receptor modulator (ospemifene). In addition to lifestyle changes, treatments for the risk of fragility fracture include calcium and vitamin D, hormone treatment, selective estrogen receptor modulators (raloxifene, BZA), bisphosphonates, strontium ranelate, denosumab, and teriparatide. This article reviews treatment options and provides treatment algorithms for women with menopausal symptoms.