- Raloxifene Retards Cartilage Degradation and Improves Subchondral Bone Micro-architecture in Ovariectomized Rats with Patella Baja-Induced- Patellofemoral Joint Osteoarthritis. [Journal Article]
- OCOsteoarthritis Cartilage 2019 Jul 18
- CONCLUSIONS: These findings demonstrate that RAL treatment retards PFJOA progression in an ovariectomized rat model, suggesting that it may be a potential candidate for amelioration of the progression of PFJOA accompanied by postmenopausal OP.
- The association between hormones and antipsychotic use: a focus on postpartum and menopausal women. [Review]
- TATher Adv Psychopharmacol 2019; 9:2045125319859973
- During the postpartum and menopausal periods of women's lives, there is a well-established and significant drop of circulating estrogens. This may be the reason why both these periods are associated …
During the postpartum and menopausal periods of women's lives, there is a well-established and significant drop of circulating estrogens. This may be the reason why both these periods are associated with an increased risk for onset or exacerbation of psychiatric disorders. Whether symptoms are mainly affective or mainly psychotic, these disorders are frequently treated with antipsychotic medications, which calls for an examination of the relationship between hormone replacement and antipsychotic agents at these time periods. The aim of this narrative review is to summarize what is known about the association of hormones and antipsychotics in the postnatal period and at menopause. In the review, we focus on estrogen and oxytocin hormones and include, for the most part, only papers published within the last 10 years. Both estradiol and oxytocin have at various times been implicated in the etiology of postpartum disorders, and estrogens, sometimes combined with progesterone, have been tested as potential treatments for these conditions. The role of estradiol as an adjunct to antipsychotics in the prevention of postpartum relapses is currently controversial. With respect to oxytocin, studies are lacking. Psychosis in menopausal and postmenopausal women has been successfully treated with estrogens and selective estrogen-receptor modulators, mainly raloxifene, in addition to antipsychotics. Some symptoms appear to respond better than others. No oxytocin study has specifically targeted postmenopausal women. Because of feedback mechanisms, there is a theoretical danger of therapy with exogenous hormones interfering with endogenous secretion and disturbing the balance among inter-related hormones. When used with antipsychotics, hormones may also affect the metabolism and, hence, the brain level of specific antipsychotics. This makes treatment with antipsychotics plus hormones complicated. Dose, timing and route of intervention may all prove critical to efficacy. While much remains unknown, this literature review indicates that, within standard dose ranges, the combination of hormones and antipsychotics for postnatal and menopausal women suffering severe mental distress can be beneficial, and is safe.
- Effects of ospemifene on bone in postmenopausal women. [Journal Article]
- CClimacteric 2019 Jul 11; :1-6
- Ospemifene is a selective estrogen-receptor modulator approved for treating menopause-related moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy (VVA), in the United…
Ospemifene is a selective estrogen-receptor modulator approved for treating menopause-related moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy (VVA), in the United States, and for treating menopause-related, symptomatic VVA in women not appropriate for local estrogen therapy in Europe. This review summarizes the effects of ospemifene on bone, including bone biomarker data from a phase 3 vaginal dryness study. Early-phase studies of postmenopausal women showed that ospemifene dose-dependently decreased bone turnover markers versus placebo, similar to raloxifene. A 12-week, phase 3 study of ospemifene 60 mg/day in postmenopausal women showed improvements in all VVA parameters and significantly greater decreases in seven of nine bone biomarkers versus placebo. Lower bone resorption markers with ospemifene were observed regardless of time since menopause (≤5 years or >5 years) or baseline bone mineral density (BMD) (normal [n = 18], osteopenia [n = 164], or osteoporosis [n = 21]). Biomarker studies (n = 565 who took ospemifene) therefore support a potential role for ospemifene in maintaining bone health (and possibly reducing fracture risk) in postmenopausal women taking it for VVA; however, caution is warranted because data are limited to biochemical markers, rather than fracture and BMD. Although studies show that bone turnover predicts BMD and fractures, any hypothesis about a bone-sparing effect of ospemifene needs testing in rigorous, long-term, phase 3 studies monitoring fractures and BMD.
- An Approach for Using In Vitro and In Silico Data to Identify Pharmaceuticals with Potential (Anti-)Estrogenic Activity in Aquatic Vertebrates at Environmentally Relevant Concentrations. [Journal Article]
- ETEnviron Toxicol Chem 2019 Jul 10
- Endocrine-active pharmaceuticals can cause adverse reproductive and developmental effects in non-target organisms. Aquatic vertebrates may be susceptible to the effects of such pharmaceuticals given …
Endocrine-active pharmaceuticals can cause adverse reproductive and developmental effects in non-target organisms. Aquatic vertebrates may be susceptible to the effects of such pharmaceuticals given that the structure of hormone receptors and the physiology of the endocrine system are highly conserved across vertebrates. To aid in the regulatory review of the environmental impact of drugs, we demonstrate an approach to screen and support the prioritization of pharmaceuticals based on their ability to interact with estrogen receptors (ERs) at environmentally relevant concentrations. Tox21 in vitro results from ER agonist and antagonist assays were retrieved for 1,123 pharmaceuticals. In silico predictions from the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) models were used to estimate ER agonist and antagonist activity for an additional 170 pharmaceuticals not tested in the Tox21 assay platform. The "estrogenic effect ratio" (EER) and "anti-estrogenic effect ratio" (AEER) were calculated by comparing the activity concentration at half-maximal response (AC50) for ER agonism and antagonism, respectively, to estimated pharmaceutical concentrations in fish tissue based on estimates of environmental exposures. A total of 73 and 127 pharmaceuticals were identified as ER agonists and antagonists, respectively. As expected, 17β-estradiol and 17α-ethinylestradiol displayed EERs > 1, and raloxifene and bazedoxifene acetate displayed AEERs > 1, thus indicating that these pharmaceuticals have potential to reach fish tissue levels that exceed concentrations estimated to interact with ERs. Four pharmaceuticals displayed EERs between 0.1 and 1, while six displayed AEERs between 0.1 and 1. This approach may help determine the need for submission of environmental assessment data for new drug applications and support prioritization of pharmaceuticals with potential to disrupt endocrine signaling in vertebrates. This article is protected by copyright. All rights reserved.
- In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues. [Journal Article]
- JPJ Pharmacol Exp Ther 2019 Jul 09
- Tamoxifen, raloxifene, and nafoxidine are selective estrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). How these drugs interact with A…
Tamoxifen, raloxifene, and nafoxidine are selective estrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). How these drugs interact with AOX1 and whether other SERMs inhibit this drug-metabolizing enzyme are not known. Therefore, a detailed in vitro and in silico study involving parent drugs and their analogues was conducted to investigate the effect of specific SERMs, particularly acolbifene, bazedoxifene, and lasofoxifene on AOX1 catalytic activity, as assessed by carbazeran 4-oxidation, an AOX1-selective catalytic marker. The rank-order in the potency (based on IC50 values) of AOX1 inhibition by SERMs was raloxifene > bazedoxifene ~ lasofoxifene > tamoxifen > acolbifene. Inhibition of liver cytosolic AOX1 by bazedoxifene, lasofoxifene, and tamoxifen was competitive, whereas that by raloxifene was noncompetitive. Loss of 1-azepanylethyl group increased the inhibitory potency of bazedoxifene, whereas the N-oxide group decreased it. The 7-hydroxy group and the substituted pyrrolidine ring attached to the tetrahydronaphthalene structure contributed to AOX1 inhibition by lasofoxifene. These results are supported by molecular docking simulations in terms of predicted binding modes, encompassing binding orientation and efficiency, and analysis of key interactions, particularly hydrogen bonds. The extent of AOX1 inhibition by bazedoxifene was increased by estrone sulfate and estrone. In summary, SERMs differentially inhibited human AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contributed to AOX1 inhibition, whereas those of acolbifene rendered it considerably less susceptible to AOX1 inhibition. Overall, our novel biochemical findings and molecular docking analyses provide new insights into the interaction between SERMs and AOX1. SIGNIFICANCE STATEMENT: Aldehyde oxidase (AOX1) is a molybdo-flavoprotein and has emerged as a drug-metabolizing enzyme of potential therapeutic importance because drugs have been identified as AOX1 substrates. Selective estrogen receptor modulators (SERM), which are drugs used to treat and prevent various conditions, differentially inhibit AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contribute to AOX1 inhibition, whereas those of acolbifene render it considerably less susceptible to AOX1 inhibition. Our novel biochemical findings, together with molecular docking analyses, provide new insights into the differential inhibitory effect of SERMs on the catalytic activity of human AOX1, how SERMs bind to AOX1, and increase our understanding of the AOX1 pharmacophore in the inhibition of AOX1 by drugs and other chemicals.
- Reasons for Initiation and Discontinuation of Pharmacological Therapies of Osteoporosis in Veterans With Spinal Cord Injury and Disorder. [Journal Article]
- JCJ Clin Densitom 2019 Jun 15
- CONCLUSIONS: The decision to initiate pharmacological therapies in SCI/D is primarily based on osteopenia or osteoporosis at the hip by screening DXAs. Gastrointestinal side effects are the major reason for discontinuation of oral bisphosphonates. New therapies for osteoporosis in SCI/D are needed.
- BIND, a novel analytical approach for monitoring powder adhesion at the die wall with use of the surface replication method. [Journal Article]
- IJInt J Pharm 2019 Aug 15; 567:118467
- Tableting failure due to binding is often caused by powder adhesion to the die wall. The present study was undertaken to develop a novel approach for analyzing the binding characteristics of various …
Tableting failure due to binding is often caused by powder adhesion to the die wall. The present study was undertaken to develop a novel approach for analyzing the binding characteristics of various formulations and manufacturing methods, named "Binding Identification for Net Detriment" (BIND). Binding characteristics with raloxifene hydrochloride as a model preparation were evaluated by visual observation, ejection force and BIND. The surface replication method was initially employed to monitor powder adhesion to the die wall. Microscopic images with replicates were analyzed qualitatively and quantitatively. For the validation, BIND and measurement of the friction between a tablet and the die wall were performed. The qualitative data on BIND agreed with visual observations; however, there were some data discrepancies between the ejection force and visual observations. For the formulation without lubricant, BIND showed a 30.2% powder adhesion rate, while the formulation containing 1% lubricant exhibited a powder adhesion rate of 4.1%. Thus, BIND demonstrated that the use of the wet tableting method reduced powder adhesion compared with the direct tableting method. BIND allowed qualitative and quantitative analysis of powder adhesion for both powder compression and tablet ejection. BIND is a promising tool for analyzing powder adhesion to the die wall.
- Zoledronate and Raloxifene combination therapy enhances material and mechanical properties of diseased mouse bone. [Journal Article]
- BONEBone 2019 Jun 21; 127:199-206
- Current interventions to reduce skeletal fragility are insufficient at enhancing both the quantity and quality of bone when attempting to improve overall mechanical integrity. Bisphosphonates, such a…
Current interventions to reduce skeletal fragility are insufficient at enhancing both the quantity and quality of bone when attempting to improve overall mechanical integrity. Bisphosphonates, such as Zoledronate (ZOL), are used to treat a variety of bone disorders by increasing bone mass to decrease fracture risk, but long-term use has been shown in some settings to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties in a cell-independent manner by binding to collagen and increasing tissue hydration. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or both from 8 weeks to 16 weeks of age. Using the OIM model allows for investigation of therapeutic effects on a quality-based bone disease. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, which are direct measures of the tissue's ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, trabecular bone volume fraction was significantly higher with combination treatment in both genotypes. Combination treatment resulted in higher ultimate stress in both genotypes. RAL and combination treatment in OIM+/- also increased resilience compared to the control. In conclusion, this study demonstrates the beneficial effects of using combination drug treatments to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a potential method to improve bone health and combat skeletal fragility on both the microscopic and macroscopic levels.
- Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review [BOOK]
- BOOKAgency for Healthcare Research and Quality (US): Rockville (MD)
- CONCLUSIONS: Long-term alendronate, zoledronate, and oral hormone therapy reduced nonvertebral fractures in older women, with oral hormone therapy also reducing hip fractures. While absolute reductions in typical fractures with long-term bisphosphonates are large relative to increases in AFF, reduced hip fracture risk with oral hormone therapy appears offset by increased risk of serious harms. Evidence is limited regarding ODT holidays for fractures and harms. Future research is needed, including randomized trials comparing ODT holiday durations and sequential treatments powered for clinical fractures, and controlled cohort studies of ODT holidays to estimate rare harms.
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- Role of Molybdenum-Containing Enzymes in the Biotransformation of the Novel Ghrelin Receptor Inverse Agonist PF-5190457: A Reverse Translational Bed-to-Bench Approach. [Journal Article]
- DMDrug Metab Dispos 2019; 47(8):874-882
- (R)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)-1-(2-(5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl)ethan-1-one (PF-5190457) was identified as a potent and selective …
(R)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)-1-(2-(5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl)ethan-1-one (PF-5190457) was identified as a potent and selective inverse agonist of the ghrelin receptor [growth hormone secretagogue receptor 1a (GHS-R1a)]. The present translational bed-to-bench work characterizes the biotransformation of this compound in vivo and then further explores in vitro metabolism in fractions of human liver and primary hepatocytes. Following oral administration of PF-5190457 in a phase 1b clinical study, hydroxyl metabolites of the compound were observed, including one that had not been observed in previously performed human liver microsomal incubations. PF-6870961 was biosynthesized using liver cytosol, and the site of hydroxylation was shown to be on the pyrimidine using nuclear magnetic resonance spectroscopy. The aldehyde oxidase (AO) inhibitor raloxifene and the xanthine oxidase inhibitor febuxostat inhibited the formation of PF-6870961 in human liver cytosol, suggesting both enzymes were involved in the metabolism of the drug. However, greater inhibition was observed with raloxifene, indicating AO is a dominant enzyme in the biotransformation. The intrinsic clearance of the drug in human liver cytosol was estimated to be 0.002 ml/min per milligram protein. This study provides important novel information at three levels: 1) it provides additional new information on the recently developed novel compound PF-5190457, the first GHS-R1a blocker that has moved to development in humans; 2) it provides an example of a reverse translational approach where a discovery in humans was brought back, validated, and further investigated at the bench level; and 3) it demonstrates the importance of considering the molybdenum-containing oxidases during the development of new drug entities. SIGNIFICANCE STATEMENT: PF-5190457 is a novel ghrelin receptor inverse agonist that is currently undergoing clinical development for treatment of alcohol use disorder. PF-6870961, a major hydroxyl metabolite of the compound, was observed in human plasma, but was absent in human liver microsomal incubations. PF-6870961 was biosynthesized using liver cytosol, and the site of hydroxylation on the pyrimidine ring was characterized. Inhibitors of aldehyde oxidase and xanthine oxidase inhibited the formation of PF-6870961 in human liver cytosol, suggesting both enzymes were involved in the metabolism of the drug. This information is important for patient selection in subsequent clinical studies.