- Pharmacogenetic study of the effects of raloxifene on negative symptoms of postmenopausal women with schizophrenia: A double-blind, randomized, placebo-controlled trial. [JOURNAL ARTICLE]
- Eur Neuropsychopharmacol 2016 Aug 18.
Several double-blind clinical trials have reported improvement in positive, negative and cognitive symptoms of schizophrenia with raloxifene, a selective receptor estrogen modulator. However, there are some inconsistencies in replicating findings between studies of different countries. The failure to replicate these findings may result from genetic factors that could explain some of the variability in the treatment response. However, pharmacogenetic studies exploring this topic in women with schizophrenia are lacking. We aimed to conduct an exploratory pharmacogenetic analysis of a double-blind, randomized, parallel, placebo-controlled study of 24 weeks' duration of raloxifene aiming to improve negative symptoms in postmenopausal women with schizophrenia. Four single nucleotide polymorphisms (SNPs) were studied: rs9340799, rs2234693 and rs1801132 in the Estrogen Receptor 1 (ESR1) gene, and rs1042597 in the UDP-glucuronosyltransferase 1A8 (UGT1A8) gene. Sixty-five postmenopausal women with schizophrenia (DSM-IV) were randomized to either 60mg/day adjunctive raloxifene (36 women) or adjunctive placebo (29 women). Psychopathological symptoms were assessed at baseline and at weeks 4, 12, and 24 with the Positive and Negative Syndrome Scale (PANSS). Of the four studied SNPs, the rs1042597 variant in the UGT1A8 gene was associated with a different treatment response in negative symptoms with raloxifene treatment, whereas the rs2234693 variant in the ESR1 gene was associated with a distinct response in general psychopathology. In conclusion, our study suggests that genetic variants in UGT1A8 and ESR1 genes modulate the treatment response to adding raloxifene to antipsychotic treatment in postmenopausal women with schizophrenia.
- The Potential of Gonadal Hormone Signalling Pathways as Therapeutics for Dementia. [JOURNAL ARTICLE]
- J Mol Neurosci 2016 Aug 15.
Dementia is an ever-expanding problem facing an ageing society. Currently, there is a sharp paucity of treatment strategies. It has long been known that sex hormones, namely 17β-estradiol and testosterone, possess neuroprotective- and cognitive-enhancing qualities. However, certain lacunae in the knowledge underlying their molecular mechanisms have delayed their use as treatment strategies in dementia. With recent advancements in pharmacology and molecular biology, especially in the development of safer selective oestrogen receptor modulators and the recent discovery of the small-molecule brain-derived neurotrophic factor receptor agonist, 7,8-dihydroxyflavone, the exploitation of these signalling pathways for clinical use has become possible. This review aims to adumbrate the evidence and hurdles underscoring the use of sex hormones in the treatment of dementia as well as discussing some direction that is required to advance the translation of evidence into practise.
- Comprehensive evaluation of liver microsomal cytochrome P450 3A (CYP3A) inhibition: comparison of cynomolgus monkey and human. [JOURNAL ARTICLE]
- Xenobiotica 2016 Aug 8.:1-9.
1. Members of the cytochrome P450 3A (CYP3A) subfamily metabolize numerous compounds and serve as the loci of drug-drug interactions (DDIs). Because of high amino acid sequence identity with human CYP3A, the cynomolgus monkey has been proposed as a model species to support DDI risk assessment. 2. Therefore, the objective of this study was to evaluate 35 known inhibitors of human CYP3A using human (HLM) and cynomolgus monkey (CLM) liver microsomes. Midazolam was employed as substrate to generate IC50 values (concentration of inhibitor rendering 50% inhibition) in the absence and presence of a preincubation (30 mins) with NADPH. 3. In the absence of preincubation, the IC50 values generated with CLM were similar to those obtained with HLM (86% within 2-fold; 100% within 3-fold difference). However, significant differences (up to 48-fold) in preincubation IC50 were observed with 17% of the compounds (raloxifene, bergamottin, nicardipine, mibefradil, ritonavir, and diltiazem). 4. Our results indicate that in most cases the cynomolgus monkey can be a viable DDI model. However, significant species differences in time-dependent CYP3A inhibition can be observed for some compounds. In the case of raloxifene, such a difference can be ascribed to a specific CYP3A4 amino acid residue.
- Context-specific functional module based drug efficacy prediction. [Journal Article]
- BMC Bioinformatics 2016.:275.
It is necessary to evaluate the efficacy of individual drugs on patients to realize personalized medicine. Testing drugs on patients in clinical trial is the only way to evaluate the efficacy of drugs. The approach is labour intensive and requires overwhelming costs and a number of experiments. Therefore, preclinical model system has been intensively investigated for predicting the efficacy of drugs. Current computational drug sensitivity prediction approaches use general biological network modules as their prediction features. Therefore, they miss indirect effectors or the effects from tissue-specific interactions.We developed cell line specific functional modules. Enriched scores of functional modules are utilized as cell line specific features to predict the efficacy of drugs. Cell line specific functional modules are clusters of genes, which have similar biological functions in cell line specific networks. We used linear regression for drug efficacy prediction. We assessed the prediction performance in leave-one-out cross-validation (LOOCV). Our method was compared with elastic net model, which is a popular model for drug efficacy prediction. In addition, we analysed drug sensitivity-associated functions of five drugs - lapatinib, erlotinib, raloxifene, tamoxifen and gefitinib- by our model.Our model can provide cell line specific drug efficacy prediction and also provide functions which are associated with drug sensitivity. Therefore, we could utilize drug sensitivity associated functions for drug repositioning or for suggesting secondary drugs for overcoming drug resistance.
- Should We Offer Medication to Reduce Breast Cancer Risk?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center. [Journal Article]
- Ann Intern Med 2016 Aug 2; 165(3):194-204.
In November 2013, the U.S. Preventive Services Task Force issued a guideline on medications for risk reduction of primary breast cancer in women. Although mammography can detect early cases, it cannot prevent development of breast cancer. Tamoxifen and raloxifene are selective estrogen receptor modulators that have been shown to reduce the risk for estrogen receptor-positive breast cancer and are approved by the U.S. Food and Drug Administration (FDA) for this indication. However, neither medication reduces the risk for estrogen receptor-negative breast cancer or all-cause mortality. The Task Force concluded that postmenopausal women with an estimated 5-year risk for breast cancer of 3% or greater will probably have more net benefit than harm and recommends that clinicians engage in shared, informed decision making about these medications. The American Society of Clinical Oncology issued a practice guideline on use of pharmacologic interventions for breast cancer in 2013. It recommends that women aged 35 years or older at increased risk, defined as a 5-year absolute risk for breast cancer of 1.66% or greater, discuss breast cancer prevention medications with their primary care practitioner. The Society includes the aromatase inhibitor exemestane in addition to tamoxifen and raloxifene as a breast cancer prevention medication, although exemestane is not FDA approved for this indication. Here, an oncologist and an internist discuss how they would balance these recommendations and what they would suggest for an individual patient.
- Efficacy of Osteoporosis Therapies in Diabetic Patients. [REVIEW, JOURNAL ARTICLE]
- Calcif Tissue Int 2016 Jul 26.
Diabetes is characterized by increased fracture risk and by reduced bone strength for a given density. Contributing factors may include lower bone turnover and accumulation of advanced glycation endproducts. There are concerns that the pharmacological therapies for osteoporosis, particularly anti-resorptive therapies that suppress bone turnover, may not be as effective in the setting of diabetes. This review considers clinical trials and observational studies that have assessed the efficacy of anti-resorptive and anabolic therapies in diabetic patients. Post hoc analyses of randomized trials indicate that raloxifene has similar efficacy for prevention of vertebral fractures in diabetic compared with non-diabetic patients. Evidence from randomized clinical trials is lacking for anti-fracture efficacy of other osteoporosis therapies in diabetes. However, observational studies suggest that bisphosphonates are effective in preventing fractures in diabetic patients. The great majority of diabetic patients in studies to date have been type 2, and efficacy of osteoporosis therapies in type 1 diabetic patients remains to be addressed. Further evaluation of the efficacy of osteoporosis therapies in the setting of diabetes is needed to provide optimal fracture prevention for this population.
- Effect of antiresorptive drugs in the alveolar bone healing. A histometric and immunohistochemical study in ovariectomized rats. [JOURNAL ARTICLE]
- Clin Oral Investig 2016 Jul 27.
The aim of this study is to evaluate the alendronate and raloxifene influence in the alveolar healing process of osteoporotic rats.Sixty-four female rats were divided in four groups: sham rats (SHAM), ovariectomized rats and no medical treatment (OVX NT), ovariectomized rats and submitted to alendronate treatment (OVX ALE), and ovariectomized and submitted to raloxifene treatment (OVX RAL). The histomorphometrical and immunohistochemical analysis was performed. The quantitative data were analyzed through Kruskal-Wallis and Dunn tests (α = 0.05).In the longest period, SHAM and OVX RAL groups showed the better bone formation responses (P < 0.05). The worst bone formation response was observed in the group OVX NT. OVX RAL group showed the better response at 42 days. OVX ALE group showed a favorable response at 14 days, in comparison with OVX RAL group, but a reduced response at 42 days. It was possible to observe a mature bone in SHAM group at 14 days and an immature bone in the OVX NT group. An intermediate quality bone was observed in the groups OVX ALE and OVX RAL.Alendronate and raloxifene treatment improved the alveolar healing process in osteoporotic rats, but not enough to achieve the histometrical and protein expression values that were observed in the SHAM group.Alendronate is largely used as a potent antiresorptive agent. Otherwise, considering the undesirable effects in relation to the alveolar healing, other antiosteoporosis medications should be studied. Raloxifene seems to be a good candidate once its action mechanism involves the activation of osteoblasts.
- Estrogens and Coronary Artery Disease: New Clinical Perspectives. [Journal Article]
- Adv Pharmacol 2016.:307-60.
In premenopausal women, endogenous estrogens are associated with reduced prevalence of arterial hypertension, coronary artery disease, myocardial infarction, and stroke. Clinical trials conducted in the 1990s such as HERS, WHI, and WISDOM have shown that postmenopausal treatment with horse hormone mixtures (so-called conjugated equine estrogens) and synthetic progestins adversely affects female cardiovascular health. Our understanding of rapid (nongenomic) and chronic (genomic) estrogen signaling has since advanced considerably, including identification of a new G protein-coupled estrogen receptor (GPER), which like the "classical" receptors ERα and ERβ is highly abundant in the cardiovascular system. Here, we discuss the role of estrogen receptors in the pathogenesis of coronary artery disease and review natural and synthetic ligands of estrogen receptors as well as their effects in physiology, on cardiovascular risk factors, and atherosclerotic vascular disease. Data from preclinical and clinical studies using nonselective compounds activating GPER, which include selective estrogen receptor modulators such as tamoxifen or raloxifene, selective estrogen receptor downregulators such as Faslodex™ (fulvestrant/ICI 182,780), vitamin B3 (niacin), green tea catechins, and soy flavonoids such as genistein or resveratrol, strongly suggest that activation of GPER may afford therapeutic benefit for primary and secondary prevention in patients with or at risk for coronary artery disease. Evidence from preclinical studies suggest similar efficacy profiles for selective small molecule GPER agonists such as G-1 which are devoid of uterotrophic activity. Further clinical research in this area is warranted to provide opportunities for future cardiovascular drug development.
- Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial. [JOURNAL ARTICLE]
- JAMA Psychiatry 2016 Jul 20.
A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects.To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia.This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis.Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks.The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed.Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24  years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups.Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice.clinicaltrials.gov Identifier: NCT00361543.
- Anti-Estrogen Withdrawal Effect With Raloxifene? A Case Report. [Journal Article]
- Integr Cancer Ther 2016 Sep; 15(3):245-9.
A 66-year-old patient presented with acute recurrent metastatic estrogen and progesterone receptor-positive, Her-2/neu-negative breast cancer, bone lesions (lumbar spine, pelvis), pulmonary nodules, hepatic metastasis, elevated cancer antigen 15 and liver enzymes, dyspepsia, and diarrhea. The patient had been taking raloxifene for approximately 8 years. After discontinuation, clinical parameters and symptoms improved rapidly without oncological therapy or other forms of treatment. Three months after raloxifene discontinuation, capecitabine was initiated by the treating oncologist who deemed an anti-estrogen withdrawal effect (AEWE) implausible. However, the lasting regression was more indicative of a raloxifene rebound effect than chemotherapy or other interventions. Today, the patient is asymptomatic with a good performance status. Hepatic metastatic regression has been confirmed, without any oncological treatment administered in the past 16 months and approximately 23 months following the withdrawal of raloxifene. This case highlights the need to screen breast cancer patients for the possibility of an AEWE if they are using raloxifene and possibly similar selective estrogen receptor modulators (SERMs) which includes tamoxifen, when diagnosed with advanced breast cancer, especially in the recurrent disease setting.