Pharmacological insights on novel oral selective estrogen receptor degraders in breast cancer.

The therapeutic landscape of estrogen receptor (ER)-positive breast cancer includes endocrine treatments with aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs). Fulvestrant is the first approved SERD with proven efficacy and good tolerability in clinical practice. However, drug resistance, low receptor affinity, and parental administration stimulated the search for new oral SERDs opening a new therapeutic era in ER + breast cancer. Elacestrant is an orally bioavailable SERD that has been recently approved by the FDA for postmenopausal women with ER+, human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Other molecules of the same class currently tested in clinical trials are amcenestrant, giredestrant, camizestrant, and imlunestrant. The current review article offers a detailed pharmacological perspective of this emerging drug class, which may help with their possible future clinical applications.

Selective estrogen receptor modulators (SERMs) with vitamin D composite agent can prevent fracture better than SERMs treatment: based on the National Health Claims Database 2017-2019.

With the analysis of nationwide health claim data, treatment with the composite agent of SERMs and vitamin D reduces the risk of osteoporotic fracture and hip fracture better compared to SERMs treatment in women with osteoporosis aged ≥ 50 years. PURPOSE: This study compared the potential of the composite agent of selective estrogen receptor modulators (SERMs) and vitamin D (SERM + VitD) with that of SERMs-only for fracture prevention and mortality reduction in women aged ≥ 50 years. METHODS: The incidence of osteoporotic fracture (fractures of the vertebrae, hip, wrist, or humerus) and all-cause death after treatment with SERM + VitD and SERMs were characterized using the Korean National Health Insurance Service database 2017-2019. The participants were divided into two groups (SERM + VitD vs SERMs). After exclusion and propensity score matching, 2,885 patients from each group were included in the analysis. Fracture incidence was compared between groups. Kaplan-Meier curves were used to compare mortality. Cox proportional hazards regression analysis was used to compare the risks of fracture occurrence and mortality between the groups. RESULTS: The incidence rate (138.6/10,000 vs. 192.4/10,000 person-years), and risk of osteoporotic fractures (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61-0.97; p = 0.024) were lower in the SERM + VitD group than in the SERMs group. Analysis for specific fractures showed a lower hazard of hip fracture in the SERM + VitD group (HR, 0.25; 95% CI, 0.09-0.71; p = 0.009). No difference was observed between the groups regarding mortality. CONCLUSION: The risk of osteoporotic fractures, especially hip fractures, was lower in the SERM + VitD group than in the SERMs group. Therefore, the composite agent of SERMs and vitamin D can be considered as a viable option for postmenopausal women with a relatively low fracture risk.

Potential role of Fbxo22 in resistance to endocrine therapy in breast cancer with invasive lobular carcinoma.

BACKGROUND: Invasive lobular carcinoma (ILC) is distinct from invasive ductal carcinoma (IDC) in terms of their hormonal microenvironments that may require different therapeutic strategies. We previously reported that selective estrogen receptor modulator (SERM) function requires F-box protein 22 (Fbxo22). Here, we investigated the role of Fbxo22 as a potential biomarker contributing to the resistance to endocrine therapy in ILC. METHODS: A total of 302 breast cancer (BC) patients including 150 ILC were recruited in the study. Fbxo22 expression and clinical information were analyzed to elucidate whether Fbxo22 negativity could be a prognostic factor or there were any correlations among clinical variables and SERM efficacy. RESULTS: Fbxo22 negativity was significantly higher in ILC compared with IDC (58.0% vs. 27.0%, P < 0.001) and higher in postmenopausal patients than premenopausal patients (64.1% vs. 48.2%, P = 0.041). In the ILC cohort, Fbxo22-negative patients had poorer overall survival (OS) than Fbxo22-positive patients, with 10-year OS rates of 77.4% vs. 93.6% (P = 0.055). All patients treated with SERMs, Fbxo22 negativity resulted in a poorer outcome, with 10-year OS rates of 81.3% vs. 92.3% (P = 0.032). In multivariate analysis regarding recurrence-free survival (RFS) in ILC patients, Fbxo22 status was independently predictive of survival as well as lymph node metastasis. CONCLUSION: Fbxo22 negativity significantly impacts on survival in BC patients with IDC and ILC, and the disadvantage was enhanced among ILC postmenopausal women or patients treated with SERMs. The findings suggest that different therapeutic strategies might be needed according to the different histopathological types when considering adjuvant endocrine therapy.

Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Colorectal cancer (CRC) belongs to the category of intestinal wind, anal ulcer, abdominal mass and other diseases in traditional Chinese medicine (TCM). Floris Sophorae Powder (F.S), is a classical prescription is recorded in Puji Benshi Fang for the treatment of intestinal carbuncle. It has been incorporated into the prescriptions for the treatment of intestinal diseases and achieved remarkable results in modern medicine. However, the mechanism of F.S in the treatment of colorectal cancer remains unclear and requires further study. AIM OF THE STUDY: To investigate F.S in treating CRC and clarify the underlying mechanism. MATERIALS AND METHODS: This study was based on Dextran Sulfate Sodium Salt (DSS) combined with Azoxymethane (AOM) induced CRC mouse model to clarify the pharmacological effects of F.S. The serum metabolomics was used to study the mechanism of action, and the chemical composition of F.S was found by UPLC-Q-TOF-MS. The rationality of serm metabolomics results was verified through the clinical target database of network pharmacology, and the upstream and downstream targets of related pathways were found. The mechanism pathway was verified by Western blot to clarify its mechanism of action. RESULTS: In vivo pharmacological experiments showed that F.S inhibited tumor growth and improved hematochezia. The vital signs of mice in the high-dose F.S group approached to those in the control group. A total of 43 differential metabolites were found to be significantly changed by serum metabolomics. F.S could modulate and recover most of the differential metabolites, which proved to be closely related to the KRAS/MEK-ERK signaling pathway. A total of 46 compounds in F.S were identified, and the rationality of serm metabolic pathway was verified by network pharmacology. Western blot results also verified that the expression of KRAS, E2F1, p-MEK and p-ERK were significantly decreased after F.S treatment. CONCLUSION: Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.

Factors associated with adherence to medications for lowering breast cancer risk between female Medicare beneficiaries in Alabama and nationwide.

PURPOSE: The U.S. Preventive Services Task Force recommends use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) for breast cancer (BC) prevention. We examined factors associated with adherence to SERMs/AI treatments among female Medicare beneficiaries in Alabama and those nationwide. METHODS: This retrospective new user cohort study analyzed the 2013-2016 Medicare administrative claims data files (100% Alabama and random 5% national samples). Female Medicare beneficiaries without invasive BC and osteoporosis, continuously enrolled in Medicare Parts A, B, and D for at least 18 months (with a 6-month washout and a 12-month follow-up period) in 2013-2016. Among beneficiaries who initiated (6-month washout) any of the SERMs/AIs (tamoxifen, raloxifene, anastrozole, and exemestane), we examined their 1-year treatment adherence using proportion of days covered (PDC) and operationalized as both continuous (0-1) and dichotomized (≥ 80% as adherent and < 80% as non-adherent) outcomes. Multivariable logistic models were used to identify factors associated with adherence (PDC ≥ 80%) among Alabama and national samples, respectively. RESULTS: A total of 885 women in Alabama and 1,213 women in national sample initiated these SERMs/AI treatments. Among those with ≥ 2 prescriptions (n = 479 in Alabama and n = 870 in national sample), Mean PDC was 0.74 [standard deviation (SD) = 0.30] among Alabamian women, similar to those in the national sample [0.71 (SD = 0.31), p = 0.09]. Use of mammography prior to treatment initiation was associated with higher likelihood of adherence to treatments in both samples. CONCLUSION: Our findings highlight the importance of access to preventive services such as mammography to better adherence to BC preventive treatments among female Medicare beneficiaries.

Comparing Breast Cancer and Cardiovascular Disease Risk and Use of Chemoprevention and Statins among Women with High-risk Breast Lesions.

Breast cancer chemoprevention with selective estrogen receptor modulators (SERM) or aromatase inhibitors (AI) remains underutilized among high-risk women. A potential barrier to chemoprevention is competing comorbidities such as atherosclerotic cardiovascular disease (ASCVD), due to concern for additional medication side effects. We conducted a retrospective cohort study among women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), an important target population for chemoprevention. We compared risks for breast cancer and ASCVD, as well as use of SERMs/AIs versus statins among high-risk women (defined as a 5-year invasive breast cancer risk ≥1.67% and 10-year ASCVD risk ≥7.5%, respectively). We used clinical data extracted from the electronic health record to calculate breast cancer risk according to the Breast Cancer Surveillance Consortium model and ASCVD risk according to the 2013 American College of Cardiology/American Heart Association risk calculator. Among 298 evaluable women, mean age was 58.2 years (SD, 8.34), with 33% non-Hispanic White, 41% Hispanic, 9% non-Hispanic Black, 6% Asian, and 11% other/unknown race/ethnicity. About 98% of women met high-risk criteria for breast cancer, whereas 30% were high-risk for ASCVD. Mean 10-year risk of breast cancer was higher than mean 10-year risk of ASCVD (9.14% vs. 6.69%; P < 0.001). Among women who met high-risk criteria for both diseases, use of statins was higher compared with SERMs/AIs (58% vs. 21%; P < 0.001). Among women with AH or LCIS, statin use was higher compared with breast cancer chemoprevention among eligible women, despite having a higher mean risk of breast cancer than ASCVD. PREVENTION RELEVANCE: Among women with high-risk breast lesions, mean absolute risk of breast cancer was higher compared with cardiovascular disease; however, statin use was significantly higher than chemoprevention. To address underutilization of breast cancer chemoprevention, these drugs should be placed in the context of medications used to prevent other chronic diseases.

Research progress on tamoxifen and its analogs associated with nuclear receptors.

Tamoxifen, a triphenylethylene-based selective estrogen-receptor modulator, is a landmark drug for the treatment of breast cancer and is also used for treating liver cancer and osteoporosis. Structural studies of tamoxifen have led to the synthesis of more than 20 novel tamoxifen analogs as receptor modulators, including 16 ERα modulators 2-17, an ERRß inverse agonist 19 and six ERRγ inverse agonists 20-25. This paper summarizes the research progress and structure-activity relationships of tamoxifen analogs modulating these three nuclear receptors reported in the literature, and introduces the relationship between these three nuclear receptor-mediated diseases and tamoxifen analogs to guide the research of novel tamoxifen analogs.

Osteoporosis Associated with Breast Cancer Treatments Based on Types of Hormonal Therapy: A Cross-Sectional Study Using Korean National Sample Data.

Background and Objectives: This study aimed to investigate osteoporosis-related treatments and the overall anticancer drug treatment tendencies, with a focus on selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), in Korean patients with breast cancer from 2010 to 2019. Materials and Methods: Data were obtained from the Health Insurance Review and Assessment Service. Patients with breast cancer (International Classification of Diseases, 10th Revision code: C50) as a principal diagnosis at least once from 2010 to 2019 were included. Those with osteoporosis (M80, M81, or M82) as a principal or sub-diagnosis or those who received osteoporosis treatment at least once were categorized as the osteoporosis-related treatment group, and others as the non-osteoporosis-related treatment group. The trends of drug prescriptions and treatment costs in patient groups were evaluated using descriptive statistics. Results: Among all included patients, those aged 45-54 years (40.20%) without osteoporosis treatment and those aged 55-64 years (34.11%) with osteoporosis treatment were the most common. SERM was the most commonly prescribed anticancer drug (29.20%) in the entire patient group, followed by AIs (20.83%). Patients without osteoporosis treatment had the highest prescription rate of SERM (31.48%), and those with osteoporosis treatment had a higher prescription rate of AIs (34.28%). Additionally, SERM and AIs were prescribed most frequently before and after the age of 55 years, respectively, regardless of the presence of treatment. Conclusions: This study found that osteoporosis-related treatment and patient age were associated with anticancer drug prescriptions. The present findings would help clinicians and researchers in the clinical diagnosis and treatment of breast cancer.

Comparative safety of conjugated estrogens/bazedoxifene versus estrogen/progestin combination hormone therapy among women in the United States: a multidatabase cohort study.

OBJECTIVE: To assess the risk of select safety outcomes including endometrial cancer, endometrial hyperplasia, and breast cancer among women using conjugated estrogens/bazedoxifene (CE/BZA) as compared with estrogen/progestin combination hormone therapy (EP). METHODS: We conducted a new-user cohort study in five US healthcare claims databases representing more than 92 million women. We included CE/BZA or EP new users from May 1, 2014, to August 30, 2019. EP users were propensity score (PS) matched to users of CE/BZA. Incidence of endometrial cancer, endometrial hyperplasia, breast cancer, and eight additional cancer and cardiovascular outcomes were ascertained using claims-based algorithms. Rate ratios (RR) and differences pooled across databases were estimated using random-effects models. RESULTS: The study population included 10,596 CE/BZA and 33,818 PS-matched EP new users. Rates of endometrial cancer and endometrial hyperplasia were slightly higher among CE/BZA users (1.6 and 0.4 additional cases per 10,000 person-years), although precision was limited because of small numbers of cases (endometrial cancer: RR, 1.50 [95% confidence interval {CI}, 0.79-2.88]; endometrial hyperplasia: RR, 1.69 [95% CI, 0.51-5.61]). Breast cancer incidence was lower in CE/BZA users (9.1 fewer cases per 10,000 person-years; RR, 0.79; 95% CI, 0.58-1.05). Rates of other outcomes were slightly higher among CE/BZA users, but with confidence intervals compatible with a wider range of possible associations. CONCLUSIONS: CE/BZA users might experience slightly higher rates of endometrial cancer and endometrial hyperplasia, and a lower rate of breast cancer, than EP users in the first years of use.

Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges.

Estrogen receptor alpha (ERα) is a well-established therapeutic target for the treatment of ER-positive (ER+) breast cancers. Despite the tremendous successes achieved with tamoxifen, a selective ER modulator, and aromatase inhibitors (AIs), resistance to these therapies is a major clinical problem. Therefore, induced protein degradation and covalent inhibition have been pursued as new therapeutic approaches to target ERα. This Perspective summarizes recent progress in the discovery and development of oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), and proteolysis targeting chimera (PROTAC) ER degraders. We focus on those compounds which have been advanced into clinical development.

Role of Estrogen and Estrogen Receptor in GH-Secreting Adenomas.

Acromegaly is a rare disease with several systemic complications that may lead to increased overall morbidity and mortality. Despite several available treatments, ranging from transsphenoidal resection of GH-producing adenomas to different medical therapies, complete hormonal control is not achieved in some cases. Some decades ago, estrogens were first used to treat acromegaly, resulting in a significant decrease in IGF1 levels. However, due to the consequent side effects of the high dose utilized, this treatment was later abandoned. The evidence that estrogens are able to blunt GH activity also derives from the evidence that women with GH deficiency taking oral estro-progestins pills need higher doses of GH replacement therapy. In recent years, the role of estrogens and Selective Estrogens Receptor Modulators (SERMs) in acromegaly treatment has been re-evaluated, especially considering poor control of the disease under first- and second-line medical treatment. In this review, we analyze the state of the art concerning the impact of estrogen and SERMs on the GH/IGF1 axis, focusing on molecular pathways and the possible implications for acromegaly treatment.

[Research Progress in the Role of Tamoxifen in Nervous System and Cognitive Function].

Neurological diseases include a variety of neurodegenerative diseases and other brain damage diseases.The treatment schemes for neurological diseases are still in research.The existing clinical and basic studies have confirmed that traditional estrogen therapy has certain protective effect on the nervous system,while it increases the risk of breast or endometrial cancer.The emergence of the selective estrogen receptor modulators (SERMs) can avoid the above mentioned problems.The available studies have confirmed the protective effect of tamoxifen as a SERM on the nervous system.This paper reviews the role and functioning mechanisms of tamoxifen in the nervous system and cognitive function,aiming to provide guidance for the future application of tamoxifen in the treatment of neurological diseases and the improvement of cognitive function.

Selective Estrogen receptor degraders (SERDs) for the treatment of breast cancer: An overview.

Discovery of SERDs has changed the direction of anticancer research, as more than 70% of breast cancer cases are estrogen receptor positive (ER+). Therapies such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI's) have been effective, but due to endocrine resistance, SERDs are now considered essential therapeutics for the treatment of ER+ breast cancer. The present review deliberates the pathophysiology of SERDs from the literature covering various molecules in clinical trials. Estrogen receptors active sites distinguishing characteristics and interactions with currently available FDA-approved drugs have also been discussed. Designing strategy of previously reported SERDs, their SAR analysis, in silico, and the biological efficacy have also been summarized along with appropriate examples.

Impact of vulvovaginal atrophy therapies on postmenopausal women's quality of life in the CRETA study measured by the Cervantes scale.

OBJECTIVE: To assess the correlation of different vulvovaginal atrophy therapeutic options with the quality of life of postmenopausal women. STUDY DESIGN: The CRETA study is a descriptive, observational, cross-sectional, multicenter study designed to measure, besides treatment satisfaction and adherence, the quality of life of postmenopausal women diagnosed with vulvovaginal atrophy in 29 hospitals and centers across Spain. MAIN OUTCOME MEASURES: The study enrolled postmenopausal women currently receiving treatment with vaginal moisturizers, local estrogen therapy or ospemifene. Clinical features and treatment perceptions were collected by self-report questionnaire and quality of life was evaluated using the Cervantes scale. RESULTS: Among the 752 women included, the ospemifene cohort showed a statistically significant lower global score (44.9 ± 21.7) on the Cervantes scale (and therefore, a better quality of life) than the cohorts treated with moisturizers (52.5 ± 21.6, p = 0.003) or local estrogen therapy (49.2 ± 23.8, p = 0.0473). In the analysis by domains, ospemifene-treated women showed statistically significant better scores in menopause & health and psychological status than moisturizers-treated women (p < 0.05). In the domains of sexuality and couple relations, the score for the quality of life of the ospemifene cohort was statistically significantly better than the scores in either of the cohorts treated with moisturizers (p < 0.001) or local estrogen therapy (p < 0.05). CONCLUSIONS: Postmenopausal women diagnosed with vulvovaginal atrophy and treated with ospemifene have better quality of life than women treated with vaginal moisturizers or local estrogen therapy. The improvement observed with ospemifene is more remarkable in those aspects related to sex life and couple relations. CLINCIALTRIALS. GOV NUMBER: NCT04607707.

Sequential treatment in vulvovaginal atrophy.

Vulvovaginal atrophy (VVA) is a chronic and progressive disease that affects sexuality and quality of life. VVA is preventable and treatable, but requires long-term and often sequential treatment. Sequential treatment consists of designing a strategy that uses one or more medications for a long enough time to achieve the desired benefits with minimal risk and maximum adherence. Currently available therapeutic options consist of topical over-the-counter products (including non-hormonal lubricants and moisturizers applied to the vagina), systemic hormone therapy and estrogens, and prescribed vaginal dehydroepiandrosterone (DHEA). In addition, we have a selective estrogen receptor modulator, ospemifene, and new energy-based treatments (laser and radiofrequency). There are clear differences between the treatments both in the mechanism of action and in the efficacy. Compliance is very low, and patients complain about the use of the vaginal route, often due to its low efficacy, or express fear of the long-term use of estrogens or the price of the treatments. We believe that, as a first option, and for physiological, preventive and efficacy reasons, we should consider the prescription of treatments that work on estrogen receptors. As a second option, there are vaginal moisturizers, which are effective on symptoms but do not prevent or improve conditions. Finally, techniques using heat, which although each time represent a clearer alternative, but on the other hand are the cost and the long-term safety data, give us a third option. Of course, we consider that vulvar moisturizers and lubricants can be used at any time.

The Clinical Effectiveness of Denosumab (Prolia®) for the Treatment of Osteoporosis in Postmenopausal Women, Compared to Bisphosphonates, Selective Estrogen Receptor Modulators (SERM), and Placebo: A Systematic Review and Network Meta-Analysis.

To assess the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs; bazedoxifene, raloxifene) or placebo, for the treatment of osteoporosis in postmenopausal women (PMW). Systematic searches were run in PubMed, Embase & Cochrane Library on 27-April-2022. Randomized controlled trials (RCTs) that included osteoporotic PMW allocated to denosumab, SERMs, bisphosphonates, or placebo were eligible for inclusion. RCTs were appraised using Cochrane Risk of Bias 2.0. Bayesian network and/or pairwise meta-analyses were conducted on predetermined outcomes (i.e. vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, adverse events [AEs], serious AEs (SAEs), withdrawals due to AEs, AEs caused by denosumab discontinuation). A total of 12 RCTs (k = 22 publications; n = 25,879 participants) were included in the analyses. Denosumab, reported a statistically significant increase in lumbar spine (LS) and total hip (TH) BMD, compared to placebo. Similarly, denosumab also resulted in a statistically significant increase in TH BMD compared to the raloxifene and bazedoxifene. However, relative to denosumab, alendronate, ibandronate and risedronate resulted in significant improvements in both femoral neck (FN) and LS BMD. With regards to vertebral fractures and all safety outcomes, there were no statistically significant differences between denosumab and any of the comparator. Relative to placebo, denosumab was associated with significant benefits in both LS and TH BMD. Additionally, denosumab (compared to placebo) was not associated with reductions in vertebral and nonvertebral fractures. Finally, denosumab was not associated with improvement in safety outcomes, compared to placebo. These findings should be interpreted with caution as some analyses suffered from statistical imprecision.

Statins synergize with phosphodiesterase type 5 inhibitors but not with selective estrogen receptor modulators to prevent myofibroblast transformation in an in vitro model of Peyronie's disease.

BACKGROUND: Peyronie's disease (PD) is a fibrotic disorder characterized by plaque formation in the tunica albuginea (TA) of the penis, and we have previously shown that inhibition of transformation of TA-derived fibroblasts to myofibroblasts using a combination phosphodiesterase type 5 (PDE5) inhibitors and selective estrogen receptor modulators (SERMs) is effective in slowing the progression of early PD. AIM: The study sought to investigate whether combinations of statins with PDE5 inhibitors or SERMs would affect myofibroblast transformation in vitro. METHODS: Primary fibroblasts were isolated from TA of patients with PD and stimulated with transforming growth factor ß1 in the absence and presence of a range of concentrations of statins, PDE5 inhibitors, SERMs, and their combinations for 72 hours before quantifying α-smooth muscle actin using in-cell enzyme-linked immunosorbent assay. OUTCOMES: The prevention of transforming growth factor ß1-induced transformation of TA-derived fibroblasts to myofibroblasts was measured in vitro. RESULTS: Statins (simvastatin, lovastatin) inhibited myofibroblast transformation in a concentration-dependent manner with half maximal inhibitory concentration values of 0.77 ± 0.07 µM and 0.8 ± 0.13 µM, respectively. Simvastatin inhibited myofibroblast transformation in a synergistic fashion when combined with vardenafil (a PDE5 inhibitor; log alpha >0). Combination of tamoxifen (a SERM) and simvastatin did not show synergy (log alpha <0). When 3 drugs (simvastatin, vardenafil, and tamoxifen) were combined, the effect was not synergistic, but rather was additive. CLINICAL IMPLICATIONS: A combination of a statin with a PDE5 inhibitor might be useful in the clinic to slow the progression of the disease in patients with early PD; however, caution should be taken with such a combination because of the reported myopathy as a side effect. STRENGTHS AND LIMITATIONS: The use of primary human cells from patients with PD is a strength of this study. The mechanisms by which these drug classes exert synergy when used in combination was not investigated. CONCLUSION: This is the first demonstration of an antifibrotic synergy between statins and PDE5 inhibitors.