Efficacy Of Ormeloxifene Research Articles

Efficacy of Ormeloxifene vs Norethisterone in the Management of Perimenopausal DUB

Background: Disorders of menstruation are the most common reason for a gynaecological consultation among women of reproductive age group. Dysfunctional Uterine Bleeding is defined as abnormal uterine bleeding in the absence of organic, systemic or iatrogenic causes. It can be managed both medically and surgically. In medical management, several drugs have been used. However there is lack of studies suggesting the most appropriate drug. The objective of our study is to compare the treatment efficacy of Norethisterone acetate (a progesterone derivative) versus Ormeloxifene (selective estrogen receptor modulator) in the treatment of DUB. Methodology: Total of 100 perimenopausal women with DUB were enrolled in our prospective study. They were randomly assigned into group A and group B. Group A was treated with 60mg Ormeloxifene two times a week for 3 months followed by once a week for another 3months. Group B was treated with Norethisterone 5 mg two times a day from Day5 to Day26 for 6 months. Primary outcome parameters noted were reduction in menstrual blood loss that was measured by fall in Pictorial Blood Loss Assessment Chart (PBAC) score, increase in haemoglobin, and decrease in endometrial thickness at the end of study. Results: In our study, the reduction in mean PBAC score with Ormeloxifene was significantly more than that seen with norethisterone after 6 months of therapy. There was a significant increase in hemoglobin level and reduction in endometrial thickness with Ormeloxifene compared to norethisterone. Patients were more compliant to Ormeloxifene because of better tolerance and convenient dosage schedule. Conclusion: In our study Ormeloxifene was found to be more effective than Norethisterone in reducing blood loss, improving haemoglobin level and reducing endometrial thickness in DUB patients.

Efficacy of ormeloxifene in the management of DUB

Efficacy of ormeloxifene in the management of DUB

Abstract 2101: Ormeloxifene suppresses the growth of prostate tumor via inhibition of β-catenin induced AR signaling

Abstract Background: Prostate cancer (PrCa) first manifests as an androgen-dependent disease and can be treated with androgen-deprivation therapy. Despite the initial success of androgen ablation therapy, resistance to anti-androgen therapy displays by progression to hormone refractory (androgen-independent) advanced stage PrCa which is primary cause of patient’s death. Main underlying cause for the onset of hormone refractory cancer is ligand independent activation of AR signaling in PrCa cells. It has been shown that β-catenin acts as a non-androgen activator of AR which enhances AR transactivation in PrCa cells. Thus, identification of agents with excellent pharmacokinetics and pharmacodynamics parameters that can inhibit ligand independent activation of AR signaling might be highly useful for the treatment of advanced stage PrCa. Herein, we identified a synthetic molecule, ormeloxifene (ORM), which efficiently represses β-catenin mediated ligand independent activation of AR signaling, thus, inhibits growth and metastatic features of PrCa cells. Methods: Androgen-refractory but AR positive PrCa cell (C4-2) was used as an in vitro and in vivo model systems. Effect of ORM on AR and PSA protein levels was determined by Western blot analysis. Effect of ORM treatment was analyzed on AR and PSA luciferase activities by transiently transfecting the C4-2 cells by AR and PSA luciferase plasmids. Renilla construct was used as an internal control. C4-2 cells nuclear and cytoplasmic lysates were prepared using Active Motif kit. Immunoprecipitation analysis was performed to determine if ORM inhibits physical interaction of β-catenin with AR. Therapeutic efficacy of ORM was evaluated in cell lines and PrCa xenograft mouse models. Results: ORM dose-dependently (10, 15 and 20 µM) inhibited the protein levels of AR and its downstream target protein PSA. ORM (10 and 20μM) treatment also inhibited AR transactivation as determined by decreased promoter activities of AR and its target gene PSA. ORM (10 and 20μM) treatment inhibited protein levels of nuclear β-catenin and physical interaction of β-catenin with AR in PrCa cells. ORM administration dose- dependently (intra-peritoneal; 100 and/or 500µg/mouse; thrice/week) significantly (P<0.01) inhibited growth of C4-2 cells derived xenograft tumors in athymic nude mice. ORM treatment significantly (P<0.01) inhibited the expressions of nuclear AR and β-catenin expressions in xenograft tumor tissues. These ORM treated mice did not show any apparent toxicity in our study. Conclusion: Our study demonstrates that ORM is a potent inhibitor of β-catenin-mediated activation of AR signaling. Based on its safety profile, ORM might be an ideal candidate for repurposing to treat advanced stage PrCa alone or in combination with other therapies. Citation Format: Aditya Ganju, Bilal Bin Hafeez, Mohammed Sikander, Vivek Kumar Kashyap, Murali Mohan Yallapu, Subhash C. Chauhan, Meena Jaggi. Ormeloxifene suppresses the growth of prostate tumor via inhibition of β-catenin induced AR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2101. doi:10.1158/1538-7445.AM2017-2101

Abstract 4392: Generation of a novel ormeloxifene nanoparticle formulation for pancreatic cancer treatment

Abstract Pancreatic cancer (PanCa) is the fourth leading cancer with 85% mortality rate in the United States. Therefore, there is an utmost need to discover new modalities that can result in enhanced therapeutic efficacy with low to minimal side effects. Ormeloxifene (ORM) is a synthetic molecule which is widely used as an oral contraceptive in humans. Numerous studies indicate that ORM exhibits potent anti-cancer effects through inhibition of important oncogenic signaling events in several cancers. Our studies also demonstrate the anticancer effects of ORM in various cancer cells. However, the ORM effects can be improved by encapsulating in a nanoformulation which provides targeted delivery of ORM to the tumors. Therefore, in order to increase the therapeutic efficacy of ORM, we have developed a novel ORM encapsulated poly(lactic-co-glycolic acid) formulation (PLGA-ORM NPs). This formulation has been characterized for particle size, zeta potential, chemical composition, drug loading efficiency using various physico-chemical methods such as DLS, TEM, FT-IR, DSC, and TGA. Because of its facile composition (PLGA core, PVA, PLL and PEG-linker) this novel formulation is compatible for antibody/aptamer conjugation to achieve tumor specific targeting. The PLGA-ORM formulations indicate efficient encapsulation of ORM. The particle size of PLGA-ORM formulation (∼ 100 nm) indicates that this formulation can preferentially reach and accumulate in tumors by the Enhanced Permeation and Retention (EPR) effect. The uptake and internalization studies demonstrate that PLGA-ORM NPs escape lysosomal degradation providing its efficient endosomal release to cytosol in PanCa cells. PLGA-ORM NPs showed superior anti-cancer potential in various pancreatic cancer cells (HPAF-II, BXPC-3, Panc-1, MiaPaca) and in BXPC-3 xenograft mice. PLGA-ORM NPs suppressed pancreatic xenograft tumor growth and improved the mice survival. In addition, PLGA-ORM NPs also reduce the metastasis potential. PLGA-ORM NPs inhibit tumorigenic and metastatic phenotypes via suppression of AKT phosphorylation and inhibition of key oncogenes involved in pancreatic progression such as MUC1, HER2 and CD31. Additionally, PLGA-ORM NPs treated xenograft tumors showed reduced staining of the proliferating cell nuclear antigen (PCNA), cytokeratin-19 (CK19), MUC1, HER2 and CD31 in immunohistochemical analysis. In conclusion, this study suggests that PLGA-ORM formulation is highly efficient for the inhibition of pancreatic tumor growth and can be valuable for the treatment of pancreatic cancer in future. Citation Format: Sheema Khan, Neeraj Chauhan, Murali M. Yallapu, Mara C. Ebeling, Swathi Balakrishna, Robert T. Ellis, Paul A. Thompson, Stephen W. Behrman, Nadeem Zafar, Man M. Singh, Fathi T. Halaweish, Meena Jaggi, Subhash C. Chauhan. Generation of a novel ormeloxifene nanoparticle formulation for pancreatic cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4392. doi:10.1158/1538-7445.AM2015-4392

A double blinded randomized controlled trial to compare Ormeloxifene and Norethisterone in the treatment of Dysfunctional Uterine Bleeding

Aims: To compare the safety and efficacy of ormeloxifene and norethisterone in treatment of dysfunctional uterine bleeding as measured by decrease in menstrual blood loss using pictorial blood assessment chart. To assess the percentage change in haemoglobin and endometrial thickness before and after treatment. To assess the subjective improvement in life style as evaluated by a five point Likert scale. Methods: A double blinded randomized control trial was conducted on patients attending gynaecology OPD with complaints of menorrhagia with following inclusion criteria women between 18 and 51 years of age, absence of coagulopathies and any pelvic pathology, not taking any drug affecting menstruation, no hormonal therapy in previous three months and normal renal function. Findings and Interpretation: The menstrual blood loss was observed to decrease by 19.31% at end of two months, 30.74% at the end of four months and 43.25% at end of six months in case of norethisterone and 20.72% at the end of two months, 43.37% at end of four months and 59.50% at the end of six months in case of Ormeloxifene. There was an increase in haemoglobin percentage in both the groups and it was significantly better in case of Ormeloxifene. PBAC score and endometrial thickness improvement was better in case of ormeloxifene compared to norethisterone. The side effects were similar in both the cases except for follicular cyst which was seen in Ormeloxifene group. I. Introduction A woman can expect roughly 400 menstrual cycles during her reproductive lifespan, and it is estimated that up to 20% of women will have excessive menstrual blood loss. Although age of menopause has remained the same over this century, the magnitude of menstrual disorders has increased, likely because of shortened breast-feeding intervals, fewer pregnancies per woman, higher frequency of permanent sterilization, and later age of conception. Dysfunctional uterine bleeding is a diagnosis of exclusion when organic, systemic and pelvic pathology all have been ruled out. Once a diagnosis has been reached with the aid of history, examination, haematological and endocrine investigations, and dilatation and curettage when appropriate, medical treatment is the usual first line approach. The treatment options for dysfunctional uterine bleeding are diverse, which can be finally tailored to cater the needs of patients of different socioeconomic background, different age groups and different reproductive needs. Treatment options range from offering medical measures such as cyclooxygenase inhibitors, tranexamic acid, hormonal agents and in cases not managed by medical therapy offering surgical management. Trials comparing the various modalities have flooded the literature but ambiguity still exists. Norethisterone is still the most frequently prescribed drug for dysfunctional uterine bleeding serving 38% of the patient population the reason being cost effectiveness and absence of side effects. Ormeloxifene (also known as centchroman) is one of the selective estrogen receptor modulators used primarily as a contraceptive, but it is also effective in dysfunctional uterine bleeding. We undertook the study to compare the safety and efficacy of the two drugs in dysfunctional uterine bleeding.

Abstract 2882: Therapeutic effects of ormeloxifene on cervical cancer

Abstract Background: Cervical cancer is one of the most common and deadly cancers among women worldwide and is strongly associated with persistent Human Papillomavirus (HPV) infection. HPV E6/E7 oncoproteins are well known to interfere with p53 and retinoblastoma (Rb) proteins and drive the development of cervical cancer. While screening for cervical cancer can reduce the incidence and mortality, treatment of advanced stage cervical cancer is difficult and often unsuccessful. Therefore, there is an urgent need for the development of additional treatment modalities. Ormeloxifene is a non-hormonal anti-estrogen oral contraceptive for human use and it effectively suppresses the highly proliferative decidual cells in the endometrium to inhibit egg implantation. Considering its strong anti-proliferative effect, we hypothesized that ormeloxifene may inhibit the growth of cervical cancer cells and may suppress the expression of HPV oncoproteins E6/E7. Methods: The effect of ormeloxifene on the proliferation of various cervical cancer cell lines (Caski, SiHa, C33A, and HT3) was determined by MTS and colony formation assay. Annexin V/7AAD and propidium iodide (PI) staining was analyzed by flow cytometry to determine ormeloxifene's effect on apoptosis and cell cycle inhibition, respectively. The expression of apoptotic proteins such as poly (ADP-ribose) polymerase (PARP), Caspase 3 and Caspase 9 was determined by immunoblotting. The potential of ormeloxifene to repress the expression of HPV E6/E7 oncogenes was determined by quantitative RT-PCR and immunoblotting analyses. Further, the efficacy of ormeloxifene to restore tumor suppressor proteins, such as p53 and Rb, was also determined by immunoblotting. Results: In all 4 cell lines, ormeloxifene effectively inhibited cervical cancer cell growth. Ormeloxifene treatment induced apoptosis in cervical cancer cells as determined by staining for Annexin V/7AAD and immunoblotting for cleaved PARP, Caspase 3, and Caspase 9. PI staining also clearly revealed that ormeloxifene treatment arrests Caski cells in the G0-G1 phase. Additionally, ormeloxifene treatment caused a marked decrease in the levels of HPV E6 and E7 oncogenes and restored the levels of p53 and Rb proteins in Caski cells. Conclusion: Our findings show that ormeloxifene significantly inhibits cervical cancer cell growth and down-regulates HPV E6/E7 oncogenes, therefore; ormeloxifene may be novel chemo-preventive and treatment method for the management of cervical cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2882. doi:1538-7445.AM2012-2882