Tamoxifen Is Effective in the Treatment of Leishmania amazonensis Infections in Mice

Leishmaniasis is an antropozoonotic disease with a wide range of clinical manifestations. In humans, signs of disease vary from skin and mucosal ulcers to enlargement of internal organs such as the liver and spleen. The unicellular parasite Leishmania amazonensis is able to infect humans and cause localized or diffuse skin lesions. The treatment for this disease is difficult, as it requires prolonged and painful applications of toxic drugs that are poorly tolerated. Therefore, a key area in leishmaniasis research is the study of new therapeutic schemes and less toxic drugs. The present report is based on the investigation of tamoxifen's activity (a compound that has been in clinical use since the 1970s for the treatment of breast cancer) in the treatment of mice experimentally infected with L. amazonensis. We observed that infected mice treated with 20 mg/kg/day of tamoxifen for 15 days showed a significant clinical and parasitological response, with reduction in the size of lesions and ulcers and decreased numbers of parasites. These promising results pave the way for further testing of this drug as a new alternative in the chemotherapy of leishmaniasis

Tamoxifen-elicited uterotrophy: cross-species and cross-ligand analysis of the gene expression program

<p>Abstract</p> <p>Background</p> <p>Tamoxifen (TAM) is a well characterized breast cancer drug and selective estrogen receptor modulator (SERM) which also has been associated with a small increase in risk for uterine cancers. TAM's partial agonist activation of estrogen receptor has been characterized for specific gene promoters but not at the genomic level <it>in vivo</it>.Furthermore, reducing uncertainties associated with cross-species extrapolations of pharmaco- and toxicogenomic data remains a formidable challenge.</p> <p>Results</p> <p>A comparative ligand and species analysis approach was conducted to systematically assess the physiological, morphological and uterine gene expression alterations elicited across time by TAM and ethynylestradiol (EE) in immature ovariectomized Sprague-Dawley rats and C57BL/6 mice. Differential gene expression was evaluated using custom cDNA microarrays, and the data was compared to identify conserved and divergent responses. 902 genes were differentially regulated in all four studies, 398 of which exhibit identical temporal expression patterns.</p> <p>Conclusion</p> <p>Comparative analysis of EE and TAM differentially expressed gene lists suggest TAM regulates no unique uterine genes that are conserved in the rat and mouse. This demonstrates that the partial agonist activities of TAM extend to molecular targets in regulating only a subset of EE-responsive genes. Ligand-conserved, species-divergent expression of carbonic anhydrase 2 was observed in the microarray data and confirmed by real time PCR. The identification of comparable temporal phenotypic responses linked to related gene expression profiles demonstrates that systematic comparative genomic assessments can elucidate important conserved and divergent mechanisms in rodent estrogen signalling during uterine proliferation.</p

Safety and efficacy of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy due to menopause

Gregory T Wurz, Chiao-Jung Kao, Michael W DeGregorio Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, CA, USA Abstract: During the menopausal transition, women experience a number of symptoms due to declining estrogen levels, including vasomotor symptoms and vulvar and vaginal atrophy (VVA). Unlike vasomotor symptoms, vaginal dryness and dyspareunia, the main symptoms of VVA, typically worsen without treatment and can significantly impact the quality of life. Up to 60% of postmenopausal women may be affected by VVA, but many women unfortunately do not seek treatment due to embarrassment or other factors. After 20+ years in development, ospemifene (Osphena&trade;) was approved by the US Food and Drug Administration in 2013 for treatment of moderate-to-severe dyspareunia associated with VVA due to menopause. As the first non-hormonal alternative to estrogen-based products for this indication, the approval of ospemifene represents a significant milestone in postmenopausal women&rsquo;s health. Ospemifene is a non-steroidal estrogen receptor agonist/antagonist, also known as a selective estrogen receptor modulator (SERM), from the same chemical class as the breast cancer drugs tamoxifen and toremifene. Unlike other selective estrogen receptor modulators, ospemifene exerts a strong, nearly full estrogen agonist effect in the vaginal epithelium, making it well suited for the treatment of dyspareunia in postmenopausal women. Results of Phase III clinical trials showed that ospemifene significantly improved the vaginal maturation index (decreased parabasal cells and increased superficial cells), decreased vaginal pH, and decreased severity of the self-identified most bothersome symptom (dyspareunia or vaginal dryness) compared to placebo. Long-term safety studies revealed that 60 mg ospemifene given daily for 52 weeks was well tolerated and was not associated with any endometrium or breast-related safety concerns. This review discusses the preclinical and clinical data supporting the use of ospemifene for the treatment of dyspareunia associated with VVA due to menopause and provides an overview of its clinical safety. Keywords: genitourinary syndrome of menopause, SERM, sexual dysfunctio

Ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy: potential benefits in bone and breast

Lin H Soe, Gregory T Wurz, Chiao-Jung Kao, Michael W DeGregorio Department of Internal Medicine, Division of Hematology and Oncology, School of Medicine, University of California, Davis, Sacramento, CA, USA Abstract: Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women. Ospemifene is the first and only nonestrogen compound approved for this indication. Compared with other approved SERMs, such as tamoxifen, toremifene, bazedoxifene, and raloxifene, the estrogen-like effects of ospemifene in the vaginal epithelium are unique. This review first discusses the rationale for developing ospemifene, including its mechanism of action, and then focuses on the clinical development of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy. Included are discussions of the effects of ospemifene on the endometrium, serum lipids, coagulation markers, bone, and breast cancer. In conclusion, ospemifene is a SERM with a unique estrogen agonist/antagonist tissue profile that was recently approved in the US for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. Ospemifene warrants further clinical investigation for the treatment and prevention of osteoporosis and breast cancer. Keywords: ospemifene, dyspareunia, vulvar and vaginal atrophy, osteoporosis, breast cance